WO2022022388A1 - 一种地佐辛衍生物晶型a及其制备方法和应用 - Google Patents

一种地佐辛衍生物晶型a及其制备方法和应用 Download PDF

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WO2022022388A1
WO2022022388A1 PCT/CN2021/107934 CN2021107934W WO2022022388A1 WO 2022022388 A1 WO2022022388 A1 WO 2022022388A1 CN 2021107934 W CN2021107934 W CN 2021107934W WO 2022022388 A1 WO2022022388 A1 WO 2022022388A1
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crystal form
dezocine
derivative
pain
mixed solution
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French (fr)
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宣景安
邹贻泉
徐开祥
朱云龙
夏雨
纪娅婷
齐敬敬
董达文
胡涛
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扬子江药业集团有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • 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
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings

Definitions

  • the invention relates to the technical field of medicine, in particular to a dezocine derivative crystal form A and a preparation method and application thereof.
  • Dezocine is a mixed agonist-antagonist of opioid receptors with a structure similar to pentazocine. It was developed by the Wyeth-Ayerst laboratory in the United States in the 1970s and was approved by the FDA in 1989. The name Dalgan is marketed by Astrazeneca for the treatment of post-operative pain. Since its launch in China in 2009, it has been widely used for induction of general anesthesia, postoperative analgesia and preemptive analgesia, and for the treatment of visceral pain and cancer pain.
  • the present invention aims to solve the technical problems existing in the prior art at least to a certain extent.
  • the present invention proposes a crystal form A of a dezocine derivative, a pharmaceutical composition containing the same, and a use and treatment method thereof.
  • the crystal form A of the dezocine derivative has good stability and solubility. It can be used as an opioid receptor modulator to play analgesic effect and has a wide application prospect.
  • the present invention proposes a crystal form A of a dezocine derivative, the dezocine derivative being a compound
  • the hydrochloride specifically, the dezocine derivative is
  • the X-ray powder diffraction pattern of the crystal form A represented by a diffraction angle of 2 ⁇ 0.2° shows characteristic peaks at 8.894, 9.496, 10.974, 13.334, 15.338, 15.942, 17.707 and 24.178.
  • the crystal form A of the dezocine derivative may also have the following additional technical features:
  • the X-ray powder diffraction pattern of the crystal form A represented by the diffraction angle of 2 ⁇ 0.2° is further at 12.603, 14.768, 16.683, 18.099, 18.925, 20.286, 22.666, 25.510, 26.325, 26.785 and A characteristic peak is displayed at 27.766.
  • the X-ray powder diffraction spectrum of the crystal form A is shown in FIG. 1 .
  • the 2 ⁇ angle and relative intensity of each peak on the X-ray powder diffraction pattern will vary. Generally, the 2 ⁇ angle changes within ⁇ 0.2°, and the relative intensity is within ⁇ 5%. reasonable error.
  • the crystal form A of the present invention has good stability and solubility, does not change crystals during the grinding process, can be used as an opioid receptor modulator, has analgesic effect, and has wide application prospects.
  • the present invention provides a preparation method for preparing the aforementioned crystal form A.
  • the method includes: (1) mixing the dezocine derivative with the first solvent, so that the dezocine derivative is completely dissolved to obtain a mixed solution; (2) cooling the mixed solution To crystallize, filter to obtain the crystal form A.
  • the invention obtains the crystal form A by adopting the crystallization method, has the advantages of simple operation, less time, high yield, high purity, low energy consumption, etc., and is suitable for industrial production and application.
  • step (1) after mixing the dezocine derivative with the first solvent, the temperature is raised to 40-80° C. to completely dissolve the dezocine derivative to obtain a mixed solution.
  • the dissolution of the dezocine derivative can be accelerated, the time spent can be reduced, and the preparation efficiency can be improved.
  • step (1) further includes: after the mixed solution is kept warm for a predetermined time, filtering is performed to filter out mechanical impurities, and when solids are precipitated after filtering out mechanical impurities, further filtering out mechanical impurities
  • the mixed solution is heated until the solid is completely dissolved, and the final obtained mixed solution is subjected to the operation of step (2).
  • mechanical impurities used in the present invention mainly refers to precipitates or colloidal suspensions that are insoluble in solvents such as gasoline, ethanol and benzene, which are present in lubricating oil. Most of these impurities are sand and iron filings, as well as some organic metal salts that are insoluble in solvents brought by additives. Since the presence of mechanical impurities will affect the subsequent cooling crystallization, and then affect the purity and yield of the crystal form, the de-filtration is removed in advance, and then the mixed solution after filtering the mechanical impurities is subjected to the operation of step (2). If there is solid precipitation, the operation of step (2) is performed after the solid precipitation is completely dissolved.
  • the temperature of the heated mixed solution is 40-80°C, preferably 50-60°C.
  • the temperature of the heated mixed solution is 40-80°C, preferably 50-60°C.
  • the predetermined time is 0-2 hours.
  • the mixed solution is kept warm to grow crystals and improve the yield of crystal form A.
  • the cooling includes: first cooling to 25 ⁇ 5°C naturally, then cooling to 0 ⁇ 5°C in an ice-water bath, and keeping the temperature for 4-25 hours, preferably 15-20 hours.
  • step (2) further comprises: washing the filter cake obtained by the filtration with a second solvent, and then drying the washed filter cake to obtain the crystal form A.
  • the purity of Form A is improved by washing to remove impurities.
  • the first solvent or the second solvent is each independently selected from at least one of acetonitrile, lower alkyl alcohol, ethyl acetate and water.
  • the use of the above-mentioned first solvent can make the dezocine derivative fully dissolve therein, and the crystal form A can be cooled and crystallized in the system.
  • Using the above-mentioned second solvent can wash off other impurities in the filter cake and improve the purity of crystal form A.
  • the types of the first solvent and the second solvent can be the same or different, and can be selected flexibly according to actual needs.
  • the first solvent and the second solvent are each independently selected from a mixed solution of lower alkyl alcohol and water, a mixed solution of acetonitrile and water, or a mixed solution of lower alkyl alcohol and ethyl acetate.
  • the lower alkyl alcohol is selected from C 1 -C 4 alkyl alcohol, preferably methanol, ethanol, isopropanol, n-propanol, and n-butanol.
  • the first solvent system when the first solvent system is selected from the mixed solution of the lower alkyl alcohol and water, the mixed solution of acetonitrile and water or the mixed solution of the lower alkyl alcohol and ethyl acetate, the The dosage of lower alkyl alcohol or acetonitrile is 0.8 to 10 times (ml/g) of the dezocine derivative, preferably 1 to 5 times (ml/g); the dosage of the water is 1 to 1 of the dezocine derivative. ⁇ 10 times (ml/g), preferably 1 to 5 times (ml/g); the amount of ethyl acetate used is 1 to 30 times (ml/g) of the dezocine derivative, preferably 10 to 20 times.
  • the first solvent system is selected from the mixed solution of lower alkyl alcohol and water, wherein the consumption of the lower alkyl alcohol is 0.8 to 10 times of the dezocine derivative ( ml/g), preferably 1 to 5 times (ml/g); the amount of water used is 1 to 10 times (ml/g) of the dezocine derivative, preferably 1 to 5 times (ml/g) .
  • the drying is vacuum drying at 45 ⁇ 5°C, and the drying time is 16-30 hours.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the aforementioned crystal form A of the dezocine derivative and a pharmaceutically acceptable carrier.
  • a carrier in the pharmaceutical composition is "acceptable" which is compatible with (and preferably, is capable of stabilizing) the active ingredient of the composition and which is not deleterious to the subject being treated.
  • One or more solubilizers can be used as pharmaceutical excipients for delivery of the active compounds.
  • the pharmaceutical compositions of the present invention comprise a second therapeutic agent comprising a MOR modulator, eg, an antagonist, such as selected from the group consisting of naloxone, naltrexone, tramadol, one or more of samidorphan.
  • a MOR modulator eg, an antagonist, such as selected from the group consisting of naloxone, naltrexone, tramadol, one or more of samidorphan.
  • Such pharmaceutical compositions can be used to treat opioid receptor-related disorders, such as pain, via an opioid modulator-mediated activation mechanism of the MOR.
  • the crystal form A of the dezocine derivative or the pharmaceutical composition of the present invention can be injected intravenously, subcutaneously, intramuscularly, intraperitoneally, perineurally, neuraxially, intraarticularly, orally or orally. Topical application.
  • the pharmaceutical compositions of the present invention for oral use can be in any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, suppositories, sprays, inhalants, dispersions, and solutions.
  • aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with an emulsifying or suspending agent. Certain sweetening, flavoring, or coloring agents may be added if desired.
  • Oral solid dosage forms can be prepared by spray drying techniques; hot melt extrusion strategies, micronization and nanomilling techniques. Spray or inhalation compositions can be prepared according to techniques well known in the pharmaceutical formulation arts.
  • compositions can be prepared as saline solutions using benzoic acid or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Compositions with active compounds can also be administered in the form of suppositories for rectal administration.
  • the Dezocine Derivative Form A or a pharmaceutical composition containing the same can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantation Reservoir administration.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • the crystal form A of the dezocine derivative of the present invention has opioid receptor modulator activity and can be used for the treatment of opioid receptor-related disorders. The conditions include pain, hyperalgesia, and cardiovascular and cerebrovascular diseases.
  • the present invention proposes the use of the aforementioned crystal form A of the dezocine derivative or the pharmaceutical composition in the preparation of a medicament.
  • the medicament is used to treat an opioid receptor-related disorder.
  • the crystal form A of the present invention and the pharmaceutical composition containing the same can be used as opioid receptor modulators to treat opioid receptor-related disorders, such as analgesia.
  • the condition is pain.
  • the pain comprises neuropathic pain or nociceptive pain.
  • the pain comprises acute pain or chronic pain.
  • the pain includes at least one of the following: post-operative pain, pain due to neuralgia, pain due to diabetic neuropathy, toothache, pain associated with arthritis, and pain associated with cancer or its treatment of pain.
  • the pain due to neuralgia includes postherpetic neuralgia or trigeminal neuralgia.
  • the drug is used to modulate the activity of opioid receptors.
  • the present invention provides a method of treating an opioid receptor-related disorder.
  • the method comprises: administering to the subject the aforementioned crystal form A of the dezocine derivative or the pharmaceutical composition.
  • the crystal form A of the present invention and the pharmaceutical composition containing the same can be used as opioid receptor modulators, and can be used as opioid receptor modulators to treat opioid receptor-related disorders, such as analgesia.
  • the opioid receptor-related disorder is selected from pain.
  • the crystal form A of the dezocine derivative of the present invention has good stability and solubility, and does not crystallize during the grinding process.
  • the crystal form A was encapsulated in a medicinal low-density polyethylene bag and a polyester/aluminum/polyethylene medicinal composite film. Under the influence factors of light, high temperature and high humidity, and high humidity, the indicators did not change significantly, and all of them were in line with the quality Standard requirements, good stability, and can maintain good chemical stability and crystal stability under intermediate conditions and long-term storage cycles.
  • the preparation method of the crystal form A of the dezocine derivative of the present invention adopts the cooling crystallization method, which has the advantages of simple operation, less time, high yield, high purity and low energy consumption, and is suitable for industrial production and application.
  • the crystal form A of the dezocine derivative of the present invention can be used as an opioid receptor modulator to effectively modulate the opioid receptor activity, thereby treating opioid receptor-related disorders, such as analgesia.
  • Fig. 1 is the X-ray powder diffraction spectrum of dezocine derivative crystal form A
  • Fig. 2 is the X-ray powder diffractogram of the crystal form prepared by ethanol/water as crystallization solvent;
  • Fig. 3 is the X-ray powder diffraction pattern of the crystal form prepared by methanol/water as crystallization solvent;
  • Fig. 4 is the X-ray powder diffractogram of the crystal form prepared by isopropanol/water as crystallization solvent;
  • Fig. 5 is the X-ray powder diffractogram of the crystal form prepared by ethanol/ethyl acetate as crystallization solvent;
  • Fig. 6 is the X-ray powder diffractogram of the crystal form prepared as acetonitrile/water as crystallization solvent;
  • Fig. 7 is the X-ray powder diffraction spectrum of ground crystal form
  • Fig. 8 is the X-ray powder diffraction spectrum of spray crystal form
  • Fig. 9 is the X-ray powder diffraction spectrogram of 5 days of illumination crystal form
  • Fig. 10 is the X-ray powder diffraction spectrum of high temperature and high humidity 5 days crystal form
  • Fig. 11 is the X-ray powder diffraction spectrum of the high-humidity 5-day crystal form
  • Fig. 12 is the X-ray powder diffraction spectrum of 10 days of illumination crystal form
  • Fig. 13 is the X-ray powder diffraction spectrum of high temperature and high humidity 10 days crystal form
  • Fig. 14 is the X-ray powder diffraction spectrum of high-humidity 10-day crystal form
  • Fig. 15 is the X-ray powder diffraction spectrum of crystalline form of illuminating for 30 days;
  • Fig. 16 is the X-ray powder diffraction spectrum of high temperature and high humidity 30 days crystal form
  • Fig. 17 is the X-ray powder diffraction spectrum of high-humidity 30-day crystal form
  • Figure 18 is the TG spectrum of dezocine derivative crystal form A
  • Figure 19 is the DSC chart of the crystal form A of the dezocine derivative.
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 phaser X-ray powder diffractometer.
  • the ethyl acetate solution of hydrochloric acid is subjected to a salt-forming reaction to obtain the hydrochloride of compound 2, that is, the dezocine derivative (in the form of hydrochloride), the target of the present invention, with a mass of 23 mg.
  • a mixed solution of 1 g of the dezocine derivative of the present invention, 10 mL (1v/2v) of methanol and purified water was added to the reaction flask. The temperature was raised to 60-70°C, and 8mL (1v/2v) of methanol and purified water mixed solution was added until the system was dissolved, and the heating was turned off. , filtered, and the filter cake was vacuum-dried at 45 ⁇ 5°C to obtain 0.59 g of the product with a purity of 99.4%. The product was confirmed to be Form A of the dezocine derivative by X-ray powder diffraction. See Figure 3.
  • a mixed solution of 1 g of the dezocine derivative of the present invention, 10 mL (1v/2v) of isopropanol and purified water was added to the reaction flask.
  • the temperature was raised to 60-70°C and dissolved, the heating was turned off, the temperature was naturally cooled to 25 ⁇ 5°C, cooled to 0 ⁇ 5°C in an ice-water bath, kept for 20h, filtered, and the filter cake was vacuum-dried at 45 ⁇ 5°C to obtain 0.57g of product with a purity of 0.57 g. was 99.4%.
  • the product was confirmed to be Form A of the dezocine derivative by X-ray powder diffraction. See Figure 4.
  • the crystal form A of the dezocine derivative provided in Example 2 was encapsulated in a medicinal low-density polyethylene bag and a polyester/aluminum/polyethylene medicinal composite film, and subjected to illumination, high temperature and high humidity, High humidity 5 days, 10 days, 30 days test, the results are as follows:
  • the crystal form A of dezocine derivative has 12 crystals under intermediate conditions (30°C ⁇ 2°C/65% ⁇ 5%RH) and long-term conditions (25°C ⁇ 2°C/60% ⁇ 5%RH). It can maintain good chemical stability and crystal stability under the storage period of 1 month. It shows that the crystal form provided by the present invention has good stability and is beneficial to the storage of the raw medicine.
  • the affinity of the compound for ⁇ , ⁇ and ⁇ opioid receptors was evaluated by the competitive binding experiment of radioisotope ligands.
  • Tris base (Sigma,Cat:T6066-1KG),prepare 1M stock and adjust pH to 7.4.
  • PEI Poly ethyleneimine
  • test compound negative control (ie DMSO) and positive control (ie non-specific binding well compound) are ready, transfer 1 ⁇ L to a 96-well plate;
  • the table below shows the IC50 values of the compounds tested against mu, kappa and delta opioid receptors. It can be seen that the crystal form A of the dezocine derivative of the present invention can effectively regulate the activity of opioid receptors, so that it can play a better effect on treating opioid receptor-related diseases.

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Abstract

提供一种地佐辛衍生物晶型A，所述晶型A以2θ±0.2°衍射角表示的X-射线粉末衍射谱图在8.894、9.496、10.974、13.334、15.338、15.942、17.707、24.178处显示特征峰。地佐辛衍生物的晶型A具有很好的稳定性及溶解性，在研磨过程中不转晶，可作为阿片受体调节剂，起到镇痛作用，应用前景广泛。

Description

一种地佐辛衍生物晶型A及其制备方法和应用 技术领域
本发明涉及医药技术领域，具体涉及一种地佐辛衍生物晶型A及其制备方法和应用。
背景技术
地佐辛(dezocine)是一个结构类似喷他佐辛(pentazocine)的阿片受体混合激动－拮抗剂，于上世纪70年代由美国Wyeth-Ayerst实验室研发，1989年经FDA批准上市，以商品名Dalgan由Astrazeneca进行市场销售，用于治疗手术后疼痛。2009年在中国上市以来被广泛应用于全麻诱导、术后镇痛和超前镇痛，并用于治疗内脏疼痛和癌症疼痛。其化学名为：(-)-[5R-(5α,11α,13S*)]-13-氨基-5,6,7,8,9,10,11,12-八氢-5-甲基-5,11-甲撑苯并环癸烯-3-醇，结构式如下：
Figure PCTCN2021107934-appb-000001
通过对地佐辛结构的修饰/改造有望得到具有更好活性和/或成药性能的衍生物结构，这些衍生物的晶型开发亦能进一步拓展药品的应用潜力。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题。为此，本发明提出了一种地佐辛衍生物的晶型A、含有其的药物组合物及其用途和治疗方法，该地佐辛衍生物的晶型A具有很好的稳定性及溶解性，在研磨过程中不转晶，可作为阿片受体调节剂，起到镇痛作用，应用前景广泛。
为此，在本发明的一个方面，本发明提出了一种地佐辛衍生物的晶型A，所述地佐辛衍生物为化合物
Figure PCTCN2021107934-appb-000002
的盐酸盐，具体的，所述地佐辛衍生物为
Figure PCTCN2021107934-appb-000003
根据本发明的实施例，所述晶型A以2θ±0.2°衍射角表示的X-射线粉末衍射谱图在8.894、9.496、10.974、13.334、15.338、15.942、17.707和24.178处显示特征峰。
根据本发明的实施例，所述地佐辛衍生物的晶型A还可以具有下列附加技术特征：
根据本发明的实施例，所述晶型A以2θ±0.2°衍射角表示的X-射线粉末衍射谱图还在12.603、14.768、16.683、18.099、18.925、20.286、22.666、25.510、26.325、26.785和27.766处显示特征峰。
根据本发明的实施例，所述晶型A的X-射线粉末衍射谱图如图1所示。
需要说明的是，由于测量条件的不同，X-射线粉末衍射图上各峰的2θ角和相对强度会有所变动，一般2θ角变化在±0.2°以内，相对强度在±5％以内认为是合理误差。
本发明的晶型A具有很好的稳定性及溶解性，在研磨过程中不转晶，可作为阿片受体调节剂，起到镇痛作用，应用前景广泛。
在本发明的另一方面，本发明提出了一种制备前面所述晶型A的制备方法。根据本发明的实施例，所述方法包括：(1)将地佐辛衍生物与第一种溶剂混合，使得地佐辛衍生物完全溶解，得到混合液；(2)将所述混合液冷却至析晶，过滤，得到所述晶型A。
本发明通过采用结晶的方法获取晶型A，具有操作简便、用时少、收率高、纯度高、能耗小等优点，适于工业化生产应用。
根据本发明的实施例，步骤(1)中，将地佐辛衍生物与第一种溶剂混合后，升温至40～80℃，使得地佐辛衍生物完全溶解，得到混合液。由此，可以加快地佐辛衍生物溶解，减少用时，提高制备效率。
根据本发明的实施例，步骤(1)进一步包括：将所述混合液保温预定时间后，进行过滤，滤除机械杂质，当滤除机械杂质后有固体析出时，进一步将滤除机械杂质后的混合液进行升温至固体完全溶解，将最终所得混合液进行步骤(2)的操作。
需要说明的是，本发明所使用的术语“机械杂质”主要是指存在于润滑油中不溶于汽油、乙醇和苯等溶剂的沉淀物或胶状悬浮物。这些杂质大部分是砂石和铁屑之类，以及由添加剂带来的一些难溶于溶剂的有机金属盐。由于机械杂质的存在会影响后续的冷却结晶，进而影响晶型的纯度和收率，因此预先将去过滤去除，然后将将滤除机械杂质后的混合液进行步骤(2)的操作。若有固体析出，待将固体析出完全溶解后再进行步骤(2)的操作。
根据本发明的实施例，所述升温后的混合液温度为40～80℃，优选50～60℃。由此，以 便于使得固体物质充分溶解于第一种溶剂中，便于后续充分冷却结晶，提高晶型A的收率和纯度。
根据本发明的实施例，所述预定时间为0～2小时。进行过滤之前，将混合液进行保温，以便养晶，提高晶型A的收率。
根据本发明的实施例，所述冷却包括：先自然冷却至25±5℃，再冰水浴冷却至0±5℃，保温4～25小时，优选15～20h。采用上述梯度冷却方式，可以使得晶型A充分析出，而其他杂质不易析出，从而提高晶型A的收率和纯度。
根据本发明的实施例，步骤(2)进一步包括：将所述过滤所得滤饼用第二种溶剂洗涤，再将洗涤后的滤饼进行干燥，得到所述晶型A。通过洗涤以去除杂质，提高晶型A的纯度。
根据本发明的实施例，所述第一种溶剂或第二种溶剂各自独立地选自乙腈、低级烷基醇、乙酸乙酯和水的至少之一。采用上述第一种溶剂可以使得地佐辛衍生物充分溶解其中，并可使得晶型A可在该体系中冷却结晶析出。采用上述第二种溶剂可以洗去滤饼中的其他杂质，提高晶型A的纯度。第一种溶剂和第二种溶剂的类型可以相同，也可以不同，具体根据实际需要灵活选择。具体地，所述第一种溶剂、第二种溶剂各自独立地选自低级烷基醇与水的混合溶液、乙腈和水的混合溶液或者低级烷基醇与乙酸乙酯的混合溶液。
根据本发明的实施例，所述低级烷基醇选自C 1-C 4烷基醇，优选甲醇、乙醇、异丙醇、正丙醇、正丁醇。
根据本发明的具体实施例，当第一种溶剂体系选自所述低级烷基醇与水的混合溶液、乙腈和水的混合溶液或低级烷基醇与乙酸乙酯的混合溶液时，所述低级烷基醇或乙腈的用量为地佐辛衍生物的0.8～10倍(ml/g)，优选为1～5倍(ml/g)；所述水的用量为地佐辛衍生物的1～10倍(ml/g)，优选为1～5倍(ml/g)；所述乙酸乙酯的用量为地佐辛衍生物的1～30倍(ml/g)，优选为10～20倍(ml/g)；更优选的，第一种溶剂体系选自低级烷基醇与水的混合溶液，其中，所述低级烷基醇的用量为地佐辛衍生物的0.8～10倍(ml/g)，优选为1～5倍(ml/g)；所述水的用量为地佐辛衍生物的1～10倍(ml/g)，优选为1～5倍(ml/g)。
根据本发明的实施例，所述的干燥是采用45±5℃真空干燥，干燥时间为16-30小时。
在本发明的又一方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包含前面所述地佐辛衍生物的晶型A以及药学上可接受的载体。
所述药物组合物中的载体为“可接受的”，其可与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。
在一些实施方案中，本发明所述的药物组合物包含第二治疗剂，所述第二治疗剂包括MOR调节剂，例如拮抗剂，如选自纳洛酮、纳曲酮、曲马多、samidorphan中的一种或多种。这样的药物组合物可以经由MOR的阿片调节剂介导的活化机制，用于治疗阿片受体相关病症，如疼痛。
本发明所述地佐辛衍生物晶型A或药物组合物可静脉内注射、皮下注射、肌内注射、腹膜内注射、神经周围注射、轴索(neuraxial)注射、关节内注射、口服施用或局部施用。
在一些实施方案中，口服使用的本发明药物组合物可以是任何口服可接受的剂型，包括胶囊、片剂、乳剂、水性混悬剂、栓剂、喷雾剂、吸入剂、分散体及溶液。
在片剂的情形下，常用的载体包括乳糖及玉米淀粉。通常还添加润滑剂，如硬脂酸镁。对于胶囊形式，可用的稀释剂包括乳糖及干玉米淀粉。当口服施用水性混悬剂或乳剂时，活性成分可以悬浮或溶解于组合有乳化剂或悬浮剂的油相中。如有需要，可以添加某些甜味剂、调味剂或着色剂。口服固体剂型可以通过喷雾干燥技术；热熔挤出策略、微粉化及纳米研磨技术制备。喷雾剂或吸入剂组合物可以根据药物制剂领域熟知的技术制备。例如，这种组合物可以制备成盐水溶液，使用苯甲酸或其它适合的防腐剂、吸收促进剂以增强生物利用度、氟碳化合物和/或本领域已知的其它增溶剂或分散剂。具有活性化合物的组合物还可以以栓剂的形式施用用于直肠施用。
在一些实施方案中，所述地佐辛衍生物晶型A或含有其的药物组合物可以口服、肠胃外、通过吸入喷雾、局部、经直肠、经鼻、经颊、经阴道或经由植入式贮存器施用。如本文中所用，术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内及颅内注射或输注技术。本发明所述地佐辛衍生物晶型A具有阿片受体调节剂活性，可用于治疗阿片受体相关病症。所述病症包括疼痛、痛觉过敏和心脑血管疾病等。
在本发明的又一方面，本发明提出了前面所述的地佐辛衍生物的晶型A或药物组合物在制备药物中的用途。根据本发明的实施例，所述药物用于治疗阿片受体相关病症。本发明的晶型A及含有其的药物组合物可以作为阿片受体调节剂，从而治疗阿片受体相关病症，例如镇痛。
根据本发明的实施例，所述病症为疼痛。
根据本发明的实施例，所述疼痛包括神经性疼痛或伤害性疼痛。
根据本发明的实施例，所述疼痛包括急性疼痛或慢性疼痛。
根据本发明的实施例，所述疼痛包括下列至少之一：手术后疼痛、由于神经痛导致的疼痛、由于糖尿病神经病变导致的疼痛、牙痛、与关节炎相关的疼痛和与癌症或其治疗相 关的疼痛。
根据本发明的实施例，所述由于神经痛导致的疼痛包括疱疹后神经痛或三叉神经痛。
根据本发明的实施例，所述药物用于调节阿片受体的活性。
在本发明的又一方面，本发明提出了一种治疗阿片受体相关病症的方法。根据本发明的实施例，所述方法包括：向受试者施加前面所述的地佐辛衍生物的晶型A或权药物组合物。如前所述，本发明的晶型A及含有其的药物组合物可以作为阿片受体调节剂，可以作为阿片受体调节剂，从而治疗阿片受体相关病症，例如镇痛。
根据本发明的实施例，所述阿片受体相关病症选自疼痛。
有益效果：
1、本发明的地佐辛衍生物的晶型A具有好的稳定性及溶解性，在研磨过程中不转晶。该晶型A以药用低密度聚乙烯袋和聚酯/铝/聚乙烯药用复合膜封装后在影响因素光照、高温高湿、高湿条件下，各项指标无明显变化，均符合质量标准要求，稳定性良好，且在中间条件以及长期条件的存放周期下均可以保持良好的化学稳定性和晶型稳定性。
2、本发明的地佐辛衍生物的晶型A制备方法是采用冷却结晶法进行，具有操作简便、用时少、收率高、纯度高、能耗小等优点，适于工业化生产应用。
3、本发明的地佐辛衍生物的晶型A可以作为阿片受体调节剂，有效地调节阿片受体活性，从而治疗阿片受体相关病症，例如镇痛。
附图说明
图1是地佐辛衍生物晶型A的X-射线粉末衍射谱图；
图2是乙醇/水作为结晶溶剂制备的晶型的X-射线粉末衍射谱图；
图3是甲醇/水作为结晶溶剂制备的晶型的X-射线粉末衍射谱图；
图4是异丙醇/水作为结晶溶剂制备的晶型的X-射线粉末衍射谱图；
图5是乙醇/乙酸乙酯作为结晶溶剂制备的晶型的X-射线粉末衍射谱图；
图6是乙腈/水作为结晶溶剂制备的晶型的X-射线粉末衍射谱图；
图7是研磨晶型的X-射线粉末衍射谱图；
图8是喷雾晶型的X-射线粉末衍射谱图；
图9是光照5天晶型的X-射线粉末衍射谱图；
图10是高温高湿5天晶型的X-射线粉末衍射谱图；
图11是高湿5天晶型的X-射线粉末衍射谱图；
图12是光照10天晶型的X-射线粉末衍射谱图；
图13是高温高湿10天晶型的X-射线粉末衍射谱图；
图14是高湿10天晶型的X-射线粉末衍射谱图；
图15是光照30天晶型的X-射线粉末衍射谱图；
图16是高温高湿30天晶型的X-射线粉末衍射谱图；
图17是高湿30天晶型的X-射线粉末衍射谱图；
图18是地佐辛衍生物晶型A的TG图谱；
图19是地佐辛衍生物晶型A的DSC图谱。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器做出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明所述的X-射线粉末衍射图在Bruker D2 phaser X-射线粉末衍射仪上采集。
本发明所述的X-射线粉末衍射的方法参数如下：
电压：30KV
电流：10mA
扫描范围：3°～40°
步长：0.02°
步速：0.5s/步
当提及本发明化合物，本发明地佐辛衍生物，均对应代表如下结构：
Figure PCTCN2021107934-appb-000004
本发明地佐辛衍生物的制备方法
Figure PCTCN2021107934-appb-000005
O-甲基地佐辛(1-1，0.732mmol)溶于5ml甲醇,依次加入苯甲醛(0.805mmol)， NaBH3CN(1.464mmol)和乙酸(0.2ml),室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相用乙酸乙酯洗(30ml),合并有机相，饱和食盐水清洗，无水硫酸钠干燥，硅胶柱层析(DCM/MeOH＝200:1),得到化合物1，质量为159mg。
1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.5Hz,2H),7.41(t,J＝7.4Hz,2H),7.33(t,J＝7.2Hz,1H),7.07(d,J＝8.4Hz,1H),6.84(s,1H),6.76(d,J＝8.3Hz,1H),4.14(d,J＝12.9Hz,1H),3.85(s,3H),3.77(d,J＝12.9Hz,1H),3.10(dd,J＝16.4,6.8Hz,1H),2.94(d,J＝4.7Hz,1H),2.75(d,J＝16.4Hz,1H),2.59(s,1H),2.10(t,J＝13.4Hz,1H),1.87–1.72(m,3H),1.67(s,3H),1.56(dd,J＝14.0,6.4Hz,1H),1.45(s,3H),1.16(s,1H),1.08–0.86(m,2H).Ms(m/z):350.3[M+H]
Figure PCTCN2021107934-appb-000006
将化合物1(0.09mmol)溶于40％HBr水溶液(2ml)中，升至回流反应8小时至原料完全转化，旋去大部分HBr，10ml乙酸乙酯稀释，冰浴下用氨水调至PH＝9，分液，水相EA洗(10ml)，合并有机相，brine洗，无水硫酸钠干燥，柱层析(DCM/MeOH＝20:1)，得到化合物2，所述化合物2和少量的盐酸乙酸乙酯溶液进行成盐反应得到化合物2的盐酸盐，即本发明目标地佐辛衍生物(为盐酸盐形式)，质量为23mg。
1H NMR(400MHz,CDCl3)δ7.35(d,J＝7.3Hz,2H),7.25(t,J＝7.3Hz,2H),7.18(d,J＝7.3Hz,1H),6.83(d,J＝8.1Hz,1H),6.61(s,1H),6.52(d,J＝8.1Hz,1H),4.05(q,J＝7.1Hz,1H),3.99(d,J＝12.9Hz,1H),3.61(d,J＝12.9Hz,1H),3.27(s,1H),2.92(dd,J＝16.4,6.6Hz,1H),2.77(d,J＝4.3Hz,1H),2.57(d,J＝16.4Hz,1H),2.42(s,1H),1.98(s,2H),1.91(t,J＝13.5Hz,1H),1.58(dt,J＝29.0,21.5Hz,5H),1.43–1.31(m,1H),1.24(s,3H),0.98(s,1H).Ms(m/z):336.2[M+H]
实施例1
向反应瓶中加入1g本发明地佐辛衍生物、1ml无水乙醇和2ml纯化水。升温至50～60℃溶清，关闭加热，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤，滤饼用乙醇-水混合溶液淋洗，滤饼45±5℃真空干燥得产物0.66g，纯度为99.8％。该产物 经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图1。
实施例2
向反应釜中加入803g本发明地佐辛衍生物、800ml无水乙醇和1600ml纯化水。升温至50～60℃溶清，保温0.5h后过滤除去机械杂质。若有固体析出，升温使其完全溶解后，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤，滤饼用乙醇-水混合溶液淋洗，滤饼45±5℃真空干燥得产物554g，纯度为99.8％。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图2。
实施例3
向反应瓶中加入1g本发明地佐辛衍生物、10mL(1v/2v)甲醇和纯化水混合溶液。升温至60～70℃，补加8mL(1v/2v)甲醇和纯化水混合溶液至体系溶清，关闭加热，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤，滤饼45±5℃真空干燥得产物0.59g，纯度为99.4％。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图3。
实施例4
向反应瓶中加入1g本发明地佐辛衍生物、10mL(1v/2v)异丙醇和纯化水混合溶液。升温至60～70℃溶清，关闭加热，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤，滤饼45±5℃真空干燥得产物0.57g，纯度为99.4％。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图4。
实施例5
向反应瓶中加入1g本发明地佐辛衍生物、5mL乙醇和20mL乙酸乙酯。升温至60～70℃溶清，关闭加热，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤，滤饼45±5℃真空干燥得产物0.12g，纯度为99.3％。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图5。
实施例6
向反应瓶中加入1g本发明地佐辛衍生物、6mL乙腈和8mL纯化水。升温至60～70℃溶清，关闭加热，自然冷却降温至25±5℃，冰水浴冷却降温至0±5℃，保温20h，过滤， 滤饼45±5℃真空干燥得产物0.35g，纯度为99.4％。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A。见附图6。
实施例7
称取1g本发明地佐辛衍生物晶型A至玛瑙研钵中，充分研磨半小时。收集样品，称重得0.98g。该产物经X-射线粉末衍射证明为地佐辛衍生物的晶型A，晶型A在此条件下未转晶，见附图7。
实施例8
称取1g本发明地佐辛衍生物，加入2mL甲醇、2mL二氯甲烷溶解，将上述溶液快速喷至热烧杯底部，溶剂快速挥发，得无色透明固体。45±5℃真空干燥得0.82g泡沫状固体。该产物经X-射线粉末衍射证明为地佐辛衍生物的无定型。见附图8。
实施例9
将实施例2提供的地佐辛衍生物晶型A，以药用低密度聚乙烯袋和聚酯/铝/聚乙烯药用复合膜封装后在影响因素条件下，进行光照、高温高湿、高湿5天、10天、30天试验，结果如下：
实验条件 晶型
0天 晶型A
光照5天 晶型A
高温高湿5天 晶型A
高湿5天 晶型A
光照10天 晶型A
高温高湿10天 晶型A
高湿10天 晶型A
光照30天 晶型A
高温高湿30天 晶型A
高湿30天 晶型A
由表中数据得知，地佐辛衍生物晶型A在高温高湿、高湿和光照条件下晶型均能够很 好的保持稳定。地佐辛衍生物晶型A的X-射线衍射谱与初始数据一致(见附图9～17)，没有发生转晶现象，表明本发明提供的晶型稳定性良好，利于原料药的储存。
实施例10地佐辛衍生物晶型A的稳定性
Figure PCTCN2021107934-appb-000007
由表中数据得知地佐辛衍生物晶型A在中间条件(30℃±2℃/65％±5％RH)和长期条件(25℃±2℃/60％±5％RH)12个月的存放周期下均可以保持很好的化学稳定性和晶型稳定性。表明本发明提供的晶型稳定性良好，利于原料药的储存。
实施例11地佐辛衍生物晶型A的理化性质
Figure PCTCN2021107934-appb-000008
实施例12体外活性实验
1.实验目的
通过放射性同位素配体竞争性结合实验，以本发明的地佐辛衍生物晶型A的IC 50为指标，来评价该化合物对μ、κ和δ阿片类受体的亲和力。
2.实验材料
(1)试剂
细胞膜提取自上海药明康德构建的稳转细胞。
3H-diprenophrine(PerkinElmer,Cat:NET1121250UC,Lot:2143599)
3H-DAMGO(PerkinElmer,Cat:NET902250UC,Lot:2139100)
3H-DADLE(PerkinElmer,Cat:NET648250UC,Lot:2060549)
Tris base(Sigma,Cat:T6066-1KG),prepare 1M stock and adjust pH to 7.4.
0.5M EDTA(Invitrogen,Cat:15575-038)
1M MgCl 2(Sigma,Cat:M1028-100ml)
PEI(Poly ethyleneimine)(Sigma,Cat:P3143)
Microscint 20 cocktail(PerkinElmer,Cat:6013329)
Naltrindole(Sigma,Cat；N115)
(±)trans-U-50488(Sigma,Cat:D8040)
DAMGO(Sigma,Cat:E7384)
(2)实验缓冲液和洗板缓冲液
Figure PCTCN2021107934-appb-000009
(3)耗材及仪器
GF/C滤板,Perkin Elmer(Cat#6005174)
96-孔板,Agilent(Cat#5042-1385)
封板膜,Perkin Elmer(Cat#6005250)
MicroBeta2(PerkinElmer)
Cell harvest C961961,(Perkin Elmer)
3.方法步骤
1)细胞膜及放射性同位素配制
Figure PCTCN2021107934-appb-000010
2)化合物配制
Figure PCTCN2021107934-appb-000011
3)实验步骤
(1)待测试化合物、阴性对照(即DMSO)和阳性对照(即非特异性结合孔化合物)准备好之后，转移1μL至96孔板中；
(2)加入99μL配制好的阿片受体膜蛋白至含有1μL化合物的96孔板中；
(3)加入100μL 2x对应放射性同位素配体；
(4)置于摇床上300rpm室温孵育1小时；
(5)提前将GF/C板每孔用50μL 0.3％的PEI至少浸泡半小时以上；
(6)待孵育结束后，先用Harvest将GF/C板用洗板缓冲液冲洗1次。然后用Harvest将96孔板中的细胞膜收集到GF/C板上，再用洗板缓冲液洗涤GF/C板四次，每次250μL左右；
(7)将GF/C板子置于50℃烘箱烘烤1小时；
(8)用封底膜将GF/C板底部封上，每孔加入50μL Microscint-20闪烁液，然后用透明封板膜封住板子；
(9)使用MicroBeta2读取放射性信号值CPM；
(10)用Prsim 5分析数据。计算百分百抑制率，计算公式为％Inh＝(1-Background subtracted Assay value/Background subtracted HC value)*100。
下表为待测化合物针对μ、κ和δ阿片类受体的IC 50值。可以看出，本发明的地佐辛衍生物晶型A有效地调节阿片受体活性，从而可以起到较好的治疗阿片受体相关病症的效果。
供试样品 μIC 50 κIC 50 δIC 50
地佐辛衍生物晶型A A A A
注：A：<10nM
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (28)

  1. 一种地佐辛衍生物的晶型A，所述地佐辛衍生物的结构为
    Figure PCTCN2021107934-appb-100001
    其特征在于，所述晶型A以2θ±0.2°衍射角表示的X-射线粉末衍射谱图在8.894、9.496、10.974、13.334、15.338、15.942、17.707和24.178处显示特征峰。
  2. 根据权利要求1所述的晶型A，其特征在于，所述晶型A以2θ±0.2°衍射角表示的X-射线粉末衍射谱图还在12.603、14.768、16.683、18.099、18.925、20.286、22.666、25.510、26.325、26.785和27.766处显示特征峰。
  3. 根据权利要求1或2所述的晶型A，其特征在于，所述晶型A的X-射线粉末衍射谱图如图1所示。
  4. 根据权利要求1所述的晶型A，其特征在于，所述晶型A是通过冷却结晶法制备。
  5. 一种权利要求1-4任一项所述晶型A的制备方法，其特征在于，包括：
    (1)将地佐辛衍生物与第一种溶剂混合，使得地佐辛衍生物完全溶解，得到混合液；
    (2)将所述混合液冷却至析晶，过滤，得到所述晶型A。
  6. 根据权利要求5所述晶型A的制备方法，其特征在于，步骤(1)中，将地佐辛衍生物与第一种溶剂混合后，升温至40～80℃，使得地佐辛衍生物完全溶解，得到混合液。
  7. 根据权利要求5所述晶型A的制备方法，其特征在于，步骤(1)进一步包括：将所述混合液保温预定时间后，进行过滤，滤除机械杂质，当滤除机械杂质后有固体析出时，进一步将滤除机械杂质后的混合液进行升温至固体完全溶解，将最终所得混合液进行步骤(2)的操作。
  8. 根据权利要求7所述晶型A的制备方法，其特征在于，所述升温后的混合液温度为40～80℃。
  9. 根据权利要求7所述晶型A的制备方法，其特征在于，所述升温后的混合液温度为50～60℃。
  10. 根据权利要求7所述晶型A的制备方法，其特征在于，所述预定时间为0～2小时。
  11. 根据权利要求5所述晶型A的制备方法，其特征在于，所述冷却包括：先自然冷却至25±5℃，再冰水浴冷却至0±5℃，保温4～25小时。
  12. 根据权利要求5所述晶型A的制备方法，其特征在于，步骤(2)进一步包括：将所述过滤所得滤饼用第二种溶剂洗涤，再将洗涤后的滤饼进行干燥，得到所述晶型A。
  13. 根据权利要求12所述晶型A的制备方法，其特征在于，所述第一种溶剂或第二种溶剂各自独立地选自乙腈、低级烷基醇、乙酸乙酯和水的至少之一。
  14. 根据权利要求13所述晶型A的制备方法，其特征在于，所述第一种溶剂、第二种溶剂各自独立地选自低级烷基醇与水的混合溶液、乙腈和水的混合溶液或者低级烷基醇与乙酸乙酯的混合溶液。
  15. 根据权利要求13所述晶型A的制备方法，其特征在于，所述低级烷基醇选自C 1-C 4烷基醇。
  16. 根据权利要求13所述晶型A的制备方法，其特征在于，所述低级烷基醇选自甲醇、乙醇、异丙醇、正丙醇或正丁醇。
  17. 一种药物组合物，其特征在于，包含权利要求1-4任一项所述的地佐辛衍生物的晶型A以及药学上可接受的载体。
  18. 根据权利要求17所述的药物组合物，其特征在于，进一步包含第二治疗剂，所述第二治疗剂包括MOR调节剂。
  19. 根据权利要求17所述的药物组合物，其特征在于，所述第二治疗剂包括纳洛酮、纳曲酮、曲马多、samidorphan中的一种或多种。
  20. 权利要求1-4任一项所述的地佐辛衍生物的晶型A或权利要求17-19任一项所述的药物组合物在制备药物中的用途，其特征在于，所述药物用于治疗阿片受体相关病症。
  21. 根据权利要求20所述的用途，其特征在于，所述病症为疼痛。
  22. 根据权利要求21所述的用途，其特征在于，所述疼痛包括神经性疼痛或伤害性疼痛。
  23. 根据权利要求21所述的用途，其特征在于，所述疼痛包括急性疼痛或慢性疼痛。
  24. 根据权利要求21所述的用途，其特征在于，所述疼痛包括下列至少之一：手术后疼痛、由于神经痛导致的疼痛、由于糖尿病神经病变导致的疼痛、牙痛、与关节炎相关的疼痛和与癌症或其治疗相关的疼痛。
  25. 根据权利要求21所述的用途，其特征在于，所述由于神经痛导致的疼痛包括疱疹后神经痛或三叉神经痛。
  26. 根据权利要求20所述的用途，其特征在于，所述药物用于调节阿片受体的活性。
  27. 一种治疗阿片受体相关病症的方法，其特征在于，包括：向受试者施加权利要求1-4任一项所述的地佐辛衍生物的晶型A或权利要求17-19任一项所述的药物组合物。
  28. 根据权利要求27所述的方法，其特征在于，所述阿片受体相关病症选自疼痛。
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