CN113979875A

CN113979875A - Dezocine derivative crystal form A and preparation method and application thereof

Info

Publication number: CN113979875A
Application number: CN202110819358.7A
Authority: CN
Inventors: 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
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2020-07-27
Filing date: 2021-07-20
Publication date: 2022-01-28
Anticipated expiration: 2041-07-20
Also published as: CN113979875B; TW202204308A; WO2022022388A1

Abstract

The invention provides a crystal form A of a dezocine derivative, wherein an X-ray powder diffraction spectrum of the crystal form A expressed by a2 theta +/-0.2-degree diffraction angle 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 has good stability and solubility, does not change crystals in the grinding process, can be used as an opioid receptor regulator, plays a role in relieving pain, and has wide application prospect.

Description

Dezocine derivative crystal form A and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a crystal form A of a dezocine derivative, and a preparation method and application thereof.

Background

Dezocine (dezocine) is an opioid receptor mixed agonist-antagonist structurally resembling pentazocine (pentazocine), developed in the last 70 th century by the U.S. Wyeth-Ayerst laboratory, approved by the FDA for marketing in 1989, and marketed under the trade name Dalgan by Astrazeneca for the treatment of postoperative pain. It has been widely used in general anesthesia induction, postoperative analgesia, and advanced analgesia in china in 2009, and is used for the treatment of visceral pain and cancer pain. The chemical name is as follows: (-) - [5R- (5 α,11 α, 13S) ] -13-amino-5, 6,7,8,9,10,11, 12-octahydro-5-methyl-5, 11-methylenebenzocyclodecen-3-ol, having the following structural formula:

derivative structures with better activity and/or medicament performance are expected to be obtained through modification/transformation of dezocine structures, and the application potential of medicaments can be further expanded through crystal form development of the derivatives.

Disclosure of Invention

The present invention aims to solve, at least to some extent, the technical problems of the prior art. Therefore, the crystal form A of the dezocine derivative has good stability and solubility, does not change crystals in the grinding process, can be used as an opioid receptor regulator, plays a role in analgesia, and has wide application prospect.

To this end, in one aspect of the invention, the invention proposes a crystalline form a of a dezocine derivative, which is a compound

Hydrochloride salt, in particular, the dezocine derivative is

According to an embodiment of the present invention, the form a shows characteristic peaks at 8.894, 9.496, 10.974, 13.334, 15.338, 15.942, 17.707 and 24.178 in an X-ray powder diffraction pattern expressed by a2 θ ± 0.2 ° diffraction angle.

According to embodiments of the present invention, the crystalline form a of the dezocine derivative may also have the following additional technical features:

according to an embodiment of the present invention, the form a further shows characteristic peaks at 12.603, 14.768, 16.683, 18.099, 18.925, 20.286, 22.666, 25.510, 26.325, 26.785 and 27.766 in an X-ray powder diffraction pattern expressed by a2 θ ± 0.2 ° diffraction angle.

According to the embodiment of the invention, the X-ray powder diffraction spectrum of the crystal form A is shown in figure 1.

It should be noted that, depending on the measurement conditions, the 2 θ angle and the relative intensity of each peak on the X-ray powder diffraction pattern vary, and generally, the variation of the 2 θ angle is within ± 0.2 °, and the relative intensity is within ± 5% is considered as a reasonable error.

The crystal form A disclosed by the invention has good stability and solubility, does not change crystals in the grinding process, can be used as an opioid receptor modulator, plays an analgesic role, and has a wide application prospect.

In another aspect of the present invention, the present invention provides a process for preparing form a as described above. According to an embodiment of the invention, the method comprises: (1) mixing the dezocine derivative with a first solvent to completely dissolve the dezocine derivative to obtain a mixed solution; (2) and cooling the mixed solution to crystallize, and filtering to obtain the crystal form A.

The invention obtains the crystal form A by adopting a crystallization method, has the advantages of simple and convenient operation, less time consumption, high yield, high purity, low energy consumption and the like, and is suitable for industrial production and application.

According to the embodiment of the invention, in the step (1), the dezocine derivative and the first solvent are mixed, and then the temperature is raised to 40-80 ℃ to completely dissolve the dezocine derivative, so as to obtain the mixed solution. Therefore, the dissolution of the dezocine derivative can be accelerated, the time consumption is reduced, and the preparation efficiency is improved.

According to an embodiment of the present invention, the step (1) further comprises: and (3) preserving the temperature of the mixed solution for a preset time, filtering to remove mechanical impurities, when solids are separated out after the mechanical impurities are removed, further heating the mixed solution after the mechanical impurities are removed until the solids are completely dissolved, and carrying out the operation of the step (2) on the finally obtained mixed solution.

It should be noted that the term "mechanical impurities" as used herein refers primarily to precipitates or colloidal suspensions present in lubricating oils that are insoluble in solvents such as gasoline, ethanol, and benzene. The impurities are mostly sand and iron filings, and some organic metal salts which are difficult to dissolve in the solvent and are brought by the additive. Because the existence of mechanical impurities can influence the subsequent cooling crystallization, and further influence the purity and yield of the crystal form, the mixed liquid is removed by filtration in advance, and then the operation of the step (2) is carried out on the mixed liquid after the mechanical impurities are removed by filtration. And (3) if the solid is precipitated, carrying out the operation of the step (2) after the solid is completely dissolved.

According to an embodiment of the present invention, the temperature of the heated mixed solution is 40 to 80 ℃, preferably 50 to 60 ℃. Therefore, the solid substance is fully dissolved in the first solvent, the subsequent full cooling crystallization is facilitated, and the yield and the purity of the crystal form A are improved.

According to the embodiment of the invention, the preset time is 0-2 hours. Before filtering, the mixed solution is subjected to heat preservation so as to grow crystals and improve the yield of the crystal form A.

According to an embodiment of the invention, the cooling comprises: naturally cooling to 25 +/-5 ℃, then cooling to 0 +/-5 ℃ in an ice water bath, and preserving heat for 4-25 hours, preferably 15-20 hours. By adopting the gradient cooling mode, the crystal form A can be fully separated out, and other impurities are not easy to separate out, so that the yield and the purity of the crystal form A are improved.

According to an embodiment of the present invention, the step (2) further comprises: and washing the filter cake obtained by filtering with a second solvent, and drying the washed filter cake to obtain the crystal form A. Impurities are removed by washing, and the purity of the crystal form A is improved.

According to an embodiment of the invention, the first solvent or the second solvent is each independently selected from at least one of acetonitrile, a lower alkyl alcohol, ethyl acetate and water. The first solvent can be adopted to fully dissolve the dezocine derivative, and the crystal form A can be cooled and crystallized in the system. The second solvent can be used for washing off other impurities in the filter cake, so that the purity of the crystal form A is improved. The types of the first solvent and the second solvent can be the same or different, and are flexibly selected according to actual needs. Specifically, the first solvent and the second solvent are respectively and 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.

According to an embodiment of the invention, the lower alkyl alcohol is selected from C₁-C₄Alkyl alcohols, preferably methanol, ethanol, isopropanol, n-propanol, n-butanol.

According to a specific embodiment of the present invention, when the first solvent system is selected from a mixed solution of the lower alkyl alcohol and water, a mixed solution of acetonitrile and water, or a mixed solution of the lower alkyl alcohol and ethyl acetate, the lower alkyl alcohol or acetonitrile is used in an amount of 0.8 to 10 times (ml/g), preferably 1 to 5 times (ml/g) that of the dezocine derivative; the using amount of the water is 1-10 times (ml/g) of that of the dezocine derivative, and preferably 1-5 times (ml/g); the using amount of the ethyl acetate is 1-30 times (ml/g) of that of the dezocine derivative, and preferably 10-20 times (ml/g); more preferably, the first solvent system is selected from a mixed solution of a lower alkyl alcohol and water, wherein the lower alkyl alcohol is used in an amount of 0.8 to 10 times (ml/g), preferably 1 to 5 times (ml/g) that of the dezocine derivative; the amount of water is 1-10 times (ml/g), preferably 1-5 times (ml/g) of that of the dezocine derivative.

According to the embodiment of the invention, the drying is carried out by adopting vacuum drying at 45 +/-5 ℃ for 16-30 hours.

In yet another aspect of the invention, a pharmaceutical composition is provided. According to an embodiment of the present invention, the pharmaceutical composition comprises crystalline form a of the aforementioned dezocine derivative, and a pharmaceutically acceptable carrier.

The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with (and preferably capable of stabilizing) the active ingredient of the composition and is not deleterious to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients for the delivery of the active compound.

In some embodiments, the pharmaceutical compositions of the invention comprise a second therapeutic agent comprising a MOR modulator, e.g., an antagonist, such as one or more selected from naloxone, naltrexone, tramadol, samidylphan. Such pharmaceutical compositions may be used to treat opioid receptor-related disorders, such as pain, via an opioid modulator-mediated activation mechanism of MOR.

The crystalline form a or the pharmaceutical composition of the dezocine derivative of the present invention may be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, perineurally, intraarticularly, orally or topically.

In some embodiments, the pharmaceutical compositions of the present invention for oral use may be in any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, suppositories, sprays, inhalants, dispersions, and solutions.

In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For capsule forms, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added. Oral solid dosage forms can be prepared by spray drying techniques; hot melt extrusion strategy, micronization and nano-milling technology. The spray or inhalation composition may be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such compositions may be prepared as aqueous salt solutions, employing benzoic acid or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Compositions with active compounds may also be administered in the form of suppositories for rectal administration.

In some embodiments, the crystalline form a of the dezocine derivative, or the pharmaceutical composition containing it, may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "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 has the activity of an opioid receptor modulator and can be used for treating opioid receptor related diseases. The symptoms comprise pain, hyperalgesia, cardiovascular and cerebrovascular diseases and the like.

In a further aspect of the invention, the invention proposes the use of the aforementioned crystalline form a of a dezocine derivative or of a pharmaceutical composition for the preparation of a medicament. According to an embodiment of the invention, the medicament is for the treatment of an opioid receptor-related disorder. The crystal form A and the pharmaceutical composition containing the crystal form A can be used as an opioid receptor modulator, so as to treat opioid receptor related diseases, such as analgesia.

According to an embodiment of the invention, the condition is pain.

According to an embodiment of the invention, the pain comprises neuropathic pain or nociceptive pain.

According to an embodiment of the invention, the pain comprises acute pain or chronic pain.

According to an embodiment of the invention, the pain comprises at least one of: post-operative pain, pain due to neuropathic pain, pain due to diabetic neuropathy, dental pain, pain associated with arthritis, and pain associated with cancer or treatment thereof.

According to an embodiment of the invention, the pain due to neuralgia comprises post-herpetic neuralgia or trigeminal neuralgia.

According to an embodiment of the invention, the medicament is for modulating the activity of opioid receptors.

In yet another aspect of the invention, the invention features a method of treating an opioid receptor-related disorder. According to an embodiment of the invention, the method comprises: administering to the subject the aforementioned crystalline form a or pharmaceutical composition of a dezocine derivative. As mentioned above, the crystal form a and the pharmaceutical composition containing the same of the present invention can be used as an opioid receptor modulator, and can be used as an opioid receptor modulator, thereby treating opioid receptor-related disorders, such as analgesia.

According to an embodiment of the invention, the opioid receptor-related disorder is selected from pain.

Has the advantages that:

1. the crystal form A of the dezocine derivative has good stability and solubility, and does not change crystals in the grinding process. After the crystal form A is packaged by a medical low-density polyethylene bag and a polyester/aluminum/polyethylene medical composite film, under the conditions of influence factors such as illumination, high temperature, high humidity and high humidity, all indexes of the crystal form A have no obvious change, the crystal form A meets the requirements of quality standards, the stability is good, and good chemical stability and crystal form stability can be kept under intermediate conditions and long-term storage periods.

2. The preparation method of the crystal form A of the dezocine derivative is carried out by adopting a cooling crystallization method, has the advantages of simple and convenient operation, less time consumption, high yield, high purity, low energy consumption and the like, and is suitable for industrial production and application.

3. The crystal form A of the dezocine derivative can be used as an opioid receptor modulator to effectively modulate the activity of opioid receptors, thereby treating opioid receptor related diseases, such as analgesia.

Drawings

Figure 1 is an X-ray powder diffraction pattern of crystalline form a of a dezocine derivative;

FIG. 2 is an X-ray powder diffraction pattern of a crystalline form prepared with ethanol/water as the crystallization solvent;

FIG. 3 is an X-ray powder diffraction pattern of a crystalline form prepared with methanol/water as the crystallization solvent;

FIG. 4 is an X-ray powder diffraction pattern of a crystalline form prepared with isopropanol/water as the crystallization solvent;

FIG. 5 is an X-ray powder diffraction pattern of a crystalline form prepared with ethanol/ethyl acetate as the crystallization solvent;

FIG. 6 is an X-ray powder diffraction pattern of a crystalline form prepared with acetonitrile/water as the crystallization solvent;

FIG. 7 is an X-ray powder diffraction pattern of the milled crystalline form;

FIG. 8 is an X-ray powder diffraction pattern of a spray crystalline form;

FIG. 9 is an X-ray powder diffraction pattern of the crystalline form at 5 days of illumination;

FIG. 10 is an X-ray powder diffraction pattern of the 5-day crystal form at elevated temperature and humidity;

FIG. 11 is an X-ray powder diffraction pattern of the high humidity 5 day crystalline form;

FIG. 12 is an X-ray powder diffraction pattern of the crystalline form at 10 days of light;

FIG. 13 is an X-ray powder diffraction pattern of the high temperature high humidity 10 day crystal form;

FIG. 14 is an X-ray powder diffraction pattern of the high humidity 10 day crystalline form;

FIG. 15 is an X-ray powder diffraction pattern of the crystalline form after 30 days of light exposure;

FIG. 16 is an X-ray powder diffraction pattern of the high temperature, high humidity 30 day crystalline form;

FIG. 17 is an X-ray powder diffraction pattern of the high humidity 30 day crystalline form;

figure 18 is a TG profile of crystalline form a of a dezocine derivative;

figure 19 is a DSC profile of crystalline form a of the dezocine derivative.

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the scope of protection of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

The X-ray powder diffractogram according to the invention was collected on a Bruker D2 phaser X-ray powder diffractometer.

The parameters of the X-ray powder diffraction method are as follows:

voltage: 30KV

Current: 10mA

Scanning range: 3 degree to 40 degree

Step length: 0.02 degree

The pace speed is as follows: 0.5 s/step

When referring to the compounds of the invention, the dezocine derivatives of the invention, each correspond to the following structure:

the invention relates to a method for preparing dezocine derivatives

O-methyldezocine (1-1, 0.732mmol) was dissolved in 5ml of methanol, benzaldehyde (0.805mmol), NaBH3CN (1.464mmol) and acetic acid (0.2ml) were sequentially added, the reaction was allowed to proceed overnight at room temperature, after a large amount of the starting materials were reacted by TLC, aqueous ammonia was added dropwise until PH 9,30ml of ethyl acetate was diluted, the aqueous phase was washed with ethyl acetate (30ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (DCM/MeOH 200:1) to obtain compound 1, the mass of which was 159 mg.

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]

Dissolving compound 1(0.09mmol) in 40% aqueous HBr (2ml), heating to reflux for 8 hours until the raw material is completely converted, removing most of HBr by rotation, diluting with 10ml of ethyl acetate, adjusting the PH to 9 with ammonia water under ice bath, separating, washing with aqueous phase EA (10ml), combining organic phases, washing with bromine, drying with anhydrous sodium sulfate, performing column chromatography (DCM/MeOH ═ 20:1) to obtain compound 2, and performing salt formation reaction between compound 2 and a small amount of ethyl acetate hydrochloride solution to obtain the hydrochloride of compound 2, namely the target dezocine derivative (in the form of hydrochloride) with the mass of 23 mg.

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]

Example 1

To a reaction flask were added 1g of the dezocine derivative of the invention, 1ml of absolute ethanol and 2ml of purified water. Heating to 50-60 ℃ for dissolving, closing heating, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in ice water bath, preserving heat for 20 hours, filtering, leaching a filter cake with an ethanol-water mixed solution, and drying the filter cake at 45 +/-5 ℃ in vacuum to obtain 0.66g of a product with the purity of 99.8%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 1.

Example 2

803g of dezocine derivative according to the invention, 800ml of absolute ethanol and 1600ml of purified water are added to the reaction vessel. Heating to 50-60 ℃ for dissolving, keeping the temperature for 0.5h, and filtering to remove mechanical impurities. And if solids are separated out, heating to completely dissolve the solids, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in an ice-water bath, preserving the temperature for 20 hours, filtering, leaching a filter cake with an ethanol-water mixed solution, and drying the filter cake at 45 +/-5 ℃ in vacuum to obtain 554g of a product with the purity of 99.8%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 2.

Example 3

To the reaction flask, a mixed solution of 1g of the dezocine derivative of the present invention, 10mL (1v/2v) of methanol and purified water was added. Heating to 60-70 ℃, supplementing 8mL (1v/2v) of mixed solution of methanol and purified water until the system is clear, closing the heating, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in an ice water bath, preserving the heat for 20 hours, filtering, and drying a filter cake at 45 +/-5 ℃ in vacuum to obtain 0.59g of a product with the purity of 99.4%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 3.

Example 4

To the reaction flask, a mixed solution of 1g of the dezocine derivative of the present invention, 10mL (1v/2v) of isopropanol, and purified water was added. Heating to 60-70 ℃ for dissolving, closing heating, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in ice water bath, preserving heat for 20 hours, filtering, and drying a filter cake at 45 +/-5 ℃ in vacuum to obtain 0.57g of a product with the purity of 99.4%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 4.

Example 5

To the reaction flask were added 1g of the dezocine derivative of the invention, 5mL of ethanol and 20mL of ethyl acetate. Heating to 60-70 ℃ for dissolving, closing heating, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in ice water bath, preserving heat for 20 hours, filtering, and drying a filter cake at 45 +/-5 ℃ in vacuum to obtain 0.12g of a product with the purity of 99.3%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 5.

Example 6

To a reaction flask were added 1g of the dezocine derivative of the invention, 6mL of acetonitrile and 8mL of purified water. Heating to 60-70 ℃ for dissolving, closing heating, naturally cooling to 25 +/-5 ℃, cooling to 0 +/-5 ℃ in ice water bath, preserving heat for 20 hours, filtering, and drying a filter cake at 45 +/-5 ℃ in vacuum to obtain 0.35g of a product with the purity of 99.4%. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction. See figure 6.

Example 7

1g of crystal form A of the dezocine derivative is weighed into an agate mortar and fully ground for half an hour. The sample was collected and weighed to obtain 0.98 g. The product is proved to be crystal form A of the dezocine derivative by X-ray powder diffraction, and the crystal form A is not transformed under the condition, as shown in figure 7.

Example 8

Weighing 1g of dezocine derivative, adding 2mL of methanol and 2mL of dichloromethane for dissolving, quickly spraying the solution to the bottom of a hot beaker, and quickly volatilizing the solvent to obtain a colorless transparent solid. Vacuum drying at 45 + -5 deg.C to obtain 0.82g of foamed solid. The product was confirmed to be amorphous by X-ray powder diffraction as a dezocine derivative. See figure 8.

Example 9

The crystal form a of the dezocine derivative provided in example 2 is packaged by a medical low-density polyethylene bag and a polyester/aluminum/polyethylene medical composite film, and then is subjected to tests of 5 days, 10 days and 30 days under the conditions of influencing factors, and the results are as follows:

conditions of the experiment	Crystal form
		Day
0	Crystal form A
		Illuminating for 5 days	Crystal form A
High temperature and high humidity for 5 days	Crystal form A
		High humidity for 5 days	Crystal form A
Illuminating for 10 days	Crystal form A
		High temperature and high humidity for 10 days	Crystal form A
High humidity for 10 days	Crystal form A
		Irradiating for 30 days	Crystal form A
High temperature and high humidity for 30 days	Crystal form A
		30 days under high humidity	Crystal form A

The data in the table show that the crystal form A of the dezocine derivative can be well kept stable under the conditions of high temperature, high humidity and illumination. The X-ray diffraction spectrum of the crystal form A of the dezocine derivative is consistent with the initial data (see the attached figures 9-17), and the crystal transformation phenomenon does not occur, so that the crystal form provided by the invention has good stability and is beneficial to storage of raw medicines.

Example 10 stability of crystalline form a of dezocine derivative

The data in the table show that the dezocine derivative crystal form A can keep good chemical stability and crystal form stability under the intermediate condition (30 ℃ plus or minus 2 ℃/65 percent plus or minus 5 percent RH) and the long-term condition (25 ℃ plus or minus 2 ℃/60 percent plus or minus 5 percent RH) for a storage period of 12 months. The crystal form provided by the invention has good stability and is beneficial to storage of raw material medicines.

Example 11 physicochemical Properties of crystalline form A of dezocine derivative

Example 12 in vitro Activity assay

1. Purpose of experiment

IC of crystal form A of dezocine derivative of the invention by competitive binding experiment of radioisotope ligand₅₀As an index, the affinity of the compound for mu, kappa and delta opioid receptors was evaluated.

2. Experimental Material

(1) Reagent

The cell membrane is extracted from the stable cell constructed by Shanghai medicine Mingkude.

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 MgCl₂(Sigma,Cat:M1028-100ml)

PEI(Poly ethyleneimine)(Sigma,Cat:P3143)

Microscint 20cocktail(PerkinElmer,Cat:6013329)

Naltrindole(Sigma,Cat；N115)

(±)trans-U-50488(Sigma,Cat:D8040)

DAMGO(Sigma,Cat:E7384)

(2) Experiment buffer solution and plate washing buffer solution

(3) Consumable and instrument

GF/C filter plates, Perkin Elmer (Cat #6005174)

96-well plate, Agilent (Cat #5042-

Closure membrane, Perkin Elmer (Cat #6005250)

MicroBeta2(PerkinElmer)

Cell harvest C961961,(Perkin Elmer)

3. Method step

1) Cell membrane and radioisotope formulation

2) Compound preparation

3) Experimental procedure

(1) After the test compound, negative control (i.e., DMSO), and positive control (i.e., non-specifically binding well compound) were prepared, 1 μ L was transferred to a 96-well plate;

(2) adding 99 μ L of the formulated opioid receptor membrane protein to a 96-well plate containing 1 μ L of the compound;

(3) adding 100 μ L of 2x corresponding radioisotope ligand;

(4) incubating at 300rpm on a shaker for 1 hour at room temperature;

(5) soaking each hole of the GF/C plate in 50 microliter of 0.3% PEI for at least half an hour;

(6) after incubation was complete, the GF/C plates were washed 1 time with washing buffer using Harvest. Collecting cell membranes in a 96-well plate onto a GF/C plate by using Harvest, and washing the GF/C plate for four times by using a plate washing buffer solution, wherein each time is about 250 mu L;

(7) placing the GF/C plate in an oven at 50 ℃ for baking for 1 hour;

(8) sealing the bottom of the GF/C plate by using a bottom sealing film, adding 50 mu L of Microscint-20 scintillation liquid into each hole, and sealing the plate by using a transparent sealing plate film;

(9) the radioactive signal values CPM were read using MicroBeta 2;

(10) data were analyzed using Prsim 5. The percent inhibition was calculated as% Inh (1-Background analyzed value/Background analyzed HC value) 100.

The following table shows the IC of the test compounds against the mu, kappa and delta opioid receptors₅₀The value is obtained. The crystal form A of the dezocine derivative can effectively regulate the activity of opioid receptors, so that the crystal form A can play a good role in treating opioid receptor-related diseases.

Test sample	μIC₅₀	κIC₅₀	δIC₅₀
				Crystalline form a of dezocine derivative	A	A	A

Note: a: <10nM

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A crystal form A of dezocine derivative, wherein the structure of the dezocine derivative is

Characterized in that the X-ray powder diffraction spectrum of the crystal form A expressed by a2 theta +/-0.2 DEG diffraction angle shows characteristic peaks at 8.894, 9.496, 10.974, 13.334, 15.338, 15.942, 17.707 and 24.178.

2. Form a according to claim 1, characterized in that it further shows characteristic peaks in the X-ray powder diffraction pattern expressed in 2 Θ ± 0.2 ° diffraction angles at 12.603, 14.768, 16.683, 18.099, 18.925, 20.286, 22.666, 25.510, 26.325, 26.785 and 27.766.

3. Form a according to claim 1 or 2, characterized in that the form a has an X-ray powder diffraction pattern as shown in figure 1.

4. Form a according to claim 1, characterized in that it is prepared by a cooling crystallization process.

5. A process for preparing form A according to any one of claims 1 to 4, comprising:

(1) mixing the dezocine derivative with a first solvent to completely dissolve the dezocine derivative to obtain a mixed solution;

(2) and cooling the mixed solution to crystallize, and filtering to obtain the crystal form A.

6. The process for preparing form a according to claim 5, wherein step (1) further comprises: preserving the temperature of the mixed solution for a preset time, filtering to remove mechanical impurities, when solids are separated out after the mechanical impurities are removed, further heating the mixed solution after the mechanical impurities are removed until the solids are completely dissolved, and carrying out the operation of the step (2) on the finally obtained mixed solution;

optionally, the temperature of the mixed solution after temperature rise is 40-80 ℃;

optionally, the temperature of the mixture after temperature rise is 50-60 ℃;

optionally, the predetermined time is 0 to 2 hours.

7. The preparation method of the crystal form A according to claim 5, characterized in that in the step (1), the temperature is raised to 40-80 ℃ after the dezocine derivative and the first solvent are mixed, so that the dezocine derivative is completely dissolved to obtain a mixed solution;

optionally, the cooling comprises: naturally cooling to 25 +/-5 ℃, then cooling to 0 +/-5 ℃ in an ice water bath, and preserving heat for 4-25 hours;

optionally, step (2) further comprises: washing the filter cake obtained by filtering with a second solvent, and drying the washed filter cake to obtain the crystal form A;

optionally, the first solvent or the second solvent are each independently selected from at least one of acetonitrile, a lower alkyl alcohol, ethyl acetate, and water;

optionally, the first solvent and the second solvent are respectively and 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;

optionally, the lower alkyl alcohol is selected from C₁-C₄An alkyl alcohol;

optionally, the lower alkyl alcohol is selected from methanol, ethanol, isopropanol, n-propanol or n-butanol.

8. A pharmaceutical composition comprising crystalline form a of a dezocine derivative according to any one of claims 1-4 and a pharmaceutically acceptable carrier;

optionally, further comprising a second therapeutic agent comprising a MOR modulator;

optionally, the second therapeutic agent comprises one or more of naloxone, naltrexone, tramadol, samidorphan.

9. Use of crystalline form a of a dezocine derivative according to any of claims 1-4 or of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of an opioid receptor-related disorder.

10. Use according to claim 9, wherein the condition is pain;

optionally, the pain comprises neuropathic pain or nociceptive pain;

optionally, the pain comprises acute pain or chronic pain;

optionally, the pain comprises at least one of: post-operative pain, pain due to neuralgia, pain due to diabetic neuropathy, dental pain, pain associated with arthritis, and pain associated with cancer or treatment thereof;

optionally, the pain due to neuropathic pain comprises post-herpetic neuralgia or trigeminal neuralgia;

optionally, the medicament is for modulating the activity of opioid receptors.