WO2020073985A1 - Crystalline structure of mu opioid receptor (mor) agonist and preparation method therefor - Google Patents

Abstract

The invention provides a crystalline structure of mu opioid receptor (MOR) agonist and a preparation method therefor. Specifically, the invention provides (1S4S)-4-ethoxy-N-(2-((R)-9-(pyridine-2-yl)-6-oxaspiro [4.5] decano-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine fumarate and a preparation method therefor. The crystalline form has good crystalline form stability, and is more suitable for clinical use.

Description

Crystal form and preparation method of opioid receptor (MOR) agonist

This application requires the priority of Chinese patent application 201811186743.7 with an application date of 2018/10/12. This application refers to the entire text of the aforementioned Chinese patent application.

Technical field

The present disclosure provides (1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethane Group) -1,2,3,4-tetrahydronaphthalene-1-amine fumarate III crystal form and preparation method, application of the III crystal form in the pharmaceutical composition and preparation of the III crystal form and composition Use in medicine for the treatment and / or prevention of diseases associated with opioid receptor (MOR) agonists.

Background technique

Opioid receptors are an important class of G protein-coupled receptors (GPCRs). They are targets for the binding of endogenous opioid peptides and opioids. After activation, opioid receptors are immune to the nervous system and endocrine system. With regulatory effects, opioids are currently the strongest and most commonly used central analgesics. Endogenous opioid peptides are naturally-occurring opioid-like active substances in mammals, and currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins, and neomorphin (Pharmacol Rev 2007 ; 59: 88-123). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), and κ (KOR) receptors. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.

Long-term use of opioids will produce side effects such as tolerance, respiratory depression, and constipation. These side effects have been shown to be closely related to the function of β-arrestin. In order to reduce the side effects of opioids, the drugs can be designed based on the negative β-arrestin preference ligand of MOR to reduce the side effects mediated by β-arrestin and enhance the therapeutic effect. For the oxaspiro derivatives of the present disclosure In the study as a MOR selective drug, Trevena Inc research found that the activity of aryl benzyl substitution is poor (J. Med. Chem. 2013, 56, 8019-8031), but WO2017063509 discovered an aryl benzyl After the ring, it shows high activity, Emax is significantly improved, hERG is significantly improved, and the single-configuration MOR compound has the structure shown in formula (II):

The crystalline structure as a medicinal active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystalline forms. In general, amorphous drug products do not have a regular crystal structure, and often have other defects, such as poor product stability, difficult filtration, easy caking, and poor fluidity. Therefore, it is necessary to improve various properties of the compound represented by formula (II).

Summary of the invention

The disclosure provides a crystal form III of the compound represented by formula (I), an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, at 6.44, 10.16, 11.99, 13.65, 14.00, 16.43, 17.05, There are characteristic peaks at 19.56, 21.40 and 22.64,

Some embodiments provide the III crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, 17.98 , 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94 and 29.26 have characteristic peaks.

In some embodiments, the III crystal form is provided, and the diffraction angle 2θ angle is 6.44, 7.11, 9.78, 10.16, 11.99, 12.90, 13.22, 13.65, 14.00, 14.38, 14.82, 15.32, 16.08, 16.43, 17.05, 17.63 , 17.98, 18.90, 19.56, 20.12, 20.58, 20.92, 21.40, 22.64, 22.91, 23.18, 23.94, 24.50, 25.32, 25.88, 26.67, 28.47, 29.26, 30.16, 30.96, 32.52, 33.38, 35.74, 37.02, 40.38 And 42.41 have characteristic peaks.

In some other embodiments, the III crystal form is provided, and the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in FIG. 1.

The present disclosure also provides a method of preparing the III crystal form, the method including:

The free state of the compound represented by formula (I) is dissolved in a solvent, fumaric acid is added, heated to a slight boiling, and crystallized by cooling to obtain crystal form III; the slight boiling temperature is selected from 40 ° C-the boiling point of the solvent, and the solvent is preferably An alcohol-based solvent, and the alcohol-based solvent is preferably isopropyl alcohol.

On the other hand, in some embodiments, the method for preparing the crystalline form of the present disclosure further includes steps such as filtration, washing, or drying.

The present disclosure provides a pharmaceutical composition prepared from the compound III crystal form represented by the aforementioned formula (I), and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the crystalline form III or pharmaceutical preparation of the compound represented by formula (I) of the present disclosure can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, injections Use sterile powders and concentrated solutions for injection), suppositories, inhalants or sprays.

In addition, the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment by any suitable method of administration, such as oral, parenteral, rectal, pulmonary or local administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc. When prepared as an oral preparation, the pharmaceutical preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When prepared as an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing an injection, no additional agent may be added to the pharmaceutical preparation, or an appropriate additional agent may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays. In certain preferred embodiments, the crystalline form III of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in a therapeutically and / or prophylactically effective amount. In certain preferred embodiments, the crystalline form III of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in unit dosage form.

The present disclosure also provides a method for preparing a pharmaceutical composition, including the step of mixing the aforementioned III crystal form or the III crystal form obtained by the foregoing method with a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides the use of the crystalline form III and the crystalline form III pharmaceutical composition in the preparation of medicaments for treating diseases related to opioid receptor (MOR) agonists.

The use described in the present disclosure, wherein the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, Preferably pain.

The present disclosure also provides use of the crystalline form III and the crystalline form III of the compound represented by formula (I) in the preparation of a medicament for preventing or treating pain and pain-related diseases.

The pain described in the present disclosure is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.

The cancer described in the present disclosure is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia, and leukemia.

The present disclosure also provides the use of the crystalline form III and the crystalline form III of the compound represented by formula (I) in the preparation of a medicament for agonizing or antagonizing the MOR receptor. In addition, the present application also provides a method of inhibiting a disease associated with an opioid receptor (MOR) agonist, which includes administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of the disclosed formula ( I) Compound III crystal form, or the pharmaceutical composition of the present disclosure.

In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain.

The structure III of the obtained compound of formula (I) was determined by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).

The method of recrystallization of the III crystal form is not particularly limited, and can be carried out by a general recrystallization operation method. For example, the compound represented by the raw material formula (I) can be dissolved in an organic solvent and then added to an anti-solvent for crystallization. After the crystallization is completed, the desired crystal can be obtained by filtration and drying.

The crystallizing methods of the present disclosure include room temperature crystallizing, cooling crystallizing, and adding seed crystals to induce crystallizing.

The starting material used in the crystalline form preparation method of the present disclosure may be any form of the compound represented by formula (I), and specific forms include but are not limited to: amorphous, any crystalline form, and the like.

Disclosure details

In the description and claims of this application, unless otherwise stated, the scientific and technical terms used herein have the meanings generally understood by those skilled in the art. However, in order to better understand the present disclosure, definitions and explanations of some related terms are provided below. In addition, when the definitions and interpretations of the terms provided in this application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and interpretations of the terms provided in this application shall prevail.

The "C _1-6 alkyl group" in the present disclosure means a linear or branched alkyl group containing 1-6 carbon atoms, and specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -Methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

The "hydroxyl group" in the present disclosure refers to a group such as -OH.

The "cyano" in this disclosure refers to a group such as -CN.

The "ether solvent" described in the present disclosure refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, and propylene glycol methyl ether , Methyl tert-butyl ether or 1,4-dioxane.

The "alcoholic solvent" described in the present disclosure refers to a group derived from one or more "hydroxyl groups" in place of one or more hydrogen atoms on the "C _1-6 alkyl group". The "hydroxyl group" and "C _"1-6 alkyl" is as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.

The "mixed solvent" in the present disclosure refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio, or a solvent in which an organic solvent and water are mixed in a certain ratio; the mixed solvent is preferably A mixed solvent of alcohols and ethers; the mixed solvent of alcohols and ethers is preferably a mixed solvent of methanol and ether, and the ratio is preferably 1:10.

The "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-Kα radiation, where,

The “X-ray powder diffraction pattern or XRPD” described in this disclosure refers to the Bragg formula 2d sinθ = nλ (where, λ is the wavelength of X-ray,

The order of diffraction n is any positive integer, generally the first order diffraction peak is taken, n = 1), when X-rays enter the crystal or part of the crystal sample at a grazing angle θ (coincidence of incident angle, also known as Bragg angle) When an atomic plane with a d-lattice plane spacing meets the Bragg equation, the X-ray powder diffraction pattern is measured.

The "differential scanning calorimetry or DSC" mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature to characterize all physical changes and chemistry related to the thermal effect Change, get the phase change information of the sample.

The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ± 0.3, which can be -0.30, -0.29, -0.28, -0.27,- 0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, more preferably ± 0.2.

The "crystal plane spacing or crystal plane spacing (d value)" described in this disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, and they will point The array is divided into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight-line grids, called space grids or lattices. The lattice and lattice reflect the periodicity of the crystal structure with geometric dots and lines, respectively. Different crystal planes have different surface spacings (ie, the distance between two adjacent parallel crystal planes); the unit is

Or Egypt.

The drying temperature in the present disclosure is generally 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C, and can be dried under normal pressure or under reduced pressure. Preferably, the drying is done under reduced pressure.

The beneficial effects of the present disclosure

Compared with the prior art, the technical solution of the present disclosure has the following advantages:

Studies have shown that the compound III of the formula (I) prepared by the present disclosure has a high melting point, good solubility, and high purity. The crystal form has not been changed by XRPD detection under the conditions of high temperature, high humidity, and light. 3. The crystal form has good stability; the III crystal form of the compound represented by the formula (I) obtained by the technical scheme of the present disclosure can meet the pharmaceutical requirements for production, transportation and storage.

BRIEF DESCRIPTION

Fig. 1 is an XRPD pattern of the compound III crystal form represented by formula (I).

FIG. 2 is a DSC chart of the crystal form of compound III represented by formula (I).

Fig. 3 is a TGA pattern of the compound III crystal form represented by formula (I).

Fig. 4 is an XRPD pattern of the compound III crystal form represented by formula (I) at 25 ° C and 60% RH for 3 months.

FIG. 5 is an XRPD pattern of the compound III crystal form represented by formula (I) at 40 ° C. and 75% RH for 3 months.

detailed description

The present disclosure will be explained in more detail in conjunction with embodiments below. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

Test conditions of the instrument used in the experiment:

1. Differential Scanning Calorimeter (DSC)

Instrument model: TAQ2000

Purge gas: nitrogen (50mL / min)

Heating rate: 10.0 ℃ / min

Temperature range: 30-300 ℃

2. X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)

Instrument model: Rigaku Ultima IV X-ray powder diffractometer

Ray: Monochrome Cu-Kα Ray

Scanning method: θ / 2θ, scanning range: 3-45 ^o

Voltage: 40kV, current: 40mA

3. Thermogravimetric Analysis (TGA)

Instrument model: Mettler Toledo TGA2 STAR ^e System

Purge gas: nitrogen

Heating rate: 10.0 ℃ / min

Temperature range: 20-250 ℃

Comparative Example 1 (1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl ) -1,2,3,4-tetrahydronaphthalene-1-amine (amorphous compound 19)

first step

(S) -1,2,3,4-Tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a

(S) -1,2,3,4-Tetrahydro-1-naphthylamine 10a (3g, 20.41mmol, prepared by the method disclosed in "Angewandte Chemie-International Edition, 45 (28), 4641-4644, 2006" (Acquired) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tert-butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was washed successively with water (100 mL), saturated sodium bicarbonate solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 11a (5.6 g, light yellow oil), product The next step was carried out without purification.

MS m / z (ESI): 248.3 [M + 1]

Second step

(S) -4-Carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b

Dissolve crude (S) -1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a (5.6 g, 20.41 mmol) in 90 mL of acetone and water (V / V = 2: 1) mixed solvent In it, magnesium sulfate (5.5g, 45.66mmol) was added, potassium permanganate (7.22g, 45.66mmol) was slowly added with stirring, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane and ethyl acetate as eluents to obtain the title product 11b (3.1 g, off-white solid), yield: 52%.

MS “m / z (ESI): 262.3 [M + 1]

third step

(1S, 4S) -4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a

Dissolve (S) -4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b (100 mg, 0.883 mmol) in 5 mL of toluene, cool to 0 ° C, and add (R) -2-Methyl-CBS-oxazolylborane (0.1 ml, 0.076 mmol), stirred for 5 minutes, added borane methyl sulfide (0.88 ml, 0.76 mmol), and stirred to react for 2 hours. The reaction was quenched by adding 50ml of saturated sodium chloride solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to obtain the title product 14a (60 mg, white solid) in 60% yield.

MS “m / z (ESI): 208.3 [M-55]

the fourth step

(1S, 4S) -4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 19a

The crude (1S) -4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a (850 mg, 3.23 mmol), silver oxide (76 mg, 0.33 mmol) and iodoethane ( 1.3 mL, 16.15 mmol) was dissolved in dichloromethane (30 mL), and the reaction was stirred for 48 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title product 19a (800 mg, yellow oil). The product was directly subjected to the next step without purification.

MS “m / z (ESI): 236.1 [M-55]

the fifth step

(1S, 4S) -4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-amine 19b

The crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 mL of dichloromethane, 8 mL of 4M hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, slurried with ethyl acetate (30 mL), filtered, and the filter cake was dissolved in a mixed solvent of dichloromethane and methanol (20 mL, V: V = 5: 1), and the reaction solution was adjusted with saturated sodium bicarbonate solution The pH is 7-8. The reaction solution is concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V: V = 5: 1) (30 mL × 2), filtered, and the filtrate is concentrated under reduced pressure to obtain the crude title product 19b ( 310 mg, yellow liquid), the product was directly subjected to the next reaction without purification.

MS m / z (ESI): 191.1 [M + 1]

The sixth step

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine 19

(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-yl) acetaldehyde 5a (500mg, 1.85mmol, using the patent application "WO2012129495" published (Prepared by the method), the crude compound 19b (310mg, 1.85mmol) was dissolved in dichloroethane (30mL), the reaction was stirred for 40 minutes, sodium triacetoxyborohydride (980mg, 4.63mmol) was added, and the reaction was stirred for 2 hours . It was sequentially washed with saturated sodium bicarbonate solution (30 mL × 3), washed with saturated sodium chloride solution (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using thin layer chromatography with dichloromethane The resulting residue was purified using methane and methanol as eluents to obtain the title product 19 (280 mg, yellow sticky solid), yield: 35%.

Example 1

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl)- Preparation of 1,2,3,4-tetrahydronaphthalene-1-amine fumarate (crystalline form III)

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (2.6g, 5.96mmol) was dissolved in isopropanol (10mL), heated to 80 ℃, fumaric acid (695mg, 5.96mmol) and isopropyl Propyl alcohol (10mL) was added to another reaction flask, heated to 80 ° C, stirred and dissolved, then added dropwise to the above solution, stirred at reflux for 10 minutes, naturally cooled to 40 ° C, white solid precipitated in the solution, and then cooled to room temperature, The reaction was stirred for 1.5 hours. The reaction solution was filtered, and the filter cake was rinsed with isopropyl alcohol (2 mL × 5) and ethyl acetate (2 mL × 3) in sequence. The filter cake was collected and dried in vacuo to give a white solid product (2.0 g, yield 60%). The XRPD pattern of the sample is shown in Figure 1, and its DSC spectrum is shown in Figure 2. The starting point of the endothermic peak is near 175.44 ℃, and the peak value is about 176.65 ℃. The TGA pattern is shown in Figure 3, indicating that the crystal form III is anhydrous; its characteristic peak The location is shown in the table below:

MS m / z (ESI): 435.5 [M + 1]

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.49-8.61 (m, 1H), 7.68-7.80 (m, 1H), 7.41-7.53 (m, 1H), 7.28-7.37 (m, 1H), 7.15-7.28 (m, 4H), 6.51 (s, 2H), 4.25-4.38 (m, 1H), 3.88-4.01 (m, 1H), 3.51-3.69 (m, 3H), 3.40-3.51 (m, 1H ), 2.52-2.64 (m, 1H), 2.29-2.46 (m, 2H), 2.08-2.22 (m, 1H), 1.85-2.08 (m, 3H), 1.23-1.85 (m, 12H), 1.11 (t , 3H), 0.92-1.03 (m, 1H), 0.56-0.71 (m, 1H).

Table 1. Characteristic peaks of crystal form III

Example 2. Stability of factors affecting the III crystal form

Place the III crystal sample obtained in Example 1 flat and open to investigate the chemical stability of the sample under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH75%, RH90%). The sampling time is 10 days and 17 days. The chemical purity and chiral purity of the samples are investigated. The HPLC detection purity is shown in the table below.

test results:

Table 2. Influencing factors of III crystal form samples (HPLC purity)

Test Conclusions:

The III crystal form is exposed to light and high temperature (40 ° C, 60 ° C) for 17 days, and the chemical purity and chiral purity decrease significantly. Under high humidity (RH75%, RH90%), it is exposed for 17 days, chemical The purity and chiral purity change little; XRPD detection III crystal form is placed under light (4500Lux), high temperature (40 ℃, 60 ℃), high humidity (RH75%, RH90%) conditions for 17 days, the crystal form has not changed , Indicating that the III crystal form has better stability.

Example 3. Long-term and accelerated stability of the III crystal form

The III crystal sample obtained in Example 1 was placed in a light-proof, sealed flat position, and the stability of the sample under long-term (25 ° C, 60% RH) and acceleration (40 ° C, 75% RH) was investigated, and the sampling time was 0.5 Months, 1 months, 2 months, 3 months, XRPD detects whether the crystal form has changed.

test results:

Table 3. Stability of crystalline form III samples (HPLC purity)

Test Conclusions:

The III crystal form has good stability under long-term (25 ° C, 60% RH) and accelerated (40 ° C, 75% RH) conditions when protected from light and sealed for 3 months. The XRPD pattern is shown in Fig. 4 and the XRPD pattern at 40 ° C and 75% RH for 3 months is shown in Fig. 5. The XRPD peak shape of the III crystal form is basically unchanged, and the crystal form is stable.

Claims (10)

1. The III crystal form of a compound represented by formula (I) is characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ at 6.44, 10.16, 11.99, 13.65, 14.00, 16.43, 17.05, 19.56, 21.40 And characteristic peaks at 22.64,

   
2. The III crystal form according to claim 1, wherein the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, There are characteristic peaks at 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94 and 29.26.
3. The III crystal form according to claim 2, wherein the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is 6.44, 7.11, 9.78, 10.16, 11.99, 12.90, 13.22, 13.65, 14.00, 14.38, 14.82, 15.32, 16.08, 16.43, 17.05, 17.63, 17.98, 18.90, 19.56, 20.12, 20.58, 20.92, 21.40, 22.64, 22.91, 23.18, 23.94, 24.50, 25.32, 25.88, 26.67, 28.47, 29.26, 30.16, 30.96 There are characteristic peaks at 32.52, 33.38, 35.74, 37.02, 40.38, 41.19 and 42.41.
4. The III crystal form according to at least one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in FIG. 1.
5. The III crystal form according to at least one of claims 1 to 4, wherein the 2θ angle error range is ± 0.30.
6. A method for preparing the III crystal form according to at least one of claims 1-5, characterized in that the method comprises:

   Dissolve the free state of the compound represented by formula (I) in a solvent, add fumaric acid, heat to slightly boil, cool to precipitate crystals to obtain crystal form III; An alcohol-based solvent, and the alcohol-based solvent is preferably isopropyl alcohol.
7. A pharmaceutical composition prepared from the crystal form III according to at least one of claims 1-5 and one or more pharmaceutically acceptable carriers, diluents or excipients.
8. A method for preparing a pharmaceutical composition, comprising combining the crystalline form III of at least one of claims 1-5 or the crystalline form III prepared by the method of claim 6 with a pharmaceutically acceptable carrier, diluent or excipient The step of mixing agent.
9. A pharmaceutical composition of crystal form III according to at least one of claims 1 to 5, or the crystal form of crystal III according to claim 7 in the preparation of a therapy mediated by an opioid receptor (MOR) agonist Use in medicine for related diseases.
10. The use according to claim 9, wherein the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory tract Disease, preferably pain.

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