TWI717859B - Crystalline form of opioid receptor agonist and manufacturing method thereof - Google Patents

Abstract

The present disclosure provides a crystalline form of an opioid receptor (MOR) agonist and a manufacturing method thereof. Specifically, the present disclosure provides a crystalline form III of (1S ,4S )-4-ethoxy-N- (2-((R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)- 1,2,3,4-tetrahydronaphthalen-1-amine fumarate and a manufacturing method thereof. The crystalline form III of a compound of formula (I) of the present disclosure has good stability and can be better used for clinical treatment.

Description

Crystal form of opioid receptor agonist and preparation method

The present disclosure provides (1 S , 4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl )Ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate III crystal form and preparation method, application of III crystal form in pharmaceutical composition, and the III crystal form and composition Use in the preparation of medicines for treating and/or preventing diseases related to opioid receptor (MOR) agonists.

This application claims the priority of the Chinese patent application 201811186743.7 whose filing date is 2018/10/12. This application quotes the full text of the aforementioned Chinese patent application.

Opiate receptors are an important type of G protein coupled receptor (GPCR), which is the target of endogenous opioid peptides and opioid drugs. After the opioid receptors are activated, they can affect the immune system of the nervous system and the endocrine system. Regulating effect, opioids are currently the strongest and commonly used central analgesics. Endogenous opioid peptides are opioid active substances naturally produced in mammals. The currently known endogenous opioid peptides can be roughly divided into enkephalins, endorphins, dynorphins and neoorphins ( Pharmacol Rev 2007 ; 59: 88-123). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), κ (KOR) receptors and so on. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.

。Long-term use of opioids can produce side effects such as tolerance, respiratory depression and constipation, and these side effects have been shown to be closely related to the function of β-arrestin. To reduce the side effects of opioid drugs may be based on negative β-arrestin preference MOR ligand drug design, so that side effects mediated β -arrestin reduced, enhance the therapeutic effect, for the present disclosure oxaspiro derivative In the research as a MOR selective drug, Trevena Inc. found that the aryl benzylic position was less active when substituted ( J. Med. Chem . 2013, 56, 8019-8031), but WO2017063509 found that an aryl benzylic ring formed However, it exhibits high activity, significantly improved Emax, significantly improved hERG, and a single-configuration MOR compound. The structure is shown in formula (II):

.

As a medicinal active ingredient, the crystal structure 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 crystal forms . Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve various properties of the compound represented by formula (II).

。The present disclosure (The disclosure) to provide a formula (I), Form III compound, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle in 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,

.

In some embodiments, the crystal form III is provided, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, There are characteristic peaks at 17.98, 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94 and 29.26.

In some embodiments, the III crystal form is provided, and the diffraction angle 2 θ 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 There are characteristic peaks at 41.19 and 42.41.

Some other embodiments provide Form III according, X- ray powder diffraction pattern at the diffraction angle 2 θ represents the angle shown in Figure 1.

The present disclosure also provides a method for preparing crystal form III, the method comprising: 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 cooled to crystallize 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 solvent, and the alcohol solvent is preferably isopropanol.

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

The present disclosure provides a pharmaceutical composition, which is prepared from the aforementioned compound III crystal form of formula (I), and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the III crystal form or pharmaceutical preparations 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 powder and concentrated solution 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 in any suitable administration mode, such as oral, parenteral, rectal, pulmonary or topical 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, etc. Suspension, syrup, etc. When made into oral preparations, the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When made into an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing injections, the pharmaceutical preparations may not be added with additives, or appropriate additives may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparations 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 medicine 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 a pharmaceutical composition or medicine in the form of a unit dose.

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

The present disclosure also provides the use of the pharmaceutical composition of crystal form III and crystal form III in the preparation of drugs for treating related diseases mediated by opioid receptor (MOR) agonists.

The use according to 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, Pain is preferred.

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

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

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 pharmaceutical composition of crystal form III and crystal form III of the compound represented by formula (I) in the preparation of drugs for agonizing or antagonizing MOR receptors. In addition, the present application also provides a method for inhibiting diseases related to opioid receptor (MOR) agonists, which comprises administering to a subject in need thereof a therapeutically and/or preventively effective amount of the formula (I ) The III crystal form of the compound, 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.

X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) were used to determine the structure and the crystal form of the obtained compound of formula (I) III crystal form.

The method of recrystallization of crystal type III is not particularly limited, and it can be performed by a usual recrystallization operation method. For example, the compound represented by formula (I) as a raw material 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 filtering and drying.

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

The starting material used in the method for preparing the crystal form of the present disclosure can be any form of the compound represented by formula (I), and the specific form includes but is not limited to: amorphous, any crystal form, and the like.

Disclosure details:

In the description of this application and the scope of the patent application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly 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 explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

The "C _1-6 alkyl group" mentioned in the present disclosure means a straight or branched chain alkyl group containing 1-6 carbon atoms. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, second butyl, tertiary 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 Group, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

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

The "cyano group" in the present disclosure refers to groups such as -CN.

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

The "alcohol solvent" mentioned in the present disclosure refers to a group derived from one or more "hydroxyl groups" substituting one or more hydrogen atoms on the "C _1-6 alkyl group". The "hydroxyl group" and "C _1-6 alkyl group" _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" mentioned in the present disclosure refers to a solvent formed by mixing one or more different types of organic solvents in a certain ratio, or a solvent formed by mixing an organic solvent and water in a certain ratio; the mixed solvent is preferably an alcohol A mixed solvent with 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 the present disclosure is measured using Cu-Kα radiation, where λ=1.5418 Å.

The "X-ray powder diffraction pattern or XRPD" mentioned in this disclosure refers to the Bragg formula 2d sin θ = nλ (where λ is the wavelength of X-rays, λ=1.5418Å, and the diffraction order n is any positive integer , Generally take the first-order diffraction peak, n=1), when X-rays are incident on the crystal or some atoms of the crystal sample with d lattice plane spacing at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle) When surfaced, the Bragg equation can be satisfied, and this set of X-ray powder diffraction patterns can be measured.

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

The “2 θ or 2 θ angle” mentioned in the present disclosure refers to the diffraction angle , θ is the Bragg angle, in degrees or degrees, 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 "interplanar spacing or interplanar spacing ( d value)" mentioned in the present disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, and c connecting two adjacent lattice points. The matrix is divided into juxtaposed parallelepiped units called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, which are called spatial lattices or lattices. Lattice and crystal lattice use geometric points and lines to reflect the periodicity of the crystal structure. For different crystal planes, the interplanar spacing (that is, the distance between two adjacent parallel crystal planes) is different; the unit is Å Or angstrom.

The drying temperature in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and it can be dried under normal pressure or under reduced pressure. Preferably, drying is 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 crystal form III of the compound represented by formula (I) prepared by the present disclosure has a higher melting point, good solubility, and higher purity, and the crystal form has not changed by XRPD under conditions of high temperature, high humidity, and light. The crystal form stability is good; the crystal form III of the compound represented by the formula (I) obtained by the technical solution of the present disclosure can meet the medicinal requirements of production, transportation and storage, the production process is stable, repeatable and controllable, and can be adapted to industrial production.

In order to make the above and other objects, features and advantages of the present invention more comprehensible, the following specific examples are given in conjunction with the accompanying drawings to describe in detail as follows.

The present disclosure will be explained in more detail below in conjunction with embodiments. 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.

The test conditions of the instrument used in the experiment: 1. Differential Scanning Calorimeter (DSC) Instrument model: TA Q2000 Purge gas: Nitrogen (50mL/min) Heating rate: 10.0℃/min Temperature range: 30-300 ℃ 2. X-ray Powder Diffraction (XRPD) Instrument model: Rigaku UltimaIV X-ray powder diffractometer Ray: monochromatic Cu-Kα rays (λ=1.5418 Å) Scan mode: 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: (1 S ,4 S )-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)

The first step, ( S )-1,2,3,4-tetrahydronaphthalene-1-t-butyl carbamate (11a)

( S )-1,2,3,4-tetrahydro-1-naphthylamine 10a (3 g, 20.41 mmol, using the method disclosed in " Angewandte Chemie-International Edition, 45(28), 4641-4644, 2006" Prepared) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tertiary butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was washed with water (100 mL) and saturated sodium bicarbonate solution (100 mL) successively, 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, pale yellow oil) , The product is directly subjected to the next step without purification.

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

The second step, ( S )-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (11b)

The crude ( S )-1,2,3,4-tetrahydronaphthalene-1-carbamate (11a) (5.6 g, 20.41 mmol) was dissolved in 90 mL of acetone and water (V/V = 2: 1) In the mixed solvent, magnesium sulfate (5.5 g, 45.66 mmol) is added, potassium permanganate (7.22 g, 45.66 mmol) is slowly added with stirring, and the reaction is 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].

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

唑硼烷(0.1 ml，0.076 mmol)，攪拌5分鐘，加入硼烷甲基硫醚(0.88 ml，0.76 mmol)，攪拌反應2小時。加入50 ml飽和氯化鈉溶液淬滅反應，用乙酸乙酯萃取(30 mL×3)，合併有機相，有機相用飽和氯化鈉溶液洗滌(30 mL×3)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以二氯甲烷和甲醇為洗脫劑純化所得殘餘物，得到標題產物14a (60 mg，白色固體)，產率60%。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, and cool to 0°C , Add ( R )-2-methyl-CBS-

Azaboridine (0.1 ml, 0.076 mmol) was stirred for 5 minutes, borane methyl sulfide (0.88 ml, 0.76 mmol) was added, and the reaction was stirred for 2 hours. Add 50 ml of saturated sodium chloride solution to quench the reaction, extract with ethyl acetate (30 mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (30 mL×3), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin-layer chromatography using dichloromethane and methanol as eluents to obtain the title product 14a (60 mg, white solid) with a yield of 60%.

MS m/z (ESI): 208.3 [M-55].

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

The crude product (1 S )-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) were 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), which was directly subjected to the next reaction without purification.

MS m/z (ESI): 236.1 [M-55].

The fifth step, (1 S ,4 S )-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 4 M 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 adjusted with saturated sodium bicarbonate solution The pH of the reaction solution 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 step without purification.

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

The sixth step, (1 S ,4 S )-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) (500 mg, 1.85 mmol, using patent application "WO2012129495 "Prepared by the published method), the crude compound 19b (310 mg, 1.85 mmol) was dissolved in dichloroethane (30 mL), stirred for 40 minutes, and sodium triacetoxyborohydride (980 mg, 4.63 mmol), the reaction was stirred for 2 hours. Wash with saturated sodium bicarbonate solution (30 mL×3) and saturated sodium chloride solution (30 mL×3) successively, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified with methyl chloride and methanol as eluents to obtain the title product 19 (280 mg, yellow viscous solid), yield: 35%.

Example 1

。(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl )-1,2,3,4-Tetrahydronaphthalene-1-amine fumarate (III crystal form) preparation

.

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Base)-1,2,3,4-tetrahydronaphthalene-1-amine (2.6 g, 5.96 mmol) was dissolved in isopropanol (10 mL), heated to 80°C, and fumaric acid (695 mg, 5.96 mmol) and isopropanol (10 mL) were added to another reaction flask. The temperature was raised to 80°C and stirred to dissolve and then added dropwise to the above solution. The reaction was stirred at reflux for 10 minutes, and cooled to 40°C naturally. A white solid precipitated in the solution. Then cool to room temperature, stir and react for 1.5 hours. The reaction solution was filtered, and the filter cake was rinsed with isopropanol (2 mL×5) and ethyl acetate (2 mL×3) in sequence. The filter cake was collected and dried under vacuum to obtain a white solid product (2.0 g, yield 60%). The XRPD spectrum of the crystalline sample is shown in Figure 1, and the DSC spectrum is shown in Figure 2. The endothermic peak starts at around 175.44°C and the peak is about 176.65°C. The TGA spectrum is shown in Figure 3, indicating that the crystal form III is anhydrous; its characteristics The peak positions are shown in Table 1 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. Investigation on the stability of factors affecting crystal form III

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

Test results: Table 2. Stability of factors affecting crystal form III samples (HPLC purity)

Test Conclusions:

Crystal Form III was placed in the open for 17 days under the conditions of light and high temperature (40℃, 60℃), the chemical purity and chiral purity decreased significantly, and it was left open for 17 days under high humidity (RH75%, RH90%) conditions. The purity and chiral purity have little change; XRPD detects crystal form III under the conditions of light (4500Lux), high temperature (40℃, 60℃), high humidity (RH75%, RH90%) for 17 days, the crystal form has not changed , Which shows that the stability of crystal form III is better.

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

The crystal type III sample obtained in Example 1 was placed flat in the dark and sealed, and the stability of the sample under long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) was investigated, and the sampling time was 0.5 Month, 1 month, 2 months, 3 months, XRPD detects whether the crystal form changes.

Test results: Table 3. Stability of crystal form III samples (HPLC purity)

Test Conclusions:

Crystal Form III has good stability when stored for 3 months under long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) conditions under dark and sealed conditions. It has good stability when placed at 25°C and 60%RH for 3 months. The XRPD pattern is shown in Figure 4, and the XRPD pattern after 3 months of storage at 40°C and 75% RH is shown in Figure 5. The XRPD peak shape of crystal form III has basically not changed, and the crystal form is stable.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to those defined by the attached patent application scope.

no

Figure 1 is the XRPD pattern of the crystal form of compound III represented by formula (I). Fig. 2 is a DSC chart of the crystal form of compound III represented by formula (I). Figure 3 is a TGA chart of the crystal form of compound III represented by formula (I). Figure 4 shows the XRPD pattern of the compound III crystal form of formula (I) stored for 3 months at 25° C. and 60% RH. Figure 5 shows the XRPD pattern of the compound III crystal form of formula (I) stored for 3 months under the conditions of 40°C and 75%RH.

Claims (11)

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

The crystal form III according to claim 1, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ angle is at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, There are characteristic peaks at 17.98, 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94 and 29.26. The crystal form III according to claim 2, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ angle is at 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, There are characteristic peaks at 33.38, 35.74, 37.02, 40.38, 41.19 and 42.41. The crystal form III according to claim 1, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in FIG. 1. The crystal form III according to any one of claims 1-4, wherein the error range of the 2θ angle is ±0.30. A method for preparing the III crystal form according to claim 1, wherein the method comprises: dissolving the free state of the compound represented by formula (I) in a solvent, adding fumaric acid, heating to a slight boiling, and cooling to precipitate crystals Crystal form III; the slight boiling temperature is selected from 40° C. to the boiling point of the solvent, and the solvent is selected from alcohol solvents. The method according to claim 6, wherein the alcohol solvent is isopropanol. A pharmaceutical composition prepared from the crystal form III described in any one of claims 1-5, and one or more pharmaceutically acceptable carriers, diluents or excipients. A method for preparing a pharmaceutical composition, comprising combining the crystal form III of any one of claims 1-5 or the crystal form III prepared by the method of claim 6 with a pharmaceutically acceptable carrier, diluent or excipient Mixed steps. A use for preparing a medicine for treating diseases by using the crystal form III according to at least one of claims 1 to 5 or the pharmaceutical composition according to claim 8, the diseases being selected from pain, immune dysfunction, inflammation , Esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases. The use according to claim 10, wherein the disease is selected from pain.

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