Fumarate crystal form of oxaspirocyclic derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to a fumarate crystal form of an oxaspirocyclic derivative, and a preparation method therefor and the use thereof. Particularly, the present invention relates to a fumarate crystal form A of an (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine compound, a preparation method therefor and the use thereof, and a pharmaceutical composition containing a therapeutically effective amount of the fumarate crystal form A of the compound, and the use thereof in the preparation of a drug for preventing and / or treating a related disease mediated by a μ-opioid receptor agonist.

Description

Oxaspiro derivative fumarate salt crystal form and preparation method and application thereof

[0001] This application claims priority to Chinese Patent Application No. 202411028777.9, filed on July 30, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application belongs to the technical field of drug synthesis, and particularly relates to an oxaspiro derivative fumarate salt crystal form and a preparation method and application thereof. BACKGROUND

[0003] Opioid receptors belong to one of the members of the G protein-coupled receptor (GPCR) family. Currently, nine kinds of opioid receptors, such as μ, δ, κ, ORL1, have been found, and are widely expressed in the central and peripheral nerves, as well as in neuroendocrine cells, immune cells and endothelial cells. μ (MOR), δ (DOR), and κ (KOR) opioid receptors regulate a series of behaviors of the body through the central nervous system, including pain, emotion, stress response, and addictive behavior. Among them, μ, δ, and κ opioid receptors are classic opioid receptors, and the basic structures of the three types of receptors are the same, that is, they both have an extracellular amino-terminal region and an intracellular fusiform-terminal region. Agonists of the three subtypes of opioid receptors are mainly coupled with Gi-type G proteins, causing the β and γ subunits of G proteins to dissociate from the α subunit. The β and γ subunits and the α subunit respectively mediate the activation of multiple intracellular signaling pathways, such as the inhibition of adenylyl cyclase activity, the activation of G protein-coupled receptor kinases (GRKs), protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Multiple regions of the cerebral cortex and subcortex are involved in MOR-mediated anti-nociceptive responses. Some regions show special functions, mainly regulating the sensory (such as the ipsilateral nucleus accumbens and amygdala) or emotional (such as the anterior cingulate cortex) responses of pain. Studies have shown that the activation of amygdala MOR mediates anti-nociceptive responses. In the ACC region, the activation of MOR during persistent pain is negatively correlated with pain-specific MPQ emotional scores. High levels of opioid receptors are expressed in the ACC region. Opioid drugs are widely used to treat persistent pain and have been suggested to play a role in the brain.

[0004] International Patent Application PCT / CN2022 / 109503 discloses a compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine, which has good agonistic effect on MOR receptors, and can prevent and / or treat μ-opioid receptor agonist-mediated related diseases, such as pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases. SUMMARY

[0005] The inventors found that the free base of the compound is in solid form under certain conditions, and is easily converted into amorphous gel at room temperature. The solid form of the compound has poor stability, and is not suitable for industrial production and storage, and is not conducive to subsequent formulation development.

[0006] In order to find a solid form with better drug properties, the inventors found through a large number of experimental studies that the fumarate salt of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine has the most optimal physicochemical properties. After the fumarate salt is formed, there can be multiple solid forms, but they are not very stable. The polymorphs will undergo crystal transformation under physical or chemical means, and will eventually be converted into the fumarate salt crystal form A of the present application. The inventors further found that the fumarate salt crystal form A of the present application has good drug properties, including good water solubility, long-term stability, hygroscopicity, thermodynamic stability, and / or pharmacokinetic properties. In particular, the fumarate salt crystal form A is the most thermodynamically stable crystal form, has more excellent drug properties, and is more conducive to the development of formulations.

[0007] All the contents involved in Chinese Patent Application 202410125231.9 are added to the present application by reference.

[0008] The purpose of the present application is to provide a fumarate salt crystal form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine, which has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 11.59±0.2°, 21.24±0.2°, and 28.52±0.2°.

[0009] In a preferred embodiment of the present application, the X-ray powder diffraction pattern of the fumarate salt crystal form A further contains diffraction peaks at one or more of 2θ of 15.13±0.2°, 18.31±0.2°, 17.03±0.2°, 19.77±0.2°, 21.82±0.2°, and 26.82±0.2°.

[0010] For example, the X-ray powder diffraction pattern of the fumarate salt crystal form A contains diffraction peaks at 2θ of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, and 28.52±0.2°.

[0011] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta values of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 26.82±0.2°;

[0012] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta values of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 26.82±0.2°, 18.31±0.2°;

[0013] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta values of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 26.82±0.2°, 18.31±0.2°, 19.77±0.2°;

[0014] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta values of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 26.82±0.2°, 18.31±0.2°, 19.77±0.2°, 15.13±0.2°;

[0015] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta values of 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 26.82±0.2°, 18.31±0.2°, 19.77±0.2°, 15.13±0.2°, 21.82±0.2°.

[0016] In a preferred embodiment of the present application, the X-ray powder diffraction pattern of the fumarate salt Form A further comprises one or more of diffraction peaks at 2-theta values of 6.94±0.2°, 8.48±0.2°, 9.75±0.2°, 14.40±0.2°, 16.35±0.2°, 20.42±0.2°, 23.49±0.2°, 24.57±0.2°, 25.47±0.2°, 29.01±0.2°, 30.20±0.2°, 33.76±0.2°;

[0017] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 6.94±0.2°, 8.48±0.2°, 9.75±0.2°, 14.40±0.2°, 16.35±0.2°, 20.42±0.2°, 23.49±0.2°, 24.57±0.2°, 25.47±0.2°, 29.01±0.2°, 30.20±0.2°, 33.76±0.2°;

[0018] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 15.13±0.2°, 18.31±0.2°, 19.77±0.2°, 21.82±0.2°, 26.82±0.2°, 6.94±0.2°, 8.48±0.2°, 9.75±0.2°, 14.40±0.2°, 16.35±0.2°, 20.42±0.2°, 23.49±0.2°, 24.57±0.2°, 25.47±0.2°, 29.01±0.2°, 30.20±0.2°, 33.76±0.2°.

[0019] In a preferred embodiment of the application, the X-ray powder diffraction pattern of the fumarate salt Form A further comprises one or more diffraction peaks at 2-theta of 14.05±0.2°, 15.54±0.2°, 22.50±0.2°, 23.08±0.2°, 33.19±0.2°, 35.63±0.2°;

[0020] For example, the X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 11.59±0.2°, 17.03±0.2°, 21.24±0.2°, 28.52±0.2°, 15.13±0.2°, 18.31±0.2°, 19.77±0.2°, 21.82±0.2°, 26.82±0.2°, 6.94±0.2°, 8.48±0.2°, 9.75±0.2°, 14.40±0.2°, 16.35±0.2°, 20.42±0.2°, 23.49±0.2°, 24.57±0.2°, 25.47±0.2°, 29.01±0.2°, 30.20±0.2°, 33.76±0.2°, 14.05±0.2°, 15.54±0.2°, 22.50±0.2°, 23.08±0.2°, 33.19±0.2°, 35.63±0.2°.

[0021] In a more preferred embodiment of the present application, the X-ray diffraction peaks of the fumarate salt Form A are shown in Table 1 using Cu-Ka radiation, expressed in terms of 2 theta angle and interplanar spacing d value.

[0022] Table 1 XRPD data of fumarate salt Form A

[0023] In a preferred embodiment of the present application, the X-ray powder diffraction pattern of the fumarate salt Form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine is substantially as shown in Figure 1; its DSC pattern is substantially as shown in Figure 2; and its TGA pattern is substantially as shown in Figure 3.

[0024] In another aspect, the present application also provides a method for preparing the fumarate salt Form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine by mixing (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine free base, fumaric acid and a solvent, and stirring to crystallize.

[0025] The molar ratio of the free base to fumaric acid is 1:0.5-2.0;

[0026] The solvent is selected from one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isooctane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene and toluene, preferably selected from one or more of ethanol, dichloromethane and ethyl acetate, and more preferably selected from ethanol or dichloromethane.

[0027] It should be noted that in the above preparation method, the operation of stirring and crystallization to finally obtain the final product is not limited by the present application, and any method commonly used by those skilled in the art can be used, for example, solid-liquid separation can be performed by centrifugation, filtration, suction filtration, etc., and the specific operation can be selected according to the reaction environment or requirements. The obtained solid can be a wet solid obtained without any post-treatment method, or a dry solid obtained by using conventional post-treatment methods such as drying, air drying, etc.

[0028] In another aspect, the present application also provides a method for preparing compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate crystal form A by converting (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate crystal form I.

[0029] The fumarate crystal form I is the compound A fumarate crystal form I disclosed in Chinese Patent Application 202410125231.9, which can be prepared according to the preparation method of compound A fumarate crystal form I on page 53 of the specification.

[0030] The conversion method is not particularly limited by the present application, and common conversion or crystallization methods can be listed, such as thermal conversion, solvent out, suspension conversion (beating) method, solvent evaporation method, cooling method, gas-liquid / liquid-liquid diffusion method, and poor solvent addition method.

[0031] Specifically, the suspension conversion (beating) method is a method of suspending one crystal form in a crystallization solvent and beating to crystallize; the solvent evaporation method is a method of evaporating the crystallization solvent from a crystallization system (or solution) containing one crystal form and the crystallization solvent to form a supersaturated state, and crystallizing from the supersaturated state; the cooling method is a method of cooling a crystallization system (or solution) containing one crystal form and a crystallization solvent to crystallize; the gas-liquid / liquid-liquid diffusion method is a method of adding a suitable gas or liquid to a crystallization system (or solution) containing one crystal form and a crystallization solvent to form a gas-liquid / liquid-liquid interface to crystallize; the poor solvent addition method is a method of adding a poor solvent to a solution containing one crystal form and a good solvent to crystallize; by these methods, another crystal form can be efficiently prepared.

[0032] As the crystallization solvent, for example, there are included, but not limited to, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and the like; alkanes such as pentane, hexane, dichloromethane, dichloroethane, isooctane, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, and the like; cyclic ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, and the like; esters such as ethyl acetate, ethyl formate, methyl acetate, or isopropyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and the like; acetic acid, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, water, toluene, and the like. Preferred are water, dichloromethane, tetrahydrofuran, methanol, ethanol, acetone, acetonitrile, toluene, 1,4-dioxane, acetic acid, ethyl acetate, N,N-dimethylacetamide, methyl tert-butyl ether, or isooctane. These solvents can be used as the crystallization solvent alone or in a mixture of two or more, and the ratio of each solvent in the mixture can be arbitrary, for example, the volume ratio of a mixture of two solvents is usually 1:50-50:1, preferably 1:20-20:1, more preferably 1:10-10:1, and further preferably 1:2-2:1.

[0033] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of the fumarate salt crystalline Form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine as described above, and one or more pharmaceutically acceptable carriers.

[0034] The present application further relates to the use of the fumarate salt crystalline Form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine as described above, or a pharmaceutical composition thereof, for the preparation of a medicament.

[0035] In a preferred embodiment of the present application, the medicament is a medicament for preventing and / or treating a disease associated with a μ-opioid receptor agonist.

[0036] In a further preferred embodiment of the present application, the disease associated with a μ-opioid receptor agonist is selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urological and reproductive diseases, cardiovascular diseases, and respiratory diseases.

[0037] In a further preferred embodiment of the present application, the medicament is a medicament for preventing and / or treating pain and pain-related diseases.

[0038] In a further preferred embodiment of the present application, the pain is selected from the group consisting of postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, and inflammation-induced pain.

[0039] Detailed Description of the Invention

[0040] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably and mean that X can be any one of A, B, or C, or any two or more of A, B, or C.

[0041] "Room temperature" means a temperature from 10 °C to 40 °C. In some embodiments, "room temperature" means a temperature from 15 °C to 30 °C; in other embodiments, "room temperature" means a temperature from 18 °C to 25 °C.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally (substituted with alkyl) cycloalkyl" means that alkyl can or can not be present, and that the description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0043] "Pharmaceutical composition" means a composition comprising one or more compounds of the present application, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, and other components such as a physiologically / pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject and to facilitate absorption of the active ingredient so that it exerts its biological activity.

[0044] "Pharmaceutically acceptable salt" means a salt of a compound of the present application which is safe and effective for use in a mammal and possesses the desirable biological activity.

[0045] "Polymorph" or "polymorphic form" refers to crystalline forms of the same chemical composition but different spatial arrangement of the molecules, atoms, and or ions making up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement, and can exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. The relative stabilities between the two solid phases are exchanged according to their temperature-stability relationship. The phenomenon of a compound existing in different crystal lattice structures is known as pharmaceutical polymorphism.

[0046] The crystal structures disclosed or claimed herein can exhibit similar, but not identical, analytical characteristics within a reasonable error range depending on the test conditions, purity, equipment, and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made in the present application without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the application indicated by the following claims.

[0047] "X-ray powder diffraction pattern" or "XRPD" refers to a set of X-ray powder diffraction patterns measured according to Bragg's equation 2d sin θ = n λ (where λ is the wavelength of the X-rays, "2θ" or "2θ angle" refers to the diffraction angle, θ is the Bragg angle, in ° or degrees. When X-rays are incident on a crystal or partial crystal sample at a grazing angle θ (complementary angle of the incident angle, also known as the Bragg angle) on a certain atomic plane with a d interplanar spacing, the Bragg equation is satisfied, and a set of X-ray powder diffraction patterns is measured.

[0048] It is well known to those skilled in the art that XRPD can have certain displacement and intensity deviation due to sample flatness, detection method, conditions and instruments. The same sample of the same crystal form usually has the same main XRPD characteristic peaks, but there can be certain operational errors. When the same crystal form sample obtained by the corresponding method is detected by the same instrument and detection method by those skilled in the art, the characteristic peak error is usually within ±0.2°, however, different instruments used by different technicians may occasionally have a few characteristic peaks with errors exceeding this range, such as errors within ±0.5° or ±0.3° should be considered as XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of the present application, its XRPD is shown in Spectrum X, but the ordinary skilled person understands that when the key characteristic peak displacement 2θ deviation is within ±0.5°, ±0.3° or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form, and can be explained as within the scope of the present application.

[0049] In addition, the absolute and relative intensities of the peaks shown in the foregoing tables and figures can vary due to a variety of factors, such as the effect of the selected orientation of the crystalline solid on the x-ray beam, the effect of coarse particles, the purity of the material being analyzed, or the degree of crystallinity of the sample. In addition, the peak positions can shift depending on the variation in sample height. Furthermore, if different wavelengths are used for the measurement, different values of displacement are obtained according to Bragg's law (nλ = 2dsinθ). Such different XRPD patterns obtained by using different wavelengths are also included in the scope of the present application.

[0050] "Interplanar spacing" or "interplanar spacing (d-value)" refers to the spatial lattice selecting three non-parallel unit vectors a, b, c that join adjacent points of the lattice, which divides the lattice into congruent parallelepiped units, called interplanar spacing. The spatial lattice is divided according to the connecting lines of the determined parallelepiped units to obtain a set of straight line grids, which is called a spatial lattice or a crystal lattice. The lattice and the crystal lattice are respectively reflected the periodicity of the crystal structure by geometric points and lines. Different crystal planes have different interplanar spacings (i.e. the distance between two adjacent parallel crystal planes); the unit is A or angstrom.

[0051] "Relative intensity (I%)" refers to the ratio of the intensity of other peaks to the intensity of the first strong peak when the intensity of the first strong peak is 100% in the X-ray powder diffraction pattern (XRPD) of all diffraction peaks.

[0052] "Differential scanning calorimetry" or "DSC" measures the transition temperature when the crystal absorbs or releases heat due to changes in its crystal structure or the melting of the crystal. For the same crystal form of the same compound, the error of the thermal transition temperature and the melting point can be within about 5°C, usually within about 3°C in a continuous analysis. When a certain compound is described as having a certain given DSC peak or melting point, it refers to the DSC peak or melting point ± 5°C, and essentially the variation of this temperature is also taken into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified according to their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point can vary within a larger range. In addition, since decomposition occurs during the melting process of the substance, the melting temperature is related to the heating rate.

[0053] "Thermogravimetric analysis (TGA)" is a common method for measuring the thermal stability of a compound. In the present application, TGA can also be used to determine the hydration state of the compound. The heating rate during the test process will have some effect on the graph. The error of TGA can be within about ± 0.5 mass%.

[0054] "Amorphous", "amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in three-dimensional space without periodicity, which is characterized by a diffuse, non-peak X-ray powder diffraction pattern. Amorphous is a special physical form of solid matter, which has local ordered structure characteristics, suggesting that it is closely related to crystalline substances.

[0055] "Equivalent" or its abbreviation "eq" is based on the equivalent relationship of chemical reactions, taking the basic raw material used in each step as the basis (1 equivalent), and the equivalent amount of other raw materials required.

[0056] "Substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or Raman spectrum or infrared spectrum are shown in the figure.

[0057] In the context of the present application, when "about" or "approximately" or the like is used, it means within 10% of the given value or range, suitably within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard deviation of the mean. Whenever a number with a value of N is disclosed, any number within N+ / –1%, N+ / –2%, N+ / –3%, N+ / –5%, N+ / –7%, N+ / –8% or N+ / –10% of the value is explicitly disclosed, where "+" or "–" means plus or minus. Beneficial effects

[0058] The fumarate salt crystal form A of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine not only performs well in product performance parameters such as melting point, water solubility, hygroscopicity, long-term stability and / or pharmacokinetics, but also is more thermodynamically stable than the fumarate salt crystal form I in the crystal form competition experiment, and is the most thermodynamically stable crystal form of fumarate, which is more beneficial for formulation development. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 is an XRPD pattern of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate salt crystal form A.

[0060] Figure 2 is a DSC pattern of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9- dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate Form A.

[0061] Figure 3 is a TGA pattern of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9- dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate Form A.

[0062] Figure 4 is a DVS pattern of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9- dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate Form A. DETAILED DESCRIPTION

[0063] The application is further described below in connection with specific embodiments. It will be understood, however, that these embodiments are intended to be illustrative only and the scope of the application is not intended to be limited to the embodiments. Furthermore, it will be understood that various modifications and changes can be made to the application by those skilled in the art to which the present application pertains, and it is intended to encompass such modifications or changes as fall within the scope of the claims.

[0064] The compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4- yl)ethyl)-2,3-dihydro-1H-inden-2-amine, hereinafter referred to as Compound A, has the chemical structural formula

[0065] The free base thereof is prepared according to the preparation method of Example 9 in International Patent Application PCT / CN2022 / 109503;

[0066] The fumarate salt Form I thereof is prepared according to the preparation method of Compound A fumarate salt Form I in the specification of Chinese Patent Application 202410125231.9 on page 53.

[0067] Study on Compound A fumarate salt Form

[0068] Experimental instruments or reagents:

[0069] 1. Preparation of Compound A fumarate salt Form A

[0070] 1.1 Preparation of Compound A fumarate salt Form A

[0071] Compound A free base (5.0 g) was weighed into a reaction flask, fumaric acid solid (1.16 g) was added, 125 mL of ethanol was added, stirred at room temperature for 48 h, filtered, dried at 60 °C for 24 h to obtain white solid.

[0072] It was identified as fumarate salt Form A by testing and analysis, which has an XRPD pattern as shown in Figure 1, a DSC pattern as shown in Figure 2 and a TGA pattern as shown in Figure 3, and the results of its DSC and TGA analysis show that it is a non-solvate, and the ratio of compound and fumaric acid is about 1:1.

[0073] 1.2 Preparation of Compound A fumarate salt Form A

[0074] Compound A free base (5.0 g) was weighed into a reaction flask, fumaric acid solid (1.16 g) was added, 125 mL of dichloromethane was added, stirred at room temperature for 48 h, filtered, dried at 60 °C for 24 h to obtain white solid. It was identified as fumarate salt Form A by testing and analysis, which has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0075] 1.3 Preparation of Compound A fumarate salt Form A

[0076] The fumarate salt Form I was converted into fumarate salt Form A by the following methods (1)-(11) listed below, and the white solid obtained was identified as fumarate salt Form A by testing and analysis, which has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0077] (1) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of dichloromethane solution was added, and stirred at room temperature for 12 h, centrifuged, and the filter cake was dried to obtain white solid.

[0078] (2) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of water solution was added, and stirred at room temperature for 12 h, centrifuged, and the filter cake was dried to obtain white solid.

[0079] (3) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of tetrahydrofuran solution was added, and stirred at room temperature for 12 h, centrifuged, and the filter cake was dried to obtain white solid.

[0080] (4) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 3 mL of a mixture of methanol: ethanol (1:1) was added, and after the solution was clear, it was filtered, and the filtrate was placed in a -20 °C refrigerator, and cooled to crystallize white solid.

[0081] (5) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 3 mL of ethanol: acetone (1 : 1) was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was placed in a -20 °C refrigerator, and white solid was precipitated by cooling crystallization.

[0082] (6) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 3 mL of acetonitrile: water (2: 1) was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was placed in a -20 °C refrigerator, and white solid was precipitated by cooling crystallization.

[0083] (7) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 3 mL of methanol: toluene (1 : 1) was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was placed in a -20 °C refrigerator, and white solid was precipitated by cooling crystallization.

[0084] (8) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 5 mL of methanol: 1,4-dioxane (1 : 1) was added, and the solution was dissolved and then filtered. The filtrate was slowly added to methyl tert-butyl ether to form an interface, and liquid-liquid diffusion was performed to precipitate white solid.

[0085] (9) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of methanol: acetone (1 : 1) was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was magnetically stirred, and isooctane was added dropwise at room temperature to precipitate white solid.

[0086] (10) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of acetic acid was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was magnetically stirred, and methyl tert-butyl ether was added dropwise at room temperature to precipitate white solid.

[0087] (11) Compound A fumarate salt Form I (100 mg, 0.19 mmol) was weighed into a 10 mL glass vial, 2 mL of N,N-dimethylacetamide was added, and the solution was dissolved at 60 °C and then filtered. The filtrate was magnetically stirred, and methyl tert-butyl ether was added dropwise at room temperature to precipitate white solid.

[0088] 2. Solubility experiment

[0089] 2.1 Purpose of the experiment

[0090] The equilibrium solubility of Compound A fumarate salt Form A in water was investigated for 24 h.

[0091] 2.2 Experimental method

[0092] An excess of Compound A fumarate salt Form A was weighed into a 10 mL centrifuge tube, 2 mL of deionized water was added, and the tube was sealed with a parafilm and shaken at 600 rpm for 24 h at room temperature. After shaking, the sample was diluted and analyzed by HPLC.

[0093] 2.3 Experimental Results

[0094] The equilibrium solubility of Compound A fumarate salt Form A in water was 4.03 mg / mL, indicating good solubility.

[0095] 3. Long-term stability experiment

[0096] 3.1 Purpose of the experiment

[0097] The chemical stability of Compound A fumarate salt Form A under high humidity, high humidity and light conditions was investigated.

[0098] 3.2 Experimental method

[0099] An appropriate amount of Compound A fumarate salt Form A was placed in a 5 mL glass vial, and was placed in a 60°C oven, a desiccator with RH 92.5%, and a stability test box with light intensity of 4500 lx, respectively. The apparent color of the sample was recorded, and at 0 days, 7 days and 15 days, the sample was taken and observed for color change. After dissolution in acetonitrile and water, the content and impurity change were detected by HPLC, and the salt form was detected by XRPD, and the results were recorded.

[0100] 3.3 Experimental results

[0101] Under high humidity, high humidity and light conditions, the color of Compound A fumarate salt Form A did not change after 7 days and 15 days, and the maximum single impurity content was not more than 0.45% at 7 days and 15 days, indicating that Compound A fumarate salt Form A had good chemical stability.

[0102] 4. Hygroscopicity experiment

[0103] 4.1 Purpose of the experiment

[0104] The hygroscopicity and deliquescence of Compound A fumarate salt Form A were investigated.

[0105] 4.2 Experimental scheme

[0106] At room temperature 25°C, Compound A fumarate salt Form A sample was placed in a DVS sample pan for testing.

[0107] 4.3 Experimental results

[0108] The DVS graph of compound A fumarate salt crystal form A is shown in Figure 4, in which two curves represent the adsorption curve and the desorption curve, respectively, and the two curves do not coincide due to the hysteresis phenomenon during desorption. As can be seen from Figure 4, the sample slowly absorbs moisture with the increase of humidity, and when the RH increases to 80%, the crystal form A absorbs moisture and increases by 0.26%, indicating that it has slight hygroscopicity.

[0109] 5. Competition experiment

[0110] 5.1 Purpose of the experiment

[0111] To investigate the thermodynamic stability of different crystal forms of compound A fumarate salt.

[0112] 5.2 Experimental scheme

[0113] An appropriate amount of a mixture of compound A fumarate salt crystal form I and fumarate salt crystal form A in equal proportions was weighed into a sample bottle, an appropriate amount of solvent (different solvents were used in different groups) was added, and the sample was slurried at room temperature for 24 h. After filtration and drying, the sample was characterized by XRPD.

[0114] 5.3 Experimental results

[0115] XRPD characterization showed that the product was compound A fumarate salt crystal form A, which indicated that compound A fumarate salt crystal form A was more thermodynamically stable than compound A fumarate salt crystal form I, and was the most thermodynamically stable crystal form.

[0116] Although the specific embodiments of the present application have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present application according to all the teachings disclosed herein, and these changes are all within the protection scope of the present application. The entire scope of the present application is given by the appended claims and any equivalents thereof.

Claims

1. A crystalline Form A of the fumarate salt of the compound (R)-N-(2-(4-(5-fluoropyridin-2-yl)- 1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1 H-inden-2-amine characterized by, The X-ray powder diffraction pattern of the fumarate salt Form A comprises diffraction peaks at 2-theta of 11.59±0.2°, 21.24±0.2°, 28.52±0.2°.

2. The fumarate salt Form A of claim 1, characterized by, The X-ray powder diffraction pattern of the fumarate salt Form A further comprises one or more diffraction peaks at 2-theta of 15.13±0.2°, 17.03±0.2°, 18.31±0.2°, 19.77±0.2°, 21.82±0.2°, 26.82±0.2°.

3. The fumarate salt Form A of claim 1 or 2, characterized in that, The X-ray powder diffraction pattern of the fumarate salt Form A further comprises one or more diffraction peaks at 2-theta of 6.94±0.2°, 8.48±0.2°, 9.75±0.2°, 14.40±0.2°, 16.35±0.2°, 20.42±0.2°, 23.49±0.2°, 24.57±0.2°, 25.47±0.2°, 29.01±0.2°, 30.20±0.2°, 33.76±0.2°.

4. The fumarate salt Form A of any one of claims 1-3, characterized by, The X-ray powder diffraction pattern of the fumarate salt Form A further comprises one or more diffraction peaks at 2-theta of 14.05±0.2°, 15.54±0.2°, 22.50±0.2°, 23.08±0.2°, 33.19±0.2°, 35.63±0.2°.

5. The fumarate salt Form A of any one of claims 1-4, characterized by, The X-ray powder diffraction pattern of the fumarate salt Form A is substantially as shown in Figure 1.

6. The fumarate salt Form A of any one of claims 1-5, characterized by, The DSC pattern of the fumarate salt Form A has an endothermic peak at 231±5°C, preferably has a DSC pattern as shown in Figure 2 and / or has a TGA pattern as shown in Figure 3.

7. A process for preparing the fumarate salt crystalline Form A according to any one of claims 1 to 6, characterized in that, The method is prepared by mixing (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine free base, fumaric acid and a solvent, stirring to crystallize; Alternatively, by converting (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine fumarate salt Form I; The molar ratio of the free base to fumaric acid is 1:0.5-2.0; The solvent is selected from one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isooctane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene and toluene, preferably selected from one or more of ethanol, dichloromethane and ethyl acetate, more preferably selected from ethanol or dichloromethane.

8. A pharmaceutical composition comprising a therapeutically effective amount of the fumarate salt Form A of any one of claims 1-6, and one or more pharmaceutically acceptable carriers.

9. Use of the fumarate salt Form A of any one of claims 1-6, or the pharmaceutical composition of claim 8, for the manufacture of a medicament, wherein the medicament is preferably a medicament for the prevention and / or treatment of a μ-opioid receptor agonist-mediated related disease.

10. The use of claim 9, wherein the μ-opioid receptor agonist-mediated related disease is selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urological and reproductive disorders, cardiovascular disorders, and respiratory disorders, preferably one or more of pain, more preferably postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, and inflammation-induced pain.

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