Anhydrous polymorphs of an androgen receptor antagonist and methods of making and using the same

Abstract

The present application belongs to the technical field of pharmaceutical crystal chemistry, and specifically relates to anhydrous polymorphs of androgen receptor antagonists, and a preparation method and use thereof. Specifically, the present application provides four anhydrous polymorphs (having crystal forms A, B, C and D respectively) of a compound of formula I, a preparation method of each of the anhydrous polymorphs, a pharmaceutical composition containing the anhydrous polymorphs, and use in preventing, alleviating and / or treating diseases or disorders related to androgen receptor activity.

Description

[0001] Citation of relevant applications

[0002] This invention claims priority to Chinese Patent Application No. 202110310216.8, filed on March 23, 2021, entitled "Anhydrous Polymorphs of Androgen Receptor Antagonists and Their Preparation Methods and Uses", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of pharmaceutical crystal chemistry technology, specifically relating to four anhydrous polymorphs of androgen receptor antagonists, their preparation methods, and their uses in the pharmaceutical field. Background Technology

[0004] The same substance (element or compound) may form multiple crystals with completely different structures, morphologies and physical properties under different conditions. This phenomenon is called crystal polymorphism, and each of these crystals can be called a polymorph.

[0005] Polymorphism is also quite common in the pharmaceutical field. Under certain conditions, a pharmaceutical active ingredient can exist in a specific crystalline form (crystal form), thus forming a specific polymorph. Since different polymorphs of the same pharmaceutical active ingredient usually have different crystal lattice structures, they may result in different bioavailability, solubility, melting point, and physicochemical stability, thereby affecting the safety and efficacy of the drug. In particular, physicochemical stability is a prerequisite for determining whether a polymorph can be used as a pharmaceutical crystal form.

[0006] The androgen receptor (AR) is a 110 kDa steroidal nuclear receptor, one of its key functions being androgen-activated gene transcription. The androgen receptor plays a crucial role in a variety of androgen-related diseases or conditions, such as prostate cancer, benign prostatic hyperplasia, male pattern baldness, muscle loss, acne, and hirsutism.

[0007] Chinese invention patent CN 102757389 B discloses a small molecule AR receptor antagonist (chemical name 4-(4,4-dimethyl-3-(6-methylpyridin-3-yl)-5-oxo-2-thioimidazolidine-1-yl)-3-fluoro-2-methoxybenzonitrile (as shown in Formula I), which is currently in the clinical research stage). It is prepared by microwave-assisted cyclization reaction of intermediates 3a and 6e and purified by silica gel column chromatography. The small-scale test results show that it is basically in a gel or viscous state.

[0008] Summary of the Invention

[0009] The problem the invention aims to solve

[0010] To ensure the physicochemical stability of drugs during production, processing, and storage, four different anhydrous polymorphs of Formula I compounds were obtained through in-depth research on their different aggregation states. All of these polymorphs possess excellent physicochemical properties, such as crystallinity, solubility, hygroscopicity, chemical stability, and crystal form stability. Furthermore, the corresponding preparation processes are feasible, providing a scientific basis for clinical drug research.

[0011] Solution for solving the problem

[0012] In a first aspect, the present invention provides an anhydrous polymorph of a compound of formula I.

[0013]

[0014] The anhydrous polymorph of the compound of Formula I has crystal form D, and the X-ray powder diffraction (XRPD) spectrum of crystal form D contains peaks at the following 2θ values: 5.3±0.2°, 10.7±0.2°, 13.5±0.2°, 15.1±0.2° and 21.3±0.2°.

[0015] Furthermore, the XRPD spectrum of the crystal form D contains peaks located at the following 2θ values: 5.3±0.2°, 10.7±0.2°, 12.0±0.2°, 12.7±0.2°, 13.5±0.2°, 14.8±0.2°, 15.1±0.2°, 16.4±0.2°, 17.3±0.2°, 20.3±0.2°, 21.3±0.2°, 24.2±0.2°, and 24.8±0.2°.

[0016] Furthermore, the XRPD spectrum of the crystal form D contains peaks located at the following 2θ values: 5.3±0.2°, 10.7±0.2°, 12.0±0.2°, 12.7±0.2°, 13.5±0.2°, 14.8±0.2°, 15.1±0.2°, 16.4±0.2°, 17.3±0.2°, 19.7±0.2°, 20.3±0.2°, 21.3±0.2°, 22.5±0.2°, 23.1±0.2°, 24.2±0.2°, 24.8±0.2°, 27.3±0.2°, 28.5±0.2°, 29.7±0.2°, and 32.3±0.2°.

[0017] More preferably, the XRPD spectrum of the crystal form D is substantially the same as... Figure 1 Consistent.

[0018] Furthermore, the thermogravimetric analysis (TGA) spectrum of the crystal form D showed a weight loss of approximately 1.6% at 150±1 °C.

[0019] Preferably, the TGA spectrum of crystal form D is substantially the same as... Figure 2 Consistent.

[0020] Furthermore, the differential scanning calorimetry (DSC) spectrum of the crystal form D shows endothermic activity at 167±1℃.

[0021] Preferably, the DSC spectrum of the crystal form D is substantially the same as... Figure 2 Consistent.

[0022] Secondly, the present invention provides a method for preparing anhydrous polymorphs having crystal form D, which is selected from slow volatilization method, gas-solid diffusion method, gas-liquid diffusion method, polymer-induced method, grinding method and suspension stirring method, with suspension stirring method being preferred.

[0023] Preferably, the solvent used in the slow evaporation method is a volatile haloalkane or a straight-chain or branched C2-C6 nitrile; more preferably, the volatile haloalkane is dichloromethane or chloroform, and the straight-chain or branched C2-C6 nitrile is acetonitrile.

[0024] Preferably, the solvent used in the gas-solid diffusion method is a volatile alcohol or a volatile ether; more preferably, the volatile alcohol is methanol or ethanol, and the volatile ether is diethyl ether or methyl tert-butyl ether.

[0025] Preferably, the good solvent used in the gas-liquid diffusion method is a straight-chain or branched C2-C6 nitrile, preferably acetonitrile, and the antisolvent used is water; more preferably, the good solvent / antisolvent combination used in the gas-liquid diffusion method is acetonitrile / water.

[0026] Preferably, the good solvent used in the polymer-induced method is a straight-chain or branched C2-C6 nitrile, preferably acetonitrile, and the polymer used is any one or a mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose, preferably an equal mass mixture.

[0027] Preferably, the grinding process may be carried out without the use of a solvent or by using water as a solvent.

[0028] Preferably, the solvent used in the suspension stirring method is water, alkane, alkyl alcohol, alkyl ketone, alkyl ester, chlorinated hydrocarbon, ether, aromatic hydrocarbon, straight-chain or branched C2-C6 nitrile, dimethyl sulfoxide, or chain or cyclic amide; more preferably, the alkane is n-heptane, pentane, or n-hexane, the alkyl alcohol is methanol, ethanol, or isopropanol, the alkyl ketone is acetone or methyl isobutyl ketone, the alkyl ester is ethyl acetate or isopropyl acetate, the chlorinated hydrocarbon is dichloromethane or chloroform, the ether is diethyl ether, methyl tert-butyl ether, 1,4-dioxane, or 2-methyltetrahydrofuran, and the aromatic hydrocarbon is benzene. The solvent used in the suspension stirring method is toluene or xylene, wherein the linear or branched C2-C6 nitrile is acetonitrile, the chain amide is N,N-dimethylformamide or N,N-dimethylacetamide, and the cyclic amide is N-methyl-2-pyrrolidone; more preferably, the mixed solvent used in the suspension stirring method is tetrahydrofuran / water, 1,4-dioxane / toluene, acetonitrile / water, dimethyl sulfoxide / water, N,N-dimethylacetamide / water, ethyl acetate / n-heptane, chloroform / n-heptane, toluene / n-heptane, acetone / water, dichloromethane / n-heptane, or N-methyl-2-pyrrolidone / water.

[0029] Thirdly, the present invention provides an anhydrous polymorph of a compound of formula I, the anhydrous polymorph of said compound of formula I having crystal form C, the XRPD spectrum of said crystal form C containing peaks located at the following 2θ values: 5.2±0.2°, 10.4±0.2°, 13.4±0.2°, 15.0±0.2°, 16.4±0.2° and 29.1±0.2°.

[0030] Preferably, the XRPD spectrum of crystal form C contains peaks at the following 2θ values: 5.2±0.2°, 10.4±0.2°, 13.4±0.2°, 15.0±0.2°, 16.4±0.2°, 19.6±0.2°, 20.1±0.2°, 22.8±0.2°, 24.4±0.2°, and 29.1±0.2°.

[0031] More preferably, the XRPD spectrum of crystal form C includes peaks located at the following 2θ values: 5.2±0.2°, 10.4±0.2°, 11.9±0.2°, 13.4±0.2°, 15.0±0.2°, 16.4±0.2°, 17.3±0.2°, 19.6±0.2°, 20.1±0.2°, 22.8±0.2°, 23.6±0.2°, 24.4±0.2°, 29.1±0.2°, 31.6±0.2°, and 34.1±0.2°.

[0032] More preferably, the spectrum of crystal form C is substantially the same as... Figure 6 Consistent.

[0033] Furthermore, the TGA spectrum of the crystal form C showed a weight loss of approximately 1.6% at 150±1 °C.

[0034] Preferably, the TGA spectrum of crystal form C is substantially the same as... Figure 7 Consistent.

[0035] Furthermore, the DSC spectrum of the crystal form C shows endothermic activity at 148±1℃, 167±1℃, and 177±1℃.

[0036] Preferably, the DSC spectrum of the crystal form C is substantially the same as... Figure 7 Consistent.

[0037] Fourthly, the present invention provides a method for preparing anhydrous polymorphs having crystalline form C, which is selected from slow evaporation method, slow cooling method, gas-solid diffusion method, gas-liquid diffusion method, polymer-induced method and antisolvent addition method, with antisolvent addition method being preferred.

[0038] Preferably, the solvent used in the slow evaporation method is at least one selected from volatile alkyl alcohols, volatile ketones, volatile ethers, volatile aromatics, volatile esters, and volatile chlorinated hydrocarbons; more preferably, the volatile alcohol is methanol, ethanol, or isopropanol, the volatile ketone is acetone, butanone, or methyl isobutyl ketone, the volatile ether is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or methyl tert-butyl ether, the volatile aromatic is toluene or xylene, the volatile ester is ethyl acetate or isopropyl acetate, and the volatile chlorinated hydrocarbon is dichloromethane, chloroform, or 1,2-dichloroethane; even more preferably, the mixed solvent used in the slow evaporation method is ethanol / chloroform or tetrahydrofuran / isopropyl acetate.

[0039] Preferably, the solvent used in the slow cooling method is at least one selected from alkyl alcohols, alkyl ethers, alkyl esters, aromatics, and alkanes; more preferably, the alkyl alcohol is methanol, ethanol, or isopropanol, the alkyl ether is diethyl ether or methyl tert-butyl ether, the alkyl ester is ethyl acetate or isopropyl acetate, the aromatic is toluene or xylene, and the alkane is n-pentane, n-hexane, or n-heptane; even more preferably, the mixed solvent used in the slow cooling method is toluene / isopropanol or isopropyl acetate / n-heptane. Additionally, preferably, the lower limit temperature of the slow cooling method is 0-40°C, the upper limit temperature is below the boiling point of the solvent, and the cooling rate is 0.1-5°C / min, for example, 0.1-2°C / min, 0.1-1°C / min, 0.1-0.5°C / min, 0.1-0.3°C / min, or 0.1°C / min.

[0040] Preferably, the solvent used in the gas-solid diffusion method is a volatile ketone, a volatile ether, or a volatile acid; more preferably, the volatile ketone is acetone or methyl isobutyl ketone, the volatile ether is diethyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane, and the volatile acid is acetic acid.

[0041] Preferably, the good solvent used in the gas-liquid diffusion method is an alkyl alcohol, alkyl ketone, alkyl ester, alkyl ether, chlorinated hydrocarbon, aromatic hydrocarbon, or dimethyl sulfoxide, and the antisolvent is water, an alkane, or an alkyl alcohol; more preferably, for the good solvent, the alkyl alcohol is methanol, ethanol, or isopropanol, the alkyl ketone is acetone, butanone, or methyl isobutyl ketone, the alkyl ester is ethyl acetate or isopropyl acetate, the alkyl ether is diethyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, or 2-methyltetrahydrofuran, the chlorinated hydrocarbon is dichloromethane, chloroform, or 1,2-dichloroethane, and the aromatic hydrocarbon is toluene or xylene; for the antisolvent, the alkane is n-heptane, and the alkyl alcohol is isopropanol. More preferably, the good solvent / antisolvent combination used in the gas-liquid diffusion method is methanol / water, methyl isobutyl ketone / water, tetrahydrofuran / water, isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-heptane, chloroform / n-heptane, toluene / n-heptane, ethanol / isopropanol, acetone / isopropanol, 1,4-dioxane / isopropanol, or dimethyl sulfoxide / isopropanol.

[0042] Preferably, the good solvent used in the polymer-induced method is an alkyl alcohol, alkyl ketone, alkyl ester, alkyl ether, or chlorinated hydrocarbon. Preferably, the alkyl alcohol is methanol, ethanol, or isopropanol; the alkyl ketone is acetone or methyl isobutyl ketone; the alkyl ester is ethyl acetate or isopropyl acetate; the alkyl ether is tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane; and the chlorinated hydrocarbon is dichloromethane or 1,2-dichloroethane. The polymer used is any one or a mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose, preferably an equal mass mixture; or any one or a mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose, preferably an equal mass mixture.

[0043] Preferably, the good solvent used in the antisolvent addition method is an alkyl alcohol, alkyl ketone, alkyl ester, cyclic ether, chlorinated hydrocarbon, aromatic hydrocarbon, chain or cyclic amide, or dimethyl sulfoxide, and the antisolvent used is an alkane or ether; more preferably, for the good solvent, the alkyl alcohol is methanol, ethanol, or isopropanol, the alkyl ketone is methyl isobutyl ketone, acetone, or butanone, the alkyl ester is ethyl acetate or isopropyl acetate, the cyclic ether is 1,4-dioxane or 2-methyltetrahydrofuran, the chlorinated hydrocarbon is dichloromethane, chloroform, or 1,2-dichloroethane, the aromatic hydrocarbon is benzene, toluene, or xylene, and the chain amide is N,N- Dimethylformamide or N,N-dimethylacetamide, wherein the cyclic amide is N-methyl-2-pyrrolidone; for the antisolvent, the alkane is n-pentane, n-hexane, or n-heptane, and the ether is diethyl ether or methyl tert-butyl ether; more preferably, the good solvent / antisolvent combination used in the antisolvent addition method is methyl isobutyl ketone / n-heptane, ethyl acetate / n-heptane, 1,4-dioxane / n-heptane, dichloromethane / n-heptane, toluene / n-heptane, isopropyl acetate / methyl tert-butyl ether, N-methylpyrrolidone / methyl tert-butyl ether, 2-methyltetrahydrofuran / methyl tert-butyl ether, or chloroform / methyl tert-butyl ether.

[0044] Fifthly, the present invention provides an anhydrous polymorph of a compound of formula I, the anhydrous polymorph of said compound of formula I having crystal form B, the XRPD spectrum of said crystal form B containing peaks at the following 2θ values: 7.3±0.2°, 9.9±0.2°, 12.5±0.2°, 16.5±0.2° and 17.1±0.2°.

[0045] Preferably, the XRPD spectrum of crystal form B contains peaks at the following 2θ values: 7.3±0.2°, 9.9±0.2°, 12.5±0.2°, 13.1±0.2°, 16.5±0.2°, 17.1±0.2°, 20.3±0.2°, 24.0±0.2°, 25.2±0.2°, and 26.7±0.2°.

[0046] More preferably, the XRPD spectrum of crystal form B includes peaks located at the following 2θ values: 7.3±0.2°, 9.9±0.2°, 12.5±0.2°, 13.1±0.2°, 16.5±0.2°, 17.1±0.2°, 20.3±0.2°, 21.3±0.2°, 24.0±0.2°, 25.2±0.2°, 26.7±0.2°, 27.8±0.2°, 28.6±0.2°, 29.5±0.2°, and 31.3±0.2°.

[0047] More preferably, the spectrum of crystal form B is substantially the same as... Figure 8 Consistent.

[0048] Furthermore, the TGA spectrum of crystal form B shows a weight loss of approximately 1.5% at 150±1 °C.

[0049] Preferably, the TGA spectrum of crystal form B is substantially the same as... Figure 9 Consistent.

[0050] Furthermore, the DSC spectrum of the crystal form B shows endothermic behavior at 177±1℃.

[0051] Preferably, the DSC spectrum of crystal form B is substantially the same as... Figure 9 Consistent.

[0052] In a sixth aspect, the present invention provides a method for preparing an anhydrous polymorph having crystal form B, which is an antisolvent addition method.

[0053] Preferably, the good solvent used in the antisolvent addition method is an alkyl ketone, a chain or cyclic amide, or dimethyl sulfoxide. More preferably, the alkyl ketone is methyl isobutyl ketone, acetone, or butanone, the chain amide is N,N-dimethylformamide or N,N-dimethylacetamide, and the cyclic amide is N-methyl-2-pyrrolidone. The antisolvent used is water. More preferably, the good solvent / antisolvent combination used in the antisolvent addition method is acetone / water, N,N-dimethylacetamide / water, or dimethyl sulfoxide / water.

[0054] In a seventh aspect, the present invention provides an anhydrous polymorph of a compound of formula I, the anhydrous polymorph of said compound of formula I having a crystal form A, the XRPD spectrum of said crystal form A containing peaks at the following 2θ values: 9.0±0.2°, 12.5±0.2°, 15.7±0.2°, 17.2±0.2°, 18.1±0.2° and 23.2±0.2°.

[0055] Preferably, the XRPD spectrum of crystal form A contains peaks at the following 2θ values: 3.3±0.2°, 7.5±0.2°, 9.0±0.2°, 12.5±0.2°, 12.9±0.2°, 15.2±0.2°, 15.7±0.2°, 17.2±0.2°, 18.1±0.2°, 23.2±0.2°, 24.4±0.2°, 28.4±0.2°, and 29.8±0.2°.

[0056] More preferably, the XRPD spectrum of crystal form A includes peaks located at the following 2θ values: 3.3±0.2°, 7.5±0.2°, 9.0±0.2°, 12.5±0.2°, 12.9±0.2°, 14.4±0.2°, 15.2±0.2°, 15.7±0.2°, 17.2±0.2°, 17.7±0.2°, 18.1±0.2°, 19.9±0.2°, 21.8±0.2°, 23.2±0.2°, 24.4±0.2°, 28.4±0.2°, and 29.8±0.2°.

[0057] More preferably, the spectrum of crystal form A is substantially the same as... Figure 10 Consistent.

[0058] Furthermore, the TGA spectrum of crystal form A shows a weight loss of approximately 1.0% at 150±1℃.

[0059] Preferably, the TGA spectrum of crystal form A is substantially the same as... Figure 11 Consistent.

[0060] Furthermore, the DSC spectrum of crystal form A shows endothermic activity at 160±1℃ and 177±1℃, and exothermic activity at 162±1℃.

[0061] Preferably, the DSC spectrum of crystal form A is substantially the same as... Figure 11 Consistent.

[0062] Eighthly, the present invention provides a method for preparing an anhydrous polymorph having crystal form A, which is an antisolvent addition method.

[0063] Preferably, the good solvent used in the antisolvent addition method is an alkyl alcohol, preferably methanol, ethanol or isopropanol, and the antisolvent used is water; more preferably, the good solvent / antisolvent combination used in the antisolvent addition method is methanol / water.

[0064] Preferably, the anhydrous polymorph of the compound of formula I of the present invention has a particle size of 5-100 micrometers.

[0065] More preferably, the anhydrous polymorph of the compound of formula I of the present invention has a particle size of 10-90 micrometers.

[0066] More preferably, the anhydrous polymorph of the compound of formula I of the present invention has a particle size of 30-60 micrometers.

[0067] In a ninth aspect, the present invention provides a pharmaceutical composition comprising (preferably a preventive, remission, and / or therapeutically effective amount) an anhydrous polymorph of a compound of formula I and a pharmaceutically acceptable excipient; preferably, the anhydrous polymorph of the compound of formula I has a particle size of 5-100 micrometers (preferably 10-90 micrometers, more preferably 30-60 micrometers); preferably, the pharmaceutical composition further comprises a second functional component selected from any one or more of minoxidil, deuterated ruxolitinib (CTP-543), botulinum toxin, clascoterone (CB-03-01), finasteride, and latanoprost.

[0068] Preferably, in the above pharmaceutical composition, the weight percentage of the anhydrous polymorph of the compound of formula I is 1.0%-99.0%, for example, it can be 10.0%-80.0%, 20%-80%, 25%-80%, 25%-70%, 25%-65%, 25%-60%, 25%-55%, 25%-50%, 30%-50%, 35%-50%, or 40%-50%.

[0069] In a tenth aspect, the present invention provides the use of an anhydrous polymorph of a compound of formula I or a pharmaceutical composition in the preparation of a medicament for the prevention, relief and / or treatment of androgen receptor-related diseases or conditions; preferably, the pharmaceutical composition further comprises a second functional component selected from any one or more of minoxidil, deuterated ruxotetinib, botulinum toxin, clavusone, finasteride and latanoprost.

[0070] In one aspect, the present invention provides an anhydrous polymorph of a compound of formula I or a pharmaceutical composition thereof for the prevention, relief and / or treatment of androgen receptor-related diseases or conditions; preferably, the pharmaceutical composition further comprises a second functional component selected from any one or more of minoxidil, deuterated ruxotetinib, botulinum toxin, clavusone, finasteride and latanoprost.

[0071] In a twelfth aspect, the present invention provides a method for preventing, alleviating, and / or treating androgen receptor-related diseases or conditions, comprising the steps of: administering an anhydrous polymorph of a compound of formula I or a pharmaceutical composition in a preventive, alleviating, and / or therapeutically effective amount to an individual in need; preferably, the pharmaceutical composition further comprises a second functional component selected from any one or more of minoxidil, deuterated ruxotetinib, botulinum toxin, clavusone, finasteride, and latanoprost.

[0072] Preferably, in the tenth to twelfth aspects, the androgen receptor activity-related diseases or conditions are selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, hyperspermia, and androgenetic alopecia.

[0073] The effects of the invention

[0074] This invention provides four crystalline forms of Formula I compounds, all of which are amorphous and exhibit excellent thermal stability, with a TGA weight loss (e.g., up to 150°C) not exceeding 1.6%, and also possessing high melting points. At high temperatures (e.g., above 166°C), crystalline form B is the most stable.

[0075] In this invention, crystal form D is more stable and has a low risk of crystal transformation under the conditions of 5℃ / room temperature (~20℃) / 50℃ / 90℃. The DVS results of the anhydrous polymorphs of compound I in the form of crystal form D show that, under constant temperature of 25℃, when the relative humidity increases from 0%RH to 80%RH, the hygroscopic weight gain of crystal form D is only 0.14wt%, indicating that the sample has almost no hygroscopicity. Furthermore, after being placed for one week under the conditions of 40℃ / 75%RH and 25℃ / 60%RH, there is no significant change in the crystal form and chemical purity of crystal form D, indicating that crystal form D has good physical and chemical stability. Crystal forms AD of this invention are suitable as potential pharmaceutical crystal forms, especially crystal forms B or D. Attached Figure Description

[0076] Figure 1 The XRPD spectrum of the anhydrous polymorph of compound I with crystal form D is shown.

[0077] Figure 2 The TGA / DSC spectrum of the anhydrous polymorph of compound I with crystal form D is shown.

[0078] Figure 3 The DVS diagram is shown for the anhydrous polymorph of compound I with crystal form D.

[0079] Figure 4 XRPD spectra of the anhydrous polymorph of compound I with crystal form D before and after the DVS experiment;

[0080] Figure 5 XRPD spectra of the stability test of the anhydrous polymorph of compound I with crystal form D;

[0081] Figure 6 The XRPD spectrum of the anhydrous polymorph of compound I with crystal form C is shown.

[0082] Figure 7The TGA / DSC spectrum of the anhydrous polymorph of compound I with crystal form C is shown.

[0083] Figure 8 The XRPD spectrum of the anhydrous polymorph of compound I with crystal form B is shown.

[0084] Figure 9 The TGA / DSC spectrum of the anhydrous polymorph of compound I with crystal form B is shown.

[0085] Figure 10 The XRPD spectrum of the anhydrous polymorph of compound I with crystal form A is shown.

[0086] Figure 11 The TGA / DSC spectrum of the anhydrous polymorph of compound I with crystal form A is shown.

[0087] Figure 12 XRPD comparison spectra of four anhydrous polymorphs of compound I, having crystal forms A / B / C / D, before and after suspension competition test in ethanol;

[0088] Figure 13 The XRPD comparison spectra of four anhydrous polymorphs of compound I (A / B / C / D) before and after suspension competition in methyl tert-butyl ether are shown. Detailed Implementation

[0089] Unless otherwise stated, the scientific and technical terms used in this article have the meanings commonly understood by those skilled in the art.

[0090] Unless otherwise stated, singular terms such as “a,” “an,” and “the” appearing in this document cover their corresponding plural references unless the context clearly indicates otherwise. For example, when referring to “an” crystalline or polymorphic product, it covers one or more different crystalline or polymorphic products, while when referring to “the” method, it covers equivalent steps and methods known to one of ordinary skill in the art.

[0091] For the crystal forms discussed in this paper, only the characteristic peaks in the XRPD spectra (i.e., the most characteristic, significant, unique, and / or reproducible diffraction peaks) are summarized, while other peaks can be obtained from the spectra using conventional methods. The aforementioned characteristic peaks are reproducible within the error limits (±0.2°).

[0092] Unless otherwise stated, the term "comprising" and its variations, such as "containing" and "including," as used herein mean that the collection not only covers the one or more integers, steps, or combinations thereof explicitly disclosed, but also excludes any other integers, steps, or combinations thereof. Furthermore, in certain circumstances, the term "comprising" may be replaced by the terms "containing," "including," or "having."

[0093] Unless otherwise stated, the term "effective amount" as used herein refers to the amount of a pharmaceutically active ingredient that, when administered to an individual / subject / patient, is sufficient to affect the disease or symptom of the disease or condition in order to prevent, alleviate, and / or treat the disease or condition. This "effective amount" can vary depending on factors such as the active pharmaceutical ingredient, the symptoms or severity of the disease or condition, and individual circumstances of the individual / subject / patient (e.g., age, sex, weight).

[0094] Unless otherwise stated, pharmaceutical compositions comprising the polymorphs of the present invention may be administered to individuals / subjects / patients in need via oral, inhalation, rectal, parenteral, or topical routes. For oral administration, the pharmaceutical composition may be a solid dosage form (such as tablets, powders, granules, capsules, etc.) or a liquid dosage form (such as a water-based or oil-based suspension or other liquid dosage forms, such as syrups, solutions, etc.). For parenteral administration, the pharmaceutical composition may be a solution, suspension, lyophilized powder, etc. The pharmaceutical composition may be a single unit with a precise dosage. Furthermore, the pharmaceutical composition may further comprise additional pharmacodynamically active ingredients.

[0095] Polymorphs of Formula I compounds

[0096] First, this invention provides a first anhydrous polymorph of the compound of formula I, which has crystal form D, and the measured XRPD spectrum is substantially the same as... Figure 1 Consistent.

[0097] Its XRPD spectrum reveals that crystal form D has relatively high diffraction peaks at the following 2θ values: 5.3±0.2°, 10.7±0.2°, 13.5±0.2°, 15.1±0.2° and 21.3±0.2°.

[0098] In addition, crystal form D also has diffraction peaks of moderate relative intensity at the following 2θ values: 12.0±0.2°, 12.7±0.2°, 14.8±0.2°, 16.4±0.2°, 17.3±0.2°, 20.3±0.2°, 24.2±0.2° and 24.8±0.2°.

[0099] In addition, crystal form D also has relatively low intensity diffraction peaks at the following 2θ values: 19.7±0.2°, 22.5±0.2°, 23.1±0.2°, 27.3±0.2°, 28.5±0.2°, 29.7±0.2° and 32.3±0.2°.

[0100] In one embodiment, the anhydrous polymorph of the compound of formula I of the present invention has crystal form D as described above, with a particle size of 5-100 micrometers, preferably 10-90 micrometers, more preferably 30-60 micrometers.

[0101] Secondly, this invention provides a second anhydrous polymorph of the compound of formula I, which has crystal form C, and the measured XRPD spectrum is substantially the same as... Figure 6 Consistent.

[0102] Its XRPD spectrum reveals that crystal form C exhibits relatively high intensity diffraction peaks at the following 2θ values: 5.2±0.2°, 10.4±0.2°, 13.4±0.2°, 15.0±0.2°, 16.4±0.2°, and 29.1±0.2°.

[0103] In addition, crystal form C also has diffraction peaks of moderate relative intensity at the following 2θ values: 19.6±0.2°, 20.1±0.2°, 22.8±0.2° and 24.4±0.2°.

[0104] In addition, crystal form C also has relatively low intensity diffraction peaks at the following 2θ values: 11.9±0.2°, 17.3±0.2°, 23.6±0.2°, 31.6±0.2° and 34.1±0.2°.

[0105] In one embodiment, the anhydrous polymorph of the compound of formula I of the present invention has crystal form C as described above, with a particle size of 5-100 micrometers, preferably 10-90 micrometers, more preferably 30-60 micrometers.

[0106] Furthermore, this invention provides a third anhydrous polymorph of the compound of formula I, which has crystal form B, and the measured XRPD spectrum is substantially the same as that of the compound of formula I. Figure 8 Consistent.

[0107] Its XRPD spectrum reveals that crystal form B has relatively high diffraction peaks at the following 2θ values: 7.3±0.2°, 9.9±0.2°, 12.5±0.2°, 16.5±0.2° and 17.1±0.2°.

[0108] In addition, crystal form B also has diffraction peaks of moderate relative intensity at the following 2θ values: 13.1±0.2°, 20.3±0.2°, 24.0±0.2°, 25.2±0.2° and 26.7±0.2°.

[0109] In addition, crystal form B also has relatively low intensity diffraction peaks at the following 2θ values: 21.3±0.2°, 27.8±0.2°, 28.6±0.2°, 29.5±0.2° and 31.3±0.2°.

[0110] In one embodiment, the anhydrous polymorph of the compound of formula I of the present invention has crystal form B as described above, with a particle size of 5-100 micrometers, preferably 10-90 micrometers, more preferably 30-60 micrometers.

[0111] Finally, this invention provides a fourth anhydrous polymorph of the compound of formula I, which has crystal form A, and the measured XRPD spectrum is substantially the same as that of the compound of formula I. Figure 10 Consistent.

[0112] Its XRPD spectrum reveals that crystal form A has relatively high diffraction peaks at the following 2θ values: 9.0±0.2°, 12.5±0.2°, 15.7±0.2°, 17.2±0.2°, 18.1±0.2° and 23.2±0.2°.

[0113] In addition, crystal form A also has diffraction peaks of moderate relative intensity at the following 2θ values: 3.3±0.2°, 7.5±0.2°, 12.9±0.2°, 15.2±0.2°, 24.4±0.2°, 28.4±0.2° and 29.8±0.2°.

[0114] In addition, crystal form A also has diffraction peaks of moderate relative intensity at the following 2θ values: 14.4±0.2°, 17.7±0.2°, 19.9±0.2° and 21.8±0.2°.

[0115] In one embodiment, the anhydrous polymorph of the compound of formula I of the present invention has crystal form A as described above, with a particle size of 5-100 micrometers, preferably 10-90 micrometers, more preferably 30-60 micrometers.

[0116] Preparation method of anhydrous polymorphs

[0117] In this invention, the anhydrous polymorph of the compound of formula I can be prepared by slow evaporation, slow cooling, gas-solid diffusion, gas-liquid diffusion, polymer-induced method, grinding, suspension stirring or antisolvent addition.

[0118] When anhydrous polymorphs have crystal form D, they can be prepared by slow volatilization, gas-solid diffusion, gas-liquid diffusion, polymer-induced method, grinding method, or suspension stirring method.

[0119] In one embodiment, the anhydrous polymorph having crystal form D can be prepared by a slow evaporation method. This method involves dissolving the compound of formula I in a solvent and slowly evaporating it at atmospheric pressure. Suitable solvents for this method can be, for example, volatile haloalkanes (e.g., dichloromethane, chloroform, etc.) or straight-chain or branched C2-C6 nitrile (e.g., acetonitrile, etc.).

[0120] In one embodiment, an anhydrous polymorph having crystal form D can be prepared by a gas-solid diffusion method. This method involves placing a solid compound of formula I in a gaseous atmosphere formed by solvent evaporation, allowing the solid compound of formula I to interact with the gaseous solvent. Suitable solvents for this method can be, for example, volatile alcohols (e.g., methanol, ethanol, etc.) or volatile ethers (e.g., diethyl ether, methyl tert-butyl ether, etc.).

[0121] In one embodiment, an anhydrous polymorph having crystal form D can be prepared by a gas-liquid diffusion method. This method involves dissolving a compound of formula I in a good solvent and then placing it in a gaseous atmosphere formed by the evaporation of an antisolvent, allowing the liquid compound of formula I to interact with the gaseous antisolvent. Suitable good solvents for this method can be, for example, straight-chain or branched C2-C6 nitrile (e.g., acetonitrile), while antisolvents can be, for example, water. A suitable good solvent / antisolvent combination can be, for example, acetonitrile / water.

[0122] In one embodiment, an anhydrous polymorph having crystal form D can be prepared by a polymer-induced method. This method involves dissolving a compound of formula I in a good solvent, adding a polymer, and then slowly evaporating the good solvent at atmospheric pressure. Suitable good solvents for this method can be, for example, linear or branched C2-C6 nitrile (e.g., acetonitrile), while the polymer can be, for example, any one or a mixture (e.g., an equal mass mixture) of polycaprolactone (PCL), polyethylene glycol (PEG), polymethyl methacrylate (PMMA), sodium alginate (SA), and hydroxyethyl cellulose (HEC).

[0123] In one embodiment, an anhydrous polymorph having crystal form D can be prepared by a grinding method. This method involves placing the compound of formula I in a grinding apparatus (e.g., a mortar), optionally adding a solvent, and then grinding. A suitable solvent for this method may be, for example, water.

[0124] In one embodiment, the anhydrous polymorph having crystal form D can be prepared by a suspension stirring method (also known as a pulping method). This method involves placing a solid form of Formula I compound in a solvent and stirring the resulting suspension, preferably at 0-60°C, more preferably at 20-40°C. The solvent suitable for this method may be, for example, water, alkanes (e.g., n-pentane, n-hexane, n-heptane, etc.), alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), alkyl ketones (e.g., acetone, methyl isobutyl ketone, etc.), alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, etc.), ethers (e.g., diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), straight-chain or branched C2-C6 nitrile (e.g., acetonitrile, etc.), dimethyl sulfoxide, or chain or cyclic amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.). When the method uses a mixed solvent formed from two or more solvents, the mixed solvent may be, for example, tetrahydrofuran / water (e.g., volume ratio 1:2), 1,4-dioxane / toluene (e.g., volume ratio 1:4), acetonitrile / water (e.g., volume ratio 1:2), dimethyl sulfoxide / water (e.g., volume ratio 1:1), N,N-dimethylacetamide / water (e.g., volume ratio 1:1), ethyl acetate / n-heptane (e.g., volume ratio 1:9), chloroform / n-heptane (e.g., volume ratio 1:4), toluene / n-heptane (e.g., volume ratio 1:4), acetone / water (e.g., volume ratio 1:3), dichloromethane / n-heptane (e.g., volume ratio 1:3), or N-methyl-2-pyrrolidone / water (e.g., volume ratio 1:1).

[0125] When anhydrous polymorphs have crystal form C, they can be prepared by slow evaporation, slow cooling, gas-solid diffusion, gas-liquid diffusion, polymer-induced method, or antisolvent addition method.

[0126] In one embodiment, an anhydrous polymorph having crystal form C can be prepared by a slow evaporation method. Solvents suitable for this method can be, for example, at least one of the following: volatile alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), volatile ketones (e.g., acetone, butanone, methyl isobutyl ketone, etc.), volatile ethers (e.g., diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or methyl tert-butyl ether), volatile aromatic hydrocarbons (e.g., toluene, xylene, etc.), volatile esters (e.g., ethyl acetate, isopropyl acetate, etc.), and volatile chlorinated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.). When the method uses a mixed solvent formed from two or more solvents, the mixed solvent can be, for example, ethanol / chloroform (e.g., a volume ratio of 1:1) or tetrahydrofuran / isopropyl acetate (e.g., a volume ratio of 1:1).

[0127] In one embodiment, the anhydrous polymorph of crystal form C can be prepared by a slow cooling method. This method involves dissolving the compound of formula I in a solvent at a temperature below its boiling point, and then slowly cooling (e.g., 0.1 °C / min) to 0-40 °C. Suitable solvents for this method can be at least one of, for example, alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), alkyl ethers (e.g., diethyl ether, methyl tert-butyl ether, etc.), alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), and alkanes (e.g., n-pentane, n-hexane, n-heptane, etc.). When the method uses a mixed solvent formed from two or more solvents, the mixed solvent can be, for example, toluene / isopropanol (e.g., a volume ratio of 1 / 9) or isopropyl acetate / n-heptane (e.g., a volume ratio of 1 / 4).

[0128] In one embodiment, an anhydrous polymorph having crystal form C can be prepared by a gas-solid diffusion method. Solvents suitable for this method can be, for example, volatile ketones (e.g., acetone, methyl isobutyl ketone, etc.), volatile ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, etc.), or volatile acids (e.g., acetic acid).

[0129] In one embodiment, an anhydrous polymorph having crystal form C can be prepared by a gas-liquid diffusion method. Suitable solvents for this method can be, for example, alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), alkyl ketones (e.g., acetone, butanone, methyl isobutyl ketone, etc.), alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.), alkyl ethers (e.g., diethyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), aromatic hydrocarbons (e.g., toluene, xylene, etc.), or dimethyl sulfoxide, while the antisolvent can be, for example, water, alkanes (e.g., n-heptane, etc.), or alkyl alcohols (e.g., isopropanol, etc.). Suitable good solvent / antisolvent combinations may include, for example, methanol / water, methyl isobutyl ketone / water, tetrahydrofuran / water, isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-heptane, chloroform / n-heptane, toluene / n-heptane, ethanol / isopropanol, acetone / isopropanol, 1,4-dioxane / isopropanol, or dimethyl sulfoxide / isopropanol.

[0130] In one embodiment, an anhydrous polymorph having crystal form C can be prepared by a polymer-induced method. Suitable solvents for this method can be, for example, alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), alkyl ketones (e.g., acetone, methyl isobutyl ketone, etc.), alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.), alkyl ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.) or chlorinated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), and the polymer can be, for example, any one or a mixture (e.g., an equal mass mixture) of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAc), hydroxypropyl methylcellulose (HPMC), and methylcellulose (MC), or any one or a mixture (e.g., an equal mass mixture) of polycaprolactone (PCL), polyethylene glycol (PEG), polymethyl methacrylate (PMMA), sodium alginate (SA), and hydroxyethyl cellulose (HEC).

[0131] In one embodiment, an anhydrous polymorph having crystal form C can be prepared by an antisolvent addition method. This method involves dissolving a compound of formula I in a good solvent, and then adding an antisolvent. The compound of formula I has a higher solubility in the good solvent than in the antisolvent, and adding the antisolvent to the good solvent causes the compound of formula I dissolved in the good solvent to precipitate as a solid. Suitable solvents for this method may include, for example, alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), alkyl ketones (e.g., methyl isobutyl ketone, acetone, butanone, etc.), alkyl esters (e.g., ethyl acetate, isopropyl acetate, etc.), cyclic ethers (e.g., 1,4-dioxane, 2-methyltetrahydrofuran, etc.), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), chain or cyclic amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), or dimethyl sulfoxide, while antisolvents may include, for example, alkanes (e.g., n-pentane, n-hexane, n-heptane, etc.) or ethers (e.g., diethyl ether, methyl tert-butyl ether, etc.). Suitable good solvent / antisolvent combinations may include, for example, methyl isobutyl ketone / n-heptane, ethyl acetate / n-heptane, 1,4-dioxane / n-heptane, dichloromethane / n-heptane, toluene / n-heptane, isopropyl acetate / methyl tert-butyl ether, N-methyl-2-pyrrolidone / methyl tert-butyl ether, 2-methyltetrahydrofuran / methyl tert-butyl ether, or chloroform / methyl tert-butyl ether.

[0132] When anhydrous polymorphs have crystal form B or crystal form A, they can be prepared by adding antisolvents.

[0133] In one embodiment, an anhydrous polymorph having crystal form B can be prepared by an antisolvent addition method. Suitable good solvents for this method can be, for example, alkyl ketones (e.g., methyl isobutyl ketone, acetone, butanone, etc.), chain or cyclic amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), or dimethyl sulfoxide, while antisolvents can be, for example, alkanes (e.g., n-pentane, n-hexane, n-heptane, etc.) or water. Suitable good solvent / antisolvent combinations can be, for example, acetone / water, N,N-dimethylacetamide / water, or dimethyl sulfoxide / water.

[0134] In one embodiment, an anhydrous polymorph having crystal form A can be prepared by an antisolvent addition method. Suitable good solvents for this method can be, for example, alkyl alcohols (such as methanol, ethanol, isopropanol, etc.), while antisolvents can be, for example, water. A suitable good solvent / antisolvent combination can be, for example, methanol / water.

[0135] Pharmaceutical Composition

[0136] The present invention provides a pharmaceutical composition comprising (preferably a preventive, alleviating and / or therapeutically effective amount) an anhydrous polymorph of a compound of formula I, and a pharmaceutically acceptable excipient.

[0137] In one embodiment, the pharmaceutical composition comprises: (1) an anhydrous polymorph of a compound of formula I that is effective in preventing, alleviating and / or treating, and (2) at least one pharmaceutically acceptable excipient.

[0138] In one embodiment, the anhydrous polymorph of the Formula I compound accounts for 1.0% to 99.0% by weight in the pharmaceutical composition.

[0139] In one embodiment, the anhydrous polymorph of the compound of formula I in the pharmaceutical composition (e.g., having crystal forms A, B, C and / or D) has a particle size of 5-100 micrometers, preferably 10-90 micrometers, and more preferably 30-60 micrometers.

[0140] The present invention also provides a pharmaceutical composition comprising (preferably a preventive, remission, and / or therapeutically effective amount) an anhydrous polymorph of a compound of formula I, (preferably a preventive, remission, and / or therapeutically effective amount) a second functional component, and a pharmaceutically acceptable excipient.

[0141] In one embodiment, the pharmaceutical composition comprises: (1) an anhydrous polymorph of a compound of formula I that is effective in preventing, alleviating and / or treating the disease; (2) a second functional component that is effective in preventing, alleviating and / or treating the disease; and (3) at least one pharmaceutically acceptable excipient.

[0142] In one embodiment, the second functional component in the pharmaceutical composition is selected from any one or more of minoxidil, deuterated ruxotetinib, botulinum toxin, clavusone, finasteride, and latanoprost, wherein the weight percentage and / or particle size of the anhydrous polymorph of the Formula I compound are as described above.

[0143] In one embodiment, the pharmaceutical composition of the present invention is a tablet (preferably a coated tablet), a capsule, a suppository, a nasal spray, or an injection, preferably a tablet or a capsule.

[0144] Medical Use

[0145] Compounds of Formula I, used as androgen receptor antagonists, are effective in treating androgen receptor-related diseases or conditions. Therefore, anhydrous polymorphs or pharmaceutical compositions of Formula I compounds can also be used as androgen receptor antagonists, thereby preventing, alleviating and / or treating androgen receptor-related diseases or conditions.

[0146] Meanwhile, the present invention provides the use of anhydrous polymorphs of compounds of formula I or pharmaceutical compositions in the preparation of medicaments for the prevention, relief and / or treatment of androgen receptor-related diseases or conditions.

[0147] In addition, the present invention provides a method for preventing, alleviating and / or treating androgen receptor-related diseases or conditions, comprising administering an anhydrous polymorph of a compound of formula I or a pharmaceutical composition in an effective amount for prevention, alleviation and / or treatment to an individual in need.

[0148] In one implementation, androgen receptor activity-related diseases or conditions are selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, hyperspermia, and androgenetic alopecia.

[0149] The present invention will be further illustrated by specific embodiments below. Unless otherwise stated, the instruments, equipment, and materials used in the following embodiments can be obtained through conventional commercial means.

[0150] Sources of Formula I compounds in the embodiments of the present invention

[0151] According to the contents disclosed in paragraphs

[0425] to

[0427] on page 50 of the specification of CN 102757389 B, the title compound, which is basically in a gel-like or viscous state, was prepared. After dissolving the title compound with DMSO, water was added dropwise to precipitate the solid. The filter cake was collected by filtration and dried under reduced pressure at 40-50°C to obtain the solid form of compound I.

[0152] X-ray powder diffraction (XRPD)

[0153] XRPD spectra were acquired using a PANalytacal Empyrean X-ray powder diffractometer, and the test parameters are shown in Table 1.

[0154] Table 1. XRPD Parameters

[0155]

[0156] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0157] TGA and DSC spectra were acquired on a TAQ500 / 5000 thermogravimetric analyzer and a TAQ200 / 2000 differential scanning calorimeter, respectively. The test parameters are shown in Table 2.

[0158] Table 2. TGA and DSC parameters

[0159] parameter TGA DSC method linear heating linear heating Sample tray Platinum plate, open Aluminum disc, pressure cap Temperature range Room temperature - Set endpoint temperature 25℃ - Set the final temperature Scan rate (°C / min) 10 10 Protective gas Nitrogen Nitrogen

[0160] Dynamic moisture adsorption (DVS)

[0161] DVS curves were collected using a DVS Intrinsic dynamic moisture adsorption analyzer manufactured by SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected for using the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are shown in Table 3.

[0162] Table 3. DVS Parameters

[0163]

[0164] High-performance liquid chromatography (HPLC)

[0165] The high-performance liquid chromatography (HPLC) results were acquired using an Agilent HPLC analyzer, and the test parameters are shown in Table 4.

[0166] Table 4. HPLC parameters

[0167]

[0168] Example 1: Preparation of anhydrous polymorphs with crystal form D

[0169] Method 1: Suspension and stirring method

[0170] Specific procedures: Different solvents were used to set up different suspension stirring experiments. Approximately 150 mg of compound I was placed in a 15 mL reaction flask, 5 mL of solvent was added, and the prepared suspension was stirred at room temperature (20 °C) for 2 days. The solid was then collected and XRPD was performed.

[0171] The results showed that at room temperature (approximately 20°C), the following substances were present in water, methanol, ethanol, isopropanol, methyl isobutyl ketone, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, and tetrahydrofuran / water (V... THF / V H2O =1:2), 1,4-dioxane / toluene (V diox / V tol =1 / 4), Acetonitrile / water (V ACN / V H2O =1 / 2), dimethyl sulfoxide / water (V DMSO / V H2O =1 / 1), N,N-dimethylacetamide / water (V DMAc / V H2O =1 / 1), Ethyl acetate / n-heptane (V EtOAc / V n-hept =1 / 9), chloroform / n-heptane (V TCM / V n-hept =1 / 4) or toluene / n-heptane (V tol / V n-hept Under the condition that =1 / 4) is used as a solvent, anhydrous polymorphs with crystal form D can be obtained.

[0172] This invention further verifies the products obtained by suspension stirring at ambient temperatures of 5°C and 50°C.

[0173] The results showed that at 5 °C, the following substances were used: ethanol, methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, toluene, or dichloromethane / n-heptane (V... DCM / V n-hept Under conditions where isopropanol and acetone / water (V = 1 / 3) are used as solvents, anhydrous polymorphs with crystal form D can be obtained; at 50°C, in the presence of isopropanol, acetone / water (V = 1 / 3) as solvents, anhydrous polymorphs with crystal form D can be obtained; ACTN / V H2O =1 / 3), isopropyl acetate, methyl tert-butyl ether or N-methyl-2-pyrrolidone / water (V NMP / V H2O Under the condition that =1 / 1) is used as a solvent, anhydrous polymorphs with crystal form D can be obtained.

[0174] XRPD spectra and detailed data of anhydrous polymorphs with crystal form D are as follows: Figure 1 As shown in Table 5.

[0175] Table 5. XRPD spectral data corresponding to crystal form D

[0176]

[0177] The TGA / DSC spectra of anhydrous polymorphs with crystal form D are shown below. Figure 2 As shown. By Figure 2It can be seen that when heated to approximately 150℃, the sample loses about 1.60% of its weight, and there is a sharp melting endothermic peak at approximately 164.0℃ (the initial temperature) (melting point approximately 166.9℃). Based on the above data, it can be concluded that the polymorph with crystal form D is an anhydrous polymorph.

[0178] Method 2: Slow evaporation method

[0179] Specific procedures: Different solvents were used to set up different slow evaporation experiments. Approximately 1g of compound I was placed in a reaction flask, and then 50mL of solvent was added. After stirring, the mixture was filtered, and the supernatant was collected and placed in a vial. The vial was sealed with a sealing film (e.g., Parafilm), and 3-4 small holes were punched in the sealing film (e.g., using a syringe needle). The vial was left to evaporate slowly at room temperature. After the solvent had completely evaporated, the solid was collected and XRPD was performed.

[0180] It was determined that anhydrous polymorphs with crystal form D can be obtained under conditions where acetonitrile or dichloromethane is used as a solvent.

[0181] Method 3: Gas-solid diffusion method

[0182] Specific procedures: Different solvents were used to set up different gas-solid diffusion experiments. Approximately 10 mg of compound I was placed in a 3 mL vial, and approximately 2 mL of solvent was added to a 20 mL vial. The 3 mL vial was placed open inside the 20 mL vial, and then the 20 mL vial was sealed. After standing at room temperature for 7 days, the solid was collected and XRPD was performed.

[0183] It was determined that anhydrous polymorphs with crystal form D could be obtained under conditions where methanol or methyl tert-butyl ether was used as a solvent.

[0184] Method 4: Gas-liquid diffusion method

[0185] Specific procedure: Dissolve approximately 10 mg of compound I in 1.0–2.0 mL of acetonitrile (as a good solvent), filter to obtain the supernatant, and transfer it to a 3.0 mL vial. Separately, take a 20 mL vial and add approximately 3 mL of water (as a reverse solvent). Place the 3 mL vial containing the supernatant open inside the 20 mL vial, then seal the 20 mL vial and allow it to stand at room temperature. When solid precipitation is observed, separate the solid and perform XRPD testing.

[0186] After identification, an anhydrous polymorph with crystal form D was obtained.

[0187] Method 5: Polymer-induced method

[0188] Specific procedure: Weigh about 10 mg of compound I, dissolve it in acetonitrile (as a good solvent), then add about 2 mg of polymer (an equal mass mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose), seal the vial with sealing film, make 3-4 small holes in it, allow it to evaporate at room temperature, collect the solid, and perform XRPD testing.

[0189] After identification, an anhydrous polymorph with crystal form D was obtained.

[0190] Method 6: Grinding method

[0191] Specific procedure: Weigh about 15-20 mg of compound I and add it to a mortar. Add about 100 μL of water as a solvent or do not add a solvent. Grind manually for 5-10 minutes, collect the ground solid, and perform XRPD testing.

[0192] After identification, an anhydrous polymorph with crystal form D was obtained.

[0193] Example 2: Preparation of anhydrous polymorphs with crystalline form C

[0194] Method 1: Antisolvent addition method

[0195] Specific procedures: Different combinations of good solvents / antisolvents were used to set up different antisolvent addition experiments. Approximately 10 mg of compound I was placed in a 20.0 mL vial and dissolved in 0.2-1.0 mL of good solvent. While stirring, the antisolvent was added dropwise to the clear solution. When a solid precipitated, the addition was stopped. The precipitated solid was separated by centrifugation and XRPD test was performed.

[0196] The results show that anhydrous polymorphs with crystal form C can be obtained under the conditions of using methyl isobutyl ketone / n-heptane, ethyl acetate / n-heptane, 1,4-dioxane / n-heptane, dichloromethane / n-heptane, toluene / n-heptane, isopropyl acetate / methyl tert-butyl ether, N-methyl-2-pyrrolidone / methyl tert-butyl ether, 2-methyltetrahydrofuran / methyl tert-butyl ether, or chloroform / methyl tert-butyl ether as good solvent / antisolvent combinations.

[0197] XRPD spectra and detailed data of anhydrous polymorphs with crystalline form C are as follows: Figure 6 As shown in Table 6.

[0198] Table 6. XRPD spectral data corresponding to crystal form C

[0199]

[0200] TGA / DSC spectra of anhydrous polymorphs with crystalline form C are shown below. Figure 7 As shown. By Figure 7It can be seen that when heated to approximately 150.0℃, the sample loses about 1.60% of its weight, and there are multiple endothermic / exothermic signal peaks before thermal decomposition. Based on the above data, the polymorph with crystal form C is an anhydrous polymorph.

[0201] Method 2: Slow evaporation method

[0202] Follow the corresponding method for crystal form D.

[0203] Identification revealed that the substance was resistant to methanol, acetone, ethyl acetate, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethanol / chloroform (V). EtOH / V TCM =1:1) or tetrahydrofuran / isopropyl acetate (V THF / V IPAc Under the condition of using a solvent of 1:1, anhydrous polymorphs with crystal form C can be obtained.

[0204] Method 3: Slow cooling method

[0205] Specific procedures: Different solvents were used to set up different slow cooling experiments. Approximately 15 mg of compound I was placed in a 3 mL vial, 1.0 mL of solvent was added, and the mixture was stirred at 50 °C for about 2 hours. The mixture was then filtered, and the supernatant was placed in a biological incubator that was slowly cooled from 50 °C (e.g., at a rate of 0.1 °C / min) to 5 °C and maintained at 5 °C. The precipitated solid was collected and XRPD was performed.

[0206] Identification revealed that the substance was present in ethanol, methyl tert-butyl ether, and toluene / isopropanol (V... tol / V IPA =1 / 9) or isopropyl acetate / n-heptane (V IPAc / V n-hept Under the condition that 1 / 4) is used as a solvent, anhydrous polymorphs with crystal form C can be obtained.

[0207] Method 4: Gas-solid diffusion method

[0208] Follow the corresponding method for crystal form D.

[0209] It was determined that anhydrous polymorphs with crystal form C could be obtained under the conditions of using acetone, tetrahydrofuran, 1,4-dioxane, or acetic acid as solvents.

[0210] Method 5: Gas-liquid diffusion method

[0211] Follow the corresponding method for crystal form D.

[0212] It was determined that anhydrous polymorphs with crystal form C can be obtained under the conditions of using methanol / water, methyl isobutyl ketone / water, tetrahydrofuran / water, isopropyl acetate / n-heptane, 2-methyltetrahydrofuran / n-heptane, chloroform / n-heptane, toluene / n-heptane, ethanol / isopropanol, acetone / isopropanol, 1,4-dioxane / isopropanol, or dimethyl sulfoxide / isopropanol as good solvent / antisolvent combinations.

[0213] Method 6: Polymer-induced method

[0214] Follow the corresponding method for crystal form D.

[0215] Identification revealed that an anhydrous polymorph with crystal form C could be obtained when using an equal mass mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose as the polymer, and methanol, acetone, ethyl acetate, 1,4-dioxane, or dichloromethane as a good solvent. Furthermore, an anhydrous polymorph with crystal form C could also be obtained when using an equal mass mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose as the polymer, and ethanol, methyl isobutyl ketone, isopropyl acetate, or 2-methyltetrahydrofuran as a good solvent.

[0216] Example 3: Preparation of anhydrous polymorphs with crystal form B

[0217] Method 1: Antisolvent addition method

[0218] Follow the corresponding method for crystal form C.

[0219] It was determined that anhydrous polymorphs with crystal form B could be obtained under conditions where acetone / water, N,N-dimethylacetamide / water, or dimethyl sulfoxide / water were used as good solvent / antisolvent combinations.

[0220] XRPD spectra and detailed data of anhydrous polymorphs with crystal form B are as follows: Figure 8 As shown in Table 7.

[0221] Table 7. XRPD spectral data corresponding to crystal form B

[0222] Serial Number 2θ(°) Relative strength (%) Serial Number 2θ(°) Relative strength (%) 1 7.3 24.9 10 22.7 4.8 2 9.9 31.9 11 24.0 15.6 3 12.5 100.0 12 25.2 14.6 4 13.1 19.9 13 26.7 21.1 5 16.5 35.0 14 27.8 6.1 6 17.1 41.0 15 28.6 6.2 7 18.2 4.0 16 29.5 8.4 8 20.3 18.8 17 31.3 6.0 9 21.3 11.1 18 37.5 4.8

[0223] The TGA / DSC spectra of the anhydrous polymorph with crystal form B are as follows: Figure 9 As shown. By Figure 9 It can be seen that when heated to approximately 150.0℃, the sample loses about 1.52% of its weight, and there is a sharp melting endothermic peak at approximately 175.4℃ (initial temperature) (melting point approximately 176.9℃). Based on the above data, it can be concluded that the polymorph with crystal form B is an anhydrous polymorph.

[0224] It is worth noting that the preliminary crystal form screening process employed various solid-phase transformation and solution crystallization screening methods, including the antisolvent addition method (combinations of methanol, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylacetamide or dimethyl sulfoxide (good solvent) and water (antisolvent); methyl isobutyl ketone, ethyl acetate, 1,4-dioxane, dichloromethane or toluene (good solvent) and n-heptane (antisolvent); and combinations of isopropyl acetate, N-methyl-2-pyrrolidone, 2-methyltetrahydrofuran or chloroform (good solvent) and methyl tert-butyl ether (antisolvent)), slow evaporation method, slow cooling method, suspension stirring method (5℃ / room temperature / 50℃), gas-solid permeation method, gas-liquid permeation method, polymer-induced method, and grinding method. The results showed that only through the antisolvent addition method, and under the condition of acetone / water, N,N-dimethylacetamide / water, or dimethyl sulfoxide / water as good solvent / antisolvent combinations, could anhydrous polymorphs with crystal form B be formed.

[0225] Example 4: Preparation of anhydrous polymorphs with crystal form A

[0226] Follow the corresponding methods for crystal form C or B.

[0227] It was determined that an anhydrous polymorph with crystal form A can be obtained under the condition that methanol / water is used as a good solvent / antisolvent combination.

[0228] XRPD spectra and detailed data of anhydrous polymorphs with crystal form A are as follows: Figure 10 As shown in Table 8.

[0229] Table 8. XRPD spectral data corresponding to crystal form A

[0230]

[0231] The TGA / DSC spectra of the anhydrous polymorph with crystal form A are as follows: Figure 11 As shown. By Figure 11 It can be seen that when heated to approximately 150.0℃, the sample loses about 1.01% of its weight, and there is an endothermic / exothermic peak before melting at approximately 177.6℃ (peak temperature). Based on the above data, it can be concluded that the polymorph with crystal form A is an anhydrous polymorph.

[0232] It is worth noting that the preliminary crystal form screening process employed various solid-phase transformation and solution crystallization screening methods, including the antisolvent addition method (combinations of methanol, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylacetamide or dimethyl sulfoxide (good solvent) and water (antisolvent); methyl isobutyl ketone, ethyl acetate, 1,4-dioxane, dichloromethane or toluene (good solvent) and n-heptane (antisolvent); and combinations of isopropyl acetate, N-methyl-2-pyrrolidone, 2-methyltetrahydrofuran or chloroform (good solvent) and methyl tert-butyl ether (antisolvent)), slow evaporation method, slow cooling method, suspension stirring method (5℃ / room temperature / 50℃), gas-solid permeation method, gas-liquid permeation method, polymer-induced method, and grinding method. The results showed that only through the antisolvent addition method, and under the condition of methanol / water as the good solvent / antisolvent combination, could anhydrous polymorphs with crystal form A be formed.

[0233] Experimental Example 1: Thermodynamic Transformation Relationships Between Polymorphs

[0234] To investigate the thermodynamic transformation relationships of four anhydrous polymorphs (corresponding to crystal forms A / B / C / D, respectively), samples with crystal forms A / B / C / D (approximately 5 mg each) were mixed and then added to a saturated solution (e.g., ethanol or methyl tert-butyl ether) (~1.0 mL) of compound of formula I under the conditions of 5 °C / room temperature (~20 °C) / 50 °C / 90 °C, respectively. The mixture was then stirred (magnetically stirred, ~800 rpm), separated (centrifuged, ~10000 rpm, 1 min), and XRPD was performed.

[0235] The test results show that under conditions of 50℃ / 90℃, the mixed crystal form transforms into a single crystal form D after approximately 4 hours; while under conditions of 5℃ / room temperature (~20℃), the mixed crystal form transforms into a single crystal form D after approximately 36 hours. The XRPD detection spectra are shown below. Figure 12 and 13 As shown in the figure. The experimental results show that crystal forms A / B / C can all be transformed into crystal form D by suspension and stirring at temperatures below 90°C. In other words, at room temperature, crystal form D is more stable than crystal forms A / B / C and is more suitable as a potential pharmaceutical crystal form.

[0236] Furthermore, heat treatment experiments under nitrogen protection revealed that heating crystal form A to approximately 160°C and then cooling to room temperature transforms it into crystal form B; while heating crystal form C to approximately 148°C transforms it into crystal form B / D, and further heating to approximately 166°C and then cooling to room temperature completely transforms it into crystal form B. In other words, under heating conditions, crystal form B is more stable than crystal form A / C. Simultaneously, the above-mentioned crystal transformation phenomenon can also be observed through… Figure 7 and Figure 11 The endothermic / exothermic peaks that appeared in the sample were confirmed.

[0237] Experimental Example 2: Evaluation of the hygroscopicity of anhydrous polymorphs with crystal form D

[0238] Under constant temperature conditions of 25℃, when the relative humidity increased from 0%RH to 80%RH, the crystal form D sample absorbed 0.14wt% water (e.g., Figure 3 As shown in the figure, this indicates that the crystal form D sample has almost no hygroscopicity.

[0239] In addition, XRPD tests were performed on crystal form D samples before and after the DVS experiment. The results showed that the crystal form of crystal form D samples remained consistent before and after the DVS test (e.g., Figure 4 As shown in the figure, this indicates that the crystal form D sample not only does not have hygroscopic properties under high humidity conditions, but also does not undergo crystal transformation.

[0240] Experimental Example 3: Solid-state stability assessment of anhydrous polymorphs with crystal form D

[0241] To assess the solid-state stability of crystal form D, appropriate amounts of crystal form D sample (approximately 10 mg) were weighed and left to stand open at 25°C / 60% RH and 40°C / 75% RH, respectively. Another portion of crystal form D sample was sealed and stored at 5°C as an evaluation control. After one week, the samples were retrieved and characterized using XRPD and HPLC, respectively, to detect changes in crystal form and purity.

[0242] XRPD spectra showed that the crystal form of sample D remained unchanged after being placed under the corresponding conditions for one week (e.g., Figure 5 (As shown in Table 9). Meanwhile, HPLC results showed that the purity of the crystal form D sample remained unchanged. Therefore, the anhydrous polymorph of crystal form D of the present invention exhibits good physical and chemical stability.

[0243] Table 9. Stability test results of crystal form D (purity was determined by HPLC)

[0244] Storage conditions Solid crystal form after one week Purity (peak area %) Relative purity (%) / control sample 25℃ / 60%RH, open Crystal form D 99.9 100.0 40℃ / 75%RH, open Crystal form D 99.9 100.0 5℃, sealed (control) Crystal form D 99.9 --

[0245] Experimental Example 4: Pharmacokinetic Study

[0246] The applicant administered crystal form D as the test drug to male and female Sprague-Dawley rats (SD rats) via skin application at a dose of 12 mg / kg, once daily for 7 consecutive days. The obtained plasma drug concentration data were simultaneously analyzed using the WinNonlin v5.2 non-compartmental model to calculate relevant pharmacokinetic parameters and perform plasma pharmacokinetic characterization.

[0247] The experimental results showed that, at a dose of 12 mg / kg, after repeated administration for 7 consecutive days, the ratios of the drug's AUC(0-t) on day 7 to that on day 1 in male and female SD rats were 1.30 and 0.942, respectively, and no obvious accumulation was observed in either male or female SD rats.

Claims

1. An anhydrous polymorph of a compound of Formula I, ， said anhydrous polymorph having a crystalline Form D, the XRPD pattern of said crystalline Form D comprising peaks at 5.3 ± 0.2°, 10.7 ± 0.2°, 13.5 ± 0.2°, 15.1 ± 0.2° and 21.3 ± 0.2° in terms of 2Q.

2. The anhydrous polymorph according to claim 1, characterized in that, the XRPD pattern of said crystalline Form D further comprising peaks at 12.0 ± 0.2°, 12.7 ± 0.2°, 14.8 ± 0.2°, 16.4 ± 0.2°, 17.3 ± 0.2°, 20.3 ± 0.2°, 24.2 ± 0.2° and 24.8 ± 0.2° in terms of 2Q.

3. The anhydrous polymorph of claim 1 or 2, characterized by, the XRPD pattern of said crystalline Form D further comprising peaks at 19.7 ± 0.2°, 22.5 ± 0.2°, 23.1 ± 0.2°, 27.3 ± 0.2°, 28.5 ± 0.2°, 29.7 ± 0.2° and 32.3 ± 0.2° in terms of 2Q.

4. The anhydrous polymorph of claim 1 or 2, characterized by, the XRPD pattern of said crystalline Form D is substantially in accordance with Figure 1.

5. The anhydrous polymorph of claim 1 or 2, characterized by, the DSC pattern of said crystalline Form D is substantially in accordance with Figure 2.

6. A pharmaceutical composition comprising the anhydrous polymorph according to any one of claims 1-5 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 6, wherein, said pharmaceutical composition further comprising a second functional component.

8. The pharmaceutical composition of claim 7, wherein, said second functional component is selected from any one or more of minoxidil, deuterated ruxolitinib (CTP-543), botulinum toxin, clascoterone (CB-03-01), finasteride and latanoprost.

9. Use of the anhydrous polymorph according to any one of claims 1-5 or of the pharmaceutical composition according to claim 6 or 7 or 8 for the manufacture of a medicament for the prevention, alleviation and / or treatment of a disease or disorder associated with androgen receptor activity.

10. The use according to claim 9, wherein the disease or disorder associated with androgen receptor activity is selected from prostate cancer, benign prostatic hyperplasia, acne, hirsutism, seborrhea and male pattern baldness.

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