Pharmaceutically acceptable acid salts of glp1r agonist free base and process for the preparation thereof

Abstract

To provide a pharmaceutical composition for use in the manufacture of a medicament for treating obesity.SOLUTION: A pharmaceutical composition comprising a crystalline hydrochloride form (Form B) of (S) -2 - (3S, 8S) - 3 - (4 - (3, 4-dichlorobenzyloxy) phenyl-7 - ((S) - 1-phenylpropyl) - 236789 - hexahydro - [1,4] - dioxino [2, 3-g] isoquinolin-8-ylformylamino) - 3 - (4 - (2, 3-dimethylpyridin-4-yl) phenyl) propionate ("OAD2") and a pharmaceutically acceptable carrier, the crystalline hydrochloride form is characterized as having an X-ray powder diffraction pattern (XRPD) comprising peaks at the following diffraction angles (2 θ) measured using Cu, K α radiation: 5.3 ± 0.2 °, 9.2 ± 0.2 °, 10.3 ± 0.2 °, 13.2 ± 0.2 °, and 14.8 ± 0.2 °.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention is in the field of medicine, and in particular relates to pharmaceutically acceptable acid salts of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid ("OAD2"), and methods for preparing the same. The pharmaceutically acceptable acid salts of the present invention may be useful in the treatment of various diseases and metabolic disorders, including, but not limited to, type 2 diabetes. [Background technology]

[0002] (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid dihydrochloride (referred to herein as OAD2 dihydrochloride) is an orally available, non-peptide glucagon-like peptide 1 receptor (GLP-1R) agonist. OAD2 dihydrochloride has the empirical formula C 50 H 49 C l4 N3O6, molecular weight 929.76, and has the following chemical structure:

[0003] [ka]

[0004] In addition to the patent CN102378574B which discloses OAD2 dihydrochloride and its free base, other acid salts of OAD2 or their crystalline forms have not been systematically studied. Therefore, it is desirable to further screen for pharmaceutically acceptable acid salts of OAD2 and their crystalline forms. Summary of the Invention

[0005] An object of the present invention is to provide a pharmaceutically acceptable acid salt of OAD2, (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid, and a method for preparing the same.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] The present invention provides a pharmaceutically acceptable acid salt of OAD2. In certain embodiments, the pharmaceutically acceptable acid salt of OAD2 may be crystalline. In another embodiment, the pharmaceutically acceptable salt of OAD2 is anhydrous, hydrated, or solvated. The present invention further provides a method for making a pharmaceutically acceptable acid salt of OAD2.

[0008] According to the present invention, crystalline acid salts of OAD2 include crystalline form B of the hydrochloride salt, crystalline form C of the hydrochloride salt, crystalline form C of the p-toluenesulfonate salt, crystalline form C of the tartrate salt, crystalline form C of the citrate salt, crystalline form C of the glycolate salt, crystalline form C of the methanesulfonate salt, crystalline form C of the hydrobromide salt, crystalline form D of the hydrobromide salt, and crystalline form C of the sulfate salt.

[0009] The present invention further provides pharmaceutical compositions comprising one or more pharmaceutically acceptable acid salt forms of OAD2. The present invention further provides methods of making pharmaceutical compositions comprising one or more pharmaceutically acceptable acid salt forms of OAD2.

[0010] The present invention further provides the use of a pharmaceutically acceptable acid salt of OAD2 for the preparation of a GLP-1 receptor agonist.

[0011] The present invention further provides the use of a pharmaceutically acceptable acid salt of OAD2 for the preparation of a medicament, hi one embodiment, the medicament may be for treating diabetes.

[0012] The present invention further provides a method of treatment comprising administering to a human in need thereof a therapeutically effective amount of a pharmaceutically acceptable acid salt of OAD2, which may be useful in treating a disease or disorder in which activation of the GLP1 receptor is beneficial.

[0013] These and other embodiments of the present invention are described in further detail in the detailed description of the invention that follows.

[0014] Pharmaceutically acceptable acid salts of OAD2 may achieve the following beneficial effects: Compared to OAD2 dihydrochloride, the pharmaceutically acceptable acid salts of OAD2 disclosed herein may have improved hygroscopicity. For example, but not limited to, crystalline form B of the hydrochloride salt, crystalline form C of the p-toluenesulfonate salt, and crystalline form C of the sulfate salt exhibit superior stability compared to OAD2 dihydrochloride. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the XRPD of crystalline form B of the hydrochloride salt. [Figure 2] FIG. 1 shows an XRPD of crystalline form C of the hydrochloride salt. [Figure 3] FIG. 1 shows an XRPD of crystalline form C of the p-toluenesulfonic acid salt. [Figure 4] FIG. 1 shows an XRPD of crystalline form C of the tartrate salt. [Figure 5] FIG. 1 shows an XRPD of crystalline form C of the Citrate Salt. [Figure 6] FIG. 1 shows an XRPD of crystalline form C of the glycolate salt. [Figure 7] FIG. 1 shows an XRPD of crystalline form C of the methanesulfonate salt. [Figure 8] FIG. 1 shows an XRPD of crystalline form C of the hydrobromide salt. [Figure 9] FIG. 1 shows an XRPD of crystalline form D of the hydrobromide salt. [Figure 10] FIG. 1 shows an XRPD of crystalline form C of the Sulfate Salt. [Figure 11] FIG. 1 shows the TGA thermogram of crystalline form B of the hydrochloride salt. [Figure 12] FIG. 1 shows a DSC thermogram of crystalline form B of the hydrochloride salt. [Figure 13] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the hydrochloride salt. [Figure 14] FIG. 1 shows a TGA / DSC thermogram of crystalline form C of the p-toluenesulfonic acid salt. [Figure 15] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the Tartrate Salt Salt. [Figure 16] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the Citrate Salt. [Figure 17] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the glycolate salt. [Figure 18] FIG. 1 shows a TGA / DSC thermogram of crystalline form C of the methanesulfonate salt. [Figure 19] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the hydrobromide salt. [Figure 20] FIG. 1 shows the TGA / DSC thermogram of crystalline form D of the hydrobromide salt. [Figure 21] FIG. 1 shows the TGA / DSC thermogram of crystalline form C of the Sulfate Salt. [Figure 22] FIG. 1 shows the H-NMR spectrum of crystalline form C of p-toluenesulfonic acid salt. [Figure 23] FIG. 1 shows the H-NMR spectrum of crystalline form C of the tartrate salt. [Figure 24] FIG. 1 shows the H-NMR spectrum of crystalline form C of the Citrate Salt. [Figure 25] FIG. 1 shows the H-NMR spectrum of crystalline form C of the glycolate salt. [Figure 26]FIG. 1 shows the H-NMR spectrum of crystalline form C of the methanesulfonate salt. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is further illustrated by the following specific examples. The following examples are used to explain the method of the present invention and its core concept, and any conceivable changes or substitutions that do not deviate from the concept of the present invention for those skilled in the art fall within the protection scope of the present invention. In the following examples, if no specific conditions of the experimental methods are specified, they are generally conventional conditions or those recommended by raw material or product manufacturers, and solvents without specified sources are generally commercially available conventional solvents.

[0017] In the present invention, "crystals" or "crystalline forms" are identified by characterization of the X-ray powder diffraction patterns shown. Those skilled in the art will understand that the experimental error of the characterization data generally depends on the condition of the instrument, the preparation and purity of the sample, etc. Specifically, those skilled in the art are well aware that X-ray powder diffraction patterns typically vary with changes in experimental conditions, and therefore peak intensity itself cannot be identified as the sole or decisive factor. Experimental errors for peak angles are typically within 5% or less, and peak angle data typically allow for an error of ±0.2. In addition, the peak angles may vary overall due to experimental factors such as the height of the sample, and therefore, some degree of variation is usually acceptable. Those skilled in the art will understand that any crystalline form having characteristic peaks identical or similar to those shown in the X-ray powder diffraction patterns of the present invention falls within the scope of protection of the present invention. As illustrated in the DSC thermograms above, the melting point values ​​should be interpreted as values ​​within the range of ±3.0°C, and preferably within the range of ±1.0°C.

[0018] The term "therapeutically effective amount" is used herein to denote the amount of a pharmaceutically acceptable acid salt of OAD2 that elicits a desired therapeutic response in a subject. In one embodiment, the therapeutic response may be agonizing the GLP-1 receptor.

[0019] OAD2 as a free base may be obtained by the methods described in Chinese Patent Publication No. 102378574 or related WO 2010 / 114824, the entire contents of which are incorporated herein by reference.

[0020] Pharmaceutically acceptable salts of OAD2 The present invention provides pharmaceutically acceptable acid salts of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid ("OAD2").

[0021] In one embodiment, the invention is a pharmaceutically acceptable acid salt formed between an OAD2 and a pharmaceutically acceptable acid, in one embodiment, the pharmaceutically acceptable acid is selected from the group consisting of 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, transcinnamic acid, citric acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, L-lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, p-toluenesulfonic acid, vanillic acid, and vanillin. In one embodiment, the pharmaceutically acceptable acid is selected from the group consisting of hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid, tartaric acid, citric acid, glycolic acid, methanesulfonic acid, and sulfonic acid.

[0022] In certain embodiments, the pharmaceutically acceptable acid salt of OAD2 may be crystalline, hi another embodiment, the pharmaceutically acceptable acid salt of OAD2 is anhydrous, hydrated, or solvated.

[0023] According to the present invention, crystalline acid salts of OAD2 include crystalline form B of the hydrochloride salt, crystalline form C of the hydrochloride salt, crystalline form C of the p-toluenesulfonate salt, crystalline form C of the tartrate salt, crystalline form C of the citrate salt, crystalline form C of the glycolate salt, crystalline form C of the methanesulfonate salt, crystalline form C of the hydrobromide acid form, crystalline form D of the hydrobromide acid form, and crystalline form C of the sulfate salt.

[0024] In a specific embodiment, the salt formation ratio (molecular ratio) of the above-mentioned crystalline acid salt of OAD2 is in the range of acid:free base = 0.3:1 to 1:1, but is not limited to this range because the salt formation ratio (molecular ratio) is related to the amount of acid.

[0025] Hydrochloride In a particular embodiment, the present invention provides crystalline form B of the hydrochloride salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.3±0.2°, 9.2±0.2°, 10.3±0.2°, 13.2±0.2°, and 14.8±0.2°, preferably the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG. 1, and the X-ray powder diffraction data is as shown in Table 1.

[0026] In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is 1 In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is characterized by endothermic peaks at 116°C and / or 193°C as determined by DSC. In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is characterized by a DSC profile as shown in Figure 12. In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is characterized by a TGA profile as shown in Figure 11. In another embodiment, crystalline form B of the hydrochloride salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 5.3±0.2°, 9.2±0.2°, 10.3±0.2°, 13.2±0.2°, and 14.8±0.2°; ii) a DSC profile as shown in Figure 12, or iii) TGA profile as shown in Figure 11 are characterized by at least two of the following:

[0027] In a particular embodiment, the present invention provides crystalline form C of the hydrochloride salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.9±0.2°, 11.6±0.2°, 14.3±0.2°, 15.9±0.2°, 21.4±0.2°, and 23.1±0.2°, preferably, the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG. 2, and the X-ray powder diffraction data is as shown in Table 1.

[0028] In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is 1 In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is characterized by endothermic peaks at 120.4°C and / or 177.6°C as determined by DSC. In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is characterized by a DSC profile as shown in Figure 13. In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is characterized by a TGA profile as shown in Figure 13. In another embodiment, crystalline form C of the hydrochloride salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 8.9±0.2°, 11.6±0.2°, 14.3±0.2°, 15.9±0.2°, 21.4±0.2°, and 23.1±0.2°; ii) a DSC profile as shown in Figure 13, or iii) TGA profile as shown in Figure 13 are characterized by at least two of the following:

[0029] p-Toluenesulfonate In a particular embodiment, the present invention provides crystalline Form C of p-toluenesulfonate salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 5.4±0.2°, 9.7±0.2°, 13.1±0.2°, 16.4±0.2°, and 18.2±0.2°, preferably, the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 3, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline Form C of p-toluenesulfonate salt of OAD2 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 5.4±0.2°, 9.7±0.2°, 13.1±0.2°, 16.4±0.2°, and 18.2±0.2°, preferably, the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 3, and the X-ray powder diffraction data is as shown in Table 1. 1 In another embodiment, crystalline form C of the p-toluenesulfonate salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form C of the p-toluenesulfonate salt of OAD2 is characterized by endothermic peaks at 100.4°C and / or 167.7°C as determined by DSC. In another embodiment, crystalline form C of the p-toluenesulfonate salt of OAD2 is characterized by a DSC profile as shown in Figure 14. In another embodiment, crystalline form C of the p-toluenesulfonate salt of OAD2 is characterized by a TGA profile as shown in Figure 14. In another embodiment, crystalline form C of the p-toluenesulfonate salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 5.4±0.2°, 9.7±0.2°, 13.1±0.2°, 16.4±0.2°, and 18.2±0.2°; ii) a DSC profile as shown in Figure 14; iii) a TGA profile as shown in Figure 14, or iv) Substantially similar to FIG. 22 1 H NMR are characterized by at least two of the following:

[0030] tartrate In a particular embodiment, the present invention provides crystalline Form C of the tartrate salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.8±0.2°, 9.9±0.2°, 10.1±0.2°, and 15.6±0.2°, preferably the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 4, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline Form C of the tartrate salt of OAD2 has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.8±0.2°, 9.9±0.2°, 10.1±0.2°, and 15.6±0.2°, preferably the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 4, and the X-ray powder diffraction data is as shown in Table 1. 1 In another embodiment, crystalline form C of the tartrate salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form C of the tartrate salt of OAD2 is characterized by an endothermic peak at 170.3°C as determined by DSC. In another embodiment, crystalline form C of the tartrate salt of OAD2 is characterized by a DSC profile as shown in Figure 15. In another embodiment, crystalline form C of the tartrate salt of OAD2 is characterized by a TGA profile as shown in Figure 15. In another embodiment, crystalline form C of the tartrate salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 7.8±0.2°, 9.9±0.2°, 10.1±0.2°, and 15.6±0.2°; ii) a DSC profile as shown in Figure 15; iii) TGA profile as shown in Figure 15; iv) Substantially similar to 23 1 H NMR are characterized by at least two of the following:

[0031] Citrate In a particular embodiment, the present invention provides crystalline Form C of the citrate salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.5±0.2°, 6.5±0.2°, and 15.9±0.2°, preferably the X-ray powder diffraction pattern comprising substantially the same peaks at 2θ diffraction angles as shown in Figure 5, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline Form C of the citrate salt of OAD2 has an X-ray powder diffraction pattern as shown in Figure 24. 1In another embodiment, crystalline form C of the citrate salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form C of the citrate salt of OAD2 is characterized by endothermic peaks at 122.4°C and / or 176.2°C as determined by DSC. In another embodiment, crystalline form C of the citrate salt of OAD2 is characterized by a DSC profile as shown in Figure 16. In another embodiment, crystalline form C of the citrate salt of OAD2 is characterized by a TGA profile as shown in Figure 16. In another embodiment, crystalline form C of the citrate salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 4.5±0.2°, 6.5±0.2°, and 15.9±0.2°; ii) a DSC profile as shown in Figure 16; iii) a TGA profile as shown in Figure 16, or iv) Substantially similar to 24 1 H NMR are characterized by at least two of the following:

[0032] glycolate In a particular embodiment, the present invention provides crystalline Form C of the glycolic acid salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.0±0.2°, 12.1±0.2°, 13.6±0.2°, 18.2±0.2°, and 24.3±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 6, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline Form C of the glycolic acid salt of OAD2 has an X-ray powder diffraction pattern as shown in Figure 25. 11H NMR spectrum. In another embodiment, crystalline form C of the glycolic acid salt of OAD2 is characterized by endothermic peaks at 156.8°C and / or 173.8°C as determined by DSC. In another embodiment, crystalline form C of the glycolic acid salt of OAD2 is characterized by a DSC profile as shown in Figure 17. In another embodiment, crystalline form C of the glycolic acid salt of OAD2 is characterized by a TGA profile as shown in Figure 17. In another embodiment, crystalline form C of the glycolic acid salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 6.0±0.2°, 12.1±0.2°, 13.6±0.2°, 18.2±0.2° and 24.3±0.2°; ii) a DSC profile as shown in Figure 17; iii) a TGA profile as shown in Figure 17, or iv) Substantially similar to 25 1 H NMR are characterized by at least two of the following:

[0033] Methanesulfonate In a particular embodiment, the present invention provides crystalline Form C of a methanesulfonate salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.2±0.2°, 12.8±0.2°, 13.8±0.2°, 14.4±0.2°, and 22.2±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 7, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline Form C of a methanesulfonate salt of OAD2 has an X-ray powder diffraction pattern as shown in Figure 26. 11H NMR spectrum. In another embodiment, crystalline form C of the methanesulfonate salt of OAD2 is characterized by endothermic peaks at 108.0, 164.1, and / or 224.7°C as determined by DSC. In another embodiment, crystalline form C of the methanesulfonate salt of OAD2 is characterized by a DSC profile as shown in Figure 18. In another embodiment, crystalline form C of the methanesulfonate salt of OAD2 is characterized by a TGA profile as shown in Figure 18. In another embodiment, crystalline form C of the methanesulfonate salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 10.2±0.2°, 12.8±0.2°, 13.8±0.2°, 14.4±0.2° and 22.2±0.2°; ii) a DSC profile as shown in Figure 18; iii) a TGA profile as shown in Figure 18, or iv) Substantially similar to 26 1 H NMR are characterized by at least two of the following:

[0034] Hydrobromide In a particular embodiment, the present invention provides crystalline form C of the hydrobromide salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.6±0.2°, 15.7±0.2°, and 23.7±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 8, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline form C of the hydrobromide salt of OAD2 is 11H NMR spectrum. In another embodiment, crystalline form C of the hydrobromide salt of OAD2 is characterized by an endothermic peak at 212.8°C as determined by DSC. In another embodiment, crystalline form C of the hydrobromide salt of OAD2 is characterized by a DSC profile as shown in Figure 19. In another embodiment, crystalline form C of the hydrobromide salt of OAD2 is characterized by a TGA profile as shown in Figure 19. In another embodiment, crystalline form C of the hydrobromide salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 4.6±0.2°, 15.7±0.2°, and 23.7±0.2°; ii) a DSC profile as shown in Figure 19, or iii) TGA profile as shown in Figure 19 are characterized by at least two of the following:

[0035] In a particular embodiment, the present invention provides crystalline form D of the hydrobromide salt of OAD2, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 8.8±0.2°, 15.9±0.2°, and 17.8±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 9, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline form D of the hydrobromide salt of OAD2 is 1 20 NMR spectroscopy. In another embodiment, crystalline form D of the hydrobromide salt of OAD2 is characterized by an endothermic peak at 183.3° C. as determined by DSC. In another embodiment, crystalline form D of the hydrobromide salt of OAD2 is characterized by a DSC profile as shown in FIG. 20. In another embodiment, crystalline form D of the hydrobromide salt of OAD2 is characterized by a TGA profile as shown in FIG. 20. In another embodiment, crystalline form D of the hydrobromide salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 8.8±0.2°, 15.9±0.2°, and 17.8±0.2°; ii) a DSC profile as shown in Figure 20, or iii) TGA profile as shown in Figure 20 are characterized by at least two of the following:

[0036] sulfate In a particular embodiment, the present invention provides crystalline form C of a sulfate salt of OAD2, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.4±0.2°, 8.7±0.2°, and 15.2±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in Figure 10, and the X-ray powder diffraction data is as shown in Table 1. In another embodiment, crystalline form C of a sulfate salt of OAD2 is 1 In another embodiment, crystalline form C of the sulfate salt of OAD2 is characterized by a H NMR spectrum. In another embodiment, crystalline form C of the sulfate salt of OAD2 is characterized by an endothermic peak at 191.2°C as determined by DSC. In another embodiment, crystalline form C of the sulfate salt of OAD2 is characterized by a DSC profile as shown in Figure 21. In another embodiment, crystalline form C of the sulfate salt of OAD2 is characterized by a TGA profile as shown in Figure 21. In another embodiment, crystalline form C of the sulfate salt of OAD2 is characterized by the following characteristics: i) an XRPD pattern comprising peaks at diffraction angles (2θ) of 3.4±0.2°, 8.7±0.2°, and 15.2±0.2°; ii) a DSC profile as shown in Figure 21, or iii) TGA profile as shown in Figure 21 are characterized by at least two of the following:

[0037] [Table 1-1]

[0038] [Table 1-2]

[0039] Pharmaceutical Composition The present invention further provides pharmaceutical compositions comprising one or more pharmaceutically acceptable acid salt forms of OAD2, optionally comprising a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a pharmaceutical composition comprising a crystal, a pharmaceutically acceptable acid salt of OAD2, wherein the pharmaceutical composition comprises a therapeutically effective amount of the crystal, a pharmaceutically acceptable acid salt of OAD2, and optionally a pharmaceutically acceptable carrier.

[0040] In another embodiment, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable acid salt formed between OAD2 and a pharmaceutically acceptable acid. In one embodiment, the pharmaceutically acceptable acid is selected from the group consisting of 1-hydroxy-2-naphthoic acid, 4-aminosalicylic acid, adipic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, L-lactic acid, maleic acid, L-malic acid, malonic acid, R-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, oxalic acid, palmitic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, p-toluenesulfonic acid, vanillic acid, and vanillin. In another embodiment, the pharmaceutically acceptable acid is selected from the group consisting of hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid, tartaric acid, citric acid, glycolic acid, methanesulfonic acid, and sulfonic acid.

[0041] The pharmaceutical composition may be prepared according to methods known in the art. Preferably, the crystalline acid salt of OAD2 of the present invention is 0.001% to 99% by weight of the pharmaceutical composition. In certain embodiments, the crystalline acid salt of OAD2 is combined with one or more pharmaceutically acceptable carriers and formulated into any dosage form suitable for use in humans or non-human animals.

[0042] Pharmaceutical compositions of the present invention comprising a pharmaceutically acceptable acid salt of OAD2 may be in a form suitable for oral administration, such as, for example, tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules. Compositions intended for oral administration may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation.

[0043] The tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules may comprise a pharmaceutically acceptable acid salt of OAD2 mixed with one or more pharmaceutically acceptable carriers suitable for the manufacture of such tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules.

[0044] A "pharmaceutically acceptable carrier" is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the ability of those skilled in the art to determine and account for. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent will be administered, the intended route of administration of the composition, and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may contain several different components and additives in addition to the active agent; such additional components are included in the formulation for various reasons, such as stabilizing the active agent, and are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources.

[0045] treatment method In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable acid salt of OAD2, wherein the therapeutically effective amount of the pharmaceutically acceptable acid salt of OAD2 is sufficient for the treatment of a disease or disorder in which activation of the GLP1 receptor is beneficial.

[0046] In another aspect, the present invention further provides a method of treatment comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of OAD2 to a human in need thereof. The method may comprise administering to a human in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable acid salt of OAD2. In another embodiment, the pharmaceutically acceptable salt of OAD2 may be administered in crystalline form.

[0047] The therapeutic method may be useful for treating diseases or conditions in which activation of the GLP1 receptor is beneficial, including, but not limited to, those selected from the group consisting of metabolic syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, type 1 diabetes mellitus, type 2 diabetes mellitus, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, other cardiovascular diseases, hypertension, metabolic diseases, and complications arising from or associated with diabetes, including, but not limited to, neuropathy, retinopathy, nephropathy, and wound healing disorders, in which activation of the GLP1 receptor is beneficial. In one embodiment, the disease being treated is type 2 diabetes.

[0048] The pharmaceutically acceptable acid salts of OAD2 of the present invention may be administered at dosage levels such that the amount of OAD2 administered is between 1 mg and 100 mg per day. The dosage may be tailored to the individual by a clinician based on the particular condition of the subject being treated. It is therefore understood that the specific dosage level for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the particular disease being treated. [Example]

[0049] Experimental equipment and protocols 1. X-ray powder diffraction (XRPD), see Table 2 below showing the test parameters.

[0050] [Table 2]

[0051] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) The data were collected on a TAQ5000 / 5500 thermogravimetric analyzer and a TAQ200 / Q2000 / 2500 differential scanning calorimeter, respectively. See Table 3 below for test parameters.

[0052] [Table 3]

[0053] 3. Liquid NMR was collected on a Bruker-400M NMR spectrometer using DMSO-d6 as the solvent.

[0054] 4. The salt formation molar ratio test of ions is performed by ion chromatography. The test conditions are shown in Table 4.

[0055] [Table 4]

[0056] 5. Dynamic Water Suction (DVS) Dynamic moisture sorption (DVS) curves were collected on a Surface Measurement Systems (SMS) DVS Intrinsic. Relative humidity at 25°C was corrected using the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are listed in Table 5.

[0057] [Table 5]

[0058] Example 1 Preparation of crystalline form B of the hydrochloride salt At 20°C, 1 g of OAD2 was added to 5 ml of 2-methyltetrahydrofuran, followed by dropwise addition of 1.4 ml of 1 mol / L hydrochloric acid solution. The mixture was stirred for 2 hours. XRPD was used to monitor whether a new crystalline form was formed. After the transformation and crystallization were completed, crystalline form B of the hydrochloride salt was obtained by suction filtration and drying at 50°C until the molar ratio of hydrochloric acid to base was 1:1.

[0059] Example 2 Preparation of crystalline form C of the hydrochloride salt 0.3 g of OAD2 was dissolved in an acetone / water solution containing hydrochloric acid (29.2 μl), and then the mixture was stirred at room temperature. XRPD was used to monitor whether the solid transformed into crystals. After the transformation was complete, crystalline Form C of the hydrochloride salt was obtained after centrifugation and drying until the molar ratio of hydrochloric acid to base was 1:1.

[0060] Examples 3 to 12 Screening of other crystalline salt complexes and their preparation process Other crystalline salts were prepared according to the methods of Examples 1 or 2, and the specific results are shown in Table 6. The results indicated that not all acids whose ΔpKa satisfies the required conditions can form salts with the bases, and furthermore, when the acid and free base are provided in a 1:1 ratio, they may not necessarily form 1:1 salts.

[0061] [Table 6-1]

[0062] [Table 6-2]

[0063] Example 13 Experimental characterization of crystalline salt complexes The solid crystalline forms were characterized by XRPD, DSC / TGA, etc. and the experimental data are shown in Table 7.

[0064] [Table 7]

[0065] Example 14 Examination of the characteristics of crystalline salt complexes Tests were conducted on the above crystalline salts to determine and compare their pH solubility, hygroscopicity, and solid state stability.

[0066] 1) pH solubility evaluation The solubilities of crystalline form B of the hydrochloride salt, crystalline form C of the p-toluenesulfonate salt, crystalline form C of the sulfate salt, and crystalline form C of the hydrobromide salt were determined and compared under different pH conditions, and the results are shown in Table 8. All of the above crystalline salts had low solubility in buffers of pH 3.0 and 5.0. In a buffer of pH 1.0, crystalline form C of the p-toluenesulfonate salt had significantly higher solubility than the other crystalline salts.

[0067] [Table 8]

[0068] 2) Hygroscopicity test DVS tests (25°C, 80% RH) were performed on five crystalline salts. The results demonstrated that all samples showed no change in crystalline form before and after the DVS test, and except for the sulfate salt, all the remaining samples had only slight hygroscopicity, but the hygroscopicity was significantly improved compared to OAD2 dihydrochloride dihydrochloride. The results are shown in Table 9.

[0069] [Table 9]

[0070] 3) Evaluation of solid state stability The stability of crystalline form B of the hydrochloride salt, crystalline form C of the sulfate salt, crystalline form C of the p-toluenesulfonate salt, and Compound I was compared. After storage at 40°C / 100% RH for one week, the physical and chemical stability was evaluated using XRPD and HPLC, respectively, and the results are shown in Table 10. The results demonstrated that all samples showed no decrease in purity or change in form, demonstrating excellent stability, with crystalline form C of the p-toluenesulfonate salt exhibiting the best stability.

[0071] [Table 10]

Claims

1. A crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-(phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid, wherein the crystalline acid salt is selected from the group consisting of crystalline form B of the hydrochloride, crystalline form C of the hydrochloride, crystalline form C of the p-toluenesulfonate, crystalline form C of the tartrate, crystalline form C of the citrate, crystalline form C of the glycolate, crystalline form C of the methanesulfonate, crystalline form C of the hydrobromide, crystalline form D of the hydrobromide, and crystalline form C of the sulfate.

2. the crystalline acid salt is crystalline form B of the hydrochloride salt or crystalline form C of the hydrochloride salt; Crystalline Form B of the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.3±0.2°, 9.2±0.2°, 10.3±0.2°, 13.2±0.2°, and 14.8±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG. 1; 2. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein crystalline form C of the hydrochloride salt has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.9±0.2°, 11.6±0.2°, 14.3±0.2°, 15.9±0.2°, 21.4±0.2°, and 23.1±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG.

3. The crystalline acid salt is crystalline form C of the p-toluenesulfonic acid salt, and the crystalline form has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.7±0.2°, 5.4±0.2°, 9.7±0.2°, 13.1±0.2°, 16.4±0.2°, and 18.2±0.2°, and preferably, the X-ray powder diffraction pattern includes peaks at substantially the same 2θ diffraction angles as shown in FIG. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, characterized in that it contains

4. 2. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein the crystalline acid salt is crystalline form C of tartaric acid, and the crystalline form has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.8±0.2°, 9.9±0.2°, 10.1±0.2°, and 15.6±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG.

5. 2. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein the crystalline acid salt is crystalline form C of the citrate salt, and the crystalline form has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.5±0.2°, 6.5±0.2°, and 15.9±0.2°, and preferably the X-ray powder diffraction pattern includes substantially the same peaks at 2θ diffraction angles as shown in FIG.

5.

6. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein the crystalline acid salt is crystalline form C of the glycolate salt, and the crystalline form has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 6.0±0.2°, 12.1±0.2°, 13.6±0.2°, 18.2±0.2°, and 24.3±0.2°, and preferably the X-ray powder diffraction pattern includes substantially the same peaks at 2θ diffraction angles as shown in FIG.

6.

7. 2. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein the crystalline acid salt is crystalline form C of the methanesulfonate salt, and the crystalline form has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.2±0.2°, 12.8±0.2°, 13.8±0.2°, 14.4±0.2°, and 22.2±0.2°, and preferably the X-ray powder diffraction pattern includes substantially the same peaks at 2θ diffraction angles as shown in FIG.

7.

8. the crystalline acid salt is crystalline form C of the hydrobromide salt or crystalline form D of the hydrobromide salt; Crystalline Form C of the Hydrobromide Salt has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.6±0.2°, 15.7±0.2°, and 23.7±0.2°, preferably wherein the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG. 8; 2. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein crystalline form D of the hydrobromide salt has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.7±0.2°, 8.8±0.2°, 15.9±0.2°, and 17.8±0.2°, and preferably the X-ray powder diffraction pattern comprises substantially the same peaks at 2θ diffraction angles as shown in FIG.

9. The crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to claim 1, wherein the crystalline acid salt is crystalline form C of the sulfate salt, and the crystalline form has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 3.4±0.2°, 8.7±0.2°, and 15.2±0.2°, and preferably the X-ray powder diffraction pattern includes substantially the same peaks at 2θ diffraction angles as shown in FIG.

10.

10. 10. A pharmaceutical composition comprising the crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to any one of claims 1 to 9, and optionally a pharmaceutically acceptable carrier.

11. Use of the crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to any one of claims 1 to 9 for the preparation of a GLP-1 receptor agonist.

12. Use of the crystalline acid salt of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid according to any one of claims 1 to 9 for the preparation of a medicament for treating diabetes.

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