Crystalline form a of glp-1 receptor agonist and preparation method therefor

Abstract

To provide a stable crystalline form 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").SOLUTION: There is provided a crystalline form A of OAD2, characterized in that the X-ray powder diffractogram comprises peaks at 2-theta angles of 9.53 °, 12.32 °, 13.80 °, 17.84 °, 18.56 °, 19.40 °, 20.38 °, 20.99 °, 21.78 ° and 24.69 °.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to crystalline form A 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 same. Crystalline form A 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 (hereinafter referred to as 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] OAD2 dihydrochloride is an orally available, non-peptide glucagon-like peptide 1 (GLP-1) receptor agonist.

[0005] Although OAD2 has already been described in patent of invention CN102378574B, the crystalline form of OAD2 has not been systematically studied.

[0006] It has been discovered that the dihydrochloride salt of OAD2 absorbs water and is difficult to filter, dry, and further process, which may affect its purity and production costs. Therefore, further research into OAD2 is desirable to potentially improve the purity, stability, and form of the active pharmaceutical ingredient. Summary of the Invention

[0007] The present invention provides crystalline form A of OAD2 and a method for preparing same. The present invention further provides solid forms of OAD2, said solid forms comprising crystalline form A of OAD2.

[0008] The present invention further provides the use of solid forms of OAD2, including crystalline form A, in the preparation of a medicament for treating a disease or disorder in which activation of the GLP1 receptor is beneficial.

[0009] The present invention further provides methods for preparing crystalline form A of OAD2. The present invention further provides methods for making solid forms of OAD2, including crystalline form A.

[0010] The present invention further provides a pharmaceutical composition comprising crystalline form A of OAD2, said pharmaceutical composition comprising a therapeutically effective amount of crystalline form A of OAD2, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared according to methods known in the art. The present invention further provides a pharmaceutical composition comprising a solid form of OAD2, said solid form comprising crystalline form A. The present invention further provides a method for producing a pharmaceutical composition comprising a solid form of OAD2, comprising crystalline form A of OAD2.

[0011] The present invention further provides the use of crystalline form A of OAD2 for the preparation of a GLP-1 receptor agonist.

[0012] The present invention further provides the use of crystalline form A of OAD2 for the preparation of a medicament. In one embodiment, the medicament may be for treating diabetes.

[0013] The present invention further provides a method of treatment comprising administering to a human in need thereof a therapeutically effective amount of a solid form of OAD2, wherein said solid form of OAD2 comprises crystalline form A. The method of treatment may be useful for treating a disease or disorder in which activation of the GLP1 receptor is beneficial.

[0014] These and other embodiments of the present invention are described in further detail in the detailed description of the invention that follows.

[0015] Crystalline Form A of OAD2 may have certain improved characteristics compared to the OAD2 dihydrochloride salt. For example, crystalline Form A of OAD2 showed no measurable weight gain from water absorption after 5 days under certain conditions, while the OAD2 dihydrochloride salt showed an 8.3% increase in moisture uptake after 5 days under similar conditions. Furthermore, the process for purifying OAD2 may be simpler and less costly than the process for purifying OAD2 dihydrochloride. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of crystalline form A of OAD2 of the present invention. [Figure 2] FIG. 1 shows DSC thermal analysis and thermogravimetric analysis TGA thermograms of crystalline form A of OAD2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention will be 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, specific conditions of the experimental methods are not shown, which are generally conventional conditions or those recommended by raw material or product manufacturers, and solvents without indicating the source are generally commercially available conventional solvents.

[0018] 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.

[0019] The term "therapeutically effective amount" is used herein to denote a pharmaceutically acceptable amount of OAD2 that elicits a desired therapeutic response in a subject. In one embodiment, the therapeutic response may be agonizing the GLP-1 receptor.

[0020] The dihydrochloride salt of OAD2 may be obtained according to methods such as those described in patent CN102378574B or related WO 2010 / 114824, the entire contents of which are incorporated herein by reference.

[0021] Type A The present invention provides crystalline form A of OAD2. Form A has an X-ray powder diffraction (XRPD) pattern containing characteristic peaks at 2θ angles of 9.53°, 12.32°, 13.80°, 17.84°, 18.56°, 19.40°, 20.38°, 20.99°, 21.78°, and 24.69°±0.2, as determined by Cu-Ka radiation. In one embodiment, the present invention provides crystalline form A of OAD2 having an XRPD pattern containing characteristic peaks at 2θ angles of 17.84°, 19.40°, and 20.38°±0.2. In another embodiment, the present invention provides crystalline form A of OAD2 having an XRPD pattern containing characteristic peaks at 2θ angles of 13.80° and 24.69°±0.2. In another embodiment, the present invention provides crystalline form A of OAD2 having an XRPD pattern comprising characteristic peaks at 2-theta angles of 12.32°, 18.56°, 20.99°, and 21.78°±0.2. In another embodiment, the present invention provides crystalline form A of OAD2 characterized by an XRPD pattern as shown in FIG.

[0022] In a particular embodiment, the DSC thermogram indicates that the melting point of crystalline form A of OAD2 is 240.8° C. In another embodiment, the present invention provides crystalline form A characterized by an endothermic peak at 240.8° C. as determined by DSC. In another embodiment, the present invention provides crystalline form A characterized by a DSC profile as shown in FIG.

[0023] In a particular embodiment, the TGA thermogram shows that a sample of crystalline form A of OAD2 loses 1.1% weight when heated to 150° C. In another embodiment, the present invention provides crystalline form A characterized by a weight loss of about 1.1% between room temperature and 150° C. as determined by TGA. In another embodiment, the present invention provides crystalline form A characterized by the TGA profile as shown in FIG.

[0024] In a particular embodiment, crystalline form A of OAD2 has characteristic diffraction angles (2θ), interplanar spacings (d), and relative intensities (%) as listed in Table 1.

[0025] [Table 1]

[0026] In another embodiment, the present invention provides a method for manufacturing a device comprising the steps of: i) an XRPD pattern having characteristic peaks at 2θ angles of 17.84°, 19.40°, and 20.38°±0.2; ii) a DSC profile as shown in Figure 2, or iii) TGA profile as shown in Figure 2 The present invention provides a crystalline form A of OAD2 characterized by at least two of the following:

[0027] Pharmaceutical Composition The present invention further provides a pharmaceutical composition comprising crystalline form A of OAD2, the pharmaceutical composition comprising a therapeutically effective amount of crystalline form A of OAD2, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared according to methods known in the art. Preferably, crystalline form A of OAD2 is 0.001% to 99% by weight of the pharmaceutical composition. The present invention further provides a pharmaceutical composition comprising a solid form of OAD2, wherein the solid form comprises crystalline form A. The present invention further provides a method for producing a pharmaceutical composition comprising a solid form of OAD2, the solid form comprising crystalline form A of OAD2.

[0028] In certain embodiments, crystalline form A of OAD2 is formulated in combination with one or more pharmaceutically acceptable carriers into any dosage form suitable for use in humans or non-human animals.

[0029] Manufacturing method The present invention further provides a method for preparing crystalline form A of OAD2, comprising dissolving OAD2 dihydrochloride in a mixed solvent of an organic solvent and water, neutralizing the mixture with an alkaline solution, stirring until crystallization occurs, and isolating the precipitated crystals to obtain crystalline form A of OAD2.

[0030] In certain embodiments, the organic solvent is selected from the group consisting of 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, and acetone, and preferably 2-methyltetrahydrofuran.

[0031] In a particular embodiment, the organic solvent and water are mixed in a ratio of 1: 1. In another embodiment, the total volume of the organic solvent and water and the weight of the OAD2 dihydrochloride salt are in a volume / weight ratio ranging from 4 to 8: 1, where the volume is in L and the weight is in kg.

[0032] In a particular embodiment, in the neutralization step, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and preferably sodium hydroxide.

[0033] In a particular embodiment, the temperature of the neutralization and crystallization is in the range of 10-30°C.

[0034] treatment method In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of OAD2, wherein the therapeutically effective amount of OAD2 is sufficient to treat a disease or disorder in which activation of the GLP1 receptor is beneficial.

[0035] In another aspect, the present invention further provides a method of treatment comprising administering a therapeutically effective amount of a solid form of OAD2 to a human in need thereof, wherein the solid form of OAD2 comprises crystalline Form A. The method of treatment may be useful for treating a disease or condition in which activation of the GLP1 receptor is beneficial, such as, but not limited to, a disease or condition 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.

[0036] The solid form of OAD2 of the present invention may be administered at a dosage level 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 specific 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 specific 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 specific disease being treated.

[0037] Beneficial effects OAD2 crystalline form A has several improved characteristics compared to OAD2 dihydrochloride. For example, the weight of OAD2 crystalline form A did not increase after 5 days of water absorption under experimental conditions, while OAD2 dihydrochloride showed an 8.3% weight increase after 5 days of water absorption under similar conditions. Furthermore, the method for purifying OAD2 can be simpler and cheaper than the method for purifying OAD2 dihydrochloride. [Example]

[0038] The present invention will be further described in detail below with specific embodiments. The following examples are used to understand the method and core concept of the present invention. For those skilled in the art, any possible changes or substitutions that do not deviate from the concept of the present invention belong to the protection scope of the present invention. Experimental methods for which specific conditions are not shown in the examples of the present invention are generally conventional conditions or follow the conditions suggested by raw material or commercial manufacturers, and reagents for which the source is not shown are generally conventional reagents that can be purchased through commercial channels.

[0039] Experimental equipment and protocols X-ray powder diffraction (XRPD), Empyren, test conditions: power 40 kV × 250 mA, CuKα radiation, scanning range 3 to 40° (2θ), scanning width 0.02°, scanning speed 5° / min, scanning method: continuous scanning.

[0040] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were collected on a TAQ5000 / 5500 thermogravimetric analyzer and a TAQ200 / Q2000 / 2500 differential scanning calorimeter, respectively. See Table 2 below for test parameters.

[0041] [Table 2]

[0042] Example 1: Preparation of crystalline form A 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 free base (designated OAD2)

[0043] In a 1 L three-neck bottle, 100 g of OAD2 dihydrochloride salt (HPLC purity 97.87%) was first charged, then 2-methyltetrahydrofuran and water (1:1 weight ratio, 0.4 kg each) were added and stirred until clear. The mixture was maintained at 20 °C. AN sodium hydroxide, prepared by dissolving 9 g of sodium hydroxide in water, was added, and the mixture was stirred at 20 °C for 6 hours until crystallization occurred. After filtration and vacuum drying, crystalline form A of the free base was obtained in 88.4% yield and 99.50% HPLC purity.

[0044] Example 2: Preparation of Crystalline Form A of OAD2 In a 1 L three-neck bottle, 100 g of OAD2 dihydrochloride salt (HPLC purity 97.57%) was first charged, then acetonitrile and water (1:1 weight ratio, 0.8 kg each) were added and stirred until clear. The mixture was maintained at 30°C. AN sodium hydroxide, prepared by dissolving 9 g of sodium hydroxide in water, was added, and the mixture was stirred at 30°C for 6 hours until crystallization occurred. After filtration and vacuum drying, crystalline form A of the free base was obtained with a yield of 84.6% and an HPLC purity of 99.0%.

[0045] Example 3: Stability testing A stability study was conducted on crystalline form A of OAD2. The stability of crystalline form A in HO, SGF (simulated gastric fluid), FeSSIF (simulated intestinal fluid in the fed state), and FaSSIF (simulated intestinal fluid in the fasting state) was tested. Chemical stability was expressed by HPLC purity. Crystal form stability was expressed by detecting changes in crystalline form by XPRD. The results shown in Table 3 demonstrate that crystalline form A of the free base has good chemical stability, does not change crystalline form under various conditions, does not easily absorb water, and is highly suitable for drug preparation.

[0046] [Table 3]

Claims

1. Crystalline form A 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 free base, characterized in that the X-ray powder diffraction pattern of said crystalline form A contains diffraction peaks at 2θ diffraction angles of 9.53°, 12.32°, 13.80°, 17.84°, 18.56°, 19.40°, 20.38°, 20.99°, 21.78° and 24.69°.

2. 2. The crystalline form A 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 free base according to claim 1, wherein the X-ray powder diffraction pattern contains substantially the same diffraction peaks at 2θ diffraction angles as shown in FIG.

3. 10. A process for preparing crystalline form A 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 free base according to claim 1, wherein the process comprises: 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 in water and an organic solvent, neutralizing the mixture with an alkaline solution, precipitating the solid, and filtering.

4. 4. The method according to claim 3, wherein the organic solvent is one or two selected from the group consisting of 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, and acetone, and / or the organic solvent and the water are mixed in a 1:1 ratio, and / or the total volume of the organic solvent and the water to the weight 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 dihydrochloride is in a volume / weight ratio ranging from 4 to 8:

1.

5. 4. The method according to claim 3, wherein in the neutralization, the base is one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide; and / or the temperature of the neutralization and crystallization is in the range of 10 to 30°C.

6. A pharmaceutical composition, characterized in that said composition comprises 0.001% to 99% by weight of crystalline form A according to claim 1 or 2, and optionally a pharmaceutically acceptable carrier.

7. Use of crystalline form A 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 dihydrochloride free base according to claim 1 or 2 for the preparation of a GLP-1 receptor agonist.

8. Use of crystalline form A 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 dihydrochloride free base according to claim 1 or 2 for the preparation of a medicament for treating diabetes.

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