Crystal form of an aldose reductase inhibitor, preparation method and application thereof

Abstract

The present invention provides a crystalline form II of a salt of an aldose reductase inhibitor represented by Formula A-N. This crystalline form is easy to dry, has good solubility, stable quality, thermodynamic stability, low relative hygroscopicity, and is easy to formulate as a medicine. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a salt of an aldose reductase inhibitor, a preparation method and an application thereof. Background Art

[0002] Diabetes is one of the most common chronic conditions. High blood sugar levels result from a lack of insulin production and / or insulin sensitivity. Individuals with high blood sugar metabolize more glucose via the glucose-to-sorbitol-to-fructose pathway in insulin-insensitive cells such as the lens, peripheral nerves, and kidney glomeruli. This results in an excess of sorbitol in the cells, which is less able to diffuse across the cell membrane. Increased concentrations of sorbitol trigger an influx of water into the cells, causing swelling and potential damage.

[0003] Aldose reductase is an enzyme present in many parts of the body that catalyzes the reduction of glucose to sorbitol, which is one of the steps in the sorbitol pathway responsible for forming fructose from glucose. When glucose concentration rises in diabetic conditions where tissues are no longer insulin-sensitive, aldose reductase activity increases. These tissues include, for example, the lens, peripheral nerves, and glomeruli. Sorbitol cannot easily diffuse through the cell membrane and therefore accumulates, causing osmotic damage, which in turn leads to retinopathy, neuropathy, and nephropathy. Therefore, inhibiting aldose reductase can prevent sorbitol from accumulating in insulin-insensitive cells in diabetic patients, and a novel method for preventing macrovascular and microvascular complications in diabetic patients has been proposed. In addition, aldose reductase inhibitors such as zopolrestat can help treat or improve such effects and have demonstrated efficacy in wound healing of the corneal epithelium in diabetic animal models.

[0004] Chinese invention patent CN201180034944.5 discloses an aldose reductase inhibitor as shown in the following formula I:

[0005]

[0006] Wherein Examples 1 and 2 disclose compounds with the following structures:

[0007]

[0008] The compound of formula A is insoluble in water and has poor drugability. Therefore, the applicant has improved the structure of the compound of formula A to make it meet pharmaceutical requirements.

[0009] The PCT patent WO2020173495A applied for by the applicant records the compound represented by formula AN and a crystalline form thereof. The crystalline form of the compound represented by formula AN uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.2±0.2°, 21.4±0.2°, 21.9±0.2°, and 25.9±0.2°.

[0010] Summary of the Invention

[0011] The present inventors have discovered that the crystalline form of the compound of Formula AN described in WO2020173495A is obtained in water and is not easy to dry. Therefore, it is necessary to further study the crystalline form of the compound of Formula AN to meet better pharmaceutical needs.

[0012] To solve the above problems, the present invention provides a crystalline form II of a compound represented by formula AN.

[0013]

[0014] The invention is characterized in that: using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, and 27.1±0.2°.

[0015] In some embodiments, the crystalline form II of the compound represented by Formula AN has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 24.7±0.2°, 26.0±0.2°, and 27.1±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation.

[0016] In some embodiments, the crystalline form II of the compound represented by Formula AN has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.3±0.2°, 18.0±0.2°, 21.6±0.2°, 22.5±0.2°, 23.2±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2°, 30.2±0.2°, and 31.6±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation.

[0017] In some embodiments, the crystalline form II of the compound represented by formula AN has substantially Figure 1 The X-ray powder diffraction pattern (XRPD) is shown.

[0018] In some embodiments, the crystalline form II of the compound represented by Formula AN has a thermogravimetric analysis curve showing a weight loss of 0.7-0.8% during heating to 150°C.

[0019] In some embodiments, the crystalline form II of the compound represented by Formula AN has a differential scanning calorimetry curve with no melting signal before 210°C.

[0020] In some embodiments, the crystalline form II of the compound represented by formula AN has substantially Figure 2 TGA-DSC spectrum shown.

[0021] In some embodiments, the crystalline form II of the compound represented by formula AN is a short rod-shaped crystal.

[0022] In some embodiments, the crystalline form II of the compound represented by formula AN has substantially Figure 3 PLM image shown.

[0023] The present invention also provides a method for preparing the crystalline form II of the compound represented by formula AN, comprising the following steps:

[0024] The crude product of the compound represented by formula AN is suspended in a single solvent or a binary solvent for 1 to 7 days, the solid is separated, and dried to obtain the crystalline form II of the compound represented by formula AN.

[0025] The preparation of the crude product of the Chinese formula AN compound of the present invention can be prepared by referring to the method described in the examples in patent document WO2020173495A.

[0026] According to the preparation method of the present invention, the single solvent is selected from: 4-methyl-2-pentanone, isopropyl acetate, methyl tert-butyl ether, ethyl acetate, chloroform, and ethylene glycol dimethyl ether; the binary solvent is selected from: methanol-ethylene glycol dimethyl ether (volume ratio of 1:5), ethylene glycol monomethyl ether-ethylene glycol dimethyl ether (volume ratio of 1:5).

[0027] According to the preparation method of the present invention, the suspension temperature is 20-50°C.

[0028] According to the preparation method of the present invention, the suspension time is preferably 3 to 7 days.

[0029] According to the preparation method of the present invention, the separation step comprises separating the obtained crystal form II of the compound represented by formula AN from the crystallization solution by using a suitable method such as filtration and centrifugation.

[0030] According to the preparation method of the present invention, the drying method can be any suitable known method, preferably reduced pressure (vacuum drying). Specific drying conditions include, for example, a temperature of preferably 40-80°C; a pressure of preferably vacuum > 0.090 MPa; and a drying time of preferably 1-50 hours, more preferably 2-40 hours. Regardless of the drying method used, it is preferred that the residual solvent content in the resulting product meet quality standards.

[0031] In another aspect, the present invention also relates to a pharmaceutical composition comprising the crystalline form II of the compound represented by formula AN.

[0032] In another aspect, the present invention also relates to a crystalline form II of a compound represented by formula AN or a pharmaceutical composition comprising the crystalline form II of a compound represented by formula AN for use in the preparation of a drug for inhibiting aldose reductase activity in a subject, such as promoting healthy aging of the skin, treating skin disorders, treating angiogenic disorders such as cancer, treating tissue damage, treating cardiovascular disorders, treating kidney disorders, treating developing myocardial infarction, and treating various other disorders such as complications arising from diabetes. Such disorders may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infections, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosemia, and the like.

[0033] In yet another aspect, the present invention also relates to the crystalline form II of the compound represented by formula AN or a pharmaceutical composition comprising the crystalline form II of the compound represented by formula AN, which is used to inhibit aldose reductase activity in a subject, such as promoting healthy aging of the skin, treating skin disorders, treating angiogenic disorders such as cancer, treating tissue damage, treating cardiovascular disorders, treating kidney disorders, treating developing myocardial infarction, and treating various other disorders such as complications arising from diabetes. Such disorders may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infections, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosemia, and the like.

[0034] In yet another aspect, the present invention also relates to a method for treating a patient's condition by administering to the patient the crystalline form II of the compound represented by formula AN or the pharmaceutical composition comprising the crystalline form II of the compound represented by formula AN, wherein the treatment of the patient's condition is to inhibit the subject's aldose reductase activity, such as promoting healthy aging of the skin, treating skin disorders, treating angiogenic disorders such as cancer, treating tissue damage, treating cardiovascular disorders, treating kidney disorders, treating ongoing myocardial infarction, and treating various other conditions such as complications arising from diabetes. Such conditions may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infections, peripheral vascular disease, stroke, diabetic cardiomyopathy, galactosemia, and the like.

[0035] The above-mentioned "subject" and "patient" include all members of the animal kingdom, including but not limited to mammals (eg, mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.

[0036] Beneficial effects

[0037] The present invention provides a crystalline form II of a compound of formula AN. The inventors unexpectedly discovered that this crystalline form can be obtained in an organic solvent, is easy to dry, has good solubility, stable quality, thermodynamic stability, relatively low hygroscopicity, and is easy to formulate into a drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the XRPD spectrum of Form II of the compound of formula AN.

[0039] Figure 2 This is the TGA-DSC spectrum of Form II of the compound of formula AN.

[0040] Figure 3 This is the PLM diagram of Form II of the compound of formula AN. DETAILED DESCRIPTION

[0041] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. The following embodiments are intended only to illustrate and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0042] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0043] In the following examples, the detection methods of XRPD, TGA, DSC, PLM, and DVS are as follows:

[0044] 1. XRPD detection method

[0045] Instrument: German BRUKER D8 Advance X-ray powder diffractometer (BRUKER GER)

[0046] Conditions: Cu-Kα radiation, tube voltage 40 kV, tube current 40 mA, 2θ scanning range 3-45°, scanning step length 0.02°, exposure time 0.12 s, and zero-background sample plate.

[0047] 2. TGA detection method

[0048] Instrument: TA Discovery 55 thermogravimetric analyzer (TA, US)

[0049] Method: 2-5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rates of 60 mL / min at the sample and 40 mL / min at the balance.

[0050] 3.DSC detection method

[0051] Instrument: TA Discovery 2500 differential scanning calorimeter (TA, US)

[0052] Method: 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The temperature was raised to the final temperature at a rate of 10°C / min, and the nitrogen purge rate in the furnace was 50 mL / min.

[0053] 4. PLM detection method

[0054] Instrument: Motic BA310Met polarizing microscope (Motic, CN)

[0055] Method: Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.

[0056] 5. Dynamic moisture adsorption and desorption analysis (DVS) detection method

[0057] Instrument: DVS Intrinsic (SMS, UK).

[0058] Method: The test adopts gradient mode, and the humidity changes from 50% to 95% to 0% to 50%. The humidity change of each gradient in the range of 0% to 90% is 10%. The gradient endpoint is judged by dm / dt method, and the gradient endpoint is determined when dm / dt is less than 0.002% and maintained for 10 minutes.

[0059] Preparation Example 1. Preparation of Compound of Formula AN

[0060] With reference to the method described in Example 1 in the examples of patent document WO2020173495A, 4.5 g of a crude product of the compound represented by formula AN was prepared.

[0061]

[0062] PLM images showed that the AN crystal form obtained in Preparation Example 1 was short rod-shaped crystals with a particle size generally less than 10 μm and prone to aggregation. DVS results showed that the AN crystal form obtained in Preparation Example 1 gained 20.91% weight at 95% humidity, 3.34% weight at 0% humidity, and 16.49% weight gain upon moisture absorption at 50% humidity.

[0063] Example 1: Preparation of Form II of the Compound of Formula AN

[0064] The crude product of the compound of formula AN obtained in Preparation Example 1 (1.0432 g) and 4-methyl-2-pentanone (75 mL) were added to the reaction flask and stirred to form a suspension. The suspension was heated to 50°C and suspended with stirring for 24 hours. The suspension was centrifuged and the obtained solid was dried in vacuo at 40°C for 16 hours to obtain Form II (901 mg) of the compound of formula AN.

[0065] The obtained crystal form II showed good crystallinity, and its XRPD characterization spectrum was basically as follows Figure 1 The characterization data are shown in Table 1. The DSC-TGA test results are shown in Figure 2 As shown, the test results show that the sample does not contain crystal water or crystallization solvent, loses 0.783% of its weight during heating to 150℃, has no obvious melting signal before 210℃, and may decompose above 210℃. The PLM image shows the results as follows Figure 3 As shown, the image shows that Form II is short rod-shaped crystals with a particle size generally less than 10 μm and slight aggregation. DVS results show that Form II gained 18.94% weight at 95% humidity, lost 1.73% weight at 0% humidity, and gained 2.27% weight upon moisture absorption when returned to 50% humidity.

[0066] Table 1 XRPD characterization data of Form II sample of Example 1

[0067]

[0068]

[0069] Example 2-6: Preparation of Form II of the Compound of Formula AN (Single Solvent)

[0070] A certain amount of the crude compound of Formula AN obtained in Preparation Example 1 was weighed, suspended and stirred in a single solvent listed in Table 2 to obtain Form II of the compound of Formula AN.

[0071] Table 2 Preparation of Form II of Compound AN by Single Solvent

[0072] Example Sample amount (mg) solvent Volume (mL) Temperature (℃) time result 2 19.6 4-Methyl-2-pentanone 10 Room temperature 7 days Form II 3 20.1 Isopropyl acetate 10 Room temperature 7 days Form II 4 20.0 Methyl tert-butyl ether 10 Room temperature 7 days Form II 5 20.5 Ethyl acetate 3 50 1 day (24 hours) Form II 6 19.7 Chloroform 3 50 1 day (24 hours) Form II

[0073] Examples 7-8: Preparation of Form II of the Compound of Formula AN (Binary Solvent)

[0074] A certain amount of the crude compound of Formula AN obtained in Preparation Example 1 was weighed, suspended and stirred in the binary solvents listed in Table 3 to obtain Form II of the compound of Formula AN.

[0075] Table 3 Preparation of Form II of Compound AN Using Binary Solvents

[0076]

[0077] Test Example 1: Stability Study

[0078] 20 mg of the Form II sample obtained in Example 1 was weighed and placed in a weighing bottle. The solid-state stability was studied under high temperature (60°C) and light (25°C, 4500 Lux) conditions. Samples were taken for XRPD characterization on days 7 and 15. The results are shown in Table 4.

[0079] Table 4 Stability test results of Form II

[0080]

[0081] The results showed that the crystal form II did not change under high temperature (60°C) and light (25°C, 4500Lux) conditions for 15 days, and the crystal form was stable.

[0082] Test Example 2: Solubility Test

[0083] Form II samples obtained in Example 1 and the crystalline form sample obtained in Preparation Example 1 were added to buffer solutions of varying pH values (the pH buffer solution preparation process is shown in Table 5) and water to form suspensions. After constant temperature shaking at 25°C for 24 hours, the suspensions were centrifuged and the supernatant filtered through a 0.22 μm aqueous filter membrane. The sample dissolution amount and solvent usage were recorded, and the sample solubility was calculated. The solubility test results are shown in Table 6.

[0084] Table 5 Buffer preparation process

[0085]

[0086] Table 6 Solubility test results of Form II and Form 1

[0087]

[0088] Note: *The sample is clear.

[0089] Test Example 3: Competitive suspension experiment

[0090] The crystal form II of the compound of formula AN obtained in Example 1 and the crystal form of the compound of formula AN obtained in the preparation example were subjected to competitive suspension experiments in ethyl acetate and 4-methyl-2-pentanone at low temperature (10°C), room temperature (25°C), and high temperature (60°C). The results are shown in Table 7:

[0091] Table 7 Competitive suspension results

[0092]

[0093] In summary, the crystalline form II of the compound of formula AN of the present invention has good solubility, stable quality, thermodynamic stability, low relative hygroscopicity, and is easy to formulate into a drug.

Claims

1. A crystalline form II of a compound represented by formula AN, It is characterized in that Using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 14.4±0.2°, 21.6±0.2°, 24.7±0.2°, 26.0±0.2°, and 27.1±0.2°.

2. The crystalline form II of the compound represented by formula AN according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.2±0.2°, 10.7±0.2°, 13.4±0.2°, 14.4±0.2°, 16.3±0.2°, 18.0±0.2°, 21.6±0.2°, 22.5±0.2°, 23.2±0.2°, 24.7±0.2°, 26.0±0.2°, 27.1±0.2°, 30.2±0.2°, and 31.6±0.2°.

3. The crystalline form II of the compound represented by formula AN according to claim 1, characterized in that: Using Cu-Kα radiation, it has an X-ray powder diffraction pattern substantially as shown in FIG1 .

4. The crystalline form II of the compound represented by formula AN according to claim 1, characterized in that: Its thermogravimetric analysis curve shows a weight loss of 0.7-0.8% when heated to 150°C.

5. The crystalline form II of the compound represented by formula AN according to claim 4, characterized in that: It has a TGA-DSC spectrum substantially as shown in FIG2 .

6. The crystalline form II of the compound represented by formula AN according to claim 1, characterized in that: It is a short rod-shaped crystal.

7. The method for preparing the crystalline form II of the compound represented by formula AN according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: suspending a crude product of a compound represented by Formula AN in a single solvent or a binary solvent for 1 to 7 days, separating the solid, and drying to obtain a crystalline form II of the compound represented by Formula AN, wherein: The single solvent is selected from: 4-methyl-2-pentanone, isopropyl acetate, methyl tert-butyl ether, ethyl acetate, chloroform, and ethylene glycol dimethyl ether; the binary solvent is selected from: methanol-ethylene glycol dimethyl ether with a volume ratio of 1:5, and ethylene glycol monomethyl ether-ethylene glycol dimethyl ether with a volume ratio of 1:5; the suspension temperature is 20-50°C.

8. The preparation method according to claim 7, characterized in that The suspension time is 3 to 7 days.

9. A pharmaceutical composition comprising the crystalline form II of the compound represented by formula AN according to any one of claims 1 to 6.

10. Use of Form II of the compound represented by Formula AN according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 for preparing a medicament for treating diseases associated with inhibition of aldose reductase activity, wherein the diseases are diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, and galactosemia.

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