Crystalline forms of isoquinolinone compounds and methods for preparing them

Abstract

This disclosure relates to the crystalline form of isoquinolinone compounds and a method for preparing them. Specifically, this disclosure provides the crystalline form of a compound represented by formula (I) and a method for preparing it. [Formula 1] TIFF2026512778000047.tif37168

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application 2022113360457, filed on 2022 / 10 / 28. This application incorporates the full text of the aforementioned Chinese patent application.

[0002] (Technical field) This disclosure relates to the crystalline form of isoquinolinone compounds and methods for preparing them, and more specifically, provides the crystalline form of a compound represented by formula I and methods for preparing it. [Background technology]

[0003] Phosphodiesterases (PDEs) belong to a superfamily of enzymes containing 11 families, each involved in different signal transduction and regulating different physiological processes. Of these, PDE3 has hydrolytic ability for both cAMP and cGMP, but its hydrolytic ability for cAMP is approximately 10 times greater than that for cGMP. PDE3 has two gene isoforms, PDE3A and PDE3B, located on chromosomes 11 and 12, respectively. Due to differences in the start codon, PDE3A is further divided into three isoforms: PDE3A1, PDE3A2, and PDE3A3. These are mainly distributed in the heart, platelets, vascular smooth muscle, and oocytes, and regulate myocardial contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation, and renin release. PDE3B has only one isoform, PDE3B1, and is mainly distributed in adipocytes, hepatocytes, spermatocytes, and pancreas. It is mainly involved in regulating the signal transduction of insulin, insulin-like growth factor, and leptin, and plays an important role in metabolic diseases such as obesity and diabetes. PDE3 selective inhibitors mainly include cilostazol, cilostamide, milrinone, amrinone, enoximon, and cyanazodane.

[0004] For example, amrinone inhibits PDE3 activity, increases cAMP concentration in cardiomyocytes, and increases Ca in cells. 2+By increasing its concentration, the positive inotropic effect can be fully exerted. At the same time, amrinone can act directly on vascular smooth muscle cells, has a good vasodilatory effect, increases myocardial contractility, lowers pulmonary artery pressure, restores cardiopulmonary function, and has significant value in the treatment of chronic pulmonary heart disease complicated with heart failure. In addition, cilostazol is clinically used to treat antiplatelet aggregation, pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), intermittent claudication, and cerebral microvascular disease.

[0005] On the other hand, PDE4 exhibits high specificity for cAMP and exists in four isoforms: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in promoting physiological and pathological processes related to monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, and influences central nervous system function, cardiovascular function, inflammation / immune system, and cell adhesion. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators by inflammatory cells.

[0006] The development of a novel molecule possessing both PDE3 and PDE4 inhibitory activity combines the bronchodilation effect of a β-adrenergic receptor agonist with the anti-inflammatory action of glucocorticoid inhalation, resulting in a complementary dual-targeting function that offers superior efficacy compared to a single target.

[0007] For example, RPL554 (9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one) is a PDE3 / PDE4 dual-target inhibitor disclosed in WO00 / 58308. Recent Phase II clinical data have shown that it can significantly improve bronchodilation and symptoms in patients with chronic obstructive pulmonary disease, and that the drug has good tolerance and has not caused any obvious adverse events, such as mild cardiac disease, nausea, and diarrhea. The safety of the drug and its "limited systemic exposure" are reassuring. [ka]

[0008] The development of a novel molecule possessing both PDE3 and PDE4 inhibitory activity combines the bronchodilation effect of a β-adrenergic receptor agonist with the anti-inflammatory action of glucocorticoid inhalation, resulting in a complementary dual-targeting function that offers superior efficacy compared to a single target.

[0009] Patent application PCT / CN2022 / 090175 provides a compound represented by formula I, whose chemical name is 9,10-dimethoxy-2-[[2-(2-oxoimidazolin-1-yl)-ethyl]-(2,4,6-trimethylphenyl)-amino]-6,7-dihydropyrimido[6,1-a]isoquinoline-4-one, which has relatively good PDE3 and PDE4 inhibitory activity. [ka] [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] WO00 / 58308 [Patent Document 2] PCT / CN2022 / 090175 [Summary of the Invention] [Problems to be Solved by the Invention]

[0011] Generally, the crystal structure of the active ingredient of a drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the difficulty of late-stage drug preparation and production cost. Depending on the crystallization conditions and storage conditions, it may cause changes in the crystal structure of the compound and its salt, and may also be accompanied by the production of other forms of crystal structures. Therefore, considering comprehensively from the perspectives of stability, difficulty of the drug preparation process, and production cost, it is necessary to deeply study the crystal form of the compound represented by Formula I. [Means for Solving the Problems]

[0012] (Summary of the Invention) The present disclosure provides a crystal form of a compound represented by Formula (I), wherein the chemical name of the compound represented by Formula I is 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one. [Chemical Formula]

[0013] The present disclosure provides an amorphous form of the compound represented by Formula (I), and there are no obvious characteristic peaks in the diffraction angle 2θ of its powder X-ray diffraction pattern within the range of 2 to 45 ° .

[0014] The present disclosure further provides a method for preparing an amorphous form of the compound represented by Formula (I), the method comprising: a) mixing and dissolving the compound represented by Formula (I) with benzyl alcohol; and b) volatilizing and crystallizing. <...... (The original text seems to be incomplete here. If there are further parts to be translated, please provide them.)

[0015] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0016] In one embodiment, a method for preparing an amorphous form of the compound shown in (I) of this disclosure further includes the steps of filtration, washing, or drying.

[0017] This disclosure provides a type A crystal of the compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 11.0, 14.4, 15.5, 17.9, 19.1 and 23.7.

[0018] In one embodiment, the A-type crystal of the compound represented by formula (I) has characteristic peaks at 4.6, 6.6, 10.1, 11.0, 14.4, 15.5, 17.9, 19.1, 22.8, and 23.7.

[0019] In one embodiment, the A-type crystal of the compound represented by formula (I) has characteristic peaks at 4.6, 6.6, 10.1, 11.0, 13.1, 14.4, 15.5, 17.1, 17.9, 19.1, 22.8, 23.7, and 25.9.

[0020] In one embodiment, the powder X-ray diffraction pattern of the A-type crystal of the compound represented by formula (I) is as shown in Figure 2, with the diffraction angle being 2θ.

[0021] This disclosure provides a type B crystal of the compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 11.0, 12.7, 15.5, 19.1, 23.7 and 25.8.

[0022] In one embodiment, the B-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 10.0, 11.0, 11.7, 12.7, 15.5, 19.1, 23.7, 24.6, and 25.8.

[0023] In one embodiment, the B-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 8.6, 10.0, 11.0, 11.7, 12.7, 15.5, 17.8, 19.1, 23.7, 24.6, 25.8, and 26.9.

[0024] In one embodiment, the powder X-ray diffraction pattern of the type B crystal of the compound represented by formula (I) is as shown in Figure 3, with the diffraction angle being 2θ.

[0025] This disclosure further provides a method for preparing type B crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula I with dichloromethane; and b) volatilizing and crystallizing the compound.

[0026] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0027] In one embodiment, a method for preparing type B crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0028] This disclosure provides a C-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 15.6, 23.8 and 24.3.

[0029] In one embodiment, the C-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 20.7, 23.8, 24.3, and 24.7.

[0030] In one embodiment, the C-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 17.5, 19.3, 20.7, 23.8, 24.3, 24.7, and 27.0.

[0031] In one embodiment, the C-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 4.

[0032] This disclosure further provides a method for preparing C-type crystals of a compound represented by formula (I), comprising: a) mixing the compound represented by formula I with acetonitrile, methanol, or a mixture thereof; and b) volatilizing and crystallizing the compound.

[0033] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0034] In one embodiment, a method for preparing C-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0035] This disclosure provides a D-type crystal of the compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5 and 24.2.

[0036] In one embodiment, the D-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 24.2, 25.8, and 26.9.

[0037] In one embodiment, the D-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 23.3, 24.2, 24.7, 25.1, 25.8, and 26.9. In one embodiment, the D-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 5.

[0038] This disclosure further provides a method for preparing D-type crystals of the compound represented by formula (I), Method 1 comprises: a) mixing a compound represented by formula I with solvent II, heating or not heating, where solvent II is one or more selected from propylene glycol methyl ether, 1,2-dichloroethane, ethyl acetate / ethanol, n-propanol, tetrahydrofuran / ethanol, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol / acetone, ethanol / isopropyl acetate, and acetonitrile / methanol / acetone; and b) volatilizing and crystallizing. Alternatively, Method 2 comprises: a) mixing and dissolving the compound represented by formula I with solvent III, wherein solvent III is one or more selected from ethanol, N-methylpyrrolidone, dichloromethane, or acetonitrile / methanol; and b) adding solvent IV to precipitate crystals, wherein solvent IV is one or more selected from methyl tert-butyl ether, n-heptane, water, acetone, or isopropyl acetate. Alternatively, Method 3 comprises: a) mixing a compound represented by formula I with solvent V, where solvent V is one or more selected from water, acetone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, methyl isobutyl ketone, 1,4-dioxane, isoamyl alcohol, water / ethanol, water / isopropanol, water / acetone, methanol / water, ethyl acetate / n-heptane, o-xylene, isopropyl ether, and toluene; and b) stirring to crystallize. Includes.

[0039] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0040] In one embodiment, a method for preparing D-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0041] This disclosure provides an E-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.9, 22.9 and 25.6.

[0042] In one embodiment, the E-type crystal of the compound represented by formula (I) has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.0, 17.9, 18.7, 22.9, 23.8, and 25.6.

[0043] In one embodiment, the E-type crystal of the compound represented by formula (I) has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 15.9, 17.0, 17.9, 18.7, 20.1, 22.9, 23.8, and 25.6.

[0044] In one embodiment, the powder X-ray diffraction pattern of the E-type crystal of the compound represented by formula (I) is as shown in Figure 6, with the diffraction angle being 2θ.

[0045] This disclosure further provides a method for preparing type E crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula I with N-methylpyrrolidone; and b) adding isopropyl acetate and causing crystallization.

[0046] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0047] In one embodiment, a method for preparing type E crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0048] This disclosure provides F-type crystals of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 22.3, 24.2 and 26.1.

[0049] In one embodiment, the F-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 16.1, 18.6, 22.3, 24.2, 26.1, and 28.2.

[0050] In one embodiment, the F-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 8.8, 11.1, 12.9, 13.6, 15.0, 16.1, 17.7, 18.6, 22.3, 24.2, 26.1, and 28.2.

[0051] In one embodiment, the F-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 7.

[0052] This disclosure further provides a method for preparing F-type crystals of a compound represented by formula (I), Method 1 comprises a) mixing and dissolving the compound represented by formula I with N-methylpyrrolidone, and b) stirring and crystallizing the compound. Alternatively, Method 2 includes a) dissolving the compound represented by formula I in N-methylpyrrolidone, and b) crystallizing it by adding methyl tert-butyl ether or n-heptane. Includes.

[0053] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0054] In one embodiment, a method for preparing F-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0055] This disclosure provides a G-type crystal of the compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.1, 12.3, 14.2, 16.9, 19.2, 21.4 and 24.0.

[0056] In one embodiment, the G-type crystal of the compound represented by formula (I) has characteristic peaks at 6.1, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4, and 24.0.

[0057] In one embodiment, the G-type crystal of the compound represented by formula (I) has characteristic peaks at 6.1, 11.3, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4, 24.0, 26.6, and 28.8.

[0058] In one embodiment, the G-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 8.

[0059] This disclosure further provides a method for preparing G-type crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula (I) with dichloromethane; and b) adding isopropyl acetate or methyl tert-butyl ether to crystallize the compound.

[0060] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0061] In one embodiment, a method for preparing G-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0062] This disclosure provides an H-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.8, 7.5, 9.7, 13.0, 14.0, 15.1 and 16.1.

[0063] In one embodiment, the H-type crystal of the compound represented by formula (I) has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, and 26.5.

[0064] In one embodiment, the H-type crystal of the compound represented by formula (I) has characteristic peaks at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, 22.1, 23.1, 25.8, and 26.5.

[0065] In one embodiment, the H-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 9.

[0066] This disclosure further provides a method for preparing H-type crystals of a compound represented by formula (I), Method 1 comprises a) mixing type A crystals of the compound represented by formula I with methanol and heating, and b) cooling to crystallize. Method 2 comprises a) dissolving the compound represented by formula I in a mixture of acetonitrile / methanol, and b) crystallizing it by adding methyl tert-butyl ether. Includes.

[0067] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In one embodiment, a method for preparing H-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0068] This disclosure provides a type I crystal of the compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3 and 22.1.

[0069] In one embodiment, the type I crystal of the compound represented by formula (I) has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, and 22.1.

[0070] In one embodiment, the type I crystal of the compound represented by formula (I) has characteristic peaks at 5.2, 7.2, 7.9, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, 21.2, 22.1, and 23.6.

[0071] In one embodiment, the powder X-ray diffraction pattern of the type I crystal of the compound represented by formula (I) is as shown in Figure 10, with the diffraction angle being 2θ.

[0072] This disclosure further provides a method for preparing type I crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula (I) with ethanol and heating it; and b) cooling it down to crystallize it.

[0073] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0074] In one embodiment, a method for preparing type I crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0075] This disclosure provides a J-type crystal of the compound represented by formula (I), the powder X-ray diffraction pattern expressed at a diffraction angle of 2θ, which has characteristic peaks at 7.7, 11.7, 13.5, 14.0, 18.6, 21.6 and 24.3.

[0076] In one embodiment, the J-type crystal of the compound represented by formula (I) has characteristic peaks at 7.7, 10.1, 11.7, 13.5, 14.0, 18.6, 20.2, 21.6, 23.3 and 24.3.

[0077] In one embodiment, the J-type crystal of the compound represented by formula (I) has characteristic peaks at 7.7, 10.1, 10.7, 11.7, 13.5, 14.0, 16.0, 17.3, 18.6, 20.2, 21.6, 23.3, and 24.3.

[0078] In one embodiment, the J-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 11.

[0079] This disclosure further provides a method for preparing J-type crystals of a compound represented by formula (I), comprising: a) mixing A-type crystals of the compound represented by formula (I) with isopropanol and heating; and b) cooling to allow crystallization.

[0080] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0081] In one embodiment, a method for preparing J-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0082] This disclosure provides a K-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.8, 7.4, 13.8, 15.0, 15.8, 20.7 and 22.1.

[0083] In one embodiment, the K-type crystal of the compound represented by formula (I) has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 20.7, 22.1, and 27.6.

[0084] In one embodiment, the K-type crystal of the compound represented by formula (I) has characteristic peaks at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 17.9, 18.4, 20.7, 22.1, 26.5, and 27.6.

[0085] In one embodiment, the K-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 12.

[0086] This disclosure further provides a method for preparing K-type crystals of a compound represented by formula (I), comprising: a) mixing A-type crystals of the compound represented by formula (I) with acetonitrile and heating; and b) cooling to allow crystallization.

[0087] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0088] In one embodiment, a method for preparing K-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0089] This disclosure provides an L-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.1, 7.6, 12.8, 13.6, 19.5, 21.1 and 25.8.

[0090] In one embodiment, the L-type crystal of the compound represented by formula (I) has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6, and 25.8.

[0091] In one embodiment, the L-type crystal of the compound represented by formula (I) has characteristic peaks at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6, and 25.8.

[0092] In one embodiment, the L-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 13.

[0093] This disclosure further provides a method for preparing L-type crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula (I) with dichloromethane; and b) adding methyl tert-butyl ether to crystallize the compound.

[0094] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0095] In one embodiment, a method for preparing L-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0096] This disclosure provides an M-type crystal of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 12.8, 14.8, 19.9, 25.3, 28.1 and 29.9.

[0097] In one embodiment, the M-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 12.8, 14.8, 15.3, 19.9, 24.9, 25.3, 25.9, 28.1, and 29.9.

[0098] In one embodiment, the M-type crystal of the compound represented by formula (I) has characteristic peaks at 6.6, 10.9, 12.8, 14.8, 15.3, 18.0, 19.9, 24.9, 25.3, 25.9, 27.0, 28.1, and 29.9.

[0099] In one embodiment, the M-type crystal of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 14.

[0100] This disclosure further provides a method for preparing M-type crystals of a compound represented by formula (I), comprising: a) mixing and dissolving the compound represented by formula (I) with dimethyl sulfoxide; and b) volatilizing and crystallizing the compound.

[0101] In one embodiment, the volume (μL) used in the solvent described herein may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200.

[0102] In one embodiment, a method for preparing M-type crystals of the compound represented by formula (I) described herein further includes steps such as filtration, washing, or drying.

[0103] This disclosure provides an N-crystal form of a compound represented by formula (I), the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 5.8, 7.6, 16.0, 16.2, 18.6, 22.0, and 22.3.

[0104] In one embodiment, the N-crystal form of the compound represented by formula (I) has characteristic peaks at 5.8, 7.6, 13.5, 16.0, 16.2, 17.9, 18.6, 22.0, 22.3, and 24.0.

[0105] In one embodiment, the N-crystal form of the compound represented by formula (I) has characteristic peaks at 5.8, 7.6, 11.0, 13.5, 16.0, 16.2, 17.9, 18.6, 20.3, 21.2, 22.0, 22.3, and 24.0.

[0106] In one embodiment, the N-crystal form of the compound represented by formula (I) has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 15.

[0107] This disclosure further provides a method for preparing N-type crystals of a compound represented by formula (I), comprising: a) mixing the compound represented by formula I with a phosphoric acid solution and solvent II, heating to clarify, wherein solvent II is at least one selected from isopropanol, tetrahydrofuran, and ethanol; and b) cooling to crystallize.

[0108] In one embodiment, the volume (μL) used in the solvent described in this disclosure may be 1 to 200 times the mass (mg) of the compound of formula I, and in a non-limiting embodiment, it may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In one embodiment, the method for preparing the N-type crystals described in this disclosure further includes steps such as filtration, washing, or drying.

[0109] This disclosure further provides pharmaceutical compositions prepared from the crystalline form of the compound represented by formula (I) above.

[0110] This disclosure further provides pharmaceutical compositions comprising the above-mentioned crystalline form and an optional pharmaceutically acceptable carrier, diluent, or excipient.

[0111] This disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing the above-mentioned crystalline form with a pharmaceutically acceptable carrier, diluent, or excipient.

[0112] This disclosure further provides the use of the above-mentioned crystalline form, or composition, or composition prepared by the above-mentioned method, in the preparation of agents for the prevention and / or treatment of PDE-related diseases.

[0113] This disclosure further provides the use of the above-mentioned crystalline form, or composition, or composition prepared by the above-mentioned method, in the preparation of agents for the prevention and / or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0114] In this disclosure, “2θ or 2θ angle” refers to the diffraction angle, where θ is the Bragg angle, the unit is ° or degrees, and the error range of each characteristic peak 2θ is ±0.20 (including cases where numbers exceeding one decimal place are rounded), and the values ​​are -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.1 0, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20 are also acceptable.

[0115] Based on the description of hygroscopic characteristics and the definition of weight increase due to hygroscopicity in the "Guidelines for the Hygroscopicity of 9103 Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia, Deliquescence: The process of absorbing a sufficient amount of water to form a liquid. Highly hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15%, but 2% or more. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2%, but more than 0.2%. No or almost no hygroscopicity: Weight increase due to moisture absorption is less than 0.2%.

[0116] As described in this disclosure, “differential scanning calorimetry or DSC” refers to measuring the temperature difference and heat flow difference between a sample and a reference object in order to characterize all physical and chemical changes related to thermal effects during a heating or constant-temperature process of a sample and to obtain information on the phase transition of the sample.

[0117] The drying temperature described in this disclosure is generally 25°C to 150°C, preferably 40°C to 80°C, and may be dried under normal pressure or under reduced pressure.

[0118] "Pharmaceutical composition" indicates a mixture of one or more compounds of formula (I) described herein or pharmaceutically acceptable salts thereof with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living organism and contribute to the absorption of the active ingredient, thereby further exerting biological activity.

[0119] The crystalline forms described herein include, but are not limited to, solvates of compounds represented by formula (I), and the solvents include, but are not limited to, n-heptane, cyclohexane, petroleum ether, dichloromethane, acetonitrile, methanol, propylene glycol methyl ether, 1,2-dichloroethane, ethyl acetate, ethanol, n-propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide, acetone, isopropyl acetate, methyl tert-butyl ether, N-methylpyrrolidone, water, 2-butanone, 1,4-dioxane, isoamyl alcohol, o-xylene, isopropyl ether, toluene, isopropanol, dimethyl sulfoxide, and benzyl alcohol.

[0120] The “solvates” described herein include, but are not limited to, complexes formed by combining a compound of formula (I) with a solvent. [Brief explanation of the drawing]

[0121] [Figure 1] This is the amorphous XRPD pattern of the compound represented by formula (I). [Figure 2] This is the XRPD pattern of the type A crystal of the compound represented by formula (I). [Figure 3] This is the XRPD pattern of the B-type crystal of the compound represented by formula (I). [Figure 4] This is the XRPD pattern of the C-type crystal of the compound represented by formula (I). [Figure 5] This is the XRPD pattern of the D-type crystal of the compound represented by formula (I). [Figure 6] This is the XRPD pattern of the E-type crystal of the compound represented by formula (I). [Figure 7] This is the XRPD pattern of the F-type crystal of the compound represented by formula (I). [Figure 8] This is the XRPD pattern of the G-type crystal of the compound represented by formula (I). [Figure 9] This is the XRPD pattern of the H-type crystal of the compound represented by formula (I). [Figure 10] This is the XRPD pattern of a type I crystal of the compound represented by formula (I). [Figure 11] This is the XRPD pattern of a J-type crystal of the compound represented by formula (I). [Figure 12] This is the XRPD pattern of the K-type crystal of the compound represented by formula (I). [Figure 13] This is the XRPD pattern of the L-type crystal of the compound represented by formula (I). [Figure 14] This is the XRPD pattern of the M-type crystal of the compound represented by formula (I). [Figure 15] This is the XRPD pattern of the N-type crystal of the compound represented by formula (I). [Modes for carrying out the invention]

[0122] The present disclosure will be described in more detail below in combination with examples or experimental examples, but the examples or experimental examples of the present disclosure are merely for illustrating the technical concepts of the present disclosure and do not limit the substance or scope of the present disclosure.

[0123] Experimental methods in the examples provided herein that do not specify concrete conditions generally follow normal conditions or conditions recommended by the raw material or product manufacturers. Reagents whose specific sources are not specified are commercially available, standard reagents.

[0124] The structure of a compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shift ( δ ) is 10 -6 The values ​​are expressed in units of ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0125] For MS measurements, the following liquid chromatograph mass spectrometers were used: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (Manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).

[0126] High-performance liquid chromatography (HPLC) analysis was performed using high-pressure liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0127] For chiral HPLC analysis, an Agilent 1260 DAD high-performance liquid chromatograph was used.

[0128] For preparative high-performance liquid chromatography, the Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs were used.

[0129] For chiral preparative chromatography, a Shimadzu LC-20AP preparative chromatograph was used.

[0130] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf200 (TELEDYNE ISCO) was used.

[0131] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0132] For silica gel column chromatography, silica gel with a mesh size of 200-300, manufactured by Yantai Huanghai Silica Gel, was commonly used as the support material.

[0133] Kinase mean inhibition rate and IC 50 A plate reader, NovoStar (BMG GmbH, Germany), was used to measure the values.

[0134] The known starting materials of this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0135] In the examples, unless otherwise specified, all reactions can be carried out under an argon or nitrogen atmosphere.

[0136] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 liter.

[0137] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 liter.

[0138] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0139] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0140] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0141] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0142] In the examples, unless otherwise specified, the reaction temperature is room temperature between 20°C and 30°C.

[0143] Thin-layer chromatography (TLC) was used to monitor the progress of the reaction in the examples. The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin-layer chromatography included A: n-hexane / ethyl acetate system and B: dichloromethane / methanol system. The volume ratio of the solvents was adjusted according to the polarity of the compound and could be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0144] In this disclosure, the test conditions for the equipment used in the experiments are: 1. Differential Scanning Calorimeter (DSC) Equipment model number: Mettler Toledo DSC 3+STARe System Purge gas: Nitrogen gas, Nitrogen gas purging rate: 50 mL / min Heating rate: 10.0℃ / min Temperature range: 25-350°C (or 25-300°C) 2. Powder X-ray diffraction pattern (XRPD) Instrument model number: BRUKER D8 Discover Powder X-ray Diffractometer Radiation: Monochromatic Cu-Kα radiation (λ=1.5418Å) Scanning method: θ / 2θ, Scanning range (2θ range): 3~45° Voltage: 40kV, Current: 40mA 3. Thermogravimetric Analysis (TGA) Device model number: Mettler Toledo TGA2 Purge gas: Nitrogen gas, Nitrogen gas purging rate: 50 mL / min Heating rate: 10.0℃ / min Temperature range: 30~350℃

[0145] Example 1: Preparation of the compound represented by formula (I) Preparation of 9,10-dimethoxy-2-[[2-(2-oxoimidazolin-1-yl)-ethyl]-(2,4,6-trimethylphenyl)-amino]-6,7-dihydropyrimido[6,1-a]isoquinoline-4-one (Compound 1) [ka] [ka]

[0146] Preparation of intermediate 1a: 1-(2-chloroethyl)imidazolinone Under 0°C conditions, 1-(2-hydroxyethyl)imidazolinone (3.5 g, 26.9 mmol) was gradually mixed with sulfoxide chloride (5 mL), the temperature was raised to 45°C, and the mixture was stirred until the reaction was complete. The reaction was then quenched with saturated sodium chloride solution, the pH was adjusted to 7 with 10% NaOH solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain intermediate 1a (3.5 g, yield 88.4%). MS(ESI) m / z 149.1[M+H] + .

[0147] Preparation of intermediate 1b: 1-(3,4-dimethoxyphenethyl)urea At room temperature, 2-(3,4-dimethoxyphenyl)ethylamine hydrochloride (4.3 g, 19.8 mmol) was dissolved in water (25 mL), the temperature was raised to 50 °C, potassium cyanate (1.8 g, 21.8 mmol) was added in several portions, stirring was continued until the reaction was complete, the temperature was lowered to 0 °C, filtered, the filter cake was washed with ice water, and dried to obtain Intermediate 1b (4.1 g, yield 93.8%). MS(ESI) m / z 225.1[M+H] + .

[0148] Preparation of Intermediate 1c: 1-[2-(3,4-dimethoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione Under ice bath conditions, sodium ethanolate (3.8 g, 55.8 mmol) was added to anhydrous ethanol (50 mL) in several portions. After the addition was complete, the temperature was raised to reflux, diethyl malonate (5.9 g, 36.6 mmol) was added dropwise, and stirring was continued for 0.25 h - 0.5 h after the addition was complete. An ethanol solution (30 mL) of Intermediate 1b (4.1 g, 18.3 mmol) was added dropwise, stirring was continued until the reaction was complete, the temperature was lowered to 0 °C, a 5% HCl solution was added dropwise to adjust the pH to 6, 300 mL of water was added, filtered, the filter cake was washed with ice water, and dried to obtain Intermediate 1c (3.9 g, yield 77.1%). MS(ESI) m / z 293.1[M+H] + .

[0149] Preparation of Intermediate 1d: 2-chloro-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one * At room temperature, Intermediate B2 (3.9 g, 13.4 mmol) was added to phosphorus oxychloride (120 mL), the temperature was raised to 110 °C, stirring was continued until the reaction was complete, the temperature was lowered and concentrated, the solid was poured into ice water, a saturated NaOH solution was added dropwise to adjust the pH to 10, filtered, the filter cake was washed with ice water, and dried to obtain Intermediate 1d (2.4 g, yield 62.4%). MS(ESI) m / z 293.1[M+H] + .

[0150] Preparation of intermediate 1e:9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-2,3,6,7-tetrahydropyrimido[6,1-a]isoquinoline-4-one At room temperature, intermediate 1d (2.4 g, 8.2 mmol) was suspended in isopropanol (30 mL), 2,4,6-trimethylaniline (4.5 g, 24.6 mmol) was added, the system was heated to 90°C, stirred continuously until the reaction was complete, cooled, filtered, the filtered cake was washed with ice water, and dried to obtain intermediate 1e (3.0 g, yield 92.1%). MS(ESI) m / z 392.2[M+H] + .

[0151] Preparation of Compound 1:9,10-dimethoxy-2-[[2-(2-oxoimidazolin-1-yl)-ethyl]-(2,4,6-trimethylphenyl)-amino]-6,7-dihydropyrimido[6,1-a]isoquinoline-4-one At room temperature, intermediate 1e (0.72 g, 1.8 mmol) was dissolved in tetrahydrofuran (20 mL), potassium tert-butoxide (0.42 g, 3.6 mmol) was added under a nitrogen atmosphere, and after the addition was complete, the temperature was raised to 65°C and stirred for 48 hours, then cooled to 25°C and intermediate 1a (0.82 g, 5.5 mmol) was added, and after the addition was complete, the temperature was raised to 80°C and stirred until the reaction was complete, saturated sodium chloride solution was added to quench the reaction, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and target compound 1 (0.21 g, yield 46.5%) was obtained by silica gel column chromatography (n-heptane / ethyl acetate).

[0152] 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 5.39 (s, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.08-3.99 (m, 2H), 3.93 (s, 3H), 3.77-3.69 (m, 5H), 3.55-3.46 (m, 2H), 3.38-3.42 (t, J = 6.8 Hz, 2H), 2.88-2.92 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 2.18 (s, 6H).

[0153] MS(ESI) m / z 504.4 [M+H] + .

[0154] Comparative Example 1 [ka] [ka]

[0155] Intermediate 3d was prepared using 2-(3-ethoxy-4-methoxyphenyl)ethylamine hydrochloride as the starting material, following the method of Example 1.

[0156] At room temperature, intermediate 3d (1 g) was dissolved in 1,2-dichloroethane (20 mL), and 4-toluenesulfonic acid-2-(2-oxazolidinone-3-yl)ethyl (844 mg), potassium carbonate (612 mg), and sodium iodide (443 mg) were added in sequence. The mixture was heated to 80°C, stirred until the reaction was complete, cooled, filtered, concentrated, diluted with water, extracted with ethyl acetate, combined the organic phases, dried, filtered, concentrated, and obtained WX001 by column chromatography. MS(ESI) m / z 519.0[M+H] + .

[0157] Biological evaluation

[0158] The following provides further explanation of this disclosure, along with examples of tests, but these examples are not intended to limit the scope of this disclosure.

[0159] Test Example 1 In vitro PDE4B enzyme activity detection experiment: Detection based on the IMAP FP analytical method.

[0160] 1. Materials for the experiment

[0161] [Table 1]

[0162] 2. Experimental Procedure The compound was gradient-diluted fivefold with DMSO to obtain various concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compounds of various concentrations were added to 384-well plates (n=2), and simultaneously, 2 parts of 200 μL of DMSO were added to 384-well plates (n=2) as a blank control. Next, 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was added to one of the 384-well plates, and 10 μL of blank buffer without PDE4B1 enzyme was added to the other blank control. The mixture was incubated at room temperature for 15 minutes with shaking, and then 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP reaction buffer r and 1 mM DTT) was added. The mixture was incubated at room temperature for 30 minutes with shaking, and then the detection solution (0.5625 mM 5*IMAP progressive binding buffer A) was added. A) 60 μL of 0.1875 mM 5*IMAP progressive binding buffer B and 0.75 mM binding beads was added, incubated at room temperature for 60 minutes with shaking, and then data was collected. The inhibition rate was calculated using the formula: Inhibition rate = M / (MM) 対照 ) × 100, and IC is obtained from the concentration and inhibition rate fitting curve. 50 The values ​​were calculated. In this experiment, RPL554 was used as a positive control.

[0163] In vitro PDE4B1 enzyme activity inhibition by the examples of this disclosure was measured by the above test, and the measured IC 50 The values ​​are shown in Tables I and II.

[0164] Test Example 2 In vitro PDE3A enzyme activity detection experiment: Detection based on the IMAP FP analytical method.

[0165] 1. Materials for the experiment

[0166] [Table 2]

[0167] 2. Experimental Procedure The compound was gradient diluted fivefold with DMSO to obtain various concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of each concentration of the compound was added to 384-well plates (n=2), and simultaneously, two parts of 200 μL of DMSO were added to 384-well plates (n=2) as a blank control. Next, 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was added to the 384-well plates, and then 10 μL of blank buffer without PDE3A enzyme was added to one of the blank controls. The mixture was incubated at room temperature for 15 minutes with shaking. The sample was then mixed with 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT), incubated at room temperature for 30 minutes with shaking, then 60 μL of detection solution (prepared with 0.5625 mM 5*IMAP progressive binding buffer, 0.1875 mM 5*IMAP progressive binding buffer B and 0.75 mM binding beads), incubated at room temperature for 60 minutes with shaking, and data was collected. The inhibition rate was calculated using the formula: Inhibition Rate = M / (MM 対照 ) × 100, and IC is obtained from the concentration and inhibition rate fitting curve. 50The values ​​were calculated. In this experiment, RPL554 was used as a positive control.

[0168] In vitro PDE3A enzyme activity inhibition by the examples of this disclosure was measured by the above test, and the measured IC 50 The values ​​are shown in Tables I and II.

[0169] [Table 3]

[0170] [Table 4]

[0171] Conclusion: Compared to the positive compound RPL554, compound 1 showed good biological activity in in vitro enzyme experiments, and compared to compound WX001, compound 1's inhibitory activity against the PDE3A enzyme was seven times higher, indicating good potential for development.

[0172] Test Example 3: Intratracheal PK Experiment

[0173] 1. Objective of the experiment This study evaluates the pharmacokinetic characteristics and distribution in lung tissue of SD rats after intratracheal administration of the test product.

[0174] 2. Test Plan

[0175] 2.1 Test reagent Compound 1 and RPL-554

[0176] 2.2 Test animals These are 198 ICR mice (Shanghai SLAC Laboratory Animals Co., Ltd.), with an equal number of males and females.

[0177] 2.3 Preparation of drugs 1) Homogeneous solution: 0.5 g of Tween80 was weighed out and dissolved in 50 mL of pH 2.5 citrate / disodium hydrogen phosphate buffer solution, and prepared for use.

[0178] 1.0 mg of the test drug was weighed, dissolved in an appropriate amount of Tween solution, and prepared as a 0.03 mg / mL solution for use.

[0179] 2) Suspension: 0.5 g of CMC-Na and 0.5 g of Tween20 were weighed, and 50 mL of 0.9% physiological saline solution was added and mixed uniformly to obtain a 1% solution of CMC-Na and Tween20, which was prepared for use.

[0180] 1.0 mg of the test drug was weighed out and added to 10 mL of the above solution. The mixture was then dispersed using ultrasound and uniformly stirred to obtain a suspension, which was then prepared for use.

[0181] 2.4 Dosage Plan

[0182] [Table 5]

[0183] 3. Experimental Procedure / Process

[0184] 3.1 Intratracheal administration in mice Mice were anesthetized with isoflurane gas and then administered intratracheally. Plasma was collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours. 200 μL of whole blood was collected, EDTA-K2 anticoagulant was added, and the mixture was centrifuged at approximately 6800 g for 6 minutes at 2-8°C. The resulting plasma was transferred to appropriately labeled test tubes within 1 hour of collection / centrifugation and frozen at -80°C. Lung tissue was collected at 0.5, 2, 8, and 24 hours. After collecting the tissue samples, they were transferred to appropriately labeled test tubes and frozen at -80°C.

[0185] 3.2 Plasma processing and LC-MS / MS analysis A 30.0 μL plasma sample was taken and placed in a 1.5 mL centrifuge tube. 150 μL of internal standard working solution was added, and the mixture was homogeneously vortexed for 1 minute. The mixture was then centrifuged for 5 minutes (13000 rpm, 4°C). 70.0 μL of the supernatant was taken and placed in a 96-well plate. 70.0 μL of deionized water was added and the plate was shaken homogeneously. The sample was then injected and analyzed, and 2.00 μL was injected for LC-MS / MS analysis.

[0186] 3.3 Processing of lung tissue An appropriate amount of lung tissue sample was precisely weighed and placed in a homogenizer tube. Acetonitrile equivalent to five times its weight was added and mixed until homogenized, and sonication was performed for 5 minutes. 20.0 μL of the lung tissue homogenate sample was taken, 30.0 μL of internal standard working solution and 200 μL of acetonitrile were added, vortexed for 1 minute, and centrifuged for 10 minutes (4000 rpm, 4°C). 100 μL of the supernatant was taken and placed in a 96-well plate. 100 μL of deionized water was added, the plate was shaken to mix uniformly (1000 rpm, RT), and 1.00 μL was injected for LC-MS / MS analysis.

[0187] 4. Results of pharmacokinetic parameters Compared to RPL-554, compound 1 exhibits relatively higher in vivo exposure and a relatively longer retention time in the lungs. Relevant data are shown in Tables III and IV.

[0188] [Table 6]

[0189] [Table 7]

[0190] Example 2: Preparation of amorphous form of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was added to 0.04 mL of benzyl alcohol, dissolved by stirring at room temperature, and allowed to crystallize by volatilization at room temperature to obtain the product. Detection by powder X-ray diffractometer revealed that the product was amorphous.

[0191] Example 3: Preparation of type A crystals of the compound represented by formula (I) The product was prepared according to Example 1. Detection by powder X-ray diffractometer revealed that the product was of crystalline type A. The XRPD pattern is shown in Figure 2, and its characteristic peak positions are shown in Table 1. According to the DSC pattern, the endothermic peaks were at 135.93°C and 263.19°C. According to the TGA pattern, the weight decreased by 3.97% between 30°C and 275°C.

[0192] [Table 8]

[0193] Example 4: Preparation of B-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was mixed with 0.16 mL of dichloromethane, dissolved by stirring at room temperature, and allowed to crystallize by volatilization at room temperature to obtain the product. Powder X-ray diffraction detection revealed that the product was of crystalline type B. The XRPD pattern is shown in Figure 3, and its characteristic peak positions are shown in Table 2. According to the DSC pattern, the endothermic peaks were at 139.31°C and 263.02°C, and the heat dissipation peak was at 153.33°C. The TGA pattern showed a 7.14% weight reduction between 30°C and 290°C.

[0194] [Table 9]

[0195] Example 5: Preparation of C-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was added to 0.28 mL of acetonitrile / methanol (1:1), dissolved by stirring at room temperature, and crystallized by volatilization at room temperature to obtain the product. Powder X-ray diffraction detection revealed that the product was defined as crystalline form C. The XRPD pattern is shown in Figure 4, and its characteristic peak positions are shown in Table 3. According to the DSC pattern, the endothermic peak values ​​were 148.77°C and 262.90°C. The TGA pattern showed a 4.36% weight reduction between 30°C and 195°C.

[0196] [Table 10]

[0197] Example 6: Preparation of D-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was added to 0.8 mL of propylene glycol methyl ether, heated, clarified, and allowed to volatilize at room temperature to crystallize and obtain the product. Powder X-ray diffraction detection revealed the product to be a D-type crystal, with the XRPD pattern shown in Figure 5 and its characteristic peak positions shown in Table 4. According to the DSC pattern, the endothermic peaks were at 163.12°C and 263.24°C, and the heat dissipation peak was at 166.84°C. The TGA pattern showed a 3.02% weight reduction between 30°C and 165°C.

[0198] [Table 11]

[0199] Example 7: Preparation of D-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was added to 0.44 mL of ethyl acetate / ethanol (1:1), dissolved by stirring at room temperature, and crystallized by volatilization at room temperature to obtain the product. It was detected as a D-type crystal by powder X-ray diffraction.

[0200] Example 8: Preparation of D-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was added to 0.3 mL of ethanol, dissolved by stirring at room temperature, 1 mL of water was added to precipitate the solid, centrifuged, and dried under vacuum to obtain the product. It was detected as a D-type crystal by powder X-ray diffraction.

[0201] Example 9: Preparation of D-type crystals of the compound represented by formula (I) Approximately 8 mg of type A crystals of compound (I) were added to 0.8 mL of water, stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the product. It was detected as type D crystals by powder X-ray diffraction.

[0202] Example 10: Preparation of D-type crystals of the compound represented by formula (I) Approximately 8 mg of type A crystals of the compound of formula (I) were added to 0.8 mL of acetone, and the mixture was stirred at room temperature to induce crystallization. The mixture was then centrifuged, and the solid was dried under vacuum to obtain the product. The product was detected as type D crystals by powder X-ray diffraction.

[0203] Example 11: Preparation of E-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was dissolved by adding 0.3 mL of N-methylpyrrolidone and stirring. 1 mL of isopropyl acetate was added to precipitate the solid, which was then centrifuged and dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as an E-type crystal, and the XRPD pattern is shown in Figure 6, with the characteristic peak positions shown in Table 5. According to the DSC pattern, the peak value of the endothermic peak was 265.03°C. According to the TGA pattern, the weight decreased by 0.33% between 30°C and 170°C.

[0204] [Table 12]

[0205] Example 12: Preparation of F-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was mixed with 0.12 mL of N-methylpyrrolidone, stirred to dissolve, stirred to crystallize, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as an F-type crystal, and the XRPD pattern is shown in Figure 7, with the characteristic peak positions shown in Table 6. According to the DSC pattern, the endothermic peak values ​​were 96.91°C, 141.88°C, and 263.70°C. According to the TGA pattern, the weight decreased by 25.77% between 30°C and 220°C.

[0206] [Table 13]

[0207] Example 13: Preparation of F-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was dissolved by adding 0.3 mL of N-methylpyrrolidone and stirring. 1 mL of methyl tert-butyl ether was added to precipitate a solid, which was then centrifuged and dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as an F-type crystal.

[0208] Example 14: Preparation of G-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was dissolved by adding 0.2 mL of dichloromethane and stirring. 1.2 mL of isopropyl acetate was added to precipitate a solid, which was then centrifuged and dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as a G-type crystal, and the XRPD pattern is shown in Figure 8, with the characteristic peak positions shown in Table 7. According to the DSC pattern, the peak value of the endothermic peak was 264.37°C. According to the TGA pattern, the weight decreased by 0.24% between 30°C and 205°C.

[0209] [Table 14]

[0210] Example 15: Preparation of H-type crystals of the compound represented by formula (I) Approximately 8 mg of A-type crystals of compound (I) were added to 0.8 mL of methanol, insoluble by stirring at room temperature, heated to 50°C, gradually cooled to precipitate, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction detection revealed that the product was defined as an H-type crystal, and the XRPD pattern is shown in Figure 9, with the characteristic peak positions shown in Table 8. According to the DSC pattern, the endothermic peaks were at 149.99°C and 264.92°C, and the heat dissipation peak was at 158.39°C. According to the TGA pattern, the weight decreased by 2.53% between 30°C and 160°C.

[0211] [Table 15]

[0212] Example 16: Preparation of H-type crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was dissolved by adding 0.25 mL of acetonitrile / methanol (1:1) and stirring. 1.2 mL of methyl tert-butyl ether was added to precipitate a solid, which was then centrifuged and dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as an H-type crystal.

[0213] Example 17: Preparation of type I crystals of the compound represented by formula (I) Approximately 8 mg of the compound of formula (I) was dissolved by adding 0.4 mL of ethanol and stirring. The mixture was heated to 50°C, gradually cooled to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffraction detected the product as a type I crystal, and the XRPD pattern is shown in Figure 10, with the characteristic peak positions shown in Table 9. According to the DSC pattern, the endothermic peaks were at 140.16°C and 264.78°C, and the heat dissipation peak was at 159.54°C. According to the TGA pattern, the weight decreased by 6.27% between 30°C and 170°C.

[0214]

Table 16

[0215] Example 18: Preparation of the J - form crystal of the compound represented by formula (I) 0.8 mL of isopropanol was added to about 8 mg of the A - form crystal of the compound of formula (I), heated to 50 °C, gradually cooled for crystallization, centrifuged, and the solid was dried under vacuum to obtain the product. As detected by powder X - ray diffraction, the product was defined as the J - form crystal, the XRPD pattern was as shown in Figure 11, and the positions of its characteristic peaks were as shown in Table 10. According to the DSC pattern, the peak values of the endothermic peaks were 153.46 °C and 264.58 °C. According to the TGA pattern, the weight decreased by 9.46% from 30 °C to 160 °C.

[0216]

Table 17

[0217] Example 19: Preparation of the K - form crystal of the compound represented by formula (I) 0.8 mL of acetonitrile was added to about 8 mg of the A - form crystal of the compound of formula (I), heated to 50 °C, gradually cooled for crystallization, centrifuged, and the solid was dried under vacuum to obtain the product. As detected by powder X - ray diffraction, the product was defined as the K - form crystal, the XRPD pattern was as shown in Figure 12, and the positions of its characteristic peaks were as shown in Table 11. According to the DSC pattern, the peak values of the endothermic peaks were 153.65 °C, 160.48 °C, and 265.14 °C, and the peak value of the exothermic peak was 158.85 °C. According to the TGA pattern, the weight decreased by 5.27% from 30 °C to 195 °C.

[0218]

Table 18

[0219] Example 20: Preparation of the L - form crystal of the compound represented by formula (I) 5 mL of dichloromethane was added to about 200 mg of the compound of formula (I), and the mixture was stirred until dissolved. Then 30 mL of methyl tert-butyl ether was added to precipitate a solid, which was separated by centrifugation and dried under vacuum to obtain the product. As detected by powder X-ray diffraction, the product was defined as an L-type crystal, and its XRPD pattern was as shown in Figure 13, and the positions of its characteristic peaks were as shown in Table 12. According to the DSC pattern, the peak values of the endothermic peaks were 137.47 °C and 264.18 °C, and the peak value of the exothermic peak was 159.83 °C. According to the TGA pattern, the weight decreased by 9.46% from 30 °C to 195 °C.

[0220]

Table 19

[0221] Example 21: Preparation of M-type crystal of the compound represented by formula (I) 0.48 mL of dimethyl sulfoxide was added to about 8 mg of the compound of formula (I), and the mixture was stirred until dissolved. Then it was volatilized at room temperature for crystallization to obtain the product. As detected by powder X-ray diffraction, the product was defined as an M-type crystal, and its XRPD pattern was as shown in Figure 14, and the positions of its characteristic peaks were as shown in Table 13. According to the DSC pattern, the peak values of the endothermic peaks were 161.65 °C and 264.86 °C. According to the TGA pattern, the weight decreased by 13.41% from 30 °C to 235 °C.

[0222]

Table 20

[0223] Example 22: Preparation of N-type crystal of the compound represented by formula (I) 10 mg of the compound represented by formula (I) was added to 0.5 mL of isopropanol, stirred at 50°C to clarify, 11 μL of 2 M aqueous phosphoric acid solution was added, the temperature was cooled to induce crystallization, the mixture was centrifuged, and the solid was dried under vacuum to obtain the product. Powder X-ray diffractometer detection revealed that the product is an N-type crystal. The XRPD pattern is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 14. According to the DSC pattern, the peak value of the endothermic peak is 226.58°C. According to the TGA pattern, the weight decreased by 4.51% between 30°C and 235°C.

[0224] [Table 21]

[0225] Example 23: Study of the hygroscopicity of D-type crystals of the compound of formula (I) The Surface Measurement Systems Advantage 2 was adopted, and considering the temperature of 25°C, humidity from 50%, humidity range of 0% to 95%, and step size of 10%, the criteria for judgment were a mass change dM / dT of less than 0.002% for each gradient, and a maximum execution time TMAX of 360 min for each humidity gradient, with 2 cycles.

[0226] [Table 22]

[0227] Example 24: Experiment on the influence of factors on the crystal form of the compound of formula (I) D-type, E-type, G-type, H-type, and N-type crystals of the compound of formula (I) were placed flat in an open state, and the stability of the samples was examined under high temperature (40°C, 60°C) and high humidity (RH75%, RH92.5%) conditions, with a sampling and analysis period of 30 days.

[0228] [Table 23-1] [Table 23-2]

[0229] Conclusion: As is clear from the influence factor experiments, when the D-form crystals of the compound of formula (I) were subjected to conditions of high temperature of 40 °C and 60 °C and high humidity of 75% and 92.5% for 30 days, their physical and chemical stability was good. When the E-form crystals, G-form crystals and H-form crystals were subjected to conditions of high humidity of 75% and 92.5% for 30 days, their physical stability was relatively poor and their chemical stability was good.

[0230] Example 25: Long-term / accelerated stability of the crystal forms of the compound of formula (I) The D-form crystals, E-form crystals, G-form crystals and H-form crystals of the compound of formula (I) were placed under the conditions of -20 °C, 4 °C, 25 °C / 60%RH and 40 °C / 75%RH respectively to investigate their stability.

[0231]

Table 24

[0232] Conclusion: As is clear from the long-term accelerated experiments, when subjected to the conditions of 25 °C / 60RH and 40 °C / 75RH for 6 months, the physical and chemical stability of the D-form crystals was good. For the E-form crystals, G-form crystals and H-form crystals, their chemical stability was good and their physical stability was slightly poor.

Claims

1. A type B crystal of the compound represented by formula (I), 【Chemistry 1】 A type B crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 11.0, 12.7, 15.5, 19.1, 23.7, and 25.8, preferably at 6.6, 10.0, 11.0, 11.7, 12.7, 15.5, 19.1, 23.7, 24.6, and 25.8, more preferably at 6.6, 8.6, 10.0, 11.0, 11.7, 12.7, 15.5, 17.8, 19.1, 23.7, 24.6, 25.8, and 26.9, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 3.

2. A C-type crystal of the compound represented by formula (I), 【Chemistry 2】 A C-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 7.5, 10.1, 10.9, 15.6, 23.8, and 24.3, preferably at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 20.7, 23.8, 24.3, and 24.7, more preferably at 6.6, 7.5, 10.1, 10.9, 13.8, 15.6, 17.5, 19.3, 20.7, 23.8, 24.3, 24.7, and 27.0, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 4.

3. A D-type crystal of the compound represented by formula (I), 【Transformation 3】 A D-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5 and 24.2, preferably at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 24.2, 25.8 and 26.9, more preferably at 6.6, 10.1, 11.0, 15.6, 16.5, 17.5, 20.3, 23.3, 24.2, 24.7, 25.1, 25.8 and 26.9, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 5.

4. An E-type crystal of the compound represented by formula (I), 【Chemistry 4】 The powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.3, 11.1, 12.8, 14.3, 17.9, 22.9, and 25.6, preferably at 6.3, 11.1, 12.8, 14.3, 17.0, 17.9, 18.7, 22.9, 23.8, and 25.6, more preferably at 6.3, 11.1, 12.8, 14.3, 15.9, 17.0, 17.9, 18.7, 20.1, 22.9, 23.8, and 25.6, and most preferably, the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 6, characterized by this E-type crystal of the compound.

5. An F-type crystal of the compound represented by formula (I), 【Transformation 5】 The powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 11.1, 13.6, 15.0, 22.3, 24.2, and 26.1, preferably at 6.6, 11.1, 13.6, 15.0, 16.1, 18.6, 22.3, 24.2, 26.1, and 28.1, more preferably at 6.6, 8.8, 11.1, 12.9, 13.6, 15.0, 16.1, 17.7, 18.6, 22.3, 24.2, 26.1, and 28.2, and most preferably, the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 7, characterized by this F-type crystal of the compound.

6. A G-type crystal of the compound represented by formula (I), 【Transformation 6】 A G-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.1, 12.3, 14.2, 16.9, 19.2, 21.4 and 24.0, preferably at 6.1, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4 and 24.0, more preferably at 6.1, 11.3, 12.3, 13.1, 14.2, 15.2, 16.1, 16.9, 19.2, 21.4, 24.0, 26.6 and 28.8, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 8.

7. An H-type crystal of the compound represented by formula (I), 【Transformation 7】 The powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.8, 7.5, 9.7, 13.0, 14.0, 15.1, and 16.1, preferably at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, and 26.5, more preferably at 6.8, 7.5, 9.7, 10.2, 10.9, 13.0, 14.0, 15.1, 16.1, 22.1, 23.1, 25.8, and 26.5, and most preferably, the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 9, characterized by this H-type crystal of the compound.

8. A type I crystal of the compound represented by formula (I), 【Transformation 8】 A type I crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3 and 22.1, preferably at 5.2, 7.2, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5 and 22.1, more preferably at 5.2, 7.2, 7.9, 9.6, 10.2, 12.0, 13.3, 14.5, 15.0, 19.5, 21.2, 22.1 and 23.6, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 10.

9. A J-type crystal of the compound represented by formula (I), 【Chemistry 9】 A J-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.7, 11.7, 13.5, 14.0, 18.6, 21.6, and 24.3, preferably at 7.7, 10.1, 11.7, 13.5, 14.0, 18.6, 20.2, 21.6, 23.3, and 24.3, more preferably at 7.7, 10.1, 10.7, 11.7, 13.5, 14.0, 16.0, 17.3, 18.6, 20.2, 21.6, 23.3, and 24.3, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 11.

10. A K-type crystal of the compound represented by formula (I), 【Chemistry 10】 A K-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.8, 7.4, 13.8, 15.0, 15.8, 20.7, and 22.1, preferably at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 20.7, 22.1, and 27.6, more preferably at 6.8, 7.4, 9.5, 13.8, 14.2, 15.0, 15.8, 17.9, 18.4, 20.7, 22.1, 26.5, and 27.6, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 12.

11. An L-type crystal of the compound represented by formula (I), 【Chemistry 11】 An L-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.1, 7.6, 12.8, 13.6, 19.5, 21.1 and 25.8, preferably at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8, more preferably at 7.1, 7.6, 9.2, 12.8, 13.6, 16.1, 19.5, 21.1, 24.6 and 25.8, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 13.

12. An M-type crystal of the compound represented by formula (I), 【Chemistry 12】 The powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 6.6, 12.8, 14.8, 19.9, 25.3, 28.1, and 29.9, preferably at 6.6, 12.8, 14.8, 15.3, 19.9, 24.9, 25.3, 25.9, 28.1, and 29.9, more preferably at 6.6, 10.9, 12.8, 14.8, 15.3, 18.0, 19.9, 24.9, 25.3, 25.9, 27.0, 28.1, and 29.9, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 14, characterized by this M-type crystal of the compound.

13. An N-type crystal of the compound represented by formula (I), 【Chemistry 13】 An N-type crystal of a compound characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 5.8, 7.6, 16.0, 16.2, 18.6, 22.0, and 22.3, preferably at 5.8, 7.6, 13.5, 16.0, 16.2, 17.9, 18.6, 22.0, 22.3, and 24.0, more preferably at 5.8, 7.6, 11.0, 13.5, 16.0, 16.2, 17.9, 18.6, 20.3, 21.2, 22.0, 22.3, and 24.0, and most preferably the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, is as shown in Figure 15.

14. The crystal type according to any one of claims 1 to 13, characterized in that the error range of the 2θ angle is ±0.

2.

15. A pharmaceutical composition prepared from the crystalline form described in any one of claims 1 to 14.

16. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 14 and an optionally pharmaceutically acceptable carrier, diluent, or excipient.

17. A method for preparing a pharmaceutical composition, comprising the step of mixing a crystalline form described in any one of items 1 to 14 with a pharmaceutically acceptable carrier, diluent, or excipient.

18. Use of a crystalline form according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16, or a pharmaceutical composition prepared by the method of claim 17, in the preparation of a drug for preventing and / or treating PDE-related diseases.

19. Use of a crystalline form according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15 or 16, or a pharmaceutical composition prepared by the method of claim 17, in the preparation of a drug for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

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