Novel crystal form of compound containing diaza subunit sulfonyl structure

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a crystal form A of a compound I. An XRPD pattern comprises one or more or all diffraction peaks at the following 2 theta angles: 11.8 + / -0.2 degrees, 13.9 + / -0.2 degrees, 16.6 + / -0.2 degrees, 19.6 + / -0.2 degrees, 20.4 + / -0.2 degrees, 22.2 + / -0.2 degrees and 24.6 + / -0.2 degrees. The crystal form A provided by the invention has stronger stability, and the novel crystal form has the property suitable for medicine.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a novel crystal form of a compound containing a diazabylsulfonyl structure. Background Art

[0002] The related applications previously filed by the applicant of the present invention involve PCT international patent applications PCT / CN2022 / 140731, PCT / CN2024 / 090827, and PCT / CN2024 / 095232, and the entire contents of these three patent applications are incorporated into this application by way of full citation.

[0003] In the aforementioned related applications of the present invention, a novel compound containing a diazabylsulfonyl structure was provided. The compound "(S)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-biazabutaneylidene]-1(4H)-yl)propan-1-one" is one of the specific compounds provided, and its chemical structure is shown in Formula I:

[0004]

[0005] (S)-2-(2,4-Difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-biazabutaneylidene]-1(4H)-yl)propan-1-one has good PKR agonist and / or PKM2 inhibitory activities and is expected to be used for the prevention and treatment of PKR- and / or PKM2-mediated related diseases, such as sickle cell anemia, β-thalassemia, colorectal cancer, renal cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma, or multiple myeloma, etc. It is worth noting that areas with relatively severe anemia are mainly concentrated in hot and humid regions such as sub-Saharan Africa, South Asia, Southeast Asia, and the Mediterranean coast, making the storage and transportation of related therapeutic drugs face greater challenges.

[0006] However, the compounds I synthesized in the aforementioned related applications of the present invention are all in amorphous form. Therefore, it is still necessary to develop crystal forms with excellent solid-state properties, which will become the key to breaking through the bottleneck of its drugability and achieving clinical transformation. Summary of the Invention

[0007] The object of the present invention is to research and provide a new crystal form of the compound "(S)-2-(2,4-difluorophenyl)-3-hydroxy-1-(1'-(pyridin-2-ylsulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-biazetidine-1(4H)-ylidene]propyl-1-one" which has obvious properties particularly suitable for medicinal use, and this new crystal form has one or more than two medicinal property advantages among stability, solubility, impurity removal ability or hygroscopicity.

[0008] In one aspect, the present invention provides polymorph A of Compound I,

[0009]

[0010] wherein the XRPD pattern comprises one or more or all of the diffraction peaks at the following 2θ angles: 11.8 ± 0.2°, 13.9 ± 0.2°, 16.6 ± 0.2°, 19.6 ± 0.2°, 20.4 ± 0.2°, 22.2 ± 0.2°, 24.6 ± 0.2°.

[0011] In some specific embodiments of the present invention, the XRPD pattern further comprises one or more or all of the diffraction peaks at the following 2θ angles: 7.6 ± 0.2°; 11.0 ± 0.2°; 12.8 ± 0.2°; 15.7 ± 0.2°; 16.9 ± 0.2°; 21.0 ± 0.2°; 22.9 ± 0.2°; 24.1 ± 0.2°; 25.7 ± 0.2°.

[0012] In some specific embodiments of the present invention, the XRPD pattern further comprises one or more or all of the diffraction peaks at the following 2θ angles: 26.6 ± 0.2°; 27.3 ± 0.2°; 28.4 ± 0.2°; 34.3 ± 0.2°.

[0013] In some specific embodiments of the present invention, in the XRPD pattern represented by 2θ angle, it comprises the diffraction peaks shown in the following table:

[0014]

[0015]

[0016] In some specific embodiments of the present invention, the XRPD pattern of polymorph A is Figure 2 substantially the same as that shown.

[0017] Furthermore, in the present invention, X-ray powder diffraction is carried out using a Cu target for irradiation.

[0018] In some specific embodiments of the present invention, the polymorph A is anhydrous.

[0019] In some specific embodiments of the present invention, polymorph A has a melting point of 164 ± 3 °C.

[0020] In some specific embodiments of the present invention, the DSC pattern of polymorph A is substantially the same as that Figure 4 shown.

[0021] In one aspect, the present invention provides a method for preparing the above-mentioned polymorph, including one of the following methods:

[0022] (1) Mix compound I with dichloromethane and dissolve it completely, and crystallize by evaporation at room temperature to obtain polymorph A;

[0023] (2) Mix compound I with methanol, disperse and stir at room temperature, and then separate the solid and liquid to obtain polymorph A.

[0024] In some specific embodiments of the present invention, the compound I taken is in an amorphous state.

[0025] In some specific embodiments of the present invention, the method for preparing amorphous compound I is as follows: Dissolve compound I in dichloromethane and concentrate it under reduced pressure to obtain amorphous compound I.

[0026] Surprisingly, the present invention finds that the formation of the solid form of compound I is highly dependent on the crystallization method. Even if the same good solvent is used for dissolution, different solid forms can still be obtained by separating the good solvent in different ways. For example, when using the good solvent dichloromethane to dissolve completely, in Example 1, the usual treatment method of concentration and evaporation to dryness is adopted, and an amorphous white solid form can be obtained, and the crystal form cannot be obtained; while in Example 2, a powdery solid of polymorph A can be obtained by the method of drying in an open container.

[0027] In one aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned polymorph A and a pharmaceutically acceptable carrier or excipient.

[0028] In the present invention, when the above-mentioned polymorph A or pharmaceutical composition is stored under at least one of the conditions of light (4000 ± 500 lux), high humidity (92.5% RH), high temperature (60 °C), and damp heat (40 °C / 75% RH) for 30 days, the decrease in chemical purity is ≤ 1.5%, and the polymorph does not change.

[0029] In one aspect, the present invention provides the use of the above-mentioned polymorph A or pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to PKM2 or PKR-mediated regulation.

[0030] In one aspect, the present invention provides the use of the above-mentioned crystalline form A or pharmaceutical composition in the preparation of a medicament for preventing and / or treating liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, lymphoma, pancreatic cancer, kidney cancer, experimental autoimmune encephalomyelitis, inflammatory bowel disease, ulcerative colitis, hair loss, alopecia universalis or hypotrichosis.

[0031] In one aspect, the present invention provides the use of the above-mentioned crystalline form A or pharmaceutical composition in the preparation of a medicament for preventing and / or treating anemia-related diseases.

[0032] In some specific embodiments of the present invention, the anemia-related diseases include myelodysplastic syndrome (MDS), low-risk myelodysplastic syndrome (LR-MDS), hemoglobinopathy, sickle cell anemia (SCD), β-thalassemia, hereditary non-spherocytic hemolytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, congenital anemia or anemia of chronic disease.

[0033] In some specific embodiments of the present invention, the anemia-related diseases occur in hot and humid regions.

[0034] In one aspect, the present invention further provides a method for preventing and / or treating anemia-related diseases, which comprises administering a therapeutically effective amount of the crystalline form A or pharmaceutical composition to the patient.

[0035] The present invention has found through research that compared with the amorphous solid form, the crystalline form A solid form has particularly prominent stability at high temperatures. Therefore, in another aspect of the present invention, the anemia-related diseases occur in hot and humid regions. In these regions, Compound I exists in the form of crystalline form A, which can effectively reduce the environmental impact of storage and transportation. The high stability of crystalline form A can avoid the rapid decrease in purity caused by high temperature, thereby avoiding the decline in drug efficacy or the generation of toxic and side effects.

[0036] The stability and environmental resistance of the crystalline form A of Compound I prepared by the present invention are comprehensively superior to those of the amorphous product, and it is particularly suitable for the following scenarios: (1) Extreme environments: such as tropical high-temperature regions or uncontrolled temperature supply chains; (2) Highly active drugs: innovative drugs that require strict guarantee of content stability; (3) Industrial production: Simplify process control and reduce the risk of batch failure caused by crystal form problems. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 XRPD pattern of the amorphous product obtained in Example 1;

[0038] Figure 2 XRPD pattern of the crystalline form A obtained in Example 2;

[0039] Figure 3 DSC / TGA spectrum of crystalline form A obtained in Example 2;

[0040] Figure 4 DSC spectrum of crystalline form A obtained in Example 2. Detailed implementation manners

[0041] The features and other details of the present invention will now be described more specifically. Before further describing the present invention, certain terms used in the specification, examples, and appended claims are collected herein. These definitions should be read in light of the remainder of the present invention and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0042] The term "crystalline form" refers to a solid material in which the components of the solid material are arranged in a highly ordered microscopic structure, thereby forming a lattice extending in all directions.

[0043] In the present invention, those of ordinary skill in the field of solid state chemistry can use a variety of analytical methods to analyze solid forms. The term "analysis" as used herein refers to obtaining information about the solid state structure of a solid form. For example, powder X-ray diffraction (XRPD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms and for characterizing and identifying specific crystalline solid forms of a compound.

[0044] Due to differences in instrumentation, samples, and sample preparation, XRPD peaks are typically reported with a correction factor of "±0.2° 2θ". This is a common practice in the field of solid state chemistry due to the inherent variability of the peaks. The variation in peak intensity is the result of the orientation of individual crystals in the sample container relative to the external X-ray source (referred to as "preferred orientation"). This orientation effect does not provide information about the structure of the crystal.

[0045] The XRPD term "X-ray powder diffraction pattern" or "XRPD pattern" refers to the experimentally observed diffraction pattern or the parameters, data, or values derived therefrom. An XRPD pattern is typically characterized by peak position (abscissa) and / or peak intensity (ordinate).

[0046] The term "diffraction angle" or "2θ" refers to the peak position expressed in degrees (°) based on the settings in an X-ray diffraction experiment and is typically the abscissa unit in a diffraction pattern. If a reflection is diffracted when the incident beam makes an angle θ with a certain lattice plane, the experimental setup needs to record the reflected beam at a 2θ angle. It should be understood that the specific 2θ values mentioned herein for a particular crystalline form are intended to represent the 2θ values (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0047] In the present invention, the term "substantially the same" with respect to X-ray diffraction peaks means taking into account representative peak positions and intensity variations. For example, those skilled in the art will understand that the peak position (2θ) will show some variation, typically up to 0.1 to 0.2 degrees, and the instrument used to measure the diffraction will also cause some variation. Additionally, those skilled in the art will understand that the relative peak intensities will vary due to differences between instruments as well as the degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to those skilled in the art.

[0048] The term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. An amorphous solid is a substance in which the molecules are arranged in a random manner such that there is no distinct arrangement (e.g., molecular packing) and no long-range order. Amorphous solids are typically isotropic, i.e., they exhibit similar properties in all directions and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. The broad peaks are characteristic of amorphous solids. In contrast, crystalline forms produce characteristic XRPD patterns with well-defined peaks.

[0049] The term "pharmaceutically acceptable" includes molecular entities and compositions that, when administered to an animal or human, do not produce adverse, allergic, or other untoward reactions that are unacceptable when considering the benefit-risk ratio of the clinical situation.

[0050] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, etc. that are compatible with the administration of a drug. The use of such media and agents for active pharmaceutical substances is well known in the art. The composition may also contain other active compounds to provide supplementary, additional, or enhanced therapeutic functions.

[0051] An excipient is any ingredient that does not itself exert an active pharmaceutical effect but adapts the composition to a particular route of administration or aids in processing the composition into a dosage form.

[0052] Any and all examples, or the use of exemplary language (e.g., "such as", "including", or "for example") herein are merely intended to better illustrate the teachings and do not limit the scope of the invention unless claimed .

[0053] The term "comprising" or similar expressions synonymous therewith such as "including", "containing", and "having" are open-ended and do not exclude additional unrecited elements, steps, or components.

[0054] The following are abbreviations of terms:

[0055] DCM represents dichloromethane;

[0056] XRPD represents X-ray powder diffraction;

[0057] TGA represents thermogravimetric analysis;

[0058] DSC represents differential scanning calorimetry;

[0059] DSC / TGA represents simultaneous thermal analysis of thermogravimetry and differential scanning calorimetry;

[0060] In the present invention, X-ray powder diffraction (XRPD) analysis is carried out using Dandong Haoyuan DX-2700BH with Cu target irradiation. The detection range is from 3° to 40°, the step size is 0.02°, and the speed is 0.2 s·step⁻¹.

[0061] In the present invention, the simultaneous thermal analyzer (TGA / DSC) is Mettler-Toledo TGA / DSC 3+. The heating rate of the instrument is 10 K / min. Experimental conditions: 30 - 300 °C.

[0062] Example 1: Preparation of amorphous form

[0063] Compound I is prepared with reference to PCT international patent application (application number PCT / CN2022 / 140731).

[0064] Weigh 9.5 g of the prepared Compound I into a single-neck flask, add 80 mL of dichloromethane to the single-neck flask to dissolve it clearly, and concentrate it under reduced pressure in a 50 °C water bath until a white solid is obtained. The obtained white solid is detected by XRPD, and the detection results are as Figure 1 shown, and it is identified as amorphous.

[0065] Example 2: Preparation of crystal form A

[0066] Take 100 mg of the amorphous product prepared in Example 1, place it in a 7 mL vial, add 1.5 mL of dichloromethane, dissolve it clearly at room temperature, volatilize it with an open mouth to crystallize, collect the solid, and obtain a powdery solid. The obtained powdery solid is detected by XRPD, and the XRPD pattern is as Figure 2 shown, Figure 2 and the diffraction peak data are shown in Table 1, and it is named crystal form A.

[0067] Table 1 XRPD data of crystal form A

[0068]

[0069]

[0070] Powdery solid crystal form A was subjected to DSC / TGA testing (synchronous thermal analyzer model Mettler Toledo TGA / DSC3+, testing method conditions: heating rate: 10 K / min; temperature range: 30 - 300 °C), and its DSC / TGA pattern is as Figure 3 shown. The DSC / TGA test results showed a weight loss of approximately 0.5% from 30 to 180 °C, which is almost negligible.

[0071] Powdery solid crystal form A was subjected to DSC testing, and its DSC pattern is as Figure 4 shown. The DSC pattern results showed a single, sharp endothermic peak at 164 ± 3 °C (onset). Therefore, crystal form A is an anhydrous crystal form.

[0072] Example 3: Preparation of crystal form A

[0073] Take 100 mg of the amorphous product prepared in Example 1, place it in a 7 mL vial, add 1 mL of methanol, disperse it, stir it at room temperature under sealing for 72 h, filter and collect the solid to obtain a powdery solid. The obtained powdery solid was identified as crystal form A by XRPD testing.

[0074] Test Example 1: Stability test

[0075] The amorphous product of Example 1 and crystal form A of Example 2 were subjected to stability investigation of content change and crystal form change under various conditions.

[0076] The results are shown in Table 2: Under the conditions of light (4000 ± 500 lux), high humidity (92.5% RH), high temperature (60 °C), and damp heat (40 °C / 75% RH), crystal form A did not undergo crystal form transformation within the 30-day test period and always maintained the initial crystal form, which was significantly better than the amorphous form. In particular, under the light condition (30 days), the purity of the compound in the crystal form A product only decreased by 0.69% (from 99.66% → 98.97%), while the content of the amorphous product decreased to 94.99% within 5 days; in addition, under the high temperature condition (60 °C, 30 days): the content of crystal form A remained at 99.58%, while the content of the amorphous product dropped sharply to 83.40% within 5 days. The amorphous product showed crystal form transformation (partially transformed into crystal form A) within only 5 days under high temperature or light, and was accompanied by deterioration of the physical form (yellowing, caking).

[0077] It can be seen from the above that crystal form A is comprehensively superior to the amorphous product in terms of stability and environmental resistance. Especially for the influence of high temperature factors, the stability of the crystal form A product is significantly more advantageous, indicating that the crystal form A described in the present invention is more suitable for high temperature environments.

[0078] Table 2 Crystal form stability under different conditions

[0079]

[0080] Although embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Polymorph A of Compound I, Among them, The XRPD pattern includes one or more or all of the diffraction peaks at the following 2θ angles: 11.8±0.2°, 13.9±0.2°, 16.6±0.2°, 19.6±0.2°, 20.4±0.2°, 22.2±0.2°, 24.6±0.2°.

2. The crystalline form A according to claim 1, wherein The XRPD pattern further includes one or more or all of the diffraction peaks at the following 2θ angles: 7.6±0.2°; 11.0±0.2°; 12.8±0.2°; 15.7±0.2°; 16.9±0.2°; 21.0±0.2°; 22.9±0.2°; 24.1±0.2°; 25.7±0.2°; Further, the XRPD pattern also includes one or more or all of the diffraction peaks at the following 2θ angles: 26.6±0.2°; 27.3±0.2°; 28.4±0.2°；34.3±0.2°。 3. The crystalline form A according to claim 2, wherein, In its XRPD pattern expressed in 2θ angle, it includes the diffraction peaks as shown in the following table: ； Further, the XRPD pattern of Polymorph A is substantially the same as that shown in Figure 2.

4. The crystalline form A according to claim 1, wherein, The said Polymorph A is anhydrous.

5. The crystalline form A according to claim 1, characterized in that, Polymorph A has a melting point of 164±3°C.

6. The crystalline form A according to claim 1, characterized in that, The DSC graph of Polymorph A is substantially the same as that shown in Figure 4.

7. The preparation method of polymorph A according to any one of claims 1-6, characterized in that, Including one of the following methods: (1) Mix Compound I with dichloromethane, completely dissolve it, and crystallize by volatilization at room temperature to obtain the said Polymorph A; (2) Mix Compound I with methanol, disperse and stir at room temperature, and then carry out solid-liquid separation to obtain the said Polymorph A.

8. The preparation method according to claim 7, characterized in that, The taken Compound I is in amorphous state; Further, the preparation method of amorphous Compound I is as follows: Dissolve Compound I in dichloromethane and concentrate under reduced pressure to obtain the amorphous Compound I.

9. A pharmaceutical composition, characterized in that, It contains the Polymorph A described in any one of claims 1-6 and a pharmaceutically acceptable carrier or excipient.

10. Use of the Polymorph A described in any one of claims 1-6 or the pharmaceutical composition described in claim 9 in the preparation of a drug for preventing and / or treating diseases related to PKM2 or PKR-mediated regulation.

11. Use of the Polymorph A described in any one of claims 1-6 or the pharmaceutical composition described in claim 9 in the preparation of a drug for preventing and / or treating liver cancer, lung cancer, colorectal cancer, glioblastoma, breast cancer, lymphoma, pancreatic cancer, kidney cancer, experimental autoimmune encephalomyelitis, inflammatory bowel disease, ulcerative colitis, hair loss, alopecia universalis or hypotrichosis.

12. Use of the Polymorph A described in any one of claims 1-6 or the pharmaceutical composition described in claim 9 in the preparation of a drug for preventing and / or treating anemia-related diseases; Further, the said anemia-related diseases include myelodysplastic syndrome (MDS), low-risk myelodysplastic syndrome (LR-MDS), hemoglobinopathy, sickle cell anemia (SCD), β-thalassemia, hereditary non-spherocytic hemolytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia, congenital anemia or anemia of chronic disease; Further, the said anemia-related diseases occur in hot and humid areas.

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