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CN-122011077-A - High potency glucocorticoid polymorphs and methods of making and using the same

CN122011077ACN 122011077 ACN122011077 ACN 122011077ACN-122011077-A

Abstract

The invention relates to a novel polymorphism of (8R, 9R,10S,11S,13S,14S,16R, 17R) -6, 9-difluoro-17- (((fluoromethyl) thio) carbonyl) -11-hydroxy-10, 13, 16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta [ alpha ] phenanthren-17-yl furan-2-carboxylic acid ester shown in a formula (I), and a preparation method and application thereof. The crystal form has the characteristics of remarkable drug effect, good stability, high yield, high purity and the like, and is beneficial to the selection and design of drug administration routes and the determination of technological parameters of a drug preparation, so that the production quality of the drug is improved.

Inventors

  • XI ZHIJIAN
  • LU CHUNPING
  • CAO JIANXIN

Assignees

  • 浙江柏拉阿图医药科技有限公司

Dates

Publication Date
20260512
Application Date
20241112

Claims (20)

  1. 1. A polymorph of formula (I), wherein the polymorph is selected from the group consisting of amorphous form A, solvate form B, solvate form C, solvate form E, solvate form G, solvate form H, isomorphous solvate form D, isomorphous solvate form F, Wherein m is 1-10; n is 0-20; X is selected from the group consisting of water, methanol, ethanol, acetonitrile, ethyl acetate/N-heptane, 1, 4-dioxane/N-heptane, isopropanol, 2-methyltetrahydrofuran/N-heptane, N-methylpyrrolidone/water, tetrahydrofuran/water, acetone. In another preferred embodiment, m is 1,2, 3,4, 5, 6, 7, 8, 9 or 10. In another preferred embodiment, n is 0, 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5 or 14. In another preferred embodiment, the polymorph is a crystalline form of the compound of formula (I-1) (8 r,9r,10s,11s,13s,14s,16r,17 r) -6, 9-difluoro-17- (((fluoromethyl) thio) carbonyl) -11-hydroxy-10, 13, 16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta [ α ] phenanthren-17-ylfuran-2-carboxylate:
  2. 2. The crystalline form of claim 1, wherein n is 0 and the crystalline form is anhydrous form A, wherein the XRPD pattern of anhydrous form A comprises 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：7.3435±0.2°、9.7701±0.2°、12.8476±0.2°、13.4629±0.2°、14.6917±0.2°、14.9150±0.2°、15.8911±0.2°、18.7354±0.2°.
  3. 3. The crystalline form of claim 2, wherein the anhydrous crystalline form a further has one or more 2Θ diffraction peaks selected from the group consisting of ：19.6114±0.2°、20.4651±0.2°、22.4373±0.2°、22.6151±0.2°、24.2667±0.2°、25.4833±0.2°、26.7725±0.2°、27.0642±0.2°、29.4052±0.2°、32.8443±0.2°.
  4. 4. The crystalline form of claim 2, wherein the anhydrous crystalline form a further has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of anhydrous form a is substantially as characterized in figure 1; 2) The DSC profile of anhydrous form a is substantially as characterized in figure 2; 3) The DSC spectrum of the anhydrous crystal form A has an endothermic peak in the range of 256.5-260.5 ℃; 4) The anhydrous crystal form A is an anhydrous compound. In another preferred embodiment, the preparation method of the anhydrous crystal form a comprises the following steps: a) Mixing the isomorphous solvate crystal form D of the substance with ethyl acetate, ultrasonically dissolving, and filtering to obtain filtrate; b) Stirring at the temperature of 20-30 ℃, and dripping n-heptane into the filtrate to obtain a reaction liquid; c) Transferring the reaction liquid to 45-55 ℃ for suspension stirring for 2-6 hours, and centrifugally separating solids; d) And transferring the solid to 45-55 ℃ for vacuum drying for 1-3 hours, and collecting the solid to obtain the anhydrous crystal A. In another preferred embodiment, the mass to volume ratio of the solvate form D to the ethyl acetate is (10-50): 1 (mg/mL), preferably (20-40): 1 (mg/mL). In another preferred embodiment, the mass to volume ratio of the solvate form D to the n-heptane is (5-11): 1 (mg/mL), preferably (7-9): 1 (mg/mL).
  5. 5. The crystalline form of claim 1, wherein X is ethanol and the crystalline form is solvate form B, wherein the solvate form B has an XRPD pattern comprising 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：7.8241±0.2°、8.0677±0.2°、11.8678±0.2°、12.0458±0.2°、14.1289±0.2°、14.6628±0.2°、16.1633±0.2°、18.4062±0.2°、19.3972±0.2°、21.1388±0.2°、24.3347±0.2°.
  6. 6. The crystalline form of claim 5, wherein the solvate form B further has one or more 2Θ diffraction peaks selected from the group consisting of ：9.7530±0.2°、15.6548±0.2°、16.3717±0.2°、18.0425±0.2°、20.4815±0.2°、21.6118±0.2°、22.6746±0.2°、22.9815±0.2°、23.4008±0.2°、25.8514±0.2°、28.7348±0.2°.
  7. 7. The crystalline form of claim 5, wherein the solvate form B further has one or more features selected from the group consisting of: 1) The XRPD pattern of solvate form B is substantially as characterized in figure 3; 2) The DSC profile of solvate form B is substantially as characterized in figure 4; 3) The DSC spectrum of the solvate crystal form B has endothermic peaks in the range of 117.6 ℃ to 121.6 ℃, 146.0 ℃ to 150.0 ℃ and 256.2 ℃ to 260.2 ℃ and exothermic peaks in the range of 197.8 ℃ to 201.8 ℃; 4) The solvate crystal form B is ethanol solvate. In another preferred embodiment, the preparation method of the solvate form B comprises: a) Mixing a compound of formula (I-1) with ethanol; b) Stirring for 1-5 days at the temperature of 20-30 ℃; c) And (3) centrifugally separating the solid, drying the solid for 1 to 3 days at room temperature and humidity, and collecting the solid to obtain the solvate crystal form B. In another preferred embodiment, the mass to volume ratio of the compound of formula (I-1) to ethanol is (140-180): 1 (mg/mL), preferably (150-170): 1 (mg/mL).
  8. 8. The crystalline form of claim 1, wherein X is 1, 4-dioxane, the crystalline form is solvate form C, and the XRPD pattern of solvate form C comprises 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：9.3364±0.2°、10.8253±0.2°、12.4948±0.2°、13.1241±0.2°、14.4081±0.2°、15.3668±0.2°、16.4963±0.2°、17.5285±0.2°、17.9766±0.2°、19.0582±0.2°、19.5076±0.2°、21.6255±0.2°、24.9988±0.2°.
  9. 9. The crystalline form of claim 8, wherein the solvate form C further has one or more 2Θ diffraction peaks selected from the group consisting of ：8.1113±0.2°、13.9482±0.2°、14.9936±0.2°、18.7095±0.2°、22.2902±0.2°、23.0597±0.2°、24.2476±0.2°、26.1344±0.2°、26.3568±0.2°、27.0548±0.2°、28.2364±0.2°、29.4411±0.2°、31.0022±0.2°、31.8382±0.2°、37.5931±0.2°.
  10. 10. The crystalline form of claim 8, wherein the solvate form C further has one or more features selected from the group consisting of: 1) The XRPD pattern of solvate form C is substantially as characterized in figure 5; 2) The DSC profile of solvate form C is substantially as characterized in figure 6; 3) The DSC spectrum of the solvate crystal form C has endothermic peaks in the range of 154.2 ℃ to 158.2 ℃, 155.4 ℃ to 159.4 ℃ and 256.1 ℃ to 260.1 ℃; 4) The solvate crystal form C is a1, 4-dioxane solvate. In another preferred embodiment, the preparation method of the solvate form C comprises: a) Mixing a compound of formula (I-1) with 1, 4-dioxane/n-heptane (1) (1-3), v/v); b) Stirring for 1-5 days at the temperature of 20-30 ℃; c) And after centrifugally separating the solid, drying the solid for 1 to 3 days at room temperature under humidity, and collecting the solid to obtain the solvate crystal form C. In another preferred embodiment, the mass to volume ratio of the compound of formula (I-1) to 1, 4-dioxane/n-heptane (1) (1-3), v/v) is (140-180): 1 (mg/mL), preferably (150-170): 1 (mg/mL).
  11. 11. The crystalline form of claim 1, wherein X is isopropanol and the crystalline form is solvate form E, wherein the solvate form E has an XRPD pattern comprising 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：8.0799±0.2°、9.4158±0.2°、10.8909±0.2°、12.4553±0.2°、13.1421±0.2°、15.5862±0.2°、16.7023±0.2°、17.4834±0.2°、17.9850±0.2°、19.2262±0.2°、19.6761±0.2°、21.6316±0.2°.
  12. 12. The crystalline form of claim 11, wherein the solvate form E further has one or more 2Θ diffraction peaks selected from the group consisting of ：13.3591±0.2°、13.9946±0.2°、14.4352±0.2°、15.0316±0.2°、18.3663±0.2°、18.7598±0.2°、18.9295±0.2°、21.8673±0.2°、22.3063±0.2°、24.5835±0.2°、25.1068±0.2°、25.3157±0.2°、25.7008±0.2°、26.4426±0.2°、27.1314±0.2°、28.1896±0.2°、28.5237±0.2°、29.9213±0.2°、35.9890±0.2°、37.5706±0.2°.
  13. 13. The crystalline form of claim 11, wherein the solvate crystalline form E further has one or more features selected from the group consisting of: 1) The XRPD pattern of solvate form E is substantially as characterized in figure 7; 2) The DSC profile of solvate form E is substantially as characterized in figure 8; 3) The DSC spectrum of the solvate crystal form E has endothermic peaks in the range of 129.2 ℃ to 133.2 ℃ and 256.3 ℃ to 260.3 ℃; 4) The solvate crystal form E is isopropanol solvate. In another preferred embodiment, the preparation method of the solvate form E comprises: a) Mixing a compound of formula (I-1) with isopropanol; b) Stirring for 1-5 days at the temperature of 20-30 ℃; c) And after centrifugally separating the solid, drying the solid for 8-10 hours at room temperature under humidity, and collecting the solid to obtain the solvate crystal form E. In another preferred embodiment, the mass to volume ratio of the compound of formula (I-1) to isopropyl alcohol is (140-180): 1 (mg/mL), preferably (150-170): 1 (mg/mL).
  14. 14. The crystalline form of claim 1, wherein X is 2-methyltetrahydrofuran and the crystalline form is solvate form G, wherein the solvate form G has an XRPD pattern comprising 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：9.3084±0.2°、10.7288±0.2°、12.2027±0.2°、14.1646±0.2°、15.3382±0.2°、16.4599±0.2°、17.0935±0.2°、17.5680±0.2°、19.4359±0.2°.
  15. 15. The crystalline form of claim 14, wherein the solvate form G further has one or more 2Θ diffraction peaks selected from the group consisting of ：7.9625±0.2°、12.8501±0.2°、14.8697±0.2°、18.6017±0.2°、18.9050±0.2°、21.2465±0.2°、21.5707±0.2°、24.7033±0.2°、26.9966±0.2°.
  16. 16. The crystalline form of claim 14, wherein the solvate form G further has one or more features selected from the group consisting of: 1) The XRPD pattern of solvate form G is substantially as characterized in figure 9; 2) The DSC profile of solvate form G is substantially as characterized in figure 10; 3) The DSC spectrum of the solvate crystal form G has endothermic peaks in the range of 90.8 ℃ to 94.8 ℃ and 256.3 ℃ to 260.3 ℃; 4) The solvate crystal form G is 2-methyltetrahydrofuran solvate. In another preferred embodiment, the preparation method of the solvate form G comprises: a) Mixing a compound of formula (I-1) with 2-methyltetrahydrofuran/n-heptane (1) (0.5-3), v/v); b) Stirring for 3-5 hours at 40-60 ℃, filtering by using a filter membrane with the pore diameter of 0.3-0.5 mu m, and taking supernatant; c) Cooling the supernatant from 40-60 ℃ to 2-7 ℃ at a speed of 0.05-0.5 ℃ per minute, and keeping the temperature constant for 1-3 days at 2-7 ℃; d) And after centrifugally separating the solid, drying the solid at room temperature for 1-2 days under wet conditions, and collecting the solid to obtain the solvate crystal form G. In another preferred embodiment, the mass to volume ratio of the compound of formula (I-1) to 2-methyltetrahydrofuran/n-heptane (1) (0.5-3), v/v) is (20-40): 1 (mg/mL), preferably (20-30): 1 (mg/mL).
  17. 17. The crystalline form of claim 1, wherein X is N-methylpyrrolidone, the crystalline form is solvate form H, and the XRPD pattern of solvate form H comprises 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：10.8332±0.2°、12.0361±0.2°、12.8852±0.2°、14.1461±0.2°、15.7442±0.2°、16.8217±0.2°、17.4163±0.2°、19.7156±0.2°、21.0801±0.2°、21.7331±0.2°、24.7468±0.2°.
  18. 18. The crystalline form of claim 17, wherein the solvate form H further has one or more 2Θ diffraction peaks selected from the group consisting of ：7.8983±0.2°、9.4784±0.2°、13.9427±0.2°、14.9085±0.2°、18.3991±0.2°、18.9884±0.2°、19.1454±0.2°、21.9545±0.2°、23.7319±0.2°、25.4235±0.2°、25.8434±0.2°、27.4457±0.2°、28.0745±0.2°、30.3708±0.2°、35.3259±0.2°、36.5337±0.2°.
  19. 19. The crystalline form of claim 17, wherein the solvate form H further has one or more features selected from the group consisting of: 1) The XRPD pattern of solvate form H is substantially as characterized in figure 11; 2) The DSC profile of solvate form H is substantially as characterized in figure 12; 3) The DSC spectrum of the solvate crystal form H has an endothermic peak in the range of 151.9 ℃ to 155.9 ℃; 4) The solvate crystal form H is an N-methyl pyrrolidone solvate. In another preferred embodiment, the preparation method of the solvate form H comprises: a) Mixing a compound of formula (I-1) with N-methylpyrrolidone/water (1) (2-6), v/v); b) Stirring for 1-5 days at the temperature of 20-30 ℃; c) And (3) centrifugally separating the solid, drying the solid for 1 to 3 days at room temperature and humidity, and collecting the solid to obtain the solvate crystal form H. In another preferred embodiment, the mass to volume ratio of the compound of formula (I-1) to N-methylpyrrolidone/water (1) (2-6), v/v) is (140-180): 1 (mg/mL), preferably (150-170): 1 (mg/mL).
  20. 20. The crystalline form of claim 1, wherein X is acetone or tetrahydrofuran and the crystalline form is isomorphous solvate form D, wherein the XRPD pattern of isomorphous solvate form D comprises 3 or more (e.g., 4, 5, or 6) 2 theta diffraction peaks selected from the group consisting of ：8.0939±0.2°、11.0035±0.2°、12.4283±0.2°、13.1918±0.2°、14.4935±0.2°、15.8641±0.2°、17.4204±0.2°、17.9797±0.2°.

Description

High potency glucocorticoid polymorphs and methods of making and using the same Technical Field The invention relates to the field of medicinal chemistry, in particular to a high-efficacy glucocorticoid polymorphism, a preparation method and application thereof. Background At present, inflammatory and autoimmune diseases, such as asthma, arthritis, lupus and Crohn's disease, seriously threaten human health and reduce human quality of life. Glucocorticoids, such as prednisone, dexamethasone (DEX), budesonide, and the like, are highly potent anti-inflammatory drugs that are widely used in the treatment of inflammatory and autoimmune diseases. These drugs exert their physiological effects by binding to the Glucocorticoid Receptor (GR), a ligand-activated transcription factor of the nuclear receptor superfamily. In the absence of glucocorticoids, GR is present in the cytoplasm and binds to chaperones such as hsp90 and hsp 70. Binding of the hormone results in conformational changes in GR, leading to its translocation to the nucleus where it exerts its transcriptional control activity, i.e. activation (transcriptional activation) or inhibition (transcriptional inhibition). In transcriptional activation, GR dimerizes, directly binds to a specific glucocorticoid response element, and then recruits coactivators to activate transcription. In transcription inhibition, the general model is that GR binds to other transcription factors (e.g., NF-KB, AP-1) to indirectly tether its binding site through protein-protein interactions. GR inhibits downstream gene expression when tethered near the target promoter. Transcription inhibition is generally thought not to require GR dimerization. Transcriptional inhibition is the primary mechanism by which glucocorticoids act as anti-inflammatory drugs. Tethering of GR to NF-KB/AP-l promoters results in transcriptional inhibition of major downstream pro-inflammatory factors including pro-inflammatory cytokines (e.g., TNF-a, IL-113, and IL-6), chemokines (e.g., CCL2, CCL 19), and ligands associated with the onset of inflammation (e.g., COX2, MMP13, and phospholipid, as appropriate A2). Glucocorticoids remain the first choice for the treatment of inflammatory diseases due to their rapid action and sustainable effect. However, long-term use of glucocorticoids, especially at high doses, has many adverse consequences, including diabetes/glucose intolerance, hypertension, obesity and osteoporosis. Most of these consequences are due to transcriptional activation of GR. For example, glucocorticoids induce genes encoding rate-limiting enzymes of the glucose production pathway in the liver, glucose-6-phosphate and phosphoenolpyruvate carboxykinase, thereby increasing de novo synthesis of glucose and ultimately leading to weight gain or diabetes. Glucocorticoids also induce the key regulator gene for bone development Dickkopf-1 (DKKl), whose upregulation leads to osteoporosis and bone loss. Many side effects of glucocorticoids are generally observed in connection with high dose use of glucocorticoids. For example, a "threshold mode" of prednisone use was observed at 7.5mg per day, which can cause glaucoma, depression, and hypertension. These side effects are caused by non-target activation of GR transcriptional activation and other receptors, such as the Mineralocorticoid Receptor (MR), which activation causes hypertension. Furthermore, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in the treatment of common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease. Glucocorticoid resistance is also an unsolved problem for white cell cancers, especially pediatric acute leukemia, and several mechanisms of glucocorticoid resistance have been identified or proposed, including alterations in the kinase pathway, cofactor changes, and deletions or mutations in the receptor. While a common observation is that ligand affinity for the receptor is reduced in glucocorticoid resistant patients, such patients treated with high potency glucocorticoids have shown improvement, but gradually diminishing efficacy. Thus, there is a need in the art to develop higher potency, highly selective glucocorticoids to reduce unwanted side effects and to improve therapeutic efficacy. Disclosure of Invention The present invention aims to provide a more potent and highly selective glucocorticoid to reduce unwanted side effects and improve therapeutic effects, in particular to highly potent glucocorticoid polymorphs and methods of preparation and use thereof. In a first aspect of the present invention there is provided a polymorph of formula (I) wherein the polymorph is in a form selected from the group consisting of amorphous form A, solvate form B, solvate form C, solvate form E, solvate form G, solvate form H, isomorphous solvate form D, isomorphous solvate form F, Wherein m is 1-10; n is 0-20; X is selected from