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WO2023123742A1 - CRISTAL SEMI-FUMARATE DE COMPOSÉ INHIBITEUR DOUBLE DE PI3Kδ/γ ET SON PROCÉDÉ DE PRÉPARATION - Google Patents

CRISTAL SEMI-FUMARATE DE COMPOSÉ INHIBITEUR DOUBLE DE PI3Kδ/γ ET SON PROCÉDÉ DE PRÉPARATION Download PDF

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WO2023123742A1
WO2023123742A1 PCT/CN2022/086982 CN2022086982W WO2023123742A1 WO 2023123742 A1 WO2023123742 A1 WO 2023123742A1 CN 2022086982 W CN2022086982 W CN 2022086982W WO 2023123742 A1 WO2023123742 A1 WO 2023123742A1
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Prior art keywords
suspension
crystalline form
hemifumarate
isopropanol
solution
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Chinese (zh)
Inventor
郭振荣
李学飞
唐恕一
陈志宏
李增刚
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Curon Biopharmaceutical Shanghai Co Ltd
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Curon Biopharmaceutical Shanghai Co Ltd
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Priority claimed from CN202210245006.XA external-priority patent/CN116410193A/zh
Application filed by Curon Biopharmaceutical Shanghai Co Ltd filed Critical Curon Biopharmaceutical Shanghai Co Ltd
Publication of WO2023123742A1 publication Critical patent/WO2023123742A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the present invention relates to the field of medicine, in particular to a PI3K ⁇ / ⁇ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) - fumarate crystals of 4H-chromen-4-one compound and its preparation method.
  • Phosphoinositide-3 kinases belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
  • a major issue in the large-scale production of pharmaceutical compounds is that the active substance should have stable crystalline polymorphs to ensure consistent processing parameters and drug quality. If an unstable crystalline form is used, the crystalline polymorph may change during manufacturing and/or storage, leading to quality control issues and formulation irregularities. Such variations may affect the reproducibility of the manufacturing process, resulting in a final formulation that does not meet the high quality and stringent requirements imposed on the formulation of pharmaceutical compositions.
  • any modification of the solid state of a pharmaceutical composition that improves its physical and chemical stability confers significant advantages over less stable forms of the same drug.
  • it is crucial to develop stable production methods that consistently produce active substances The existence of multiple crystalline forms with similar solubility poses a difficult challenge in the large-scale manufacture of pharmaceutical compounds.
  • polymorphism When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism.” Each crystal form is called a "polymorph”. Although polymorphs of a given substance have the same chemical composition, they can differ in one or more physical properties such as solubility, degree of dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties and and/or differ from each other in terms of solid-state stability.
  • polymorphic behavior of drugs can be of great importance in pharmacology. Differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in determining bioavailability). Changes in chemical reactivity (e.g., differential oxidation, causing color to change more quickly when the dosage form is one polymorph than when the dosage form is another polymorph), mechanical changes (e.g., tablet discoloration after storage) Kinetically favorable polymorphs convert to thermodynamically more stable polymorphs) or both (e.g. tablets of one polymorph disintegrate more easily at high humidity) may lead to loss of stability difference. Additionally, the physical properties of the crystals may be important in processing.
  • one polymorph may be more likely to form solvates, causing aggregation of the solid form and making solid handling more difficult.
  • the particle shape and size distribution of one polymorph relative to another may differ, leading to increased challenges in filtering pharmaceutical actives to remove impurities.
  • WO2014195888A1 patent document discloses (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound, its structural formula It is formula I, and as a free base, it exhibits dual inhibitory functions of PI3K ⁇ / ⁇ .
  • the present invention provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one compound
  • the crystalline form 1 of maleic acid salt is characterized in that the crystalline form shows 3.30°, 6.60°, 22.70°, 28.92°, 12.08°, 27.58°, 11.70°, 20.28°, 19.44° on the X-ray diffraction pattern , 23.54°, 29.454°, 24.22°, 16.10° ( ⁇ 0.2°) diffraction angles 2 ⁇ peaks.
  • the crystalline form 1 also includes crystals at 15.66°, 14.54°, 12.98°, 24.92°, 25.28°, 13.32°, 9.82°, 18.96°, 23.54°, 29.45°, 10.80°, 17.18°, 35.85° , the peak at the diffraction angle 2 ⁇ of 21.43° ( ⁇ 0.2°).
  • said crystalline form 1 exhibits an X-ray diffraction pattern substantially as shown in FIG. 5 .
  • the present invention also provides a preparation method of crystalline form 1, which is characterized by comprising the following steps:
  • Step (1) Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound is added to a certain volume of isopropanol solvent to obtain a suspension 1;
  • Step (2) Weighing a certain amount of fumaric acid ligand, ultrasonically heating and dissolving in a certain volume of mixed solution of isopropanol and water to obtain solution 1;
  • Step (3) adding the solution 1 obtained in step (2) dropwise to the stirring suspension 1 obtained in step (1) to obtain suspension 2;
  • Step (4) Dissolve the suspension 2 obtained in step (3) immediately after stirring, add a certain volume of antisolvent to the solution, stir overnight at low temperature to precipitate solids, and obtain suspension 3;
  • Step (5) The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline Form 1.
  • the molar ratio of the free base compound described in step (1) to the fumaric acid ligand described in step (2) is 1:1-1.5.
  • the molar volume ratio of the free base compound to isopropanol in the step (1) is: 1mol:0.1-1L.
  • the volume ratio of the step (2) isopropanol to water is 1:0.4-1.
  • the antisolvent in the described step (4) is selected from n-heptane.
  • the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-
  • the crystalline form 1 of the hemifumarate of 4-ketone compound is characterized in that, described crystalline form shows 3.26 °, 9.64 °, 21.67 °, 22.46 °, 26.75 °, 16.00 ° ( ⁇ 0.2°) peak at the diffraction angle 2 ⁇ .
  • the hemifumarate salt crystalline form 1 also includes at 11.96°, 27.53°, 13.86°, 10.10°, 10.50°, 14.30°, 12.80°, 10.98°, 18.44°, 17.54°, 22.17°, Peaks at diffraction angles 2 ⁇ of 17.86°, 20.90°, 14.90°, 24.71° ( ⁇ 0.2°).
  • the crystalline form 1 of the hemifumarate salt shows an X-ray diffraction pattern substantially as shown in FIG. 11 .
  • the present invention also provides a kind of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene -
  • a process for the preparation of the crystalline form 1 of the hemifumarate salt of the 4-keto compound characterized in that it comprises the following steps:
  • Step (1) Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-
  • the ketone free base compound is added to a certain volume of acetonitrile and stirred to obtain a suspension 1;
  • Step (2) Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a certain volume of acetonitrile and water mixed solution to obtain solution 1;
  • Step (3) adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;
  • Step (4) After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred at room temperature to obtain the suspension 3;
  • Step (5) Suspension 3 was subjected to solid-liquid separation and the resulting solid was vacuum-dried at room temperature to obtain the crystalline form 1 of hemifumarate.
  • the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1.5, preferably 1:1.1.
  • step (2) wherein, the volume ratio of acetonitrile and water in step (2) is 2:1.
  • the volume ratio of the acetonitrile in the step (1) to the acetonitrile in the step (2) is 5:1.
  • the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-
  • the crystalline form 2 of the hemifumarate of the 4-keto compound is characterized in that the crystalline form shows 3.36°, 6.92°, 22.91°, 19.65°, 16.37°, 18.98°, 9.13 °, 27.52°, 6.37°, 26.32°, 25.18°, 11.64°, 9.84°, 10.92°, 15.80°, 20.26°, 24.13°, 20.98°, 27.77°, 12.12°( ⁇ 0.2°) at the diffraction angle 2 ⁇ peak.
  • the crystalline form 2 of hemifumarate also includes crystals at 22.532°, 12.67°, 24.45°, 22.03°, 17.75°, 17.52°, 23.61°, 29.08°, 13.12°, 13.74°, 17.18°
  • the crystalline form 2 of the hemifumarate salt shows an X-ray diffraction pattern substantially as shown in FIG. 17 .
  • the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-
  • the preparation method of the crystalline form 2 of 4-ketone hemifumarate is characterized in that, comprises the following steps:
  • Step (1) Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4- A ketone free base compound, adding a certain volume of isopropanol to obtain a suspension 1;
  • Step (2) Weighing a certain mass of fumaric acid ligand and ultrasonically heating and dissolving it in a mixed solution of a certain volume of isopropanol and water to obtain solution 1;
  • Step (3) adding the solution 1 obtained in step (2) dropwise to the suspension 1 obtained in step (1) under stirring to obtain suspension 2;
  • Step (4) Dissolve the suspension 2 obtained in step (3) immediately after stirring. No solid precipitates after stirring at room temperature. Stir to precipitate a white solid, continue to stir to obtain a suspension 3;
  • Step (5) The suspension 3 was suction-filtered under reduced pressure, the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature to obtain the crystalline form 2 of hemifumarate.
  • the molar ratio of the free base compound in step (1) to the fumaric acid ligand in step (2) is 1:1-1.5, preferably 1:1.1.
  • step (2) wherein, the volume ratio of the Virahol and water in step (2) is 3:2.
  • the volume ratio of the isopropanol in the step (1) to the isopropanol in the step (2) is 5:3.
  • the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned fumarate crystalline form 1, hemifumarate crystalline form 1 or hemifumarate crystalline form 2 or a combination thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides a method for inhibiting phosphoinositide-3 kinase (PI3K), comprising making (S)-2-(1-(9H-purin-6-ylamino)propane of the present invention In crystalline form 1, hemifumarate crystalline form 1 or hemifumarate crystalline form 2 of the fumarate salt of the -3-(3-fluorophenyl)-4H-chromen-4-one compound Any one or combination thereof is exposed to phosphoinositide-3 kinase, preferably, the PI3K is selected from PI3K ⁇ / ⁇ .
  • PI3K phosphoinositide-3 kinase
  • the crystal form of the samples was analyzed by X-powder diffractometer.
  • the 2 ⁇ scanning angle of the sample is from 3° to 40°, the scanning step is 0.02°, and the scanning time of each step is 0.2s.
  • the light tube voltage and current were 40kV and 40mA, respectively.
  • the samples were analyzed by TA instruments Q200DSC. Put the weighed sample (0.5mg-5mg) into the sample tray, and raise the sample to the final temperature at a rate of 10°C/min under the protection of nitrogen (50mL/min).
  • the samples were analyzed by TA instruments Q500.
  • the sample was put into a tared platinum crucible, the system automatically weighed, and then the sample was raised to the final temperature at a rate of 10°C/min under the protection of nitrogen (40mL/min).
  • the samples were analyzed using a polarizing microscope, and the morphology and microstructure of the crystals were obtained by adjusting different magnifications.
  • Dynamic moisture adsorption was carried out by TA Instruments Q5000SA. Approximately 1-10 mg of sample is placed in a sample pan and suspended from the sample chamber. The room temperature was maintained at a constant 25 ⁇ 1°C by a water bath. In the step mode, the sample is tested cyclically at the relative humidity of 0%RH-80%RH. Analysis was performed at 10% RH/step. Set the time to maintain each humidity to 90min, so that the sample and the indoor environment can reach equilibrium.
  • the samples were analyzed using Bruker Ascend 500MH, and the solvent was deuterated dimethyl sulfoxide.
  • Step (1) Weigh about 200 mg of the free base compound prepared in Example 2.1 and add it to 1 mL of isopropanol to obtain a suspension 1;
  • Step (2) Weigh about 63 mg of fumaric acid, dissolve it in a mixed solution of 0.4 mL of isopropanol and 0.4 mL of water by ultrasonic heating, and obtain solution 1;
  • Step (3) adding the solution 1 obtained in step (2) dropwise to the stirring suspension 1 obtained in step (1) to obtain suspension 2;
  • Step (4) Dissolve the suspension 2 obtained in step (3) immediately after stirring, add 16 mL of n-heptane to the solution, stir overnight at 4°C to precipitate solids, and obtain suspension 3;
  • Step (5) The suspension 3 obtained in Step 4 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 198 mg of the product.
  • the product is characterized, and its XRPD spectrum is shown in accompanying drawing 5, and TGA and DSC collection of illustrative plates are shown in attached drawing respectively.
  • Step (1) Weigh about 200 mg of the free base compound prepared in Example 2.1, add 4 mL of acetonitrile and stir to obtain suspension 1;
  • Step (2) About 63 mg of fumaric acid was heated and dissolved in a mixed solution of 0.8 mL of acetonitrile and 0.4 mL of water to obtain solution 1;
  • Step (3) adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;
  • Step (4) After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred overnight at room temperature to obtain a suspension 3;
  • Step (5) The suspension 3 was centrifuged, and the obtained solid was vacuum-dried at room temperature overnight to obtain about 119 mg of hemifumarate Form 1;
  • Step (1) Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of acetonitrile and stir to obtain suspension 1;
  • Step (2) About 64 mg of fumaric acid was heated and dissolved in a mixed solution of 0.8 mL of acetonitrile and 0.4 mL of water to obtain solution 1;
  • Step (3) adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;
  • Step (4) After the suspension 2 was stirred, it was first dissolved, and then a solid was precipitated, and stirred at room temperature for 3 days to obtain a suspension 3;
  • Step (5) The suspension 3 was suction filtered under reduced pressure, the surface of the filter cake was washed with water, and the obtained solid was vacuum-dried overnight at room temperature to obtain about 210 mg of hemifumarate Form 1.
  • the product is characterized, the XRPD spectrum is shown in Figure 11, the TGA and DSC spectra are shown in Figure 12 and Figure 13 respectively, the DVS and isotherm adsorption curve is shown in Figure 14, and the PLM is shown in Figure 15 , 1 HNMR is shown in Fig. 16 .
  • Step (1) Weigh about 202 mg of the free base compound prepared in Example 2.1, add 1 mL of isopropanol to obtain a suspension 1;
  • Step (2) About 65 mg of fumaric acid was heated and dissolved in a mixed solution of 0.6 mL of isopropanol and 0.4 mL of water to obtain solution 1;
  • Step (3) adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;
  • Step (4) Suspension 2 was dissolved immediately after stirring, and no solid precipitated after stirring at room temperature overnight. A small amount of transparent crystals precipitated on the bottle wall after volatilization through a small hole at room temperature for one day. Add a non-porous cap and stir at room temperature for 3 hours to precipitate a white solid. Stirring was continued for 1 day to obtain suspension 3;
  • Step (5) filter the suspension 3 under reduced pressure, gently rinse the surface of the filter cake with water, and dry the obtained solid under vacuum at room temperature overnight to obtain about 77 mg of hemifumarate Form 2;
  • Step (1) Weigh about 501 mg of the free base compound prepared in Example 2.1, and add 2.5 mL of isopropanol to obtain a suspension 1;
  • Step (2) About 156 mg of fumaric acid was heated and dissolved in a mixed solution of 1.5 mL of isopropanol and 1 mL of water to obtain solution 1;
  • Step (3) adding solution 1 dropwise to suspension 1 under stirring to obtain suspension 2;
  • Step (4) Suspension 2 dissolves immediately after stirring, continue to stir for 10 minutes, volatilize through small holes at room temperature for about 1 day, a white solid precipitates out at the bottle mouth, add a non-porous cap, stir at room temperature for 1 hour to precipitate a white solid, continue stirring 2 days, obtain suspension 3;
  • Step (5) The suspension 3 was suction filtered under reduced pressure, and the surface of the filter cake was gently washed with water, and the obtained solid was vacuum-dried at room temperature for about 5 days to obtain about 240 mg of hemifumarate Form 2.
  • hemifumarate Form 1 salt form has good crystallinity; compared to hemifumarate Form2, hemifumarate Form1 has more Low hygroscopicity, which is more conducive to drug development.
  • the present invention also studies (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one free base and rich Comparison of Kinetic Parameters of Oral Administration of Maleate Crystalline Form 1, Hemifumarate Salt Form 1, and Hemifumarate Salt Crystalline Form 2 in Wistar Rats, 4 Animals in Each Group of Oral Administration of Free Base , each group of animals administered orally with each salt type is 3, 6-8 weeks old, male. Oral administration of 10% Cremophor EL+90% (10% HP- ⁇ -CD in 1% HPMC (pH 2.2) in water, the animals in the oral administration group fasted overnight, and resumed eating after 4 hours of administration.
  • Animal blood collection points are before and after administration and 0.25, 0.5, 1, 2, 4, 8 and 24 hours.
  • Jugular vein blood collection the blood collection volume of each blood collection point is about 150 ⁇ L, EDTA-K2 anticoagulant, within 15 minutes after sampling 4 Centrifuge at 2000g for 5min, and analyze by LCMSMS-28 (Triple Quad 6500+).

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Abstract

L'invention concerne un cristal semi-fumarate d'un composé inhibiteur double de PI3Kδ/γ, c'est-à-dire (S)-2-(1-((9H-purin-6-yl)amino)propyl)-3-(3-fluorophényl)-4H-chromén-4-one, et un procédé de préparation du cristal. Le cristal a d'excellentes propriétés physiques et pharmacodynamiques/pharmacocinétiques.
PCT/CN2022/086982 2021-12-31 2022-04-15 CRISTAL SEMI-FUMARATE DE COMPOSÉ INHIBITEUR DOUBLE DE PI3Kδ/γ ET SON PROCÉDÉ DE PRÉPARATION Ceased WO2023123742A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202111679233.5 2021-12-31
CN202111679233 2021-12-31
CN202210245006.XA CN116410193A (zh) 2021-12-31 2022-03-11 PI3Kδ/γ双重抑制剂化合物的半富马酸盐结晶及其制备方法
CN202210245006.X 2022-03-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (zh) * 2009-11-05 2012-12-05 理森制药股份公司 新型苯并吡喃激酶调节剂
CN103702989A (zh) * 2011-05-04 2014-04-02 理森制药股份公司 作为蛋白激酶调节剂的新颖化合物
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (zh) * 2009-11-05 2012-12-05 理森制药股份公司 新型苯并吡喃激酶调节剂
CN103702989A (zh) * 2011-05-04 2014-04-02 理森制药股份公司 作为蛋白激酶调节剂的新颖化合物
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Master's Thesis", 26 May 2019, SHAN DONG UNIVERSITY, CN, article GONG, YAPING: "Design, Synthesis and Biological Activity Evaluation of PI3Kδ Inhibitors", pages: 1 - 109, XP009546890 *

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