CN118480054A - Pharmaceutically acceptable salts of sulfonamide derivatives, crystalline forms and uses thereof - Google Patents

Pharmaceutically acceptable salts of sulfonamide derivatives, crystalline forms and uses thereof Download PDF

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CN118480054A
CN118480054A CN202410176250.4A CN202410176250A CN118480054A CN 118480054 A CN118480054 A CN 118480054A CN 202410176250 A CN202410176250 A CN 202410176250A CN 118480054 A CN118480054 A CN 118480054A
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compound
formula
crystalline form
ray powder
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杨俊然
杜振兴
王捷
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Jiangsu Hengrui Medicine Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The present disclosure relates to pharmaceutically acceptable salts of sulfonamide derivatives, crystalline forms thereof, and uses thereof. Specifically, the present disclosure provides pharmaceutically acceptable salts of the compounds of formula 1, crystalline forms thereof, and uses thereof.

Description

Pharmaceutically acceptable salts of sulfonamide derivatives, crystalline forms and uses thereof
Technical Field
The present disclosure relates to a pharmaceutically acceptable salt of a sulfonamide derivative, a crystalline form thereof and uses thereof, which belong to the technical field of medicines.
Background
Lysine acetyl transferase (LYSINE ACETYLTRANSFERASES; KATs) is a class of enzymes capable of catalyzing the transfer of acetyl groups from acetyl-CoA to lysine epsilon-amino groups in protein substrates. Acetylation of lysine can affect the function of proteins, thereby playing an important role in chromosomal structure, gene transcription regulation, DNA binding capacity, enzyme activity and stability, protein interactions and intracellular localization. KATs is divided into several subfamilies, of which MYST (MOZ, YBF2/SAS3, SAS2, TIP 60) is the largest one, including KAT5 (TIP 60), KAT6A (MOZ; MYST 3), KAT6B (MORF; MYST 4), KAT7 (HBO; MYST 2) and KAT8 (MOF; MYST 1). KAT6A/B, a major member of the MYST family, plays a vital role in the development, maintenance of stem cells in the hematopoietic and immune systems, and in tumorigenesis and development and drug resistance.
Published KAT6 inhibitor patent applications include WO2016198507A1、WO2019243491A1、WO2019043139A1、WO2019108824A1、WO2020216701A1、WO2020002587A1、WO2020254946A1 and WO2020254989A1, among others.
PCT/CN2022/111395 provides a KAT6 inhibitor, which has the chemical name N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-benzopyran [8,7-d ] isoxazol-9-yl) -2, 6-dimethoxy benzenesulfonamide, having the structure shown in formula 1,
The crystal form of the pharmaceutical active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may cause a change in the crystal form structure of the compound, and sometimes other forms of crystal form are generated. Generally, amorphous pharmaceutical products have no regular crystalline structure and often have other drawbacks such as poor product stability, finer crystallization, difficult filtration, easy caking, poor flowability, etc. Salification may improve some undesirable physicochemical or biological properties of the drug. The polymorphic forms of the drug have different requirements for product storage, production and scale-up. Therefore, intensive studies on the crystalline forms of the aforementioned compounds are required to improve the properties of the aforementioned compounds in various aspects.
Disclosure of Invention
The present disclosure provides a novel pharmaceutically acceptable salt of a compound of formula 1 selected from sodium salt, potassium salt, ethanolamine salt,
In alternative embodiments, the stoichiometry of the compound of formula 1 to the base is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, 1:3.
In an alternative embodiment, the chemical ratio of the compound of formula 1 to the base is from 2:1 to 1:2.
In an alternative embodiment, the formula 1 compound is 1:1 stoichiometric to sodium ions.
In an alternative embodiment, the chemical ratio of the compound of formula 1 to potassium ion is 1:1.
The present disclosure provides a sodium salt form i of a compound of formula 1 having characteristic peaks at 6.995, 8.601, 9.895, 11.176, 13.248 and 20.234 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.
In some embodiments, the crystalline form i of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 6.995, 8.601, 9.895, 11.176, 13.248, 14.915, 17.153, 20.234, 22.961, 25.751 and 26.561.
In some embodiments, the sodium salt form I of the compound of formula 1 has an X-ray powder diffraction pattern in terms of diffraction angle 2 theta with characteristic peaks at 6.995、8.601、9.895、11.176、13.248、14.159、14.915、17.153、18.707、20.234、22.961、23.815、25.751、26.561、28.568 and 31.509.
In some embodiments, the sodium salt form I of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as a diffraction angle 2 theta angle, as shown in figure 1.
The present disclosure further provides a process for preparing the sodium salt form i of the compound of formula 1, comprising: dispersing the compound shown in the formula 1 in any crystal form or amorphous form and sodium hydroxide in an organic solvent, heating and cooling, pulping and crystallizing, wherein the organic solvent can be an alcohol solvent, preferably C 1～C6 alkyl alcohol, more preferably isopropanol.
The present disclosure also provides a crystalline form ii of the sodium salt of the compound of formula 1, having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 8.295, 10.250, 10.884, 14.371, 19.589 and 20.202.
In some embodiments, the crystalline form ii of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.295, 9.923, 10.250, 10.884, 14.371, 14.812, 18.789, 19.589, and 20.202.
In some embodiments, the crystalline form ii of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.295, 9.923, 10.250, 10.884, 14.371, 14.812, 15.246, 18.789, 19.589, 20.202, 22.406 and 24.180.
In some embodiments, the sodium salt form ii of the compound of formula 1 has an X-ray powder diffraction pattern as shown in figure 2, expressed in terms of diffraction angle 2θ.
The present disclosure further provides a process for preparing the sodium salt form ii of the compound of formula 1, comprising: dispersing the compound shown in the formula 1 in any crystal form or amorphous form and sodium hydroxide in an organic solvent, and pulping and crystallizing at room temperature, wherein the organic solvent can be an alcohol solvent, preferably C 1～C6 alkyl alcohol, and more preferably isopropanol.
The present disclosure also provides a crystalline form iii of the sodium salt of the compound of formula 1, having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 8.699, 9.894, 12.309, 18.943 and 27.298.
In some embodiments, the crystalline form iii of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.699, 9.465, 9.894, 12.309, 18.943, 21.480, 23.985, and 27.298.
In some embodiments, the crystalline form III of the sodium salt of the compound of formula 1, is shown in FIG. 3 as an X-ray powder diffraction pattern expressed in terms of diffraction angle 2. Theta. Angles.
The present disclosure further provides a process for preparing the crystalline form iii of the sodium salt of the compound of formula 1, comprising: dispersing a compound shown in a formula 1 in any crystal form or amorphous form and sodium hydroxide in an organic solvent, and pulping at room temperature; and the obtained solid is further pulped and crystallized in pure water. The organic solvent may be an alcoholic solvent, preferably a C 1～C6 alkyl alcohol, more preferably isopropanol.
The present disclosure also provides a crystalline form iv of the sodium salt of the compound of formula 1, having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 6.599, 8.722, 9.226, 9.884, 12.726 and 17.037.
In some embodiments, the crystalline form iv of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 6.599, 8.722, 9.226, 9.884, 12.364, 12.726, 17.037, 17.439, 21.737 and 22.789.
In some embodiments, the crystalline form iv of the sodium salt of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 6.599, 8.722, 9.226, 9.884, 12.364, 12.726, 16.271, 17.037, 17.439, 19.313, 21.737, 22.789, 24.000 and 24.476.
In some embodiments, the crystalline form iv of the sodium salt of the compound of formula 1, as shown in figure 4, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.
The present disclosure further provides a process for preparing the crystalline form iv of the sodium salt of the compound of formula 1, comprising: heating and dissolving the compound shown in the formula 1 in any crystal form or amorphous form and sodium hydroxide in pure water, and stirring for crystallization.
The present disclosure also provides a potassium salt form a of the compound of formula 1 having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 9.074, 11.896, 13.734, 15.470, 17.062, 21.062 and 23.323.
In some embodiments, the potassium salt form a of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 9.074, 11.896, 13.734, 15.470, 17.062, 18.717, 21.062, 22.019, 22.750, 23.323, and 26.306.
In some embodiments, the potassium salt form a of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, having characteristic peaks at 9.074, 11.896, 13.734, 15.470, 17.062, 18.717, 19.723, 21.062, 22.019, 22.750, 23.323, 23.852, 26.306, 26.973, and 28.476.
In some embodiments, the potassium salt form a of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in fig. 5.
The present disclosure further provides a process for preparing the potassium salt form a of the compound of formula 1, comprising: dispersing the compound shown in the formula 1 in any crystal form or amorphous form and potassium hydroxide in an organic solvent or water, heating and cooling, pulping and crystallizing, wherein the organic solvent can be an alcohol solvent, preferably C 1～C6 alkyl alcohol, more preferably isopropanol.
The present disclosure also provides a potassium salt form B of the compound of formula 1 having characteristic peaks at 8.109, 11.628, 14.167, 17.212, 21.281 and 24.332 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.
In some embodiments, the potassium salt form B of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 8.109, 10.758, 11.628, 13.511, 14.167, 17.212, 21.281, 22.523, 23.720, and 24.332.
In some embodiments, the potassium salt form B of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 8.109, 10.758, 11.628, 13.511, 14.167, 17.212, 21.281, 22.523, 22.953, 23.720, 24.332, and 29.537.
In some embodiments, the potassium salt form B of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in fig. 6.
The present disclosure further provides a process for preparing the potassium salt form B of the compound of formula 1, comprising: dispersing the compound shown in the formula 1 in any crystal form or amorphous form and potassium hydroxide in pure water, heating and cooling, pulping and crystallizing.
The present disclosure also provides a potassium salt form C of the compound of formula 1, having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 8.254, 10.210, 13.264, 15.908, 17.365 and 21.366.
In some embodiments, the potassium salt form C of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.254, 10.210, 12.881, 13.264, 15.908, 17.365, 21.366, and 23.219.
In some embodiments, the potassium salt form C of the compound of formula 1 has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, as shown in fig. 7.
The present disclosure further provides a process for preparing the potassium salt form C of the compound of formula 1, comprising: dispersing the compound shown in the formula 1 in any crystal form or amorphous form and potassium hydroxide in dimethyl sulfoxide, heating-cooling, pulping and crystallizing.
The present disclosure also provides an ethanolamine salt alpha form of the compound of formula 1 having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.145, 11.279, 13.900, 16.978, 20.899, and 23.572.
In some embodiments, the ethanolamine salt alpha form of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 6.963, 8.145, 11.279, 11.989, 13.900, 16.978, 17.327, 20.899, 21.145, 22.578, and 23.572.
In some embodiments, the ethanolamine salt alpha form of the compound of formula 1 has an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 6.963, 8.145, 11.279, 11.989, 13.900, 16.629, 16.978, 17.327, 20.899, 21.145, 22.578, 23.229, 23.572, and 26.702.
In some embodiments, the ethanolamine salt alpha form of the compound of formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as shown in figure 8.
The present disclosure further provides a process for preparing an ethanolamine salt α crystalline form of a compound of formula 1 comprising: dispersing a compound shown in a formula 1 in any crystal form or amorphous form and ethanolamine in a solvent, heating and cooling, pulping and crystallizing, wherein the solvent is selected from water, dimethyl sulfoxide and isopropanol.
The present disclosure still further provides a pharmaceutically acceptable salt of a compound of formula 1 selected from the group consisting of sodium, potassium, and ethanolamine salts.
The present disclosure also provides a pharmaceutical composition comprising the foregoing sodium salt form i, sodium salt form ii, sodium salt form iii, sodium salt form iv, potassium salt form a, potassium salt form B, potassium salt form C, or ethanolamine salt form a, and optionally pharmaceutical excipients from pharmaceutically acceptable excipients.
The present disclosure also provides a pharmaceutical composition prepared from the aforementioned sodium salt form i, sodium salt form ii, sodium salt form iii, sodium salt form iv, potassium salt form a, potassium salt form B, potassium salt form C, or ethanolamine salt form a, and optionally pharmaceutically acceptable excipients.
The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing the aforementioned sodium salt form i, sodium salt form ii, sodium salt form iii, sodium salt form iv, potassium salt form a, potassium salt form B, potassium salt form C, or ethanolamine salt form a with a pharmaceutically acceptable excipient.
The present disclosure also provides the use of the foregoing sodium salt form i, sodium salt form ii, sodium salt form iii, sodium salt form iv, potassium salt form a, potassium salt form B, potassium salt form C, or ethanolamine salt form a or from the foregoing compositions for the preparation of a medicament for the prevention and/or treatment of cancer.
The use of the present disclosure, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, bronchogenic carcinoma, sarcoma, chordoma, choriocarcinoma, craniopharyngeoma, cystic adenocarcinoma, embryo cancer, vascular endothelial cell tumor, ependymoma, epithelial cancer, esophageal cancer, primary thrombocytosis, ewing's tumor, testicular cancer, glioma, heavy chain disease, angioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pineal tumor, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, membranous tumor, waldenstrom's tumor, sweat gland carcinoma, and macroglobular tumor; preferably, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, and lung cancer.
According to the description of the hygroscopicity characteristic and the definition of the hygroscopicity weight increase in the '9103 medicine hygroscopicity guiding principle' in the fourth part of the 2015 edition of Chinese pharmacopoeia,
Deliquescence: absorbing a sufficient amount of moisture to form a liquid;
the moisture absorption performance is very good: the weight gain after moisture absorption is not less than 15%;
Moisture permeability: the weight gain of the wet-drawing is less than 15 percent but not less than 2 percent;
Slightly hygroscopic: the weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent;
No or little hygroscopicity: the weight gain caused by moisture is less than 0.2 percent.
The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 theta is + -0.20 (including the case where the number of more than 1 decimal place is rounded), specifically -0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-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.
The numerical values in the present disclosure are data on the determination calculation of the content of the relevant substances, and a certain degree of error is unavoidable. Generally, ±10% all fall within a reasonable error range. There is a degree of variation in error, depending on the context in which it is used, of no more than + -10%, which may be + -9%, + -8%, + -7%, + -6%, + -5%, + -4%, + -3%, + -2% or + -1%, preferably + -5%.
The starting materials used in the methods of preparing crystalline forms of the present disclosure may be any form of compound, including but not limited to: amorphous, any crystalline form, hydrate, solvate, etc.
The drying temperature in the present disclosure is generally 25 ℃ to 100 ℃, preferably 40 ℃ to 70 ℃, and can be either normal pressure drying or reduced pressure drying.
The term "differential scanning calorimetric analysis or DSC" in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference object during the temperature rising or constant temperature process of the sample, so as to characterize all physical changes and chemical changes related to thermal effects, and obtain phase change information of the sample.
The "excipient" as described in this disclosure includes, but is not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
Drawings
Figure 1 is an XRPD pattern of crystalline form i of compound 1 sodium salt.
Figure 2 is an XRPD pattern of crystalline form ii of compound 1 sodium salt.
Figure 3 is an XRPD pattern of crystalline form iii of compound 1 sodium salt.
Fig. 4 is an XRPD pattern of crystalline form iv of compound 1 sodium salt.
Fig. 5 is an XRPD pattern of compound 1 potassium salt form a.
Fig. 6 is an XRPD pattern of compound 1 potassium salt form B.
Fig. 7 is an XRPD pattern of compound 1 potassium salt form C.
Figure 8 is an XRPD pattern of the alpha crystalline form of compound 1 ethanolamine salt.
Detailed Description
The present disclosure will be explained in more detail below with reference to examples or experimental examples, which are only for illustrating technical solutions in the present disclosure, and do not limit the spirit and scope in the present disclosure.
Test conditions of the instrument used for the experiment:
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using Bruker AVANCE NEO M nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and Tetramethylsilane (TMS) as internal standard.
MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.
High performance liquid phase preparation was performed using Waters 2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.
The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.
XRPD is X-ray powder diffraction detection: the determination was performed using a BRUKER D8X-ray diffractometer, specifically collecting information: cu anode (40 kV,40 mA), cu-K alpha 1 rayKα2 rayKbeta raysScanning mode: θ/2θ, scan range (2θ range): 3-45 degrees.
TGA is thermogravimetric analysis: the detection adopts METTLER TOLEDO TGA type 2 thermogravimetric analyzer, the heating rate is 10 ℃/min, the specific temperature range refers to the corresponding map (25-350 ℃ at most), and the nitrogen purging speed is 50mL/min.
DVS is dynamic moisture adsorption: SMSDVS ADVANTAGE is adopted for detection, the humidity change is 50% -95% -0% -95% -50% at 25 ℃, the step is 10% (the last step is 5%) (the specific range of the humidity is based on the corresponding spectrum, the specific range is the most using method, and the judgment standard is dm/dt is not more than 0.002%).
Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), dary chemicals, and the like.
The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
EXAMPLE 1 preparation of Compounds of formula 1
N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chromen o [8,7-d ] isoxazol-9-yl) -2, 6-dimethoxy benzenesulfonamide 1
First step
4-Bromo-2- ((2, 4-dimethoxybenzyl) oxy) -6-fluorobenzonitrile 1b
4-Bromo-2, 6-difluorobenzonitrile 1a (22 g,101mmol, shao-yuan) and 2, 4-dimethoxybenzyl alcohol (18.5 g,110mmol, bi) were dissolved in N, N-dimethylformamide (200 mL), and cesium carbonate (49 g,150mmol, shao-yuan) was added. The reaction solution was stirred at 60℃for 16 hours. The reaction solution was cooled to room temperature, suction filtration was performed under reduced pressure, the filtrate was diluted with ethyl acetate (500 mL), and the obtained organic phase was washed with a saturated sodium chloride solution (30 mL. Times.5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1b (36.9 g, yield: 100%). The product was used directly in the next reaction without purification.
Second step
4-Bromo-2-fluoro-6-hydroxybenzonitrile 1c
Compound 1b (36.9 g,100.7 mmol) was dissolved in dichloromethane (250 mL), cooled to 0deg.C, trifluoroacetic acid (39 g, 348 mmol, adamas) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (9.7 g, yield: 44.5%).
Third step
2- (Allyloxy) -4-bromo-6-fluorobenzonitrile 1d
Compound 1c (10.7 g,49.5 mmol) was dissolved in N, N-dimethylformamide (120 mL), the reaction was cooled to 0deg.C, cesium carbonate (24 g,73.7mmol, pickle) and allyl bromide (11.2 g,92.6mmol, adamas) were added, and the reaction was warmed to room temperature and stirred for 4 hours. The reaction solution was suction-filtered under reduced pressure, the filtrate was diluted with ethyl acetate (400 mL), washed with saturated sodium chloride solution (30 ml×3), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to give the title product 1d (11.7 g, yield ：92％).1H NMR(500MHz,CDCl3)δ7.02(dt,1H),6.95(t,1H),6.04(m,1H),5.57-5.47(m,1H),5.41(dt,1H),4.75-4.64(m,2H).
Fourth step
3-Allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile 1e
Compound 1d (3.35 g,13.1 mmol) was dissolved in 1, 2-dichlorobenzene (80 mL), nitrogen was replaced three times, and the reaction was stirred at 180℃for 13 hours. The reaction solution was cooled to room temperature, and the resulting residue was purified by silica gel column chromatography (wet loading) with eluent system a to give the title product 1e (2.77 g, yield ：82.7％).1H NMR(500MHz,CDCl3)δ7.07(dd,1H),6.45(s,1H),5.90(dddd,1H),5.24-5.10(m,2H),3.68-3.55(m,2H).
Fifth step
4-Bromo-6-fluoro-2-hydroxy-3- (3-hydroxypropyl) benzonitrile 1f
Compound 1e (4.8 g,18.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and a solution of borane in tetrahydrofuran (1.0M, 22mL,22mmol, adamas) was added dropwise at 0deg.C. The reaction was stirred under ice bath for 2 hours. Under ice bath, 3M aqueous sodium hydroxide solution (13 mL,39 mmol) and 30% hydrogen peroxide (3.0 mL) were added successively, and stirring was completed for 10min. The reaction solution was adjusted to ph=2 with 2M hydrochloric acid, extracted with ethyl acetate (100 ml×2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 1f (3.5 g, yield ：68.1％).MS m/z(ESI):275.8[M+1].1H NMR(500MHz,CDCl3)δ7.04(d,1H),3.71(t,2H),3.00-2.98(m,2H),2.01-1.96(m,2H).
Sixth step
5-Bromo-7-fluorochromane-8-carbonitrile 1g
Compound 1f (3.8 g,13.9 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), the reaction solution was cooled to 0℃and triphenylphosphine (4.4 g,16.8mmol, guozhi) and diisopropyl azodicarboxylate (3.4 g,16.8mmol, shaoyuan) were added thereto, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to give the title product 1g (3.0 g, yield) ：84.5％).1H NMR(500MHz,CDCl3)δ7.03(d,1H),4.33(t,2H),2.77-2.74(m,2H),2.12-2.08(m,2H).MS m/z(ESI):257.8[M+1].
Seventh step
8-Cyano-7-fluorochromane-5-carboxylic acid methyl ester 1h
1G (2.6 g,10.2 mmol) of the compound was dissolved in a mixed solvent of 40mL of methanol and N, N-dimethylformamide (V: V=1:3), and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (800 mg,1.09mmol, adamas) and triethylamine (3.0 g,2.93mmol, national medicine) were added in this order. Carbon monoxide was replaced 3 times and stirred at 10bar and 90℃for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (150 mL), washed with saturated sodium chloride solution (50 ml×3), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to give the title product 1h (2.1 g, yield ：87.9％).1H NMR(500MHz,CDCl3)δ7.26(d,1H),4.38-4.36(m,2H),3.93(s,3H),3.10-3.07(m,2H),2.08-2.03(m,2H).MS m/z(ESI):235.9[M+1].
Eighth step
7-Fluoro-5- (hydroxymethyl) chromane-8-carbonitrile 1i
Compound 1h (2.1 g,8.93 mmol) was dissolved in dry tetrahydrofuran (40 mL), nitrogen was replaced 3 times, the reaction was cooled to 0deg.C, and lithium borohydride (2M, 18mmol,9.0mL, adamas) was added. The reaction solution was heated to 70℃and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (1 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (50 mL. Times.2), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1i (1.84 g, yield: 99.5%). MS m/z (ESI): 207.9[ M+1].
Ninth step
5- ((1H-pyrazol-1-yl) methyl) -7-fluorochrome-8-carbonitrile 1k
Compound 1i (1.8 g,8.69 mmol) and 1- (methylsulfonyl) -1H-pyrazole 1j (1.5 g,10.3mmol, prepared using the procedure disclosed in patent application "page 63 Scheme 8 intermediate 13, WO2020254946A 1") were dissolved in acetonitrile (30 mL) and cesium carbonate (4.2 g,12.9mmol, shao) was added and reacted at 70℃for 1 hour. The residue obtained was purified by silica gel column chromatography with eluent system A, and the title product 1k (1.9 g, yield: 85.0%) was obtained. MS m/z (ESI) 258.0[ M+1].
Tenth step
5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chromen [8,7-d ] isoxazol-9-amine 1l
Compound 1k (1.9 g,7.39 mmol), acetohydroxamic acid (1.7 g,22.2mmol, adamas) was dissolved in N, N-dimethylformamide (30 mL) and water (4.0 mL), and potassium carbonate (6.2 g,44.9mmol, guozhi) was added. The reaction solution was stirred at 70℃for 24 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the cake was collected by filtration and dried to give the title product 1l (1.65 g, yield) ：82.7％).1H NMR(500MHz,DMSO-d6)δ7.78(d,1H),7.52(d,1H),6.34(s,1H),6.32(t,1H),5.85(s,2H),5.39(s,2H),4.25-4.23(m,2H),2.68(t,2H),2.03-1.98(m,2H).MS m/z(ESI):271.0[M+1].
Eleventh step
N- (5- ((1H-pyrazol-1-yl) methyl) -3, 4-dihydro-2H-chromen o [8,7-d ] isoxazol-9-yl) -2, 6-dimethoxy benzenesulfonamide 1
Compound 1l (200 mg,0.740 mmol) and compound 1m (300 mg,1.27 mmol) were dissolved in pyridine (5.0 mL) and nitrogen was replaced 3 times. The reaction solution was subjected to microwave reaction at 120℃for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Xtimate phenyl-hexyl Prep C, 18 μm,30×150mm; mobile phase: a-aqueous phase (0.1% aqueous ammonia): B-acetonitrile=5% -45% (20 min), flow rate: 30 mL/min) to give the title product 1 (40 mg, yield) ：11.5％).1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),7.79(d,1H),7.52(d,1H),7.48(t,1H),6.77(d,2H),6.43(s,1H),6.32(t,1H),5.42(s,2H),4.25(t,2H),3.78(s,6H),2.70(t,2H),2.04-1.99(m,2H).MS m/z(ESI):470.8[M+1].
Test example 1 detection of the enzymatic Activity of KAT6 (AlphaScreen method) of Compound of formula 1
1. Experimental materials
Kat6a (CHEMPARTNER custom)
2. Ovalbumin (Sigma-Aldrich, A5378-5G)
3.2M Tris-HCl solution, pH 7.8, sterile (Protect B548140-0500)
4.5M NaCl solution (Industry B548121-0100)
5.EDTA(0.5M),pH 8.0,RNase-free(Thermofisher,AM9260G)
6. Tween-20 (for engineering, A100777-0500)
7.DTT,1M(Invitrogen,P2325)
8. Acetyl CoA (Ac-CoA, CAYMAN, cat.No.16160)
9. Biotin-labeled recombinant histone H3.1 (human) (Recombinant Histone H3.1.1 biotinylated (Human)) (Active Motif 31696)
10.384 Orifice plate, light gray (PERKIN ELMER, CAT.NO.6005350)
11. Anacardic acid (MCE, cat.No. HY-N2020)
Alpha Screen streptavidin Donor beads (ALPHASCREEN STREPTAVIDIN Donor beads) 5mg (Perkinelmer, 670002)
Alpha Screen protein A receptor beads (ALPHASCREEN PROTEIN A ACCEPTOR BEADS), 5mg (Perkinelmer, 67680137M)
14. Acetylated Lysine Antibody (ACETYLATED-Lysine Antibody # 9441) (CST 9441S)
PHERAstar enzyme label instrument (BMG labtech)
2. Experimental method
1. Reagent preparation
A.1×detection buffer: 100mM Tris-HCl, pH7.8;15mM NaCl;1mM EDTA;0.01% tween-20; 1mM DTT;0.01% m/v ovalbumin.
Kat enzyme solution: 1 Xdetection buffer was formulated at a final concentration of 1.25nM.
Ac-CoA and H3 mixed substrate: 1 Xassay buffer A mixed substrate of Ac-CoA at a final concentration of 1000nM and H3 at a final concentration of 55nM is formulated.
D. A compound: initial concentration 100. Mu.M, 3-fold dilution, 10 concentration gradients. All concentrations of compounds were diluted 83-fold with 1 Xdetection buffer for use.
E. Detection reagent: 1 Xdetection buffer preparation final concentration of 8 ng/L alpha screen protein A receptor beads, 8 ng/L alpha screen streptavidin donor beads, acetylated lysine antibodies 1:1500 dilution, 100 u M lacquer tree acid.
2. Experimental procedure
Mu.l of 1 Xdetection buffer was added to each well of 384 well plates with 3. Mu.l of the prepared enzyme solution, column 23 and 24 (Min). mu.L of the compound solution was added to each well, and Min was added to each well with 3. Mu. Lbuffer; columns 1 and 2 (Max) were controlled by adding 3. Mu. LDMSO of solution per well. Centrifuging, uniformly mixing and vibrating for 2 minutes; incubate for 15 minutes at room temperature. mu.L of Ac-CoA and H3 mixed substrate is added to each well, the mixture is centrifuged, and the mixture is stirred for 2 minutes and incubated for 20 minutes at room temperature. 6 mu L of detection reagent is added into each hole, the mixture is centrifuged, and the mixture is evenly mixed and vibrated for 2 minutes, incubated for 120 minutes at room temperature and protected from light. The microplate reader reads the plate and records the value of the AlphaScreen count. Graphpad software was plotted and compound IC 50 values were calculated as IC 50 =0.3 nM
Conclusion: the compound of formula 1 has good inhibition effect on KAT 6A.
Test example 2 anti-ZR-75-1 proliferation assay of Compounds of formula 1
1. Reagents and apparatus
1.ZR-75-1(ATCC CRL1500)
2.1640 Medium (Gibco, 22400-089)
3.0.25% Trypsin-EDTA (1 x) (Gibco, 25200-072)
4. Penicillin-streptomycin (Gibco, 15140-122)
5.DPBS(1×)(Gibco，14190-144)
6.FBS(Gibco，10091148)
7.96 Hole bottom transparent black detection plate (Corning, 3603)
8.96 Kong Yuande dispensing plate (96 well non-treated round bottom) (JET BIOFIL, TCP-002-096)
CellTiter-Glo buffer (Promega, G756B)
CellTiter-Glo substrate (Promega, G755B)
11. Automatic cell counter (Countstar, IC 1000)
12. Constant temperature incubator (Thermo, I160)
13.PHERAstar FS(BMG labtech,PHERAstar FS)
2. Experimental method
1. Cell plating (day 0)
A. The state of the cells was observed under a microscope, and the degree of fusion of the cells was ensured to be about 90%.
B. The cell supernatant was discarded, DPBS was rinsed once, and DPBS was decanted. The cells were digested with an appropriate amount of trypsin and allowed to stand at 37℃for 5 minutes.
C. Digestion was stopped with an equal volume of 1640 medium containing 10% FBS and the cell suspension was collected. 300g, and centrifuged for 3 minutes. Cells were suspended with an appropriate amount of fresh medium.
D. The resuspended cell suspension was counted.
E. The cell suspension was diluted to 5X 104/mL, 50. Mu.L/well with 1640 medium containing 10% FBS. ZR-75-1 was 2500 cells/well.
F. the cell culture plates were incubated overnight at 37℃in an incubator with 5% carbon dioxide.
2. Medicine (day 1)
A. Each compound was serially diluted to 9 concentration points (initial 100. Mu.M, 3-fold dilution; different compounds were adjusted accordingly for different maximum concentrations of IC 50) in DMSO. For example, in a 96 well round bottom dispensing plate, 3 μl of compounds are serially diluted in a gradient to 6 μl DMSO.
B. Each concentration point of each compound was diluted 500-fold into the corresponding volume 1640 culture broth.
C. to 50. Mu.L/well of cell supernatant in each cell plate was added sequentially 50. Mu.L of the diluted compound solution described above.
D. the medicated cell plates were incubated in an incubator at 37℃with 5% carbon dioxide.
3. Re-digestion of the plates and dosing (day 7)
A. after 6 days of dosing, the drug-containing medium was discarded, and then DPBS was added at 150. Mu.L/well for one rinse, immediately blotting DPBS.
B. Cells were digested with 50. Mu.L trypsin, allowed to stand at 37℃for 3 minutes, and then the digestion was stopped by adding 1640 medium containing 10% FBS at 150. Mu.L/well.
C. The mixed cells were blown with a row gun and re-plated at a 1:8 ratio by pipetting 25. Mu.L of cell suspension into a new 96-well plate (25. Mu.L of 1640 medium with 10% FBS was added in advance to the new plate).
D. compound formulation and dosing were performed according to steps a.to c.in 2, 50 μl per well.
E. The medicated cell plates were incubated in an incubator at 37℃with 5% carbon dioxide.
CTG test (day 14)
A. Before use, the CellTiter-Glo buffer and the lyophilized CellTiter-Glo substrate are placed and balanced to room temperature, and the CellTiter-Glo buffer and the lyophilized CellTiter-Glo substrate are fully mixed and uniformly mixed to prepare 100mL of CellTiter-Glo reagent (or the mixed CellTiter-Glo reagent is taken out from the temperature of minus 20 ℃ to be balanced to room temperature).
B. The plates to be tested were removed from the incubator, equilibrated to room temperature and 50. Mu. L CELLTITER-Glo reagent was added to each well.
C. The cells were thoroughly lysed by shaking for 2 minutes.
D. after 28 minutes at room temperature, the signal was stabilized and then detected on PHERASTAR FS.
TABLE 1 IC 50 values and maximum inhibition of ZR-75-1 proliferation inhibition by Compounds of formula 1
Compounds of formula (I) ZR-75-1/IC50(nM) Maximum inhibition/Imax%
Compounds of formula 1 0.4 96
Conclusion: the compound shown in the formula 1 has good inhibition effect on ZR-75-1 proliferation.
EXAMPLE 2 preparation of the crystalline form I of the sodium salt of the Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of isopropyl alcohol, 18. Mu.L of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred and beaten overnight at 50℃to 5℃at.+ -. 0.75℃per minute, centrifuged, and dried under vacuum to obtain a solid. The product was defined as form i sodium salt by X-ray powder diffraction, the XRPD pattern shown in figure 1 and the characteristic peak positions shown in table 2. The DSC spectrum shows an endothermic peak at 146.77 ℃and an exothermic peak at 278.26 ℃. TGA profile showed a weight loss of 5.37% at 30-170 ℃.
TABLE 2
Example 3: preparation of sodium salt form II of Compound of formula 1
The compound (100 mg,0.21 mmol) of formula 1 was added to 2mL of isopropanol, 240. Mu.L of 2M aqueous sodium hydroxide solution was added, stirred and slurried overnight at room temperature, centrifuged, and dried under vacuum to obtain a solid. The product was defined as form ii sodium salt by X-ray powder diffraction, the XRPD pattern shown in figure 2 and the characteristic peak positions shown in table 3. The DSC spectrum shows an endothermic peak at 134.11 ℃and an exothermic peak at 276.24 ℃. TGA profile shows a weight loss of 7.56% at 30-170 ℃.
TABLE 3 Table 3
Example 4: preparation of sodium salt III crystal form of compound of formula 1
The compound (100 mg,0.21 mmol) shown in the formula 1 is added into 2mL of isopropanol, 240 mu L of 2M sodium hydroxide aqueous solution is added, stirred and beaten overnight at room temperature, centrifuged, and dried in vacuum to obtain solid; the solid sample was slurried in pure water for a further 2h. The product was defined as form III of the sodium salt as detected by X-ray powder diffraction, the XRPD pattern is shown in FIG. 3 and the characteristic peak positions are shown in Table 4. The DSC spectrum shows an endothermic peak at 172.11 ℃and an exothermic peak at 230.07 ℃. TGA profile shows a weight loss of 3.69% at 30-240 ℃.
TABLE 4 Table 4
Example 5: preparation of sodium salt of Compound of formula 1 Crystal form IV
The compound (100 mg,0.21 mmol) shown in formula 1 was added to 2.5mL of pure water, 1.5mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at 37℃for about 10min to dissolve out, and the mixture was stirred continuously to precipitate, centrifuged and dried under vacuum to obtain a solid. The product was defined as the crystalline form iv of the sodium salt as measured by X-ray powder diffraction, the XRPD pattern shown in figure 4 and the characteristic peak positions shown in table 5. The DSC spectrum shows an endothermic peak at 175.60 ℃and an exothermic peak at 233.07 ℃. TGA profile showed a weight loss of 2.08% at 30-216 ℃. The ion chromatography result shows that the content of sodium ions in the obtained sodium salt IV crystal form is 5.89%.
TABLE 5
Example 6: preparation of Potassium salt A Crystal form of Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of isopropyl alcohol, 18. Mu.L of 2M aqueous potassium hydroxide solution was added, and the mixture was stirred and beaten overnight at 50℃to 5℃at.+ -. 0.75℃per minute, centrifuged, and dried under vacuum to obtain a solid. The product was defined as potassium salt form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 5 and the characteristic peak positions shown in table 6. The DSC profile showed an exothermic peak-to-peak value of 308.60 ℃. TGA profile showed a weight loss of 0.54% at 30-257 ℃. The result of ion chromatography showed that the potassium ion content of the obtained potassium salt form a was 9.32%.
TABLE 6
Example 7: preparation of Potassium salt A Crystal form of Compound of formula 1
The compound (100 mg,0.21 mmol) represented by formula 1 was added to 0.7mL of water, 240. Mu.l of a 2M aqueous potassium hydroxide solution was added, and the mixture was stirred overnight at a temperature in the range of 50℃to 5℃at.+ -. 0.75℃per minute, centrifuged, and dried under vacuum to obtain a solid. The product is a potassium salt A crystal form through X-ray powder diffraction detection.
Example 8: preparation of Potassium salt B Crystal form of Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of pure water, 18. Mu.L of 2M aqueous potassium hydroxide solution was added, stirred and beaten overnight at 50℃to 5℃with circulation, centrifuged, and dried under vacuum to obtain a solid. The product was defined as potassium salt form B as measured by X-ray powder diffraction, the XRPD pattern shown in figure 6 and the characteristic peak positions shown in table 7. The DSC spectrum shows an endothermic peak 123.78 ℃ and an exothermic peak 254.51 ℃. TGA profile shows a weight loss of 3.55% at 30-140 ℃.
TABLE 7
Example 9: preparation of Potassium salt C Crystal form of Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of dimethyl sulfoxide, 36. Mu.L of 2M aqueous potassium hydroxide solution was added, and the mixture was stirred at a temperature in the range of 50℃to 5℃at.+ -. 0.75℃per minute over night, centrifuged and dried under vacuum to obtain a solid. The product was defined as the potassium salt form C as measured by X-ray powder diffraction, the XRPD pattern shown in figure 7 and the characteristic peak positions shown in table 8. DSC spectra showed an endothermic peak at 85.80 ℃, 176.78 ℃, 198.94 ℃. TGA profile shows a weight loss of 11.65% at 30-240 ℃.
TABLE 8
Example 10: preparation of the alpha Crystal form of the ethanolamine salt of the Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of isopropyl alcohol, 36. Mu.L of 2M aqueous ethanolamine solution was added, and the mixture was stirred overnight at 50℃to 5℃at.+ -. 0.75℃per minute under cyclic temperature rise and fall, centrifuged, and dried under vacuum to obtain a solid. The product was defined as the ethanolamine salt alpha form as measured by X-ray powder diffraction, the XRPD pattern shown in figure 8 and the characteristic peak positions shown in table 9. The DSC spectrum shows an endothermic peak at 207.04 ℃and 240.83 ℃. TGA profile showed a weight loss of 11.49% at 30-225 ℃.
TABLE 9
Example 11: preparation of the alpha Crystal form of the ethanolamine salt of the Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of water, 36. Mu.L of 2M aqueous ethanolamine solution was added, and the mixture was stirred overnight at 50℃to 5℃at.+ -. 0.75℃per minute under cyclic temperature rise and fall, centrifuged, and dried under vacuum to obtain a solid. The product is ethanolamine salt alpha crystal form through X-ray powder diffraction detection
Example 12: preparation of the alpha Crystal form of the ethanolamine salt of the Compound of formula 1
The compound (15 mg,0.032 mmol) shown in formula 1 was added to 0.4mL of dimethyl sulfoxide, 36. Mu.L of 2M aqueous ethanolamine solution was added, and the mixture was stirred at a temperature in the range of 50℃to 5℃at.+ -. 0.75℃per minute over night, centrifuged, and dried under vacuum to obtain a solid. The product is ethanolamine salt alpha crystal form through X-ray powder diffraction detection
Example 13: hygroscopicity study of different salts of Compounds of formula 1
Surface Measurement SYSTEMS INTRINSIC DVS is adopted, the range of the detected humidity is 0-95% at 25 ℃, the step is 10%, the judgment standard is that the quality change dM/dT of each gradient is less than 0.002%, TMAX is 360min, and the two circles are circulated.
Table 10
Example 14: stability study of different salt forms of Compound of formula 1
The salt samples were spread open and placed in a flat state, and the stability of the samples under conditions of light (4500 Lux), high temperature (40 ℃,60 ℃) and high humidity (75% RH, 92.5%) were examined, respectively, with a sampling examination period of 30 days.
TABLE 11
Table 12
TABLE 13
The experimental results show that the potassium salt A crystal form, the sodium salt IV crystal form and the ethanolamine salt alpha crystal form have good physical and chemical stability under high temperature, high humidity and illumination. .
Example 15: long term/accelerated stability of different salts of the compound of formula 1
The samples were sealed with aluminum foil bags and stability was examined by placing conditions at 25 ℃/60% RH and 40 ℃/75% RH, respectively, and the results are shown below.
TABLE 14
Experimental results show that the sodium salt IV crystal form, the potassium salt A crystal form and the ethanolamine salt alpha crystal form are placed for 9 months under the condition of long-term acceleration, and the chemical and physical stability is good.

Claims (15)

1. A pharmaceutically acceptable salt of a compound of formula 1 selected from the group consisting of sodium, potassium, ethanolamine salts,
2. The pharmaceutically acceptable salt according to claim 1, wherein the chemical ratio of the compound of formula 1 to the base is 3:1-1:3, preferably 2:1-1:2, more preferably 1:1 or 1:2.
3. A crystalline form iv of the sodium salt of a compound of formula 1, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, having characteristic peaks at 6.599, 8.722, 9.226, 9.884, 12.726 and 17.037, preferably at 6.599, 8.722, 9.226, 9.884, 12.364, 12.726, 17.037, 17.439, 21.737 and 22.789, more preferably at 6.599, 8.722, 9.226, 9.884, 12.364, 12.726, 16.271, 17.037, 17.439, 19.313, 21.737, 22.789, 24.000 and 24.476.
4. A crystalline form iv of the sodium salt according to claim 3, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ as shown in figure 4.
5. A process for the preparation of crystalline form iv of the sodium salt of claim 3 or 4 comprising: heating and dissolving the compound shown in the formula 1 in any crystal form or amorphous form and sodium hydroxide in pure water, and stirring for crystallization.
6. A crystalline form a potassium salt of a compound of formula 1, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, having characteristic peaks at 9.074, 11.896, 13.734, 15.470, 17.062, 21.062 and 23.323, preferably at 9.074, 11.896, 13.734, 15.470, 17.062, 18.717, 21.062, 22.019, 22.750, 23.323 and 26.306, more preferably at 9.074, 11.896, 13.734, 15.470, 17.062, 18.717, 19.723, 21.062, 22.019, 22.750, 23.323, 23.852, 26.306, 26.973 and 28.476.
7. The crystalline form a of potassium salt according to claim 6, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, as shown in figure 5.
8. A process for the preparation of the potassium salt form a of claim 6 or 7 comprising: dispersing a compound shown in a formula 1 in any crystal form or amorphous form and potassium hydroxide in an organic solvent or water, heating and cooling, pulping and crystallizing, wherein the organic solvent is selected from C 1～C6 alkyl alcohol, preferably isopropanol.
9. An ethanolamine salt alpha form of a compound of formula 1, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, having characteristic peaks at 8.145, 11.279, 13.900, 16.978, 20.899 and 23.572, preferably at 6.963, 8.145, 11.279, 11.989, 13.900, 16.978, 17.327, 20.899, 21.145, 22.578 and 23.572, more preferably at 6.963, 8.145, 11.279, 11.989, 13.900, 16.629, 16.978, 17.327, 20.899, 21.145, 22.578, 23.229, 23.572 and 26.702.
10. The crystalline form α of ethanolamine salt according to claim 9, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, as shown in figure 8.
11. A process for the preparation of the alpha crystalline form of ethanolamine salt according to claim 9 or 10 comprising: dispersing a compound shown in a formula 1 in any crystal form or amorphous form and ethanolamine in a solvent, heating and cooling, pulping and crystallizing, wherein the solvent is selected from water, dimethyl sulfoxide and isopropanol.
12. The crystalline form of any one of claims 3-4, 6-7, 9-10, the 2Θ angle error range is ± 0.20.
13. A pharmaceutical composition comprising the following components:
i) A pharmaceutically acceptable salt according to claim 1 or 2, or a crystalline form according to any one of claims 3-4, 6-7, 9-10; and
Ii) one or more pharmaceutically acceptable excipients.
14. A process for the preparation of a pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable salt according to claim 1 or 2, or a crystalline form according to any one of claims 3-4, 6-7, 9-10, with a pharmaceutically acceptable excipient.
15. Use of a pharmaceutically acceptable salt according to claim 1 or 2, or a crystalline form according to any one of claims 3-4, 6-7, 9-10, or a composition according to claim 13, in the manufacture of a medicament for the prevention and/or treatment of cancer.
CN202410176250.4A 2023-02-10 2024-02-08 Pharmaceutically acceptable salts of sulfonamide derivatives, crystalline forms and uses thereof Pending CN118480054A (en)

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