WO2020015745A1 - 一种lsd1抑制剂的盐及其晶型 - Google Patents

一种lsd1抑制剂的盐及其晶型 Download PDF

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Publication number
WO2020015745A1
WO2020015745A1 PCT/CN2019/096842 CN2019096842W WO2020015745A1 WO 2020015745 A1 WO2020015745 A1 WO 2020015745A1 CN 2019096842 W CN2019096842 W CN 2019096842W WO 2020015745 A1 WO2020015745 A1 WO 2020015745A1
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WIPO (PCT)
Prior art keywords
compound iii
compound
pattern
lsd1
crystal form
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Ceased
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PCT/CN2019/096842
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English (en)
French (fr)
Chinese (zh)
Inventor
赵乐乐
孙建军
吴凌云
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to JP2021525358A priority Critical patent/JP7358466B2/ja
Priority to AU2019303777A priority patent/AU2019303777B2/en
Priority to CN201980047189.0A priority patent/CN112424175B/zh
Priority to US17/261,322 priority patent/US12024494B2/en
Priority to EP19837636.0A priority patent/EP3825309B1/en
Priority to KR1020217005112A priority patent/KR102778948B1/ko
Priority to CA3106484A priority patent/CA3106484C/en
Publication of WO2020015745A1 publication Critical patent/WO2020015745A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • 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

Definitions

  • the present invention relates to a compound III as an LSD1 inhibitor and its crystal form, and the application of the compound and its crystal form in the preparation of a medicament for treating a disease associated with LSD1.
  • Lysine-specific demethylase (LSD1 also known as KDM1A) was the first demethylase discovered in 2004 and belongs to the family of flavin adenine dinucleotide (FAD) -dependent aminooxidases.
  • the LSD1 structure consists of three main parts: the N-terminal SWIRM domain, the C-terminal aminooxidase domain (AOL), and the centrally protruding Tower domain.
  • the C-terminal amino oxidase domain includes two active pockets, one for FDA binding sites and the other for recognition and binding to substrates.
  • the function of the SWIRM domain has not been clearly defined. It does not directly participate in the binding of FAD or substrates, but mutation or removal of this region will reduce the activity of LSD1.
  • the Tower domain is the binding domain of LSD1 to other protein factors.
  • LSD1 combines with different protein factors and acts on different substrates, thus playing different roles in regulating histones and gene expression.
  • the combination of LSD1 and CoREST will preferentially act on histone H3K4.
  • the related histone markers will be removed and gene transcription will be inhibited.
  • recombinant LSD1 will preferentially act In H3K9, androgen receptor-related gene transcription is activated by demethylation.
  • LSD1 also has some non-histone receptors, such as p53, E2F1, DNMT1, and MYPT1.
  • LSD1 is a FAD-dependent amino oxidase, of which proton transfer is considered to be its most likely oxidation mechanism.
  • the N-CH 3 bond of the substrate is converted into an imine bond through proton transfer.
  • This imine ion intermediate undergoes a hydrolysis reaction to generate demethylated amines on one side and formaldehyde on the other.
  • FAD is reduced to FADH 2 , which is then oxidized back to FAD by a molecule of oxygen, and at the same time a molecule of H 2 O 2 is generated.
  • LSD1 is an indispensable regulator in epigenetics. It modifies histones through demethylation, and is therefore called the "eraser” enzyme in the body. LSD1 can regulate gene expression, and then regulate cell proliferation and differentiation.
  • the present invention provides compound III:
  • the present invention also provides Form A of Compound III, whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.72 ⁇ 0.2 °, 14.24 ⁇ 0.2 °, and 21.78 ⁇ 0.2 °.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.72 ⁇ 0.2 °, 14.24 ⁇ 0.2 °, 16.28 ⁇ 0.2 °, 17.14 ⁇ 0.2 °, 20.72 ⁇ 0.2 °, 21.78 ⁇ 0.2 °, 23.98 ⁇ 0.2 °, and 24.96 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.72 ⁇ 0.2 °, 14.24 ⁇ 0.2 °, 16.28 ⁇ 0.2 °, 17.14 ⁇ 0.2 °, 17.58 ⁇ 0.2 °, 18.70 ⁇ 0.2 °, 20.72 ⁇ 0.2 °, 21.78 ⁇ 0.2 °, 23.98 ⁇ 0.2 °, 24.96 ⁇ 0.2 °, and 26.22 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.721 °, 9.479 °, 14.242 °, 16.279 °, 17.141 °, 17.581 °, 18.082 °, 18.702 ° , 20.719 °, 21.780 °, 22.278 °, 23.978 °, 24.959 °, 26.22 °, 26.779 °, 27.358 °, 27.978 °, 28.656 °, 29.244 °, 30.738 °, 32.699 °, 33.159 °, 33.940 °, 35.201 °, and 37.637 °.
  • the XRPD pattern of the above-mentioned Form A is basically shown in FIG. 1.
  • Table 1 XRPD pattern analysis data of Form A
  • the differential scanning calorimetry (DSC) of the above-mentioned Form A has a starting point of an exothermic peak at 194.66 ⁇ 3 ° C.
  • the DSC spectrum of the above-mentioned Form A is basically shown in FIG. 2.
  • thermogravimetric analysis curve (TGA) of the above-mentioned Form A has a weight loss of 1.331% at 194.21 ⁇ 3 ° C.
  • the TGA spectrum of the above-mentioned Form A is basically shown in FIG. 3.
  • the invention also provides the application of the above-mentioned compound III or the above-mentioned A-form in the preparation of a medicament for treating a disease associated with LSD1.
  • the present invention also provides the application of the above-mentioned compound III or the above-mentioned A-form in preparing a medicine for treating lung cancer, especially small cell lung cancer.
  • the compound III of the present invention and its A crystal form have good LSD1 inhibitory activity and superior efficacy in vivo administration; and compared with its free base and other salts, it has good stability, is less affected by light, heat and humidity, and has very high solubility. Well, there is a bright future for patent medicine.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • DCM stands for dichloromethane
  • DMF stands for N, N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • TFA stands for trifluoroacetic acid
  • TsOH stands for P-toluenesulfonic acid
  • mp melting point
  • EtSO 3 H for ethanesulfonic acid
  • MeSO 3 H for methanesulfonic acid
  • ATP for adenosine triphosphate
  • HEPES for 4-hydroxyethylpiperazineethanesulfonic acid
  • EGTA for ethylene glycol bis (2 -Aminoethyl ether) tetraacetic acid
  • MgCl 2 represents magnesium dichloride
  • MnCl 2 represents manganese dichloride
  • DTT represents dithiothreitol
  • DCC dicyclohex
  • XRPD X-ray powder diffraction
  • Test method about 10-20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 30mA
  • Test method Take a sample ( ⁇ 1mg) in a DSC aluminum pan for testing. Under 50mL / min N 2 condition, heat the sample from 30 °C (room temperature) to 300 °C (or 350) ° C).
  • Thermogravimetric (Analyzer, TGA) method of the present invention is thermogravimetric (Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL / min N 2 , heat the sample from room temperature to 300 ° C or lose weight by 20% at a heating rate of 10 ° C / min.
  • Test conditions Take samples (10-15mg) and place them in the DVS sample tray for testing.
  • the hygroscopicity evaluation is classified as follows:
  • ⁇ W% indicates the moisture absorption gain of the test product at 25 ⁇ 1 °C and 80 ⁇ 2% RH.
  • FIG. 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A of Compound III
  • FIG. 2 is a DSC spectrum of Form A of Compound III
  • Figure 4 is the DVS isotherm of Form A of Compound III.
  • compound II (202 g, 647 mmol) was dissolved in anhydrous ethanol (500 mL), and diisopropylethylamine (209 g, 1.62 mol) and hydroxylamine hydrochloride (90.0 g, 1.30 mol) were added under stirring.
  • the reaction solution was heated to 80 ° C and stirred for 16 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, the residue was dissolved in ethyl acetate (2.00 L), the organic phase was washed with water (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Sample 1 Three 50 mg samples of Compound III Form A were accurately weighed and labeled as Sample 1; Sample 2; Sample 3. Dissolve and make up the volume with deionized water, and configure it into three solutions of 0.2 mg / mL.
  • the hygroscopic weight gain of the Form A of Compound III at 25 ° C and 80% RH was 1.14%, which was slightly hygroscopic.
  • the sample bottle was wrapped in aluminum foil and punctured, and it was also in the corresponding constant temperature and humidity box.
  • the samples were sampled and tested (XRPD) on the 5th and 10th days.
  • the test results were compared with the initial test results on 0 days.
  • the test results are shown in Table 3 below:
  • the crystal form A of compound III has good stability under high temperature, high humidity and strong light conditions.
  • LSD1 buffer composition 50mM Tris-HCl, pH7.5, 0.05% CHAPS, 1% DMSO.
  • the purpose of this experiment is to study the effect of the crystal form A of compound III of the present invention on the efficacy of human small cell lung cancer NCI-H1417 cell subcutaneous xenograft tumors in a CB-17 SCID mouse model.
  • Age and weight 6-8 weeks of age, weight: 16-21 grams
  • NCI-H1417 cells were cultured in monolayer in vitro. The culture conditions were that RPMI-1640 medium was supplemented with 10% fetal bovine serum and cultured at 37 ° C with 5% CO 2 . When the cell saturation was 80% -90%, the cells were harvested by trypsin-EDTA digestion, counted, adjusted to 10 ⁇ 10 7 cells / mL and resuspended in PBS.
  • NCI-H1417 cells baseplates glue to Volume 1: 1 were inoculated subcutaneously to the right back of each mouse, the average tumor volume reached random start packet administered at about 100-150mm 3 Grouped and started dosing.
  • the solvent used in the experiment was a 0.5% methylcellulose solution, 5g of methylcellulose was weighed, and dissolved in 800mL of ultrapure water. After stirring, the volume was adjusted to 1000mL with ultrapure water. The test substance was dissolved in a solvent to prepare a uniform solution with a certain concentration and stored at 4 ° C.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameter was measured twice a week with vernier calipers.
  • Vehicle control group Vehicle (0.5% methyl cellulose solution).
  • Table 6 Evaluation of antitumor efficacy of the crystal form A of compound III on human small cell lung cancer NCI-H1417 xenograft tumor model (calculated based on the tumor volume on day 35 after administration)
  • the crystal form A of the compound III of the present invention has excellent antitumor effect on human small cell lung cancer NCI-H1417 xenograft tumor model.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CN2019/096842 2018-07-20 2019-07-19 一种lsd1抑制剂的盐及其晶型 Ceased WO2020015745A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2021525358A JP7358466B2 (ja) 2018-07-20 2019-07-19 Ｌｓｄ１阻害剤の塩及びその結晶型
AU2019303777A AU2019303777B2 (en) 2018-07-20 2019-07-19 Salt of LSD1 inhibitor and a polymorph thereof
CN201980047189.0A CN112424175B (zh) 2018-07-20 2019-07-19 一种lsd1抑制剂的盐及其晶型
US17/261,322 US12024494B2 (en) 2018-07-20 2019-07-19 Salt of LSD1 inhibitor and a polymorph thereof
EP19837636.0A EP3825309B1 (en) 2018-07-20 2019-07-19 Salt of lsd1 inhibitor and a polymorph thereof
KR1020217005112A KR102778948B1 (ko) 2018-07-20 2019-07-19 Lsd1억제제의 염 및 이의 결정형
CA3106484A CA3106484C (en) 2018-07-20 2019-07-19 A salt of an lsd1 inhibitor and its crystal form

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CN201810804068.3 2018-07-20
CN201810804068 2018-07-20

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021228146A1 (zh) * 2020-05-12 2021-11-18 石药集团中奇制药技术（石家庄）有限公司 一种lsd1抑制剂的用途
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

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CN116069221A (zh) * 2022-12-27 2023-05-05 北京字跳网络技术有限公司 媒体内容的展示方法、装置、电子设备和存储介质

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WO2017184934A1 (en) * 2016-04-22 2017-10-26 Incyte Corporation Formulations of an lsd1 inhibitor
WO2017195216A1 (en) * 2016-05-09 2017-11-16 Jubilant Biosys Limited Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors
WO2018137644A1 (zh) * 2017-01-24 2018-08-02 南京明德新药研发股份有限公司 Lsd1抑制剂及其制备方法和应用

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WO2017184934A1 (en) * 2016-04-22 2017-10-26 Incyte Corporation Formulations of an lsd1 inhibitor
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021228146A1 (zh) * 2020-05-12 2021-11-18 石药集团中奇制药技术（石家庄）有限公司 一种lsd1抑制剂的用途
CN115551501A (zh) * 2020-05-12 2022-12-30 石药集团中奇制药技术（石家庄）有限公司 一种lsd1抑制剂的用途
CN115551501B (zh) * 2020-05-12 2024-03-22 石药集团中奇制药技术（石家庄）有限公司 一种lsd1抑制剂的用途
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2024110649A1 (en) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors and menin inhibitors for treating cancer
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

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AU2019303777A1 (en) 2021-02-11
CA3106484A1 (en) 2020-01-23
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AU2019303777B2 (en) 2023-01-19
CN112424175B (zh) 2022-10-28
US12024494B2 (en) 2024-07-02
KR102778948B1 (ko) 2025-03-07
CN112424175A (zh) 2021-02-26
US20210317096A1 (en) 2021-10-14
JP2021530565A (ja) 2021-11-11
EP3825309A1 (en) 2021-05-26
JP7358466B2 (ja) 2023-10-10
KR20210034058A (ko) 2021-03-29
CA3106484C (en) 2024-06-25

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