WO2022267495A1 - 含氮氧杂螺环类化合物及其应用 - Google Patents
含氮氧杂螺环类化合物及其应用 Download PDFInfo
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- WO2022267495A1 WO2022267495A1 PCT/CN2022/076802 CN2022076802W WO2022267495A1 WO 2022267495 A1 WO2022267495 A1 WO 2022267495A1 CN 2022076802 W CN2022076802 W CN 2022076802W WO 2022267495 A1 WO2022267495 A1 WO 2022267495A1
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- compound
- pharmaceutically acceptable
- acceptable salt
- acid
- cancer
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Classifications
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Definitions
- the present invention relates to nitrogen-containing oxaspirocyclic compounds and applications thereof, in particular to compounds of formula (I) or pharmaceutically acceptable salts thereof.
- Histone post-translational modifications include methylation, acetylation, phosphorylation, ubiquitination and other processes, which are important regulatory means of epigenetics and affect gene expression by changing chromatin structure [Xueshun Wang, Boshi Huang, Takayoshi Suzuki et al., Epigenomics, 2015, 1379-1396;]. Although these modifications do not change the basic sequence of DNA, such epigenetic changes may persist throughout the cell life cycle or cell iteration through cell division [Adrian Bird, Nature, 2007, 396-398]. Therefore, epigenetic dysfunction is closely related to the pathological process of various diseases [James T Lynch, William J Harris & Tim C P Somervaille, Expert Opin. Ther.
- LSD1A Lysine specific demethylase 1
- KDM1A is the first reported histone lysine demethylase, by regulating the methylation of histone lysine It is widely involved in transcriptional regulation, affecting many physiological processes such as cell proliferation and differentiation, and pluripotency of embryonic stem cells.
- LSD1 includes three main parts: the N-terminal SWIRM domain, the C-terminal aminooxidase domain (AOL) and the central Tower domain. [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429].
- the C-terminal aminooxidase domain includes two active pockets, one for FAD binding and the other for recognition and substrate binding [Pete Stavropoulos, Günter Blobel, André Hoelz, Nature Structural & Molecular Biology, 2006, 626-632].
- the function of the SWIRM domain has not been clearly concluded. It is not directly involved in the binding of FAD or substrate, but the mutation or removal of this region will reduce the activity of LSD1. Therefore, it is speculated that this region may affect the active region by adjusting the conformation. effect. [Yong Chen, Yuting Yang, Feng Wang et al., Biochemistry, 2006, 13956–13961].
- the Tower domain is the binding domain of LSD1 and other protein factors.
- LSD1 acts on different substrates, thereby playing different regulatory roles on histone and gene expression. For example, when LSD1 is combined with CoREST, it will preferentially act on histone H3K4, remove activation-related histone marks through demethylation, and inhibit gene transcription; and after combining with androgen receptor protein, recombinant LSD1 will preferentially act Activation of androgen receptor-related gene transcription through demethylation at H3K9 [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429; Eric Metzger, Melanie Wissmann, Na Yin et al., Nature, 2005 , 436-439.].
- LSD1 also regulates the methylation status of some non-histone substrates, including the tumor suppressor gene p53 and DNA methyltransferase 1 (DNMT1) [Yi Chao Zheng, Jinlian Ma, Zhiru Wang, Medicinal Research Reviews, 2015, 1032–1071].
- DNMT1 DNA methyltransferase 1
- LSD1 is a FAD-dependent aminooxidase, in which proton transfer is considered as its most likely oxidation mechanism [Zheng Y C, Yu B, Chen Z S, et al. Epigenomics, 2016, 8, 651-666.].
- proton transfer the N-CH 3 bond of the substrate is converted into an imine bond, and the iminium ion intermediate undergoes a hydrolysis reaction, and a demethylated amine is generated on one side, and formaldehyde is generated on the other side.
- LSD1 is aberrantly expressed in many different types of tumors.
- LSD1 is highly expressed in acute myeloid leukemia (AML) subtypes and is an important factor for maintaining the potential of leukemia stem cells (LSC).
- AML acute myeloid leukemia
- LSD1 is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, prostate cancer, liver cancer and pancreatic cancer, and is closely related to poor prognosis of tumors.
- LSD1 inhibits the expression of cadherin, which is closely related to tumor invasion and epithelial-mesenchymal transition (EMT) [Hosseini A, Minucci S. Epigenomics, 2017, 9, 1123-1142.].
- EMT epithelial-mesenchymal transition
- LSD1 inhibitors currently have no drugs approved for marketing, and 8 drugs are in the clinical research stage, mainly for the treatment of hematological tumors, small cell lung cancer, and Ewing's sarcoma.
- 8 drugs are in the clinical research stage, mainly for the treatment of hematological tumors, small cell lung cancer, and Ewing's sarcoma.
- this field still needs candidate compounds with better activity and better pharmacokinetic parameters to advance to clinical trials to meet the therapeutic needs.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
- n 1 or 2;
- n 0, 1 or 2;
- g 0, 1 or 2.
- n is 0 or 1
- other variables are as defined in the present invention.
- the above g is 0 or 1, and other variables are as defined in the present invention.
- n and g are as defined herein.
- the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
- the above-mentioned salt is selected from hydrochloride and p-toluenesulfonate.
- the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating LSD1-related diseases.
- the above-mentioned disease is hematological tumor, small cell lung cancer, squamous non-small cell lung cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, glioma or Ewing's sarcoma.
- the above-mentioned blood tumor is preferably human acute myeloid leukemia.
- the present invention also provides a method for treating LSD1-related diseases in a subject in need, the method comprising providing the subject with an effective dose of the compound defined in any of the above technical schemes or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method of treating hematologic malignancies, small cell lung cancer, squamous non-small cell lung cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, glioma, or Ewing's sarcoma in a subject in need thereof,
- the method includes providing the subject with an effective dose of the compound defined in any of the above technical schemes or a pharmaceutically acceptable salt thereof.
- the invention also provides a method for treating hematological tumor, and the hematological tumor is human acute myeloid leukemia.
- the compound of the present invention has remarkable in vitro activity and good pharmacokinetic properties.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
- the compounds of the invention may exist in particular geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
- diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
- the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2).
- the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) It exists as a mixture of isomers.
- the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). It exists in the form of a mixture.
- tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
- a substitution reaction eg, a nucleophilic substitution reaction
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
- acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
- hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl, and tert-butyl
- acyl groups such as alkanoyl (such as acetyl)
- arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
- the compounds of the present invention can be prepared by a variety of synthetic methods well 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 the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
- the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- the single crystal X-ray diffraction method SXRD
- the cultivated single crystal is collected with a Bruker D8venture diffractometer to collect diffraction intensity data
- the light source is CuK ⁇ radiation
- the scanning method is: ⁇ /scan.
- the direct method (Shelxs97 ) analysis of the crystal structure the absolute configuration can be confirmed.
- reaction solution was introduced into a liquid separator, allowed to stand for layers, separated, the aqueous phase was extracted with dichloromethane (4.0L ⁇ 2), the organic phases were combined, washed with water (6.3L ⁇ 1), and then washed with saturated brine (6.3 L ⁇ 1) washing, standing for layering, liquid separation, adding anhydrous sodium sulfate (629.31g) to the organic phase, drying, filtering, and concentrating the filtrate under reduced pressure at an external temperature of 40-50°C to obtain compound 1-2.
- compound 1-3 2349.70 g, 9.20 mol was added to the reactor in batches, and sodium acetate borohydride (4382.43 g, 20.68 mol) was added to the reactor in batches. Adjust the temperature of the reaction kettle to 15-25°C and stir for 2-3 hours.
- reaction solution Slowly add the reaction solution into a reaction kettle filled with saturated sodium carbonate aqueous solution (32.0L) to quench, control the temperature of the reaction kettle at 15-25°C, introduce the mixed solution into the liquid separator, let it stand for layers, separate the liquid, and the water phase Extract with dichloromethane (12.0L ⁇ 2), combine the organic phases, wash once with saturated aqueous sodium chloride solution (6.0L ⁇ 1), let stand to separate layers, separate the layers, add anhydrous sodium sulfate (8048.34g) to the organic phase After drying and filtering, the filtrate was concentrated under reduced pressure at an external temperature of 40-50°C to obtain compound 1-4.
- saturated sodium carbonate aqueous solution 32.0L
- the aqueous phase was extracted with dichloromethane (6.0L ⁇ 2), the organic phases were combined, washed with saturated brine (6.4L ⁇ 1), and the layers were separated after standing , liquid separation, the organic phase was dried by adding anhydrous sodium sulfate (467.51g), filtered, and the filtrate was concentrated under reduced pressure at 40-50°C to obtain compound 1-7.
- the purpose of this test is to detect the in vitro inhibitory activity of the compound on LSD1.
- the enzyme used in this experiment is human LSD1, and the standard substrate is histone H3K4me peptide (20 ⁇ M).
- the enzyme fluorescence coupling method is used to detect the H generated after the LSD1 reaction by combining horseradish peroxidase (HRP) and fluorescent reagent Amplex Red.
- HRP horseradish peroxidase
- Table 1 The results of the in vitro enzyme activity screening test of the compounds of the present invention
- the purpose of the experiment To analyze the inhibitory effect of the compound on the proliferation of kasumi-1 and MV4-11 cells.
- Cell culture medium for experiment 20% or 10% fetal bovine serum and 1% penicillin/streptomycin solution were added to RPMI1640 cell culture medium, and stored at 4°C for later use.
- Inhibition rate (%) (RFU sample-RFU negative control)/(RFU positive control-RFU negative control) ⁇ 100%
- the inhibition rate was calculated using the software Prism 8 for IC50 , the formula is as follows:
- the compounds of the present invention have significant inhibitory activity on the proliferation of kasumi-1/MV4-11 cells.
- the purpose of the experiment To analyze the inhibitory effect of the compound on the proliferation of human acute myeloid leukemia KG-1 cells.
- Fetal bovine serum (FBS) was purchased from Ekesai Biotechnology Co., Ltd.
- IMDM medium was purchased from American type culture collection (ATCC, American type culture collection)
- penicillin/streptomycin double antibody was purchased from HyClone .
- CellTiter-Glo Luminescent Cell Viability Assay cell viability chemiluminescence detection reagent
- KG-1 cells were purchased from European Collection of Authenticated Cell Cultures (ECACC). Nivo Multilabel Analyzer (PerkinElmer).
- Sow KG-1 cells in a 96-well plate 100 ⁇ L of cell suspension per well, of which 1 ⁇ 10 4 cells/mL. Cell plates were cultured in a carbon dioxide incubator.
- Inhibition rate (%) (RFU sample-RFU negative control)/(RFU positive control-RFU negative control) ⁇ 100%
- the compound of the present invention shows significant anti-proliferation activity on KG-1 cells.
- Chinese hamster ovary cells stably expressing hERG channels were cultured in cell culture dishes with a diameter of 35mm, cultured in an incubator at 37°C and 5% CO 2 , and subcultured at a ratio of 1:5 every 48 hours, medium formula: 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 g/mL G418 (Invitrogen) and 100 g/mL Hygromycin B (Invitrogen).
- the cell culture medium was sucked away, rinsed once with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added, and digested at room temperature for 3-5 minutes. Aspirate the digestion solution, resuspend the cells with extracellular solution, and transfer the cells to a laboratory dish for electrophysiological recording.
- the compound was dissolved in DMSO into a 20mM mother solution.
- the compound mother solution was serially diluted 3 times with DMSO, that is, 10 ⁇ L of the compound mother solution was added to 20 ⁇ L DMSO, and the intermediate concentrations of the compounds serially diluted with DMSO were sequentially obtained, which were 20, 6.66, 2.22, 0.74, 0.25 and 0.082 mM. Then take 10 ⁇ L of the intermediate concentration of the compound and add it to 4990 ⁇ L of extracellular fluid, and dilute it 500 times to obtain the final concentration to be tested.
- Positive control compound cisapride preparation take 150 ⁇ M cisapride mother solution and perform 3-fold serial dilution with 100% DMSO, that is, take 10 ⁇ L 150 ⁇ M cisapride mother solution and add 20 ⁇ L DMSO to obtain 5 intermediate concentrations of cisapride serially diluted with DMSO, respectively 150, 50, 16.7, 5.56 and 1.85 ⁇ M. Then take 10 ⁇ L of the intermediate concentration of cisapride and add it to 4990 ⁇ L of extracellular fluid, and dilute it 500 times to obtain the final concentration to be tested. The content of DMSO in the final test concentration was not more than 0.2%, and DMSO at this concentration had no effect on the hERG potassium channel.
- hERG potassium channel current was recorded by whole-cell patch clamp technique at room temperature.
- the glass microelectrode is made of a glass electrode blank (BF150-86-10, Sutter) drawn by a drawing machine. The tip resistance after filling the electrode inner liquid is about 2-5M ⁇ . Insert the glass microelectrode into the amplifier probe to connect To Axopatch 200B (Molecular Devices) patch clamp amplifier.
- the clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz.
- the cell was clamped at -80mV, and the step voltage of the evoked hERG potassium current (IhERG) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s. back to -80mV. Give this voltage stimulation every 10s, and start the administration process after confirming that the hERG potassium current is stable (1 minute).
- Compound concentrations were administered serially starting at the low test concentration, with each test concentration administered for at least 1 minute. At least 3 cells were tested for each concentration of the compound (n ⁇ 3), and at least 2 cells were tested for each concentration of positive compounds (n ⁇ 2).
- Inhibition% represents the inhibitory percentage of the compound on the hERG potassium current
- I and Io represent the amplitudes of the hERG potassium current after and before the drug addition, respectively.
- X is the Log value of the detected concentration of the test substance
- Y is the inhibition percentage at the corresponding concentration
- Bottom and Top are the minimum and maximum inhibition percentages, respectively.
- the compound of the present invention has no inhibitory effect on hERG potassium ion channel.
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Abstract
一种含氮氧杂螺环类化合物及其应用,具体涉及式(I)化合物或其药学上接受的盐及其作为LSD1抑制剂在治疗血液肿瘤、小细胞肺癌、鳞状非小细胞肺癌、乳腺癌、前列腺癌、肝癌、胰腺癌、胶质瘤或尤文氏肉瘤等疾病中的应用。
Description
本申请主张如下优先权:
CN202110694019.0,2021年06月22日。
本发明涉及含氮氧杂螺环类化合物及其应用,具体涉及式(Ⅰ)化合物或其药学上可接受的盐。
组蛋白翻译后修饰包括甲基化、乙酰化、磷酸化、泛素化等过程,是表观遗传学的重要调控手段,通过改变染色质结构影响基因表达[Xueshun Wang,Boshi Huang,Takayoshi Suzuki et al.,Epigenomics,2015,1379-1396;]。尽管这些修饰并不改变DNA的基础序列,但这种表观遗传的变化可能通过细胞分裂在整个细胞生命周期或者细胞迭代过程持续存在[Adrian Bird,Nature,2007,396-398]。因此表观遗传学功能异常与各种疾病的病理过程密切相关[James T Lynch,William J Harris&Tim C P Somervaille,Expert Opin.Ther.Targets,2012,1239-1249],比如各种实体瘤,血液瘤,病毒感染,神经系统异常等疾病。因此,表观遗传学现在成为药物研发领域的研究热点。组蛋白的甲基化状态由组蛋白甲基转移酶和组蛋白去甲基化酶共同调控。赖氨酸特异性去甲基化酶(Lysine specific demethylase 1,LSD1,又名KDM1A)是第一个被报道的组蛋白赖氨酸去甲基化酶,通过调控组蛋白赖氨酸的甲基化状态,广泛参与转录调控,影响细胞增殖和分化、胚胎干细胞多能性等诸多生理过程。[Yujiang Shi,Fei Lan,Caitlin Matson et al.,Cell,2004,941–953][Daniel P.Mould,Alison E.McGonagle,Daniel H.Wiseman et al.,Medicinal Research Reviews,2015,35,586–618]。LSD1结构包括三个主要部分:N-末端的SWIRM结构域,C-末端的氨基氧化酶结构域(AOL)和中央的Tower域。[Ruchi Anand,Ronen Marmorstein,Journal of Biological Chemistry,2007,35425–35429]。C-末端的氨基氧化酶结构域包括两个活性口袋,一个是FAD结合的位点,另一个是用于识别并与底物结合的位点[Pete Stavropoulos,Günter Blobel,AndréHoelz,Nature Structral&Molecular Biology,2006,626-632]。SWIRM结构域的功能还没有明确的结论,它不直接参与FAD或者底物的结合,但是这个区域的突变或者是去除都会降低LSD1的活性,因此推测该区域可能是通过调整构象,影响活性区域的作用。[Yong Chen,Yuting Yang,Feng Wang et al.,Biochemistry,2006,13956–13961]。Tower结构域是LSD1与其他蛋白因子的结合域。LSD1与不同蛋白因子相结合后,作用于不同底物,从而对组蛋白以及基因表达起到不同的调控作用。比如LSD1与CoREST相结合后,会优先作用于组蛋白H3K4,通过去甲基化,去除激活相关的组蛋白标记,抑制基因转录;而与雄激素受体蛋白结合后,重组的LSD1会优先作用于H3K9,通过去甲基化激活雄激素受体相关的基因转录[Ruchi Anand,Ronen Marmorstein,Journal of Biological Chemistry,2007,35425–35429;Eric Metzger,Melanie Wissmann,Na Yin et al.,Nature,2005,436-439.]。此外,LSD1还调控部分非组蛋白底物的甲基化状态,包括抑癌基因p53和DNA甲基转移酶1(DNA methyltransferase 1,DNMT1)等[Yi Chao Zheng,Jinlian Ma,Zhiru Wang,Medicinal Research Reviews,2015,1032–1071]。
LSD1是FAD依赖的氨基氧化酶,其中质子转移被认为是其最可能的氧化机理[Zheng Y C,Yu B,Chen Z S,et al.Epigenomics,2016,8,651-666.]。首先通过质子转移,将底物的N-CH
3键转化成亚胺键,这个亚胺离子中间体发生水解反应,一边生成去甲基的胺,另一边生成甲醛。在这个催化循环过程中,FAD被还原成FADH2,随后又被一分子的氧气氧化回到FAD,同时生成一分子H
2O
2[Yujiang Shi,Fei Lan,Caitlin Matson, Cell,2004,941–953]。
LSD1在多种不同类型的肿瘤中异常表达。LSD1在急性髓性白血病(acute myeloid leukemia,AML)亚型中高表达,是维持白血病干细胞(leukemia stem cell,LSC)潜能的重要因素。LSD1在多种实体瘤如肺癌、乳腺癌、前列腺癌、肝癌和胰腺癌中高表达,与肿瘤的预后不良密切相关。LSD1抑制钙粘蛋白的表达,与肿瘤的侵袭和上皮-间质转移(epithelial-mesenchymal transition,EMT)密切相关[Hosseini A,Minucci S.Epigenomics,2017,9,1123-1142.]。
LSD1抑制剂目前没有药物获批上市,已有8个药物处于临床研究阶段,主要用于血液肿瘤、小细胞肺癌和尤文氏肉瘤等疾病的治疗。然而,面对巨大的未满足市场,该领域仍然需要活性更好,药代动力学参数更优的候选化合物推进临床试验,以满足治疗需求。
发明内容
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐,
其中,
m为1或2;
n为0、1或2;
g为0、1或2。
本发明的一些方案中,上述n为0或1,其他变量如本发明所定义。
本发明的一些方案中,上述g为0或1,其他变量如本发明所定义。
本发明的一些方案中,上述m为1时,n为1,g为1,其他变量如本发明所定义。
本发明的一些方案中,上述m为2时,n为1,g为1,其他变量如本发明所定义。
本发明的一些方案中,上述m为1时,n为0,g为0,其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中,上述化合物为
其中,
m、n和g如本发明所定义。
本发明还提供了下式化合物或其药学上可接受的盐,
本发明的一些方案中,上述化合物为,
本发明的一些方案中,上述的盐选自盐酸盐和对苯甲磺酸盐。
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗LSD1相关疾病的药物中的应用。
本发明的一些方案中,上述的疾病为血液肿瘤、小细胞肺癌、鳞状非小细胞肺癌、乳腺癌、前列腺癌、肝癌、胰腺癌、胶质瘤或尤文氏肉瘤。
本发明的一些方案中,上述的血液肿瘤优选为人急性髓系白血病。
本发明还提供了一种在需要的受试者中治疗与LSD1相关的疾病的方法,方法包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐。
本发明还提供了一种在需要的受试者中治疗血液肿瘤、小细胞肺癌、鳞状非小细胞肺癌、乳腺癌、前列腺癌、肝癌、胰腺癌、胶质瘤或尤文氏肉瘤的方法,方法包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐。
本发明还提供了一种治疗血液肿瘤的方法,所述血液肿瘤为人急性髓系白血病。
技术效果
作为新型的LSD1抑制剂,本发明的化合物体外活性显著,具有良好的药代动力学性质。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、 有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有说明,用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型,用直形实线键
和直形虚线键
表示立体中心的相对构型,用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
和直形虚线键
除非另有说明,当化合物中存在双键结构,如碳碳双键、碳氮双键和氮氮双键,且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中,氮原子上的一对孤对电子视为其连接的一个取代基),如果该化合物中双键上的原子与其取代基之间用波浪线
连接,则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在;下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:φ/扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
合成路线:
第一步
在0~10℃下,将1M氢氧化钠(10.5L)、化合物1-1(2502.41g,8.77mol)、二氯甲烷(7.5L)依次加入反应釜。调节反应釜温度20~30℃,搅拌1~2小时。监测水相pH值,当pH值为碱性且反应液澄清,停止反应。将反应液导入分液器,静置分层,分液,水相用二氯甲烷(4.0L×2)萃取,合并有机相,用水(6.3L×1)洗涤,再用饱和食盐水(6.3L×1)洗涤,静置分层,分液,有机相加入无水硫酸钠(629.31g)干燥,过滤,滤液在外温40~50℃下减压浓缩,得到化合物1-2。
1H NMR(400MHz,CD
3OD)δ7.23-7.17(m,2H),7.13-7.07(m,1H),7.04-6.97(m,2H),2.43-2.41(m,1H),1.85-1.84(m,1H),1.03-0.93(m,2H)。
第二步
在15~25℃下,将无水二氯甲烷(19.0L)、化合物1-2(1087.12g,8.16mol)溶解在二氯甲烷(3.0L)中、依次加入反应釜。0~10℃下,分批将化合物1-3(2349.70g,9.20mol)加入反应釜,再分批将醋酸硼氢化钠(4382.43g,20.68mol)加入反应釜。调节反应釜温度15~25℃,搅拌2~3小时。反应液缓慢加入到另外装有饱和碳酸钠水溶液(32.0L)的反应釜中淬灭,控制反应釜温度15~25℃,将混合液导入分液器,静置分层,分液,水相用二氯甲烷(12.0L×2)萃取,合并有机相,用饱和氯化钠水溶液(6.0L×1)洗涤一次,静置分层,分液,有机相加入无水硫酸钠(8048.34g)干燥,过滤,滤液在外温40~50℃下减压浓缩,得到化合物1-4。
1H NMR(400MHz,CD
3OD)δ7.24-7.21(m,2H),7.14-7.10(m,1H),7.05-7.03(m,2H),4.00-3.97(m,1H),3.69-3.55(m,4H),3.35-3.32(m,2H),2.30-2.27(m,1H),2.13-2.07(m,1H),1.94-1.86(m,1H),1.71-1.58(m,4H),1.53-1.49(m,1H),1.46(s,9H),1.10-0.99(m,2H)。MS-ESI计算值[M+H]+373实测值373。
第三步
将化合物1-4(3390.58g,9.10mol)溶解在乙腈(56.0L×2)中,向反应液中加入化合物(-)-O,O-二对甲苯甲酰基-L-酒石酸(3366.99g,8.72mol),反应液在55℃下搅拌2小时,降温至25℃搅拌12小时,将反应液过滤, 固体用乙腈(8.0L×2)洗涤,在40℃下真空干燥,得到固体。将固体分散到乙腈(35.0L)中,反应液在55℃下搅拌1.5小时,在35℃下搅拌1.5小时,在25℃下搅拌12小时,将反应液过滤,固体用乙腈(4.0L×1)洗涤后真空干燥得到固体,母液浓缩得到化合物1-6。将固体加入到乙腈(23.0L)和水(6.0L)中,反应液加热到55℃下搅拌溶清,将反应液缓慢降温至25℃,搅拌12小时,将反应液过滤,固体用乙腈(4.0L×1)洗涤后真空干燥得到化合物1-5。将化合物1-5和1-6游离后送SFC检测(手性柱:Chiralpak AD-3 50×4.6mm I.D.,3um;流动相:[A:CO
2,B:0.05%的二乙胺甲醇溶液];梯度:从5%到40%2分钟,40%1.2分钟,5%0.8分钟(B:0.05%的二乙胺甲醇溶液),4mL/分钟),化合物1-5保留时间=1.550min;化合物1-6保留时间=1.121min。
第四步
在0~10℃下,将饱和碳酸氢钠(13.0L)、化合物1-5(2546.03g,3.36mol)、二氯甲烷(13.0L)依次加入反应釜。调节反应釜温度20~30℃,搅拌1~2小时。将反应液导入分液器,静置分层,分液,水相用二氯甲烷(6.0L×2)萃取,合并有机相,用饱和食盐水(6.4L×1)洗涤,静置分层,分液,有机相加入无水硫酸钠(467.51g)干燥,过滤,滤液在40~50℃下减压浓缩得到化合物1-7。
1H NMR(400MHz,CD
3OD)7.28-7.19(m,2H),7.16-7.09(m,1H),7.08-7.00(m,2H),4.04-3.96(m,1H),3.67-3.52(m,4H),3.39-3.31(m,2H),2.33-2.25(m,1H),2.15-2.07(m,1H),1.97-1.88(m,1H),1.73-1.57(m,4H),1.56-1.48(m,1H),1.45(s,9H),1.09-0.98(m,2H)。MS-ESI计算值[M+H]
+373实测值373。
第五步
将化合物1-7(7.00g,18.79mmol)溶于乙腈(70mL),向反应液中加入一水合对甲基苯磺酸(9.71g,56.38mmol),反应液在25℃搅拌12小时。反应液过滤,滤饼真空干燥得到化合物1的二对甲苯磺酸盐。
1H NMR(400MHz,CD
3OD)7.70(d,J=8.4Hz,4H),7.31-7.27(m,2H),7.23-7.21(m,5H),7.15-7.13(m,2H),4.19-4.05(m,3H),3.27-3.15(m,4H),3.00-2.97(m,1H),2.52-2.48(m,1H),2.43-2.38(m,1H),2.35(s,6H),2.04-1.95(m,4H),1.81-1.73(m,1H),1.55-1.50(m,1H),1.40-1.35(m,1H)。MS-ESI计算值[M+H]+273实测值273。
实施例2
合成路线:
第一步
将饱和碳酸氢钠(0.44mL)、化合物1-6(0.6g,0.718mmol)、二氯甲烷(10mL)搅拌混合。反应釜温度25℃,搅拌1小时。将反应液静置分层,分液,水相用二氯甲烷(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×1)洗涤,静置分层,分液,有机相加入无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物2-1。
1H NMR(400MHz,CD
3OD)7.26-7.22(m,2H),7.15-7.11(m,1H),7.07-7.05(m,2H),4.02-3.98(m,1H),3.65-3.50(m,4H),3.37-3.29(m,2H),2.30-2.22(m,1H),2.13-2.04(m,1H),1.95-1.86(m,1H),1.69-1.56(m,4H),1.51-1.48 (m,1H),1.46(s,9H),1.09–1.03(m,2H)。MS-ESI计算值[M+H]
+373实测值373。
第二步
将化合物2-1(250mg,0.603mmol)溶于乙腈(10mL),向反应液中加入一水合对甲基苯磺酸(311.56mg,1.81mmol),反应液在25℃搅拌12小时。反应液过滤,滤饼真空干燥得到化合物2的二对甲苯磺酸盐。
1H NMR(400MHz,CD
3OD)7.71(d,J=8.4Hz,4H),7.35-7.27(m,2H),7.24-7.21(m,5H),7.16-7.15(m,2H),4.24-4.14(m,1H),4.12-4.09(m,2H),3.28-3.17(m,4H),3.05-2.97(m,1H),2.56-2.52(m,1H),2.55-2.47(m,1H),2.37(s,6H),2.03-1.98(m,4H),1.84-1.74(m,1H),1.60-1.51(m,1H),1.42-1.35(m,1H).MS-ESI计算值[M+H]+273实测值273。
实施例3
合成路线:
第一步
将化合物3-1(50.0g,0.251mol)溶于无水四氢呋喃(150mL)和水(150mL)中,0℃下向反应液中加入氯化铵(49.9g,0.934mol)和锌粉(49.2g,0.753mol)。在0℃下缓慢滴加化合物3-2(91.1g,0.753mol)。反应液在20℃下搅拌12小时。过滤,滤液用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经过硅胶柱层析法分离(3:1石油醚/乙酸乙酯,R
f=0.47)得到化合物3-3。
1H NMR(400MHz,CD
3OD)δ5.88-5.80(m,1H),5.18-5.10(m,2H),3.95-3.64(m,2H),3.28-3.02(m,2H),2.23-2.21(m,2H),1.58-1.48(m,4H),1.45-1.44(m,9H)。
第二步
将化合物3-3(2.00g,8.29mmol)溶于N,N-二甲基甲酰胺(20mL)中,0℃下在氮气保护下向反应液中加入钠氢(60%,0.994mg,24.9mmol),在氮气保护下向反应液中加入化合物3-2(3.01g,24.9mmol)。反应液 在25℃下搅拌2小时。向反应液中加入饱和氯化铵(200mL),用乙酸乙酯萃取(100mL×3),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经过硅胶柱层析法分离(10:1石油醚/乙酸乙酯,R
f=0.60)得到化合物3-4。
第三步
将化合物3-4(2.15g,7.64mmol)溶于二氯甲烷(20mL)中,向反应液中加(1,3-二甲基咪唑烷-2-基亚基)(2-异丙氧基亚苄基)钌氯化钌(VI)(0.479g,0.764mmol)。反应液在25℃下搅拌反应3小时。加水(100mL)进行淬灭,用乙酸乙酯萃取(100mL×3),合并有机相,用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经过硅胶柱层析法分离(10:1石油醚/乙酸乙酯,R
f=0.51)得到化合物3-5。
1H NMR(400MHz,CD
3OD)δ5.68-5.61(m,2H),4.04-4.03(m,2H),3.71-3.60(m,2H),3.12-3.06(m,2H),1.93-1.90(m,2H),1.78-1.68(m,2H),1.62-1.61(m,1H),1.39(s,9H),1.37-1.36(m,1H)。
第四步
将化合物3-5(1.87g,7.38mmol)溶于无水四氢呋喃(10mL)中,0℃下在氮气保护下向反应液中加硼烷四氢呋喃(1M,22.1mL)。反应液在30℃下搅拌反应7小时。0℃下向反应液中加氢氧化钠(3.54g,88.6mmol),水(10mL)和双氧水(27.1g,0.295mol)。反应液在30℃下搅拌反应1小时。反应液用水(100mL)淬灭,乙酸乙酯萃取(100mL×3),合并有机相,用饱和食盐水(100mL×1)洗.无水硫酸钠干燥,过滤,滤液减压浓缩后经过硅胶柱层析法分离(2:1石油醚/乙酸乙酯,Rf=0.20)得到化合物3-6。
1H NMR(400MHz,CD
3OD)δ3.79-3.65(m,4H),3.15-2.94(m,2H),1.82-1.74(m,3H),1.67-1.53(m,6H),1.38(s,9H)。
第五步
将化合物3-6(1.65g,6.08mmol)溶于无水二氯甲烷(20mL)中,0℃下在氮气保护下向反应液中加入重铬酸吡啶鎓盐(4.58g,12.2mmol)。反应液在30℃下搅拌反应12小时。过滤,滤液用二氯甲烷萃取(80mL×1),合并有机相,有机相用盐酸(1mol/L,50mL),饱和氯化钠(100mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经过硅胶柱层析法分离(2:1石油醚/乙酸乙酯,Rf=0.59)得到化合物3-7。
1H NMR(400MHz,CD
3OD)δ4.03-4.00(m,2H),3.83-3.81(m,2H),3.22-3.16(m,2H),2.53-2.48(m,2H),1.93-1.77(m,4H),1.58-1.52(m,2H),1.48-1.47(m,9H)。MS-ESI计算值[M-Boc+H]
+170,[M-56+H]
+214,实测值170,214。
第六步
将化合物3-7(240mg,0.891mmol)和化合物1-2(142mg,1.07mmol)溶于二氯甲烷(3mL)中,将冰醋酸(53.5mg,0.891mol)加入反应液,在25℃下搅拌反应10小时,向反应液中加入三乙酰氧基硼氢化钠(378mg,1.78mmol),继续反应2小时。在25℃下向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应,用二氯甲烷(20mL×3)萃取,有机相用饱和氯化钠溶液(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经过薄层层析法分离(1:1石油醚/乙酸乙酯,Rf=0.3)分离纯化得到化合物3-8。MS-ESI计算值[M+H]
+387,实测值387。
第七步
将化合物3-8(100mg,0.259mmol)溶于乙酸乙酯(5mL)中,加入盐酸乙酸乙酯溶液(4M,10mL,40.0mmol)并在25℃搅拌1小时。反应液减压浓缩经过高效液相色谱(酸性,盐酸体系)分离纯化得到化合物3的盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.35-7.28(m,2H),7.27-7.16(m,3H),3.95-3.91(m,1H),3.86-3.78(m,1H),3.73-3.66(m,1H),3.29-3.21(m,3H),3.11-2.97(m,2H),2.59-2.52(m,2H),2.18-2.13(m,2H),1.98-1.89(m, 1H),1.84-1.68(m,3H),1.65-1.56(m,2H),1.47-1.41(m,1H)。MS-ESI计算值[M+H]
+287,实测值287。
实施例4
合成路线:
第一步
将化合物4-1(194mg,0.856mmol)和化合物1-2(114mg,0.856mmol)溶于无二氯甲烷(1mL)中,向反应液中加入冰醋酸(154mg,2.57mmol)。反应液在26℃下搅拌2小时,加入醋酸硼氢化钠(544mg,2.57mmol),在26℃下继续搅拌10小时。向反应液中加入饱和碳酸氢钠(30mL),用二氯甲烷萃取(30mL×3),合并有机相,有机相用饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经过薄层层析法分离(2:1石油醚/乙酸乙酯,Rf=0.26)得到化合物4-2。MS-ESI计算值[M+H]
+345,实测值345。
第二步
将化合物4-2(70.0mg,0.203mmol)溶于乙酸乙酯(1mL)中,在0℃下滴加盐酸乙酸乙酯(4M,0.406mL)。反应液在20℃下搅拌反应1小时,减压浓缩除去溶剂,粗产物经过高效液相色谱法(酸性,盐酸体系)制备得到化合物4的盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.35-7.32(m,2H),7.27-7.20(m,3H),4.41-4.26(m,1H),4.29-4.07(m,6H),3.05-3.03(m,1H),2.91-2.84(m,1H),2.68-2.55(m,2H),1.66-1.60(m,1H),1.50-1.41(m,1H)。MS-ESI计算值[M+H]
+245,实测值245。
实施例5
合成路线:
将化合物1-4(250mg,0.671mmol)溶于乙酸乙酯(5mL)中,在15℃下加入盐酸乙酸乙酯溶液(4M,5mL)。反应液在15℃下搅拌反应10小时,减压浓缩除去溶剂,粗产物经过高效液相色谱法(酸性,盐酸体系)制备得到化合物5的盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.35-7.31(m,2H),7.26-7.22(m,3H),4.23- 4.21(m,1H),4.19-4.13(m,2H),3.33-3.20(m,4H),3.05-3.03(m,1H),2.71-2.67(m,1H),2.49-2.44(m,1H),2.17-2.11(m,3H),2.03-2.01(m,1H),1.93-1.89(m,1H)1.70-1.66(m,1H),1.44-1.40(m,1H)。MS-ESI计算值[M+H]
+273,实测值273。
生物化学检测:
实验1:酶活性评价
本试验目的是检测化合物对LSD1的体外抑制活性。本试验采用的酶为人源LSD1,标准底物为组蛋白H3K4me肽(20μM),采用酶荧光偶联法,通过辣根过氧化酶(HRP)和荧光试剂Amplex Red联合检测LSD1反应后生成的H
2O
2的方法测定化合物的活性。从10μM开始3倍稀释,检测化合物的10个浓度下IC
50值。化合物在加入底物开始反应前,酶和底物共孵化30分钟。荧光检测器:EnVision,激发波长:Ex/Em=530/590nM。
测试化合物对LSD1抑制活性,结果如表1所示。
表1:本发明化合物体外酶活性筛选试验结果
化合物编号 | IC 50(nM) | 化合物编号 | IC 50(nM) |
化合物1的二对甲苯磺酸盐 | 28.05 | 化合物4的盐酸盐 | 72.92 |
化合物3的盐酸盐 | 17.43 | 化合物5的盐酸盐 | 4.66 |
结论:本发明化合物对LSD1抑制活性明显。
实验2:细胞活性评价
A.kasumi-1、MV-4-11细胞活性测试
实验目的:分析化合物对kasumi-1、MV4-11细胞的增殖抑制作用。
实验方法与步骤:实验用细胞培养液:在RPMI1640细胞培养基中添加终浓度为20%或10%的胎牛血清,1%的青霉素/链霉素溶液,4℃保存备用。
1)混匀kasumi-1/MV-411细胞计数,用培养基分别制成1×10
4个细胞/mL的kasumi-1细胞悬液和3×10
4个细胞/mL的MV-411细胞悬液,加入96孔细胞培养板,80μl/孔。
2)使用细胞培养液将化合物稀释到50μM,放入化合物板的第1列(1.5μL 10mM母液+300μL细胞培养液)。在第2列到第8列的孔中,加入80μL细胞培养液,从第1列取20μL化合物加入到第2列混合均匀,再从第2列取20μL化合物加入到第3列混合均匀,重复此步骤到第8列;
3)从化合物板取20μL每孔梯度稀释完成的化合物放入细胞培养板的相应位置,此时化合物的最终浓度为10μM至0.128nM。将细胞板放回含5%CO
2的二氧化碳培养箱继续孵育6天。
4)细胞培养6天后,取出96孔细胞培养板,加入CTG试剂,50μl/孔,混匀离心,室温孵育15分钟。使用Envision多标记分析仪读数。
5)抑制率计算:
抑制率(%)=(RFU样品-RFU阴性对照)/(RFU阳性对照-RFU阴性对照)×100%
6)IC
50计算:
将抑制率使用软件Prism 8进行IC
50计算,公式如下:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)×HillSlope))
实验结果如表2所示:
表2:本发明化合物体外细胞活性测试结果
结论:本发明化合物对kasumi-1/MV4-11细胞增殖抑制活性明显。
B.KG-1细胞活性评价
实验目的:分析化合物对人急性髓系白血病KG-1细胞的增殖抑制作用。
实验材料:胎牛血清(FBS)购自依科赛生物科技有限公司,IMDM培养基购自美国模式培养物集存库(ATCC,American type culture collection),青霉素/链霉素双抗购自HyClone。CellTiter-Glo Luminescent Cell Viability Assay(细胞活率化学发光检测试剂)试剂购自Promega。KG-1细胞购自欧洲标准细胞收藏中心(ECACC,European Collection of Authenticated Cell Cultures)。Nivo多标记分析仪(PerkinElmer)。
实验方法:
1)将KG-1细胞种于96孔板中,100μL细胞悬液每孔,其中1×10
4个细胞/mL。细胞板置于二氧化碳培养箱中培养。
2)将配制好的化合物转移至相应的细胞板孔中(细胞板终浓度以10μM为起始,5X递减,9个浓度)。将细胞版置于含5%CO
2的细胞培养箱中37℃培养6天。
3)第6天取出96孔细胞培养板,加入CellTiter-Glo Luminescent Cell Viability Assay试剂,50μL/孔,混匀震板10分钟,室温孵育5分钟。使用Envision Multilabel Plate Reader读细胞板荧光值。
数据分析:
1)抑制率计算:
抑制率(%)=(RFU样品-RFU阴性对照)/(RFU阳性对照-RFU阴性对照)×100%
2)IC
50计算:将抑制率使用软件GraphPad Prism 9进行IC
50计算,公式如下:结果如表3所示。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)×HillSlope))
表3:化合物对细胞增殖的抑制作用
结论:本发明化合物在KG-1细胞上显示出了显著的抗增殖活性。
实验3:hERG钾离子通道的抑制试验
实验目的:使用电生理手动膜片钳方法测试化合物1的二对甲苯磺酸盐对hERG钾通道(human Ether-a-go-goRelated Gene potassium channel,hERG)电流的影响。
实验方法
3.1细胞培养
稳定表达hERG通道的中国仓鼠卵巢细胞培养于直径35mm的细胞培养皿中,置于37℃,5%CO
2的培养箱培养,每48小时按1:5比例进行传代,培养基配方:90%F12(Invitrogen),10%胎牛血清(Gibco),100g/mL G418(Invitrogen)和100g/mL Hygromycin B(Invitrogen)。试验当天,吸走细胞培养液,用细胞外液淋洗一遍后加入0.25%Trypsin-EDTA(Invitrogen)溶液,在室温下消化3-5分钟。吸走消化液,用细胞外液重悬后将细胞转移到用于电生理记录的实验皿中备用。
3.2化合物准备
化合物用DMSO溶解成20mM母液,测试当天,将化合物母液用DMSO进行3倍连续稀释,即取10μL的化合物母液加入到20μL DMSO中,依次得到经DMSO连续稀释的化合物中间浓度,依次分别为20、6.66、2.22、0.74、0.25和0.082mM。然后再取10μL的化合物中间浓度加入到4990μL细胞外液中,500倍稀释得到需要测试的最终浓度,最高测试浓度为40μM,依次分别为40、13.3、4.44、1.48、0.49和0.16μM。阳性对照化合物cisapride准备:取150μM的cisapride母液用100%DMSO进行3倍连续稀释,即取10μL 150μM的cisapride母液加入20μL DMSO,依次得到5个经DMSO连续稀释的cisapride中间浓度,依次分别为150、50、16.7、5.56和1.85μM。然后再取10μL的cisapride中间浓度加入到4990μL细胞外液中,500倍稀释得到需要测试的最终浓度,最高测试浓度为300nM,依次分别为300、100、33.3、11.1和3.70nM共5个浓度。最终测试浓度中DMSO的含量不超过0.2%,此浓度的DMSO对hERG钾通道没有影响。
3.3电生理记录过程
稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞,在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10,Sutter)经拉制仪拉制而成,灌注电极内液后的尖端电阻为2-5MΩ左右,将玻璃微电极插入放大器探头即可连接至Axopatch 200B(Molecular Devices)膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录,采样频率为10kHz,滤波频率为2kHz。在得到全细胞记录后,细胞钳制在-80mV,诱发hERG钾电流(IhERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV,再复极化到-50mV,持续1s后回到-80mV。每10s给予此电压刺激,确定hERG钾电流稳定后(1分钟)开始给药过程。化合物浓度从低测试浓度开始连续给药,每个测试浓度至少给予1分钟。化合物每个浓度至少测试3个细胞(n≥3),阳性化合物每个浓度至少测试2个细胞(n≥2)。
3.4数据分析
数据分析处理采用pClamp 10,GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算:
Inhibition%=[1–(I/Io)]×100%
其中,Inhibition%代表化合物对hERG钾电流的抑制百分率,I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC
50使用GraphPad Prism 5软件通过以下方程拟合计算得出:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)×HillSlope))
其中,X为供试品检测浓度的Log值,Y为对应浓度下抑制百分率,Bottom和Top分别为最小和最大抑制百分率。
3.5测试结果
实施例化合物hERG IC
50值结果见表4。
表4:实施例化合物hERG IC
50值结果
供试样品 | hERG IC 50(μM) | IC 50(ng/mL) |
化合物1的二对甲苯磺酸盐 | >40 | >24671.6 |
结论:本发明化合物对hERG钾离子通道无抑制作用。
Claims (13)
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,n为0或1。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,g为0或1。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,m为1时,n为1,g为1。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,m为2时,n为1,g为1。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中,m为1时,n为0,g为0。
- 根据权利要求1-10任意一项所述的化合物或其药学上可接受的盐,其中所述的盐选自盐酸盐和对苯甲磺酸盐。
- 根据权利要求1-11任意一项所述的化合物或其药学上可接受的盐在制备治疗LSD1相关疾病的药物中的应用。
- 根据权利要求12所述的应用,所述疾病为血液肿瘤、小细胞肺癌、鳞状非小细胞肺癌、乳腺癌、前列腺癌、肝癌、胰腺癌、胶质瘤或尤文氏肉瘤,所述血液肿瘤优选为人急性髓系白血病。
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WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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CN103857393A (zh) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权(第2号)有限公司 | 环丙基胺作为lsd1抑制剂 |
WO2020052647A1 (zh) * | 2018-09-13 | 2020-03-19 | 南京明德新药研发有限公司 | 作为lsd1抑制剂的杂螺环类化合物及其应用 |
WO2020052649A1 (zh) * | 2018-09-13 | 2020-03-19 | 南京明德新药研发有限公司 | 作为lsd1抑制剂的环丙胺类化合物及其应用 |
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CN103857393A (zh) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权(第2号)有限公司 | 环丙基胺作为lsd1抑制剂 |
WO2020052647A1 (zh) * | 2018-09-13 | 2020-03-19 | 南京明德新药研发有限公司 | 作为lsd1抑制剂的杂螺环类化合物及其应用 |
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WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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