WO2021143925A1 - 作为ar拮抗剂的二芳基硫代乙内酰脲化合物 - Google Patents

作为ar拮抗剂的二芳基硫代乙内酰脲化合物 Download PDF

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WO2021143925A1
WO2021143925A1 PCT/CN2021/072671 CN2021072671W WO2021143925A1 WO 2021143925 A1 WO2021143925 A1 WO 2021143925A1 CN 2021072671 W CN2021072671 W CN 2021072671W WO 2021143925 A1 WO2021143925 A1 WO 2021143925A1
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compound
formula
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/CN2021/072671
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French (fr)
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沈春莉
曹世美
陈胜林
吴成德
陈曙辉
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正大天晴药业集团股份有限公司
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Priority to CN202180008511.6A priority Critical patent/CN114929702B/zh
Publication of WO2021143925A1 publication Critical patent/WO2021143925A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application belongs to the field of medicine. Specifically, it relates to compounds of formula (I) and formula (II), their preparation methods, pharmaceutical compositions containing the compounds, and their use in the preparation of drugs for the treatment of androgen-mediated related diseases .
  • Androgen receptor belongs to the steroid receptor in the nuclear receptor superfamily. When combined with androgens (such as testosterone and dihydrotestosterone), AR is released from the complex formed by heat shock proteins. Phosphorylation reacts to form a dimer, which is transferred to the nucleus and binds to its related DNA fragments, thereby stimulating the transcription of its target genes. The transcriptional activity of the androgen receptor activated by ligand binding is coordinated by the proteins of co-activators.
  • AR antagonists The main role of AR antagonists is to directly prevent the binding of testosterone or dihydrotestosterone to the androgen receptor, block the effect of androgen on cells, play an anti-androgen and inhibit cell growth, and ultimately promote cell apoptosis to achieve treatment
  • Enzalutamide an androgen receptor antagonist developed by Medivation & Astellas, has been on the market.
  • a compound as an active ingredient of a drug needs to have excellent properties in the following aspects: biological activity, safety, bioavailability, stability, and so on.
  • the present invention provides a diarylthiohydantoin compound with a novel structure for use as an androgen receptor antagonist, and it has been found that the compound with such a structure exhibits excellent anti-tumor effects and has the above-mentioned excellent properties .
  • the application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen, halogen and C 1-12 alkyl, wherein the C 1-12 alkyl is optionally substituted with one or more halogens;
  • R 2 and R 3 are each independently selected from C 1-12 alkyl groups
  • R 4 is selected from hydrogen, halogen and C 1-12 alkyl
  • R 5 is selected from C 1-12 alkyl.
  • R 1 is selected from hydrogen, halogen, and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens, and other variables are as defined in this application.
  • R 1 is selected from halogen, and other variables are as defined in this application.
  • R 1 is chlorine, and other variables are as defined in this application.
  • R 2 and R 3 are each independently selected from C 1-6 alkyl, and other variables are as defined in this application.
  • R 2 and R 3 are each independently a methyl group, and other variables are as defined in this application.
  • R 4 is selected from hydrogen, C 1-6 alkyl, or halogen, and other variables are as defined in this application.
  • R 4 is selected from halogen, and other variables are as defined in this application.
  • R 4 is fluorine, and other variables are as defined in this application.
  • R 5 is selected from C 1-6 alkyl, and other variables are as defined in this application.
  • R 5 is methyl, and other variables are as defined in this application.
  • R 1 is selected from halogen
  • R 2 and R 3 are each independently selected from C 1-6 alkyl
  • R 4 is selected from halogen
  • R 5 is selected from C 1-6 alkyl.
  • R 1 is selected from halogen
  • R 2 and R 3 are each independently methyl
  • R 4 is selected from halogen
  • R 5 is methyl.
  • this application relates to a compound of formula (I-1) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as those of the compound of formula (I).
  • this application relates to a compound of formula (I-2) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as those of the compound of formula (I).
  • this application relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • this application relates to a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,
  • this application relates to a compound of formula (II-2) or a pharmaceutically acceptable salt thereof,
  • the application relates to a pharmaceutical composition, which comprises the formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula (II) of the application -2)
  • the compound or a pharmaceutically acceptable salt thereof in some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application relates to a method for treating androgen-mediated diseases in mammals, including administering a therapeutically effective amount of formula (I), formula (I-1), formula (I), formula (I-1), and formula (I-1) to a mammal in need of such treatment, preferably a human.
  • the diseases include, but are not limited to, cell proliferation Diseases (e.g. cancer, including prostate cancer).
  • the application relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable compound thereof
  • a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable compound thereof Use of the accepted salt or its pharmaceutical composition in the preparation of a medicament for the treatment of androgen-mediated diseases, including but not limited to cell proliferative diseases (such as cancer, including prostate cancer).
  • the application relates to a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable compound thereof
  • a compound of formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable compound thereof Use of the accepted salt or its pharmaceutical composition in the treatment of androgen-mediated diseases, including but not limited to cell proliferative diseases (such as cancer, including prostate cancer).
  • this application relates to formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1) or formula ( II-2)
  • diseases include, but are not limited to, cell proliferative diseases (e.g., cancer, including prostate cancer).
  • the compound of the present application has high activity, low pharmacokinetic clearance rate, and good absorption; the target selectivity is good, and the safety is higher.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • wedge keys And dotted keys Represents the absolute configuration of the three-dimensional center.
  • the compounds of the present application may exist in specific geometric isomers or stereoisomers. This application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , Diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, All of these fall within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of this application.
  • treatment means administering the compounds or formulations described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, in which protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.
  • the compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the daily dose is 0.01 to 200 mg/kg body weight, with a single dose of 0.01 to 200 mg/kg body weight. Or in the form of divided doses.
  • the compounds of the present application 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 those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
  • the compound of formula (I) of the present application can be prepared by those skilled in the art of organic synthesis through the following steps and routes:
  • LCMS stands for Liquid Chromatography Mass Spectrometry.
  • the nuclear magnetic resonance chromatography (NMR) of the present invention is measured by a BRUKER 400 nuclear magnetic resonance instrument.
  • TMS tetramethylsilane
  • the format of the proton nuclear magnetic resonance spectrum data recording is: peak type (s, single Peak; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in Hz), number of protons.
  • the instrument used for mass spectrometry is SHIMADUZU LCMS-2010.
  • an aqueous lithium hydroxide solution (1M, 475 mL) was added to compound 1-2 (28 g, 237.03 mmo) in tetrahydrofuran (475 mL), and stirred at 21°C for 3 hours.
  • ethyl acetate 500 mL
  • N,N'-carbonyldiimidazole (26.5g, 163.43mmol) was added to compound 1-3 (14.06g, 135.06mmol) in tetrahydrofuran (280mL), stirred at 21°C for 2 hours, and then magnesium chloride was added (14g, 147.04mmol) and compound 1-4 (28g, 164.51mmol), continue to stir at 21°C for 2 hours.
  • Ethyl acetate (280 mL) was added to the reaction solution, stirred for 5 minutes, filtered to remove insoluble inorganic salts, and the filter cake was washed with ethyl acetate (120 mL*2). The filtrate was washed with water (170 mL*2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-5.
  • the bis(dibenzylideneacetone) palladium (111mg, 193.04 ⁇ mol), 4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene (111mg, 191.84 ⁇ mol) and cesium carbonate (1.11 g, 3.42 mmol) were added to the toluene (10 mL) solution of compound 1-7 (470.00 mg, 1.56 mmol) and tert-butyl carbamate (0.22 g, 1.90 mmol) in sequence, and heated at 120°C and stirred for 1 hour.
  • boron tribromide (780.00 mg, 3.11 mmol, 0.3 mL) was added to a dichloromethane (2 mL) solution of compound 1-13 (200 mg, 400.04 ⁇ mol), and stirred at 0°C for 15 minutes. After the reaction solution was diluted with dichloromethane (10 mL), it was slowly added to an ice-cooled saturated NaHCO 3 aqueous solution (20 mL), stirred for 10 minutes, then stood still for liquid separation, and the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative TLC, and the obtained product was purified by SFC to obtain compound 1.
  • the compound is added to the cells and incubated for 60 minutes.
  • the working concentration of the test compound is a 3-fold dilution from 10 ⁇ M, respectively: 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.67nM, followed by adding the agonist 6a-Fluorotestosterone 0.06 ⁇ M (concentration of EC80, that is, 80% agonizing compound concentration) and incubating at 37°C or room temperature for 3-16 hours.
  • IC 50 inhibition rate (%) 100% ⁇ (1-(average RLU value of the test compound -Blank control group average RLU value)/(EC80 control average RLU value-blank control group average RLU value)).
  • CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35mm, placed in a 37°C, 5% CO 2 incubator, and subcultured at a ratio of 1:5 every 48 hours.
  • Aspirate the cell culture fluid rinse with extracellular fluid, add 0.25% trypsin-EDTA (Invitrogen) solution, and digest for 3-5 minutes at room temperature. Aspirate the digestive fluid, resuspend in extracellular fluid, and transfer the cells to a laboratory dish for electrophysiological recording for later use.
  • the compound to be tested was dissolved in 100% DMSO into a 20mM mother liquor.
  • the compound mother liquor was serially diluted with DMSO by 3 times, that is, 10 ⁇ L of the compound mother liquor was added to 20 ⁇ L DMSO, and 6 compounds serially diluted by DMSO were obtained in turn.
  • the concentrations are 20, 6.66, 2.22, 0.74, 0.25 and 0.082mM in order.
  • 10 ⁇ L of the intermediate concentration of the compound was added to 4990 ⁇ L of extracellular fluid, and diluted 500 times to obtain the final concentration to be tested.
  • the highest test concentration was 40 ⁇ M, followed by 40, 13.3, 4.44, 1.48, 0.49 and 0.16 ⁇ M.
  • CHO Choinese Hamster Ovary cells stably expressing the hERG potassium channel, record the hERG potassium channel current using the 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 liquid is about 2-5M ⁇ . Insert the glass microelectrode into the amplifier probe to connect To Axopatch 200B (Molecular Devices) patch clamp amplifier. Clamping voltage and data recording are controlled and recorded by pClamp 10 software through a computer.
  • the sampling frequency is 10kHz
  • the filtering frequency is 2kHz.
  • the cell is clamped at -80mV, and the step voltage for inducing the hERG potassium current (I hERG) is given from -80mV to a depolarization voltage for 2 seconds to +20mV, and then repolarization to -50mV, continuing After 1 second, it returns to -80mV. Give this voltage stimulation every 10 seconds, and start the dosing process after confirming that the hERG potassium current is stable (1 minute).
  • the compound concentration is continuously administered starting from the low test concentration, and each test concentration is administered for 1 minute. At least 3 cells are tested for each concentration of compound (n ⁇ 3), and at least 2 cells are tested for each concentration of positive compound (n ⁇ 2).
  • hERG tail current peak induced at -50mV The inhibition degree of different compound concentration on hERG potassium current (hERG tail current peak induced at -50mV) is as follows:
  • Inhibition% [1–(I/Io)] ⁇ 100%, where Inhibition% represents the percentage of the compound's inhibition of hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • the compound IC 50 was calculated by the following equation fitting using GraphPad Prism 5 software:
  • Y Bottom+(Top-Bottom)/(1+10 ⁇ ((LogIC 50 -X)*HillSlope))
  • X is the Log value of the concentration of the test substance
  • Y is the percentage of inhibition at the corresponding concentration
  • Bottom and Top are respectively The minimum and maximum inhibition percentages
  • HillSlope is the absolute value of the maximum slope of the curve (that is, the midpoint of the curve).
  • I compound + GABA
  • I GABA is the baseline peak current after adding EC80 GABA.
  • DMEM medium for CB2 detection and DMEM medium for CCKa detection to dilute the above two groups of cells to 1 ⁇ 10 6 cells/mL (20000 cells/20 ⁇ L), and plant them in 384-well polylactide. Incubate the acid-coated cell plate at 37°C and 5% CO 2 for 16-20 hours.
  • DRC plate Run FLIPR instrument software, according to the set program, add 10 ⁇ L experimental buffer salt solution (F10471 kit, buffer salt solution component 1x HBSS, 20Mm HEPES) to the cell plate, and read the fluorescence signal. Then add 10 ⁇ L of the agonist reference compound of a predetermined concentration to the cell plate, and read the fluorescence signal. After reading, export the data through the “Max-Min” and “Read 1 to 90” methods in the software, calculate the EC 80 of each cell line, prepare 6 ⁇ EC 80 concentration of agonist, and add 30 ⁇ L/well to the corresponding compound plate , Centrifuge at 1000 rpm for 1 minute.
  • experimental buffer salt solution F10471 kit, buffer salt solution component 1x HBSS, 20Mm HEPES
  • Antagonist inhibition rate% 100-(RLU-LC)/(DMSO-LC)*100
  • RLU Relative light absorption value, reading value from 1 to 90;
  • DMSO DMSO group fluorescence signal average
  • LC antagonist highest concentration point fluorescence signal average
  • GR glucocorticoid cell detection medium: 500mL phenol red-free DMEM, 10.8mL activated carbon-treated (Charcoal-stripped) FBS, 5.4mL NEAA, 13.5mL HEPES, 5.4mL sodium pyruvate and 5.4mL penicillin-chain Mycin
  • pancreatin 3.5 mL of pancreatin to the cell culture flask and shake it gently to make the pancreatin fully contact with the cells and then remove the pancreatin. After aspirating the pancreatin, place the culture flask in a 37°C incubator containing 5% CO2 for about 1 minute ;
  • GR glucocorticoid
  • GR cells 6.7 ⁇ 10 5 cells per ml of culture medium, 30 ⁇ L per well. Place the cell plate in a 5% CO2, 37°C incubator and incubate for 30 minutes.
  • Agonist agonist rate % (RFU-DMSO)/(HC-DMSO)*100%
  • HC Mean value of fluorescence signal at the highest concentration point of agonist
  • DMSO Mean value of fluorescence signal of DMSO group
  • test compounds are shown in Table 5.
  • mice Using male CD-1 mice as the test animals, the LC/MS/MS method was used to determine the drug concentration in the plasma of mice at different times after intravenous bolus injection and intragastric administration of compound 1. The pharmacokinetic behavior of compound 1 in mice was studied, and its pharmacokinetic characteristics were evaluated.
  • mice 6 healthy adult male CD-1 mice were divided into 2 groups according to the principle of similar body weight, 3 in each group. The animals were purchased from Shanghai Sipuer-Bike Laboratory Animal Co., Ltd.
  • Intravenous administration group Weigh an appropriate amount of samples, add appropriate amounts of DMSO, PEG400 and water in order according to the volume ratio of 10:50:40, and stir to achieve 0.4mg/mL after ultrasound.
  • Gavage administration group Weigh an appropriate amount of sample, add an appropriate volume of 0.5% CMC-Na, 0.2% Tween, and stir and ultrasound to reach 0.4 mg/mL.
  • mice Six male CD-1 mice were divided into 2 groups. After fasting overnight, the first group was given intravenous administration with a volume of 2ml/kg and a dose of 1mg/kg; the second group was given intragastric administration, giving The volume of the medicine is 4ml/kg, and the dose is 2mg/kg.
  • the LC/MS/MS method was used to determine the content of the test compound in the mouse plasma after intravenous and intragastric administration.
  • the linear range of the method is 2.00 ⁇ 6000nmol/L; plasma samples are analyzed after acetonitrile-precipitated protein treatment.

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Abstract

涉及作为AR拮抗剂的式(I)化合物、其制备方法、含有该化合物的药物组合物、以及其在制备治疗雄激素介导的相关疾病的药物的用途。

Description

作为AR拮抗剂的二芳基硫代乙内酰脲化合物
相关申请的交叉引用
本申请要求于2020年01月19日向中华人民共和国国家知识产权局提交的第202010062225.5号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药领域，具体而言，涉及式(I)及式(II)化合物、其制备方法、含有该化合物的药物组合物、以及其在制备治疗雄激素介导的相关疾病的药物的用途。
背景技术
雄激素受体(AR)属于核受体超家族中的类固醇受体，当与雄激素(如睾酮和二氢睾酮等)结合后，AR从热休克蛋白形成的复合体中被释放出来，进行磷酸化反应，形成二聚体，并转移到细胞核内，结合到与它相关的DNA片段上，从而刺激其目标基因的转录。配体结合所激活的雄激素受体的转录活性由共活化子(co-activators)的蛋白质协调而完成。AR拮抗剂的主要作用是直接阻止睾酮或二氢睾酮与雄激素受体结合，阻断雄激素对细胞的作用，起到抗雄激素和抑制细胞增长的作用，最终促使细胞凋亡，达到治疗前列腺癌的重要作用。由Medivation&Astellas公司开发的雄激素受体拮抗剂恩杂鲁胺(Enzalutamide)己经上市。
鉴于雄激素受体拮抗剂的重要作用，开发适用作治疗药物的雄激素受体拮抗剂显得尤为重要。一般地，作为药物活性成分的化合物需要在以下方面具有优良的性质：生物活性、安全性、生物利用度、稳定性等。本发明提供了一种结构新颖的用作雄激素受体拮抗剂的二芳基硫代乙内酰脲化合物，并发现具有此类结构的化合物表现出优异的抗肿瘤效果，具有上述优良的性质。
发明内容
一方面，本申请涉及式(I)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000001
其中，
R 1选自氢、卤素和C 1-12烷基，其中所述C 1-12烷基任选地被一个或多个卤素取代；
R 2和R 3分别独立地选自C 1-12烷基；
R 4选自氢、卤素和C 1-12烷基；
R 5选自C 1-12烷基。
在一些实施方案中，R 1选自氢、卤素和C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代，其他变量如本申请所定义。
在一些实施方案中，R 1选自卤素，其他变量如本申请所定义。
在一些具体实施方案中，R 1为氯，其他变量如本申请所定义。
在一些实施方案中，R 2和R 3分别独立地选自C 1-6烷基，其他变量如本申请所定义。
在一些具体实施方案中，R 2和R 3分别独立地为甲基，其他变量如本申请所定义。
在一些实施方案中，R 4选自氢、C 1-6烷基或卤素，其他变量如本申请所定义。
在一些实施方案中，R 4选自卤素，其他变量如本申请所定义。
在一些具体实施方案中，R 4为氟，其他变量如本申请所定义。
在一些实施方案中，R 5选自C 1-6烷基，其他变量如本申请所定义。
在一些具体实施方案中，R 5为甲基，其他变量如本申请所定义。
在一些实施方案中，R 1选自卤素，R 2和R 3分别独立地选自C 1-6烷基，R 4选自卤素，R 5选自C 1-6烷基。在一些实施方案中，R 1选自卤素，R 2和R 3分别独立地为甲基，R 4选自卤素，R 5为甲基。
在本申请还有一些实施方案是由上述各变量任意组合而来。
另一方面，本申请涉及式(I-1)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000002
其中，
R 1、R 2、R 3、R 4和R 5的定义同式(I)化合物。
另一方面，本申请涉及式(I-2)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000003
其中，
R 1、R 2、R 3、R 4和R 5的定义同式(I)化合物。
又一方面，本申请涉及式(II)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000004
再一方面，本申请涉及式(II-1)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000005
再一方面，本申请涉及式(II-2)化合物或其药学上可接受的盐，
Figure PCTCN2021072671-appb-000006
还一方面，本申请涉及药物组合物，其包含本申请的式(I)、式(I-1)、式(I-2)、式(II)、式(II-1)或式(II-2)化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
还一方面，本申请涉及治疗哺乳动物的由雄激素介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)、式(I-1)、式(I-2)、式(II)、式(II-1)或式(II-2)化合物或其药学上可接受的盐、或其药物组合物；所述疾病包括但不限于细胞增殖性疾病(例如癌症，包括前列腺癌)。
还一方面，本申请涉及式(I)、式(I-1)、式(I-2)、式(II)、式(II-1)或式(II-2)化合物或其药学上可接受的盐、或其药物组合物在制备治疗由雄激素介导的疾病的药物中的用途，所述疾病包括但不限于细胞增殖性疾病(例如癌症，包括前列腺癌)。
还一方面，本申请涉及式(I)、式(I-1)、式(I-2)、式(II)、式(II-1)或式(II-2)化合物或其药学上可接受的盐、或其药物组合物在治疗由雄激素介导的疾病中的用途，所述疾病包括但不限于细胞增殖性疾病(例如癌症，包括前列腺癌)。
还一方面，本申请涉及用于治疗由雄激素介导的疾病的式(I)、式(I-1)、式(I-2)、式(II)、式(II-1)或式(II-2)化合物或其药学上可接受的盐、或其药物组合物。所述疾病包括但不限于细胞增殖性疾病(例如癌症，包括前列腺癌)。
技术效果
本申请的化合物活性高、药代清除率低，吸收良好；靶点选择性好，安全性更高。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术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，而应该按照本领域普通的含义去理解。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。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲 基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。
除非另有说明，用楔形键
Figure PCTCN2021072671-appb-000007
和虚线键
Figure PCTCN2021072671-appb-000008
表示立体中心的绝对构型。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、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，所有这些都属于本申请的范围之内。烷基等取代基中可以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申请的范围之内。
术语“治疗”意为将本申请所述化合物或制剂进行给药改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
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。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的中间体和化合物还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包 括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请所述的式(I)、式(I-1)、式(II)和式(II-1)化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式。
本申请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申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的羟基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.
在一些实施方案中，本申请式(I)化合物可以由有机合成领域技术人员通过以下步骤和路线来制备：
Figure PCTCN2021072671-appb-000009
本申请采用下述缩略词：
LCMS代表液相色谱质谱法。
具体实施方式
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申请，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。本申请所使用的所有溶剂是市售的，无需进一步纯化即可使用。本申请用于合成的初始化合物原料通过市售获得，也可以通过现有技术的方法制备。
本发明核磁共振色谱(NMR)使用BRUKER 400核磁共振仪测定，化学位移以四甲基硅烷(TMS＝δ0.00)为内标，核磁共振氢谱数据记录的格式为：峰型(s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰)，耦合常数(以赫兹Hz为单位),质子数。质谱使用的仪器为SHIMADUZU LCMS-2010。
实施例1化合物1的合成
Figure PCTCN2021072671-appb-000010
化合物1-2的制备
氮气保护下，将氧化银(62.50g,269.70mmol)加到化合物1-1(25g,240.14mmol)和碘甲烷(102.60g,722.85mmol)的乙腈(250mL)溶液中，在80℃搅拌2小时。反应液冷却至室温，过滤除去不溶无机盐，滤饼经二氯甲烷(250mL*2)洗涤。合并的滤液，经水(500mL)、饱和食盐水(500mL)洗涤，无水硫酸钠 干燥，过滤，浓缩得到化合物1-2。
化合物1-3的制备
在0℃下，将氢氧化锂水溶液(1M,475mL)加到化合物1-2(28g,237.03mmo)的四氢呋喃(475mL)中，在21℃下搅拌3小时。向反应液中加入乙酸乙酯(500mL)搅拌5分钟，分液，收集水相，用1M盐酸调pH＝3，浓缩水相至大约100mL，再加入200mL的二氯甲烷：甲醇＝20:1，有机相用无水硫酸钠干燥，浓缩得到化合物1-3。
化合物1-5的制备
在氮气保护下，将N,N’-羰基二咪唑(26.5g,163.43mmol)加到化合物1-3(14.06g,135.06mmol)的四氢呋喃(280mL)中，21℃搅拌2小时，再加入氯化镁(14g,147.04mmol)和化合物1-4(28g,164.51mmol)，继续在21℃搅拌2小时。向反应液中加入乙酸乙酯(280mL)，搅拌5分钟，过滤除去不溶解的无机盐，滤饼经乙酸乙酯(120mL*2)洗涤。滤液用水(170mL*2)洗涤，无水硫酸钠干燥，浓缩得到化合物1-5。MS(ESI)m/z:175.1(M+1)。
化合物1-7的制备
在氮气保护下，将三氯化铋(1g,3.17mmol)加到化合物1-5(5.30g,30.42mmol,2.91eq)和化合物1-6(2g,10.47mmol,1eq)的甲苯(30mL)溶液中，130℃搅拌16小时。反应液冷却至室温，向反应液中加二氯甲烷(10mL)，过滤除去不溶物。将反应液直接旋干，经自动过柱仪纯化得到化合物1-7。MS(ESI)m/z:303(M+3)。
化合物1-8的制备
将双(二亚苄基丙酮)钯(111mg,193.04μmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(111mg,191.84μmol)和碳酸铯(1.11g,3.42mmol)依次加入到化合物1-7(470.00mg,1.56mmol)和氨基甲酸叔丁酯(0.22g,1.90mmol)的甲苯(10mL)溶液中，升温120℃搅拌1小时。反应液冷却到室温，过滤，滤饼经乙酸乙酯(10mL*2)洗涤，滤液浓缩，经自动过柱仪纯化得到化合物1-8。MS(ESI)m/z:338.1(M+1)。
化合物1-9的制备
氮气保护下，向化合物1-8(370.00mg,1.10mmol)的二氯甲烷(5mL)溶液中滴加三氟乙酸(1.54g,13.51mmol,1mL)，室温(19℃)下搅拌2小时。向反应液中加入饱和碳酸钠水溶液中和至pH＝7，二氯甲烷(15mL*2)萃取。有机相经饱和食盐水(15mL*2)洗涤，无水硫酸钠干燥后，过滤，滤液减压浓缩得到化合物1-9。MS(ESI)m/z:238.1(M+1)。
化合物1-10的制备
室温(19℃)下，将1-9(150.00mg,632.30μmol)和氯化锌(161mg,1.18mmol)加到丙酮(395.00mg,6.80mmol,0.5mL)和四氢呋喃(4mL)的溶液中，然后将三甲基硅氰(396.50mg,4.00mmol,0.5mL)慢慢滴加到上述搅拌的悬浊液中，滴加完毕，该混合物室温(19℃)继续搅拌4小时。向反应液中加入乙酸乙酯(20mL)稀释，用饱和食盐水(20mL*2)洗涤两次。有机相用无水硫酸钠干燥，过滤，浓缩得到化合物1-10。MS(ESI)m/z:305.1(M+1)。
化合物1-12的制备
在0℃，将叔丁醇钠(0.07g,728.41μmol)加到化合物1-10(0.18g,591.48μmol)和化合物1-11(0.13g,667.90μmol)的N,N-二甲基乙酰胺(2mL)溶液中，在0℃搅拌0.5小时。得到含有化合物1-12的反应 液，直接用于下一步。
化合物1-13的制备
将稀HCl水溶液(1M,2mL,3.38eq)，丙酮(2mL)加到上步所得化合物1-12的反应液中，在20℃(室温)搅拌0.5小时。向反应液中加入水和二氯甲烷各(20ml)，搅拌10分钟，静置分液。有机相无水硫酸钠干燥，过滤，浓缩得到化合物1-13。MS(ESI)m/z:500.1(M+1)。
化合物1的制备
在0℃，将三溴化硼(780.00mg,3.11mmol,0.3mL)加到化合物1-13(200mg,400.04μmol)的二氯甲烷(2mL)溶液中，在0℃搅拌15分钟。反应液用二氯甲烷(10mL)稀释后，慢慢加到冰浴冷却的饱和NaHCO 3水溶液(20mL)中，搅拌10分钟后，静置分液，水相用二氯甲烷(10mL)萃取。合并有机相，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品经制备TLC纯化，得到的产物再经SFC纯化得到化合物1。
1H NMR(400MHz,CHLOROFORM-d)δppm 8.78(d,J＝1.76Hz,1H),7.77(d,J＝8.53Hz,1H),7.60(d,J＝1.76Hz,1H),7.41(ddd,J＝17.32,8.41,2.13Hz,2H),6.59(s,1H),4.79(quin,J＝6.40Hz,1H),3.02(d,J＝5.52Hz,1H),1.61(s,6H),1.51(d,J＝6.53Hz,3H)。MS(ESI)m/z:486.0(M+1)。
实验例1对雄激素受体(AR)核转运的拮抗作用测试
1.将PathHunter NHR细胞株复苏并培养扩增。
2.将细胞在测试前种到384孔板上，并在37℃条件下孵育。培养用血清用炭-葡萄聚糖过滤以降低其中的荷尔蒙水平。
3.在拮抗功能检测时，化合物加到细胞中孵育60分钟，待测化合物的工作浓度为从10μM以3倍浓度梯度稀释，分别为：10000、3333.3、1111.1、370.4、123.5、41.2、13.7、4.67nM，随后加入激动剂6a-Fluorotestosterone 0.06μM(浓度为EC80，即80％激动的化合物浓度)在37℃或室温下孵育3-16小时。
4.信号检测：加入12.5μL或者15μL(50％，v/v)PathHunter检测混合液(试剂盒：DiscoverX产品目录号：93-0001系列)，并在室温下孵育1小时。PerkinElmer Envision TM仪器读取化学发光信号。
5.数据分析：化合物活性使用CBIS数据分析软件(ChemInnovation,CA)进行分析，拮抗剂的抑制百分比计算公式如下：IC 50抑制率(％)＝100％×(1-(待测化合物平均RLU值-空白对照组平均RLU值)/(EC80对照平均RLU值-空白对照组平均RLU值))。
化合物对雄激素受体(AR)核转运的拮抗作用测试结果如下表1所示。
表1化合物对雄激素受体核转运的拮抗作用测试结果
化合物编号 IC 50
化合物1 0.57μM
化合物2 0.80μM
注：化合物2的制备参照文献WO2019029521公开的方法制备得到，
Figure PCTCN2021072671-appb-000011
实验例2对hERG钾通道抑制作用的安全性评价
1.细胞培养和处理
稳定表达hERG的CHO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)，100μg/mL G418(Invitrogen)和100μg/mL潮霉素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％胰蛋白酶-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。
2.化合物准备
将待测化合物用100％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6个经DMSO连续稀释的化合物中间浓度，依次为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，依次为40，13.3，4.44，1.48，0.49和0.16μM。
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(I hERG)的步阶电压从-80mV给予一个2秒的去极化电压到+20mV，再复极化到-50mV，持续1秒后回到-80mV。每10秒给予此电压刺激，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)。
4.数据处理
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))，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，HillSlope为曲线最大斜率的绝对值(即曲线中点)。
5.测试结果
测试结果如表2。
表2化合物的hERG抑制作用测试结果
化合物编号 IC 50
化合物1 20.1μM
化合物2 8.47μM
实验例3对GABA拮抗作用的安全性评价
1.GABA离子通量HT拮抗剂测定方法
所有记录均来自于-60mV的保持电位
本实验中每个化合物的添加序列都是相同的。先增加浓度为EC80的GABA建立基线反应。加入每个 测试浓度的化合物持续30秒后，再加入浓度为EC80的GABA持续2秒。每个实验3个测试浓度重低到高依次重复上述过程。
2.数据计算与分析
当存在单一浓度的化合物时，测量响应GABA的正向电流峰值。所有化合物数据均归一化为加入EC80GABA后的基线峰值电流2秒:
归一化峰值电流＝(I 化合物+GABA/I GABA)
其中I (化合物+GABA)为测试化合物加入EC80 GABA 0秒后所产生的峰值电流在测试化合物的孵育过程中，I GABA是加入EC80 GABA后的基线峰值电流。
3.测试结果见表3
表3化合物对GABA拮抗作用的测试结果
Figure PCTCN2021072671-appb-000012
实验例4对G蛋白偶联受体选择性作用的安全性评价
1.细胞准备
1)对于冻存的细胞，从液氮中取出细胞并迅速放入37℃水浴锅中。将上述细胞分成两组，其中一组加入10mL预热的用于CB2检测的DMEM培养基(培养基组成：F12+10％胎牛血清+G418 300μg/mL+杀稻瘟菌素2μg/mL)中并混悬细胞，另一组加入10mL预热的用于CCKa检测的DMEM培养基(培养基组成：DMEM+10％胎牛血清，G418 300μg/mL)中并混悬细胞。
将上述两组加入了培养基混悬的细胞分别取出1毫升，用Vi-CELL TM计数并测定活力；对于上述两组培养的细胞，分别先用预热的DPBS洗两遍，再分别加入适量胰酶37℃消化1分钟；再分别加入适量用于CB2检测的DMEM培养基和用于CCKa检测的DMEM培养基来终止消化，随后分别取出1毫升用Vi-CELL TM计数并测定活力。
2)两组细胞分别于1000转，离心5分钟。
3)轻轻弃去上清，不要碰到底部细胞块。
4)使用用于CB2检测的DMEM培养基和用于CCKa检测的DMEM培养基将上述两组细胞分别稀释至1×10 6细胞/mL(20000细胞/20μL)，并种于384孔多聚赖氨酸包被细胞板中，37℃，5％CO 2培养16-20小时。
2.化合物检测方法
1)参考和待测化合物板制备：对于参照化合物(CB2检测项的参考化合物：AM630；CCKa检测项的参考化合物：Lorglumide)，用Echo(ECHO 555,Labcyte)进行3倍8个点梯度稀释，转移900nL至相应化合物板。对于受试化合物，将2mM(用DMSO将10mM的母液稀释5倍至2mM)受试化合物用Echo转移900nL至化合物板，激动剂：12μM，三复孔；拮抗剂：10μM，三复孔。
2)加30μL实验用缓冲盐溶液(F10471试剂盒，缓冲盐溶液的成分1x HBSS,20Mm HEPES)至相应的化合物板，1000转离心1分钟；
3.FLIPR实验
1)将前一天准备好的细胞板从培养箱中取出，每孔加入20μL 2×Fluo-4Direct TM缓冲液，总体积是40μL。
2)5％CO 2，37℃培养箱孵育50分钟，室温放置10分钟。
3)将化合物板、细胞板和枪头放入仪器；
4)对于DRC板：运行FLIPR仪器软件，按照设定程序，添加10μL实验用缓冲盐溶液(F10471试剂盒，缓冲盐溶液的成分1x HBSS,20Mm HEPES)到细胞板中，读取荧光信号。再添加10μL既定浓度的激动剂参考化合物到细胞板中，读取荧光信号。读数后，通过软件中“Max-Min”，“Read 1 to 90”方法导出数据，计算每个细胞系的EC 80，准备6×EC 80浓度的激动剂，30μL/孔添加至相应的化合物板，1000转离心1分钟。5)对于化合物板：运行FLIPR仪器软件，按照设定程序，添加10μL既定浓度的检测化合物及参考化合物到细胞板中，读取荧光信号。对于化合物的激动剂检测，通过软件中“Max-Min”，“Read 1 to 90”方法导出数据。再添加10μL 6×EC 80浓度的参考化合物激动剂到细胞板中，读取荧光信号。对于化合物的拮抗剂检测，通过软件中“Max-Min”，“Read 1 to 90”方法导出数据。
6)分析数据：
拮抗剂抑制率％＝100-(RLU-LC)/(DMSO-LC)*100
RLU：相对光吸收值，1至90的读值；
DMSO：DMSO组荧光信号平均值；LC：拮抗剂最高浓度点荧光信号平均值。
7)使用Prism5.0拟合数据。
对于拮抗剂：使用“log(抑制剂)vs.反应-可变斜率”拟合IC 50。
4.实验结果
实验中关于受试化合物对靶标作用检测，实验结果见表4.
表4.待测化合物对靶点作用测试结果
Figure PCTCN2021072671-appb-000013
实验例5对糖皮质激素受体选择性作用的安全性评价
1.细胞准备
1)GR(糖皮质激素)细胞检测培养基：500mL无酚红DMEM，10.8mL活性炭处理的(Charcoal-stripped)FBS，5.4mL NEAA，13.5mL HEPES，5.4mL丙酮酸钠和5.4mL青霉素-链霉素；
2)培养基，胰蛋白酶和DPBS置于37℃水浴预热；
3)除去细胞培养瓶中原有培养基，并用6mL DPBS清洗一次；
4)向细胞培养瓶中加入3.5mL胰酶，轻轻晃动，使胰酶与细胞充分接触后除去胰酶，吸出胰酶后将培养瓶放入含5％CO2的37℃培养箱约1分钟；
5)用10mL细胞检测培养基重悬细胞，取出约0.8mL细胞悬液计数(ViCell XR)；
2.反应阶段
1)激动剂检测
a.化合物的准备：取待测化合物用DMSO稀释至工作浓度，用Echo将每个化合物按照微孔板布局图加入384孔细胞板，每孔200nL；
b.用GR(糖皮质激素)检测培养基将细胞悬液稀释到铺板所需的细胞密度(GR细胞5×10 5个细胞每毫升)；
c.在细胞板每孔中加入40μL细胞悬液，向其它孔中加入40μL细胞检测培养基，放入含5％CO 2的37℃培养箱中培养16小时。
d.以如下密度种板：GR细胞，每毫升培养基6.7×10 5个细胞，每孔30μL。将细胞板置于5％CO2，37℃培养箱孵育30分钟。
e.对于GR，用GR分析培养基配制浓度为16.252nM的地塞米松，每孔加入10μL，终浓度为4.063nM。
f.300rpm离心1分钟。
g.将细胞板置于5％CO 2，37℃培养箱过夜孵育16小时。
3.读板
1)准备溶液A：加182μL DMSO到200μg LiveBLAzer TM-FRET B/G底物(CCF4-AM)。分装并储存于-20℃冰箱中；
2)准备6×底物缓冲液：加24μL溶液A至240μL溶液B中并涡旋均匀，加入3736μL溶液C至上述溶液中并涡旋均匀；
3)取出细胞培养板，每孔加入8μL 6×底物缓冲液(LiveBLAzer TM-FRET B/G Loading Kit,Invitrogen-K1030-5mg试剂盒)，Shark 1min后，1000rpm离心10秒；封膜后，23℃孵育2小时并用Envision读板。
分析数据公式：
激动剂激动率％＝(RFU-DMSO)/(HC-DMSO)*100％RFU:相对荧光值；
HC:激动剂最高浓度点荧光信号平均值；DMSO:DMSO组荧光信号平均值；
4.实验结果
受试化合物如表5。
表5化合物在核受体GR激动剂检测结果(EC 50>10μM)
Figure PCTCN2021072671-appb-000014
实验例6化合物对PDE4D2抑制作用的安全性评价
1)将5×缓冲液(200mM Tris-HCL(PH7.5),50mM MgCl 2,0.5mg/mL BSA)用ddH 2O(重蒸水)稀释至1×(40mM Tris-HCL(pH7.5),10mM MgCl 2,0.1mg/mL BSA)。
2)制备化合物：参考化合物用Echo按4倍比稀释为10个点，并转移100nL至反应板中，最终参考化合物盐酸曲喹新(Trequinsin hydrochloride)和IBMX的终浓度分别为50nM和1mM；阳性对照孔每孔加入100nL 100％DMSO，阴性对照孔每孔加入100nL最高浓度点参考化合物；待测化合物稀释至1mM，并转移100nL至反应板中，终浓度为10μM，三复孔；对于复筛检测的化合物，将它们进行4倍梯度稀释成10个点，并转移100nL至反应板中，起始浓度为50μM，双复孔；
3)加入5μL酶混合液:140pM PDE4D2,1000rpm离心1分钟。23℃，孵育20分钟；
4)每孔加入5μL 1000nM cAMP至板中23℃，孵育60分钟；
5)每孔加入5μL AMP-Glo试剂I(AMP-Glo TMAssay Kit,Promega-V5011试剂盒)至板中23℃，孵育60分钟；
6)每孔加入10μL AMP检测溶液至板中23℃，孵育60分钟；
7)在Envision上读板。抑制剂(％)＝(1-(Readout-LC)/(HC-LC))*100％
8)使用Prism 5分析数据。使用“log(抑制剂)vs.反应-可变斜率”拟合数据。
受试化合物结果如表6
表6.化合物酶抑制活性检测结果
Figure PCTCN2021072671-appb-000015
实验例7小鼠药代动力学测试
1.摘要
以雄性CD-1小鼠为受试动物，应用LC/MS/MS法测定小鼠静脉推注和灌胃给与化合物1后不同时刻血浆中的药物浓度。研究化合物1在小鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1试验药品：化合物1
2.2试验动物：健康成年雄性CD-1小鼠6只，按照体重相近的原则分成2组，每组3只。动物购买自上海西普尔-必凯实验动物有限公司。
2.3药物配制：静脉给药组：称取适量样品，按照体积比10:50:40依次加入适量DMSO，PEG400和水，搅拌超声后达到0.4mg/mL。灌胃给药组：称取适量样品，加入适量体积的0.5％CMC-Na,0.2％Tween，搅拌超声后达到0.4mg/mL。
2.4给药
雄性CD-1小鼠6只，分成2组，禁食一夜后，第一组进行静脉给药，给药体积为2ml/kg,剂量为1mg/kg；第二组进行灌胃给药，给药体积为4ml/kg,剂量为2mg/kg。
3.操作
雄性CD-1小鼠静脉给与化合物1后，分别在0.0833、0.25、0.5、1、2、6、10、24、48及72小时点采血30ul，置于含有商品化的EDTA-K2的试管中。灌胃给药组给与化合物1后，分别在0.25、0.5、1、2、4、8、24、48及72小时点采血30μL，置于含有商品化EDTA-K2的试管中。试管在3200g离心10分钟分离血浆，并于-60℃保存。给药2小时后动物可进食。
用LC/MS/MS法测定小鼠静脉和灌胃给药后，血浆中的待测化合物含量。方法的线性范围为2.00～6000nmol/L；血浆样品经乙腈沉淀蛋白处理后进行分析。
4.药代动力学参数结果
表7化合物1的药代动力学参数如下：
Figure PCTCN2021072671-appb-000016
注：“--”表示没有测试相关参数。

Claims (13)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2021072671-appb-100001
    其中，
    R 1选自氢、卤素和C 1-12烷基，其中所述C 1-12烷基任选地被一个或多个卤素取代；
    R 2和R 3分别独立地选自C 1-12烷基；
    R 4选自氢、卤素和C 1-12烷基；
    R 5选自C 1-12烷基。
  2. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R 1选自氢、卤素和C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代；或者，R 1选自卤素；或者，R 1为氯。
  3. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R 2和R 3分别独立地选自C 1-6烷基；或者，R 2和R 3分别独立地为甲基。
  4. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R 4选自氢、C 1-6烷基或卤素；或者，R 4选自卤素；或者，R 4为氟。
  5. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R 5选自C 1-6烷基；或者，R 5为甲基。
  6. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R 1选自卤素，R 2和R 3分别独立地选自C 1-6烷基，R 4选自卤素，R 5选自C 1-6烷基；或者，R 1选自卤素，R 2和R 3分别独立地为甲基，R 4选自卤素，R 5为甲基。
  7. 权利要求1所述的式(I)化合物或其药学上可接受的盐，选自式(I-1)或式(I-2)化合物或其药学上可接受的盐，
    Figure PCTCN2021072671-appb-100002
  8. 权利要求1所述的式(I)化合物或其药学上可接受的盐，选自式(II)化合物或其药学上可接受的盐，
    Figure PCTCN2021072671-appb-100003
  9. 权利要求1所述的式(I)化合物或其药学上可接受的盐，选自式(II-1)或式(II-2)化合物或其药学上可接受的盐，
    Figure PCTCN2021072671-appb-100004
  10. 药物组合物，其包含权利要求1-9任一项所述化合物或其药学上可接受的盐。
  11. 权利要求1-9任一项所述化合物或其药学上可接受的盐、或权利要求10所述的药物组合物在制备治疗由雄激素介导的疾病的药物中的用途；任选地，所述疾病包括细胞增殖性疾病；进一步任选地，所述疾病选自癌症；还任选地，所述疾病为前列腺癌。
  12. 用于治疗由雄激素介导的疾病的权利要求1-9任一项所述化合物或其药学上可接受的盐、或权利要求10所述的药物组合物；任选地，所述疾病包括细胞增殖性疾病；进一步任选地，所述疾病选自癌症；还任选地，所述疾病为前列腺癌。
  13. 治疗哺乳动物的由雄激素介导的疾病的方法，所述方法包括对需要该治疗的哺乳动物给予治疗有效量的权利要求1-9任一项所述化合物或其药学上可接受的盐、或权利要求10所述的药物组合物；任选地，所述疾病包括细胞增殖性疾病；进一步任选地，所述疾病选自癌症；还任选地，所述疾病为前列腺癌。
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