WO2024088395A1 - Composé cyclique ponté et son utilisation pharmaceutique - Google Patents

Composé cyclique ponté et son utilisation pharmaceutique Download PDF

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WO2024088395A1
WO2024088395A1 PCT/CN2023/127198 CN2023127198W WO2024088395A1 WO 2024088395 A1 WO2024088395 A1 WO 2024088395A1 CN 2023127198 W CN2023127198 W CN 2023127198W WO 2024088395 A1 WO2024088395 A1 WO 2024088395A1
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compound
mmol
present
pharmaceutically acceptable
added
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PCT/CN2023/127198
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Chinese (zh)
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罗云富
巴庾勇
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南京明德新药研发有限公司
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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
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin

Definitions

  • the present invention relates to a series of bridged ring compounds and their pharmaceutical applications, and in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • the androgen receptor is a 110 kDa steroidal nuclear receptor that mediates the induction of a variety of biological effects through interaction with endogenous androgens, one of its key functions being androgen-activated gene transcription.
  • Endogenous androgens include steroids such as testosterone and dihydrotestosterone.
  • Testosterone is converted to dihydrotestosterone in many tissues by the enzyme 5a reductase.
  • the androgen receptor plays an important role in many androgen-related diseases, such as prostate cancer, androgenic alopecia, and acne. Compounds that weaken the action of androgens on the androgen receptor can be used to treat diseases or conditions in which the androgen receptor plays a role.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T is selected from CH and N;
  • each R 1 is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from H, C 1-4 alkyl and C 1-3 alkyl-S( ⁇ O) 2 , wherein the C 1-4 alkyl and C 1-3 alkyl-S( ⁇ O) 2 are each independently optionally substituted by 1, 2 or 3 R b ;
  • Ring A is selected from 5-8 membered bridged cycloalkyl groups, wherein the 5-8 membered bridged cycloalkyl groups are optionally substituted by 1, 2 or 3 R groups;
  • each Ra is independently selected from F, Cl, Br, I, OH, NH2 and CN;
  • each R b and R is independently selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl and C 1-3 alkoxy;
  • X is selected from O and NH
  • n is selected from 0, 1, 2 or 3.
  • each Ra is selected from F, and other variables are as defined in the present invention.
  • each R 1 is independently selected from F, OCH 3 and CF 3 , and other variables are as defined in the present invention.
  • each R 1 is selected from CF 3 , and other variables are as defined in the present invention.
  • each R b is independently selected from F, Cl, Br and OH, and other variables are as defined in the present invention.
  • each R b is selected from OH, and other variables are as defined in the present invention.
  • R 2 is selected from CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(OH)CH 2 (OH) and CH 2 CH(OH)CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from CH 2 CH 2 OH, and other variables are as defined in the present invention.
  • each R is independently selected from F, OH, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and OCH 3 , and other variables are as defined in the present invention.
  • the ring A is selected from Other variables are as defined in the present invention.
  • the ring A is selected from Other variables are as defined in the present invention.
  • the above compound has a structure shown in formula (I-1),
  • T, X, R 1 , R 2 and n are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating diseases associated with androgen receptor antagonists.
  • the above-mentioned application is characterized in that the disease associated with androgen receptor antagonists is androgenic alopecia.
  • the compound of the present invention exhibits good AR antagonistic activity at the cellular level and inhibitory activity on LNCaP cell proliferation.
  • the compound of the present invention has a significant therapeutic improvement effect on the pathological changes of C57BL/6 androgenic alopecia model mice. This study provides a good scientific basis for the regulation of hair follicles and hair growth and development and its production and utilization.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that are within the scope of medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or 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 the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group represents the nitrogen atom in the The two ends of the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group.
  • tautomer or "tautomeric form” means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomerism can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence isomers include interconversions by the reorganization 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 one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or 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 term “isomer excess” or “enantiomeric excess” refers 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 content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers and 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 present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • 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.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • C 1-3 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • C 1-4 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; they can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "5-7 membered ring” refers to a “ring” having 5-7 atoms arranged around it.
  • Cn-n+m or Cn - Cn+m includes any specific situation of n to n+m carbon atoms
  • C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , C11 , and C12 , and also includes any range from n to n+m
  • C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C9-12 , etc.
  • n- membered to n+m-membered means that the number of atoms in the ring is n to n+m .
  • a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12 membered ring includes a 3-6 membered ring, a 3-9 membered ring, a 5-6 membered ring, a 5-7 membered ring, a 6-7 membered ring, a 6-8 membered ring, and a 6-10 membered ring, etc.
  • 5-8 membered bridged cycloalkyl by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 8 ring atoms. It belongs to a bicyclic ring system.
  • the 5-8 membered bridged cycloalkyl includes 5-6 membered, 5-7 membered, 5-8 membered, 5 membered, 6 membered, 7 membered and 8 membered bridged cycloalkyl, etc. Examples of 5-8 membered bridged cycloalkyl include, but are not limited to wait.
  • 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, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. 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 relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction SXRD
  • the light source is CuK ⁇ radiation
  • the scanning mode is ⁇ / ⁇ scanning.
  • the direct method Shelxs97 is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • DMF stands for dimethylformamide
  • DIPEA stands for N,N-diisopropylethylamine
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • Triethylamine (11.75 g, 116.14 mmol) was added to a solution of compound I-A (10 g, 38.71 mmol) in dioxane (40 mL), stirred at 20 ° C for 15 min, acetone (44.97 g, 774.30 mmol) and trimethylsilyl cyanide (19.20 g, 193.57 mmol) were added, and stirred at 80 ° C for 11.75 hours.
  • reaction solution was evaporated under reduced pressure to remove excess solvent, ethyl acetate (50 mL) was added, and the reaction solution was washed with saturated sodium bicarbonate solution (50 mL*3), water (50 mL), and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove excess solvent.
  • the crude product was slurried with petroleum ether (50 mL) at 20 ° C (room temperature) for 30 minutes, filtered, and the filter cake was collected to obtain compound II.
  • reaction solution was purified by high performance liquid chromatography (preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile was gradiently eluted from 25% to 55%, and the elution time was 10 minutes) to obtain compound 1.
  • reaction solution was purified by high performance liquid chromatography (preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile gradient elution from 23% to 53%, elution time 10 minutes) to obtain compound 2.
  • reaction solution was purified by high performance liquid chromatography (preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile gradient elution from 25% to 55%, elution time 10 minutes) to obtain compound 3.
  • reaction solution was subjected to high performance liquid chromatography (preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile gradient elution from 25% to 55%, elution time 10 minutes) to obtain compound 4.
  • high performance liquid chromatography preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile gradient elution from 25% to 55%, elution time 10 minutes
  • reaction solution was purified by high performance liquid chromatography (preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile was gradiently eluted from 22% to 52%, and the elution time was 10 minutes) to obtain compound 5.
  • high performance liquid chromatography preparative column model: Xtimate C18, length ⁇ inner diameter: 150 mm ⁇ 40 mm, 5 ⁇ m; mobile phase system: acetonitrile/water (containing 0.05% HCl); gradient elution method: acetonitrile was gradiently eluted from 22% to 52%, and the elution time was 10 minutes
  • the reaction solution was dissolved in ethyl acetate (200 mL), and aqueous ammonium chloride solution (150 mL) was added for separation.
  • the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 2), and the organic phases were combined and washed with 1M dilute hydrochloric acid (50 mL ⁇ 2) and saturated brine (100 mL ⁇ 2) in turn.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1:0-0:1) to obtain compound 7-D.
  • HEK-293 cell lines were cultured in DMEM medium containing 10% fetal bovine serum; the cells were cultured in an incubator at 37°C and 5% CO 2 .
  • Cell passaging Remove the old culture medium and wash once with PBS, then add 1 mL of TrypLE TM Express solution and incubate at 37°C for about 2 minutes. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes.
  • the cell confluence was controlled at about 80%.
  • Inhibition rate (%) (1-(sample value-average value of 100% inhibition)/(average value of 0% inhibition-average value of 100% inhibition))*100;
  • Penicillin-Streptomycin Gibco (Cat. No.: 15140-122)
  • BECKMAN model: Vi-CELL XR
  • test compound was a 10 mM DMSO solution and stored in a 4°C refrigerator.
  • Cell culture medium configuration 89% phenol red-free 1640 medium, 10% fetal bovine serum and 1% penicillin-streptomycin.
  • c) Dilute the cells to 0.2 ⁇ 10 5 cells/mL with culture medium and seed 4000 cells per well in a 96-well cell plate with 200 ⁇ L.
  • the compound was first diluted with culture medium to a final concentration of 100X, and the negative control group was DMSO diluted at the same ratio. Finally, the dilution was added to the cell supernatant at a ratio of 1:100 (0.1% DMSO, 2 ⁇ L of each concentration was added to the cell culture medium). The final maximum treatment concentration of 10 ⁇ M was diluted 3 times with culture medium to 9 concentrations. After the cell culture plate was incubated with the compound, it was returned to a 5% CO 2 , 37°C incubator for 6 days.
  • variable slope (four parameters) model was used for fitting analysis to obtain the IC 50 value of each test sample.
  • the androgenic seborrheic alopecia (AGA) model was established by subcutaneous injection of testosterone propionate, and the hair growth effect of the test compound on androgenic seborrheic alopecia mice was preliminarily observed to provide a reference for the preclinical pharmacodynamic study of the test compound.
  • Testosterone propionate injection properties: light yellow clear oily liquid, specification: 1mL: 25mg, batch number: veterinary drug 110201054, manufacturer: Hangzhou Animal Drug Factory, storage method: light-shielded, sealed and stored; olive oil (pharmaceutical grade), specification: 500mL/bottle, density: 0.9135g/mL, CAS number: 8001-25-0, manufacturer: Shanghai McLean Biochemical Technology Co., Ltd.
  • Preparation method of 1.5mg/mL testosterone propionate diluent take an appropriate amount of testosterone propionate and dilute it with high-pressure olive oil, and store it at room temperature (below 25°C).
  • Pentobarbital sodium 25g/bottle, content ⁇ 95.0%, batch number: 20201214, Merck packaging.
  • Dosing frequency and cycle 2 times a day, for 17 consecutive days;
  • Dosing volume 40 ⁇ L/cm 2 ;
  • Method for locating the administration site Use a marker pen to mark the 1 ⁇ 2 cm 2 area on the shaved area at the back of the mouse as the administration area;
  • Dosing method Before each administration, gently wipe the administration site with a cotton ball soaked in 0.9% sodium chloride injection at 37 ⁇ 0.5°C, and administer the drug after it dries; use a pipette to draw 80 ⁇ L of the drug preparation of the corresponding concentration and apply it to the center of the marked area, and then use the gun tip to evenly spread the drug solution to the entire marked area; after administration, wait for the drug solution to dry before placing the mouse in the cage.
  • the first day of drug administration is defined as the first day of the trial.
  • mice After the mice were numbered and weighed, they were anesthetized with sodium pentobarbital (0.3%, 0.25 mL/10 g). A 2cm ⁇ 3cm experimental area was selected from the symmetrical parts of the body. Rosin and paraffin were mixed in a 1:1 ratio, heated in an electric furnace to melt into a liquid state, cooled to a temperature slightly higher than the mouse skin temperature, and about 1.41g was evenly applied to the experimental area. After the wax solidified, the condensed hair was gently torn off with tweezers, kept clean and dry, and confirmed that the hair growth of the unhaired mice was in the resting phase of the growth cycle, and the skin color was pink.
  • mice in the normal control group On the second day after depilation, except for the mice in the normal control group, the depilated area of the mice in other groups was subcutaneously injected with testosterone propionate 5mg/kg (testosterone propionate was diluted with olive oil to a concentration of 1.5mg/mL, 33.3 ⁇ L/10g) at multiple points, once a day, for 17 days, to create an androgenic alopecia model.
  • the day of hair removal modeling was counted as day 0, and the drug administration started 24 hours after hair removal, which was counted as day 1.
  • the skin of the hair removal area on the back of each group of mice was photographed on days 0, 2, 5, 9, 12, 14, and 16 of drug administration. Based on the photos taken, Adobe Photoshop CS6 software was used for analysis. The pictures were adjusted to grayscale mode, and the skin of the drug administration area of the mice was selected to calculate the grayscale rate of the skin of the drug administration area of each group of mice.
  • Grayscale rate grayscale value/255, grayscale value 255 is white. The lower the grayscale rate, the darker the color of the drug administration area and the denser the hair in the hair growth area.
  • Photographed animals all surviving mice in each group; Photographing method: during the administration period, the mice were fixed in prone position by hand, and the animal numbers were marked above the mice. The camera was placed perpendicular to the back to take photos.
  • the skin color change time (the skin color of the dosing area changes from pink to gray) and hair growth time (the skin color of the dosing area changes from gray to black) of each mouse in each group were observed and recorded.
  • SPSS 26.0 software was used for statistical analysis, and all data were expressed as mean ⁇ standard error. It indicates that the ANOVA analysis of variance was used to evaluate the test results of the quantitative data, and the LSD test was used for pairwise comparison. The numerical values of the statistical results were retained to 1-2 decimal places.
  • the hair weight of the model control group mice in the administration area decreased significantly, indicating that the model was successfully established.
  • the hair weight of the depilatory area of the mice in the compound of the present invention group increased significantly.
  • HE-stained skin longitudinal sections in the 100x microscope field of view show that the hair follicles in the normal group, minoxidil group, and test compound group are longer and in the fostering stage, with darker color, and the cells at the bottom of the hair follicles are fully developed, allowing the hair follicles to grow downward and wrap around the hair papilla.
  • the hair parts are complete, with inner hair root sheaths, The melanin content was high.
  • the hair follicles in the model control group were atrophic and in the resting stage, with a lighter color, apoptosis of the epithelial cells at the base of the hair follicles, and significant degeneration of the extracellular matrix of the hair papilla cells, most of which became black cell clusters, unclear hair papilla, no inner hair root sheath, and low melanin content.
  • the compound of the present invention has a therapeutic and improving effect on the pathological changes of C57BL/6 androgenic alopecia model mice.

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  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne une série de composés cycliques pontés et leur utilisation pharmaceutique, notamment un composé tel que représenté dans la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/127198 2022-10-28 2023-10-27 Composé cyclique ponté et son utilisation pharmaceutique WO2024088395A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101032483A (zh) * 2006-03-09 2007-09-12 陈德桂 调节雄激素受体活性的乙内酰脲衍生物的组成及其应用
US20110003839A1 (en) * 2006-03-27 2011-01-06 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
WO2011029392A1 (fr) * 2009-09-10 2011-03-17 Youzhi Tong Antagonistes du récepteur des androgènes et leurs utilisations
CN104341351A (zh) * 2013-07-30 2015-02-11 北京海步国际医药科技发展有限公司 一种新型的二芳基硫代乙内酰脲衍生物及其应用
CN106983749A (zh) * 2010-02-16 2017-07-28 亚拉冈制药公司 雄激素受体调节剂及其用途
WO2019029521A1 (fr) * 2017-08-07 2019-02-14 正大天晴药业集团股份有限公司 Composé diarylthiohydantoïne utilisé en tant qu'antagoniste du récepteur des androgènes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101032483A (zh) * 2006-03-09 2007-09-12 陈德桂 调节雄激素受体活性的乙内酰脲衍生物的组成及其应用
US20110003839A1 (en) * 2006-03-27 2011-01-06 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
WO2011029392A1 (fr) * 2009-09-10 2011-03-17 Youzhi Tong Antagonistes du récepteur des androgènes et leurs utilisations
CN106983749A (zh) * 2010-02-16 2017-07-28 亚拉冈制药公司 雄激素受体调节剂及其用途
CN104341351A (zh) * 2013-07-30 2015-02-11 北京海步国际医药科技发展有限公司 一种新型的二芳基硫代乙内酰脲衍生物及其应用
WO2019029521A1 (fr) * 2017-08-07 2019-02-14 正大天晴药业集团股份有限公司 Composé diarylthiohydantoïne utilisé en tant qu'antagoniste du récepteur des androgènes

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