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WO2022022616A1 - Dérivés de dihydrooxazole 2,4,4-trisubstitués, leurs procédés de préparation et leur utilisation - Google Patents

Dérivés de dihydrooxazole 2,4,4-trisubstitués, leurs procédés de préparation et leur utilisation Download PDF

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WO2022022616A1
WO2022022616A1 PCT/CN2021/109144 CN2021109144W WO2022022616A1 WO 2022022616 A1 WO2022022616 A1 WO 2022022616A1 CN 2021109144 W CN2021109144 W CN 2021109144W WO 2022022616 A1 WO2022022616 A1 WO 2022022616A1
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methyl
dihydrooxazole
triazol
phenyl
thiophen
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PCT/CN2021/109144
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English (en)
Chinese (zh)
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赵冬梅
赵立雨
程卯生
孙楠楠
田霖丰
孙印
郑阳
张储
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of drug synthesis, and relates to a class of 2,4,4-trisubstituted dihydrooxazole derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, their preparation methods and their preparations. Use as a medicament for the treatment of various diseases caused by fungal infections.
  • Fungal infection can be divided into superficial fungal infection and deep fungal infection, among which superficial fungal infection is mainly caused by ringworm, such as skin, hair and finger (toe) nail fungal infection; deep fungal infection is mainly caused by Candida albicans, Cryptophytes Cocci and Aspergillus fumigatus cause infections of deep tissues such as subcutaneous tissue and intima.
  • superficial fungal infection is mainly caused by ringworm, such as skin, hair and finger (toe) nail fungal infection
  • deep fungal infection is mainly caused by Candida albicans, Cryptophytes Cocci and Aspergillus fumigatus cause infections of deep tissues such as subcutaneous tissue and intima.
  • clinical antifungal drugs can be divided into azole drugs that inhibit ergosterol synthesis according to different mechanisms of action; echinocandicin antifungal drugs that destroy cell walls, polyene drugs that cause cell membrane leakage, and antifungal drugs that act on nucleic acids Metabolic antifungal drugs.
  • azoles block the synthesis of ergosterol by inhibiting the activity of lanosterol 14 ⁇ -demethylase (CYP51), and are the most active and mature targets in the field of antifungal research.
  • azole antifungal drugs are mainly divided into two categories: imidazoles such as Miconazole, Clotrimazole, Ketoconazole; triazoles such as fluconazole ( Fluconazole), Itraconazole (Itraconazole), Voriconazole (Voriconazole) and Posaconazole (Posaconazole).
  • imidazoles such as Miconazole, Clotrimazole, Ketoconazole
  • triazoles such as fluconazole ( Fluconazole), Itraconazole (Itraconazole), Voriconazole (Voriconazole) and Posaconazole (Posaconazole).
  • the object of the present invention is to provide a class of 2,4,4-trisubstituted dihydrooxazole derivatives, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the derivatives in view of the deficiencies of the prior art , and provide the preparation method of the derivative and the use of the derivative; and also provide the pharmaceutical composition containing the 2,4,4-trisubstituted dihydrooxazole derivative.
  • the present invention designs and synthesizes a series of 2,4,4-tri-substituted dihydrooxazole derivatives on the basis of the references.
  • the in vitro antifungal activity test shows that these compounds have strong antifungal properties. It has great research value in the treatment of fungal infections.
  • the present invention provides 2,4,4-trisubstituted dihydrooxazole derivatives represented by general formula I and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates or pro-forms thereof. medicine:
  • MBG is substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyridyl; the substituents are: hydrogen, C1-C4 alkane base, C1-C4 alkoxy;
  • Y is O or S
  • X is CH, CH2 , N, NH, or O;
  • R 1 is (C 1 -C 5 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 4 ) alkoxy, carboxyl, -COOR 2 , -CON(R 2 ) 2 , 5 -10-membered aryl or 5-10-membered heteroaryl, and the aryl or heteroaryl is optionally substituted with 0-3 identical or different R 2 ;
  • the Ar ring is a C3-C6 cycloalkyl group, a 5-10 membered heterocyclic group, a C6 - C10 aryl group or a C5 - C10 heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 0-3 identical or different M;
  • M is hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 - C 6 )alkoxy, (C 1 -C 6 )alkylthio; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy optionally substituted by hydroxy, amino or halogen, or (C 1 -C 6 )alkylthio; mono- or di(C 1 -C 6 alkyl) substituted amino, (C 1 -C 6 )alkylamido; free, salified, esterified and amidated carboxyl; (C 1 -C 6 ) alkylsulfinyl, sulfonyl; (C 1 -C 6 ) alkyl acyl, carbamoyl; substituted by mono or di(C 1
  • R 2 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, phenyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy optionally substituted by hydroxy, amino or halogen; by mono- or di(C 1 -C ) 6 alkyl) substituted amino, (C 1 -C 6 ) alkyl amido; free, salified, esterified or amidated carboxyl; (C 1 -C 6 ) alkylsulfinyl, sulfonic Acyl.
  • the present invention provides 2,4,4-trisubstituted dihydrooxazole derivatives represented by general formula I and stereoisomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
  • MBG is substituted or unsubstituted tetrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted pyridyl; the substituents are: hydrogen, C1-C4 alkane base, C1-C4 alkoxy;
  • Y is O or S
  • X is CH, CH2 , N, NH, or O;
  • R 1 is (C 1 -C 5 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 4 ) alkoxy, carboxyl, -COOR 2 , -CON(R 2 ) 2 , 5 -10 membered aryl or 5-10 membered heteroaryl, benzyl, -(CHF)Ph or -( CF2 )Ph, and said aryl or heteroaryl or benzyl, -(CHF)Ph or -
  • the benzene ring of (CF 2 )Ph is optionally substituted by 0-3 identical or different R 2 ;
  • the Ar ring is a C3-C6 cycloalkyl group, a 5-10 membered heterocyclic group, a C6 - C10 aryl group or a C5 - C10 heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 0-3 identical or different M;
  • M is hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 - C 6 )alkoxy, (C 1 -C 6 )alkylthio; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy optionally substituted by hydroxy, amino or halogen, or (C 1 -C 6 ) alkylthio; mono- or di(C 1 -C 6 alkyl) substituted amino; (C 1 -C 6 ) alkylamido; free, salified, esterified and amidated carboxyl; (C 1 -C 6 ) alkylsulfinyl, (C 1 -C 6 ) alkylsulfonyl; (C 1 -C 6 ) alkyl acyl; carbamoyl
  • R 2 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, phenyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylacyl; (C 1 -C 6 )alkyl or (C 1 -C 6 )alkane optionally substituted by hydroxy, amino or halogen oxy; mono- or di(C 1 -C 6 alkyl) substituted amino, (C 1 -C 6 )alkylamido; free, salified, esterified or amidated carboxyl; (C 1 ) -C 6 ) alkylsulfinyl, (C 1 -C 6 ) alkylsulfonyl.
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • MBG is selected from the following structures:
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • Y is O
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • Y is O
  • MBG is selected from the following structures:
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • R 1 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, benzyl, -(CHF)Ph, -(CF 2 )Ph, or phenyl, and benzyl, -(CHF )Ph, -(CF 2 )Ph and the phenyl ring of phenyl are optionally substituted with 0-3 R 2 .
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • Y is O
  • R 1 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, benzyl, -(CHF)Ph, -(CF 2 )Ph, or phenyl, and benzyl, -(CHF ) Ph, -(CF 2 )Ph and optional 0-3 R 2 substitutions on the benzene ring of phenyl;
  • MBG is one of the following structures:
  • Ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuranyl, benzothiazolyl, benzothienyl, benzopyrazole or indolyl, and Ar is optionally substituted with 0-3 identical or different Ms.
  • Ar ring is furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, phenyl, naphthyl, benzofuranyl, benzothiazolyl, benzothienyl, benzopyrazole or indolyl, and Ar is optionally substituted with 1-3 identical or different M.
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • M is phenyl, furyl, thienyl, dioxanyl, oxadiazolyl or piperazinyl.
  • the present invention is preferably the compound represented by the general formula I, and its stereoisomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • M is phenyl, furyl, thienyl, dioxanyl, oxadiazolyl.
  • the present invention preferably the following compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, but these compounds do not mean any limitation to the present invention:
  • compositions of the general formula I in the present invention have basic groups and can form pharmaceutically acceptable salts with acids.
  • Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with addition salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the present invention also includes prodrugs of the derivatives of the present invention.
  • Prodrugs of the derivatives of the present invention are derivatives of general formula I, which themselves may have weak or even no activity, but after administration, are destroyed under physiological conditions (eg by metabolism, solvolysis or otherwise) by into the corresponding biologically active form.
  • Compounds of formula I can be in unsolvated as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compounds represented by the general formula I may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (eg, racemic mixtures), are included within the scope of the present invention Inside.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • alkyl refers to straight-chain or branched alkyl
  • alkylene refers to straight-chain or branched alkylene
  • Aryl refers to an organic group obtained by removing two hydrogen atoms at one or different positions in an aromatic hydrocarbon, such as phenyl and naphthyl
  • heteroaryl refers to an organic group containing one or more selected from N, O, S heteroatom monocyclic or polycyclic ring system, the ring system refers to an organic group which is aromatic and obtained by removing two hydrogen atoms in one or different positions in the ring system, such as thiazole base, imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl , o
  • the present invention can contain derivatives of general formula I, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and Prepared into a clinically acceptable dosage form, the above-mentioned pharmaceutically acceptable excipients refer to any diluents, adjuvants and/or carriers that can be used in the pharmaceutical field.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
  • the pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field.
  • Several of the above-mentioned dosage forms can be used as injections, tablets, capsules, aerosols, suppositories, films, drop pills, external liniments, ointments and other dosage forms.
  • the carriers used in the pharmaceutical compositions of the present invention are of the common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, colorless, flavoring agents , preservatives, solubilizers and substrates, etc.
  • Pharmaceutical formulations may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric-coated tablets.
  • the compounds of general formula I of the present invention can be synthesized by methods including well-known methods in the field of chemistry, especially prepared according to the description of the present invention; room temperature in the present invention refers to ambient temperature, which is 10°C to 30°C.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared from the following materials: (a) The starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described in the present invention , (b) known starting materials that can be prepared by methods described in the literature, (c) new intermediates described in the schemes and experimental procedures herein.
  • the compounds of the present invention can be synthesized by the following reaction schemes and descriptions.
  • Scheme I above shows a general synthetic route for the preparation of compound I , wherein Ar, M, R1 and MBG are as claimed.
  • intermediate A3 reacts with SOCl 2 to obtain intermediate A4.
  • Intermediate A4 reacts with R under alkaline conditions. 1 -X (X is halogen) undergoes a substitution reaction to obtain intermediate A5, lithium tetrahydrogen reduces the ester group of intermediate A5 to obtain intermediate A6, A6 undergoes a substitution reaction with SOCl 2 to obtain intermediate A7, and A7 undergoes a substitution reaction with MBG The target compound I was obtained.
  • Scheme II above shows the preparation of compound R1 as , the general synthetic route for compounds in which Ar, M, R 1 , R 2 and MBG are as described in the claims.
  • the positive progress effect of the present invention is that the present invention provides 2,4,4-trisubstituted dihydrooxazole derivatives, its preparation method, pharmaceutical composition and application.
  • the 2,4,4-trisubstituted dihydrooxazole derivatives of the present invention have good antifungal activity against various superficial and deep fungi, and have high efficiency, low toxicity, It has the advantages of broad antifungal spectrum, etc., and can be used to prepare antifungal drugs.
  • Mass spectrometry used for compound structure confirmation was determined with an Agilent 1100 LC/MS.
  • the purified product by column chromatography used 100-200 mesh or 200-300 mesh silica gel produced by Qingdao Ocean Chemical Factory.
  • Example 1 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-methyl-4,5-dihydrooxane azole
  • step a the raw materials 1-1 (1.1 mmol), bibenzoic acid 1-2 (1.1 mmol) and PyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate) (1.2 mmol) were combined ) was added to DMF, stirred at room temperature for 8 h, TLC detected the reaction completion, added water, extracted with ethyl acetate, washed the organic layer with saturated brine, and dried over anhydrous sodium sulfate overnight. The desiccant was filtered off and concentrated under reduced pressure to obtain Intermediate 1-3.
  • step b intermediate 1-3 (5 mmol), SOCl 2 (12.5 mmol) and triethylamine (12.5 mmol) were added to dichloromethane, the reaction was stirred at room temperature, TLC detected that the reaction was complete, the organic solvent was evaporated, ethyl acetate The ester was dissolved, washed three times with water, the organic layer was washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 1-4.
  • step c the intermediate 1-4 (5 mmol) was dissolved in anhydrous THF, the THF solution of LiN(Pr-i) 2 (10 mmol) was slowly added dropwise, the reaction was carried out for about 1 h, CH 3 I (10 mmol) was added, TLC The reaction was detected to be complete, warmed to room temperature, quenched by adding saturated NH 4 Cl solution, the organic solvent was evaporated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The drying agent was filtered off and concentrated under reduced pressure to obtain Intermediate 1-5.
  • step d under ice bath condition, the intermediate 1-5 (5 mmol) was dissolved in THF, and lithium tetrahydroaluminum (10 mmol) was added in batches. TLC detected the reaction to be complete, and saturated NH 4 Cl solution was added to quench the reaction. The organic solvent was evaporated under pressure, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off and concentrated under reduced pressure to obtain Intermediate 1-6.
  • step e intermediate 1-6 (5mmol), SOCl 2 (20mmol) and triethylamine (20mmol) were added to dichloromethane, the reaction was stirred at room temperature, TLC detected that the reaction was complete, the organic solvent was evaporated, ethyl acetate Dissolved, washed three times with water, washed the organic layer with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 1-7.
  • step f under ice bath conditions, imidazole (15mmol) was added to DMF, NaH (20mmol) was added, intermediate 1-7 (5mmol) was added after stirring for 30min, the reaction was continued, TLC detected the completion of the reaction, and the reaction solution was poured into It was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure, and the target compound 1 was obtained by column chromatography.
  • Example 2 According to the method of Example 1, the corresponding haloalkanes were respectively used to prepare Examples 2-6.
  • Example 2 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-isopropyl-4,5-dihydro oxazole
  • Example 3 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-cyclopropyl-4,5-dihydro oxazole
  • Example 7 4-((1H-1,2,4-triazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl -4,5-Dihydrooxazole
  • step a AgNO 2 (10 mmol) was added to ether (30 mL), stirred at room temperature, benzyl bromide (5 mmol) was added dropwise, stirred for 5 h in the dark, the reaction solution was poured into water, extracted with ether for 3 times, and evaporated under reduced pressure. Remove ether to obtain light yellow oily liquid, and column chromatography obtains intermediate 5-2.
  • step b the intermediate 5-2 (4 mmol) is dissolved in ethanol, formaldehyde solution (24 mmol) and NaOH (4 mmol) are added, the reaction is stirred at room temperature, the completion of the reaction is detected by TLC, the organic solvent is evaporated under reduced pressure, water is added, ethyl acetate The ester was extracted three times, and the organic layers were combined, washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure and subjected to column chromatography to obtain Intermediate 5-3.
  • step c add 2,2-dimethoxypropane (4.5mmol) to the acetone solution of intermediate 5-3 (3mmol), add p-toluenesulfonic acid (0.6mmol), react at room temperature, and detect the reaction by TLC Complete, the solvent was evaporated under reduced pressure, and the intermediate 5-4 was obtained by column chromatography.
  • step d the intermediate 5-4 (2 mmol) was dissolved in methanol (10 mL) solution, Pd/C was added, H 2 was added, the reaction was carried out at room temperature, TLC detected the reaction was complete, filtered, and the solvent was evaporated under reduced pressure to obtain the intermediate Body 5-5.
  • step e the raw material bibenzoic acid 5-6 (1.1 mmol), intermediate 5-5 (1.1 mmol) and PyBOP (1.2 mmol) were added to DMF (10 mL), and the reaction was stirred at room temperature for 8 h. TLC detected the reaction and added water. , extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate overnight. The drying agent was filtered off and concentrated under reduced pressure to obtain intermediate 5-7.
  • step g add intermediate 5-8 (5mmol), SOCl 2 (25mmol) and triethylamine (25mmol) in methylene chloride, stir the reaction at room temperature, TLC detects that the reaction is complete, evaporate the organic solvent, dissolve in ethyl acetate , washed three times with water, washed the organic layer with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure and column chromatography to obtain Intermediate 5-9.
  • step h under ice bath conditions, add azole (15mmol) to DMF (10mL), add NaH (20mmol), add intermediate 5-9 (5mmol) after stirring for 30min, continue the reaction, TLC detects the completion of the reaction, and the reaction The liquid was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, and dried over anhydrous Na 2 SO 4 overnight. The desiccant was filtered off, concentrated under reduced pressure, and the target compound 7 was obtained by column chromatography.
  • Example 7 According to the method of Example 7, the corresponding raw materials were used to prepare Examples 8-56.
  • Example 8 4-((1H-imidazol-1-yl)methyl)-2-([1,1'-biphenyl]-4-yl)-4-phenyl-4,5-dihydrooxane azole
  • Example 11 4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-2-(5-phenylthiophen-2-yl)-4,5 - Dihydrooxazole
  • Example 12 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(4-(furan-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole
  • Example 13 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(thiophen-3-yl)phenyl)-4-phenyl-4 ,5-Dihydrooxazole
  • Example 14 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(naphthalen-2-yl)-4-phenyl-4,5-dihydrooxane azole
  • Example 18 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(4-(benzyloxy)phenyl)-4-phenyl-4,5 - Dihydrooxazole
  • Example 20 1-(4-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)-4-phenyl-4,5-dihydrooxazole -2-yl)phenyl)piperazin-1-yl)ethanone
  • Example 22 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 23 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(furan-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 24 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 25 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(furan-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 26 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-fluorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 27 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(4-chlorophenyl)-2-(4-(thiophen-3-yl) phenyl)-4,5-dihydrooxazole
  • Example 28 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 29 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-dichlorophenyl)-2-(4-(thiophene-3 -yl)phenyl)-4,5-dihydrooxazole
  • Example 30 4-((1H-1,2,4-triazol-1-yl)methyl)-4-(2,4-difluorophenyl)-2-(5-(trifluoromethyl) Oxy)benzo[b]thiophen-2-yl)-4,5-dihydrooxazole
  • Example 31 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 32 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • Example 33 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 34 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole
  • Example 35 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-fluorobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole
  • Example 36 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 37 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • Example 38 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 39 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole
  • Example 40 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole
  • Example 41 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Fluorophenyl)-4,5-dihydrooxazole
  • Example 42 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(4 -Chlorophenyl)-4,5-dihydrooxazole
  • Example 43 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2 ,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 44 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(3 ,5-difluorophenyl)-4,5-dihydrooxazole
  • Example 45 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(6-bromobenzo[b]thiophen-2-yl)-4-(2 ,4-Dichlorophenyl)-4,5-dihydrooxazole
  • Example 46 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Fluorophenyl)-4,5-dihydrooxazole
  • Example 47 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Chlorophenyl)-4,5-dihydrooxazole
  • Example 48 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 49 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(3,5-Difluorophenyl)-4,5-dihydrooxazole
  • Example 50 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(2'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Dichlorophenyl)-4,5-dihydrooxazole
  • Example 51 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Fluorophenyl)-4,5-dihydrooxazole
  • Example 52 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(4-Chlorophenyl)-4,5-dihydrooxazole
  • Example 53 4-((1H-1,2,4-Triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 54 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(3,5-Difluorophenyl)-4,5-dihydrooxazole
  • Example 55 4-((1H-1,2,4-triazol-1-yl)methyl)-2-(3'-fluoro-[1,1'-biphenyl]-4-yl) -4-(2,4-Difluorophenyl)-4,5-dihydrooxazole
  • Example 56 4-((1H-Tetrazol-1-yl)methyl)-2-(6-chlorobenzo[b]thiophen-2-yl)-4-(4-fluorophenyl)- 4,5-Dihydrooxazole
  • Experimental methods refer to the conventional in vitro antibacterial test methods (Reference method for broth dilution antifungal susceptibility testing of yeasts and filamentous fungi; Approved Standard M27-A3 and M38-A2).
  • RPMI-1640 medium Preparation of RPMI-1640 medium: RPMI-1640 10g, NaHCO 3 2.0g, sigma 34.5g, add 800mL sterile distilled water to dissolve, adjust the pH to 7.0 with 1mol/L NaOH, and make up to volume to 1000mL, sterilized by filtration with a 0.22 ⁇ m microporous membrane, and stored at 4°C for later use.
  • Filamentous fungi (Trichophyton rubrum, Trichophyton blemishes, Microsporum gypsum and Aspergillus fumigatus) etc. were successively inoculated on Sabouraud medium plates for two consecutive passages, and were incubated at 35 Cultivate in an incubator for 48 hours, and add 5 mL of 0.85% physiological saline to the colony to prepare a bacterial solution.
  • Use a spectrophotometer to adjust the concentration of the bacterial solution, and adjust the A value to 0.3-0.5; then dilute it 50 times with the medium to serve as the inoculated bacterial suspension.
  • Spheroids C. albicans, Candida tropicalis, Candida glabrata and Cryptococcus neoformans.
  • the activated strains were inoculated on the Sabouraud solid medium plate by the partition and streak method, and cultivated at a constant temperature of 32 °C for 2-3 days. Shake for 15 minutes, use a sterilized pipette tip to take a small amount of bacterial solution on a hemocytometer, and count under a microscope. Add RPMI-1640 medium to dilute so that the final bacterial suspension concentration is 1 ⁇ 10 6 cells/mL.
  • Liquid preparation Weigh 6.40 mg of each of the above chemically synthesized drugs, add 1.0 mL of dimethyl sulfoxide (DMSO), 1.0 mL of Tween-20 and 8.0 mL of sterilized distilled water in sequence, and mix well. The concentration of the prepared medicinal solution was 0.64 mg/mL.
  • Step 1 add RPMI-1640 medium: Add 180 ⁇ L RPMI-1640 medium to the first well of each row, 100 ⁇ L RPMI-1640 medium to wells 2-11, and 200 ⁇ L RPMI-1640 medium to 12 wells.
  • the second step adding the drug sample: add 20 ⁇ L of the drug to be tested to the first well, mix with a pipette, and draw 100 ⁇ L to the second well, and then dilute it 2-fold to the tenth well, mix well and discard 100 ⁇ L.
  • the third step, adding bacterial suspension add 100 ⁇ L of inoculating bacterial suspension to each of wells 1-11.
  • Well 11 is a growth control
  • well 12 is a blank medium control.
  • test concentration ( ⁇ g/mL) range is 32, 16, 8, 4, 2, 1, 0, 5, 0.25 , 0.125, 0.0625.
  • Cultivation and detection Aseptic growth of blank control and good growth of positive control are the criteria for judging whether the test operation is qualified. Eight samples were tested per plate, and positive drug controls were set for each bacteria. The dilution method of the drug to be tested is the same as above.
  • the compounds of general formula I in the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier depends on the desired route of administration and standard pharmaceutical practice.
  • Various drugs of this type of compound are used below.

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Abstract

La présente invention concerne des dérivés de dihydrooxazole 2,4,4-trisubstitués, leurs procédés de préparation et leur utilisation, se rapportant au domaine technique de la synthèse pharmaceutique. En particulier, la présente invention concerne une classe de dérivés de dihydrooxazole 2,4,4-trisubstitués et des sels pharmaceutiquement acceptables de ceux-ci, des hydrates, des solvates ou des promédicaments de ceux-ci, leurs procédés de préparation, et leur utilisation en tant que médicaments pour le traitement de diverses maladies provoquées par des infections fongiques. La formule générale du dérivé de dihydrooxazole 2,4,4-trisubstitué selon la présente invention et des stéréoisomères ou des sels pharmaceutiquement acceptables, des hydrates, des solvates ou des promédicaments de ceux-ci sont tels que présentés dans (I) : MBG, X, Y, M et R1 étant tels que décrits dans les revendications et la description.
PCT/CN2021/109144 2020-07-30 2021-07-29 Dérivés de dihydrooxazole 2,4,4-trisubstitués, leurs procédés de préparation et leur utilisation WO2022022616A1 (fr)

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