CN115160250B - 4, 6-Biphenol derivative and application thereof - Google Patents

4, 6-Biphenol derivative and application thereof Download PDF

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CN115160250B
CN115160250B CN202110359730.0A CN202110359730A CN115160250B CN 115160250 B CN115160250 B CN 115160250B CN 202110359730 A CN202110359730 A CN 202110359730A CN 115160250 B CN115160250 B CN 115160250B
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ethyl
biphenyl
carboxamide
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CN115160250A (en
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赵冬梅
殷文博
程卯生
张宇鑫
崔恒献
刘磊
姜洪
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Shenyang Pharmaceutical University
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    • 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
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Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a 4, 6-biphenol derivative, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method thereof and application thereof in medicines for treating various diseases caused by fungal infection. The 4, 6-biphenol derivative is a compound shown in a general formula (I), and a stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein X, Y, Z, W, L, R 1、R2 and an A ring are as defined in the claims and the specification.

Description

4, 6-Biphenol derivative and application thereof
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to a4, 6-biphenol derivative, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method thereof and application thereof in medicines for treating various diseases caused by fungal infection.
Background
Invasive fungal infections are a group of diseases with high morbidity and mortality, and hundreds of millions of patients worldwide each year are infected with pathogenic bacteria, with at least 150-200 tens of thousands of people dying each year. With the increasing number of people with low immune functions and the large use of immunosuppressants and broad-spectrum antibiotics in recent years, the normal immune functions of human bodies are seriously damaged, so that the incidence rate of invasive fungal infection is increased year by year.
Candida, cryptococcus and aspergillus are the three major pathogenic bacteria of invasive fungal infections. Candida albicans in candida is one of the main causes of blood infection under the current medical conditions, and the death rate caused by the candida albicans is up to 40%; the novel cryptococcus in cryptococcus is a conditional pathogenic bacteria, which can cause meningitis, and the fungal infection caused by the novel cryptococcus can cause death of 60 ten thousands of people each year, and the mortality rate of the cryptococcus in developing countries can be up to 60%; the mortality rate caused by the aspergillus fumigatus in the aspergillus in the immunodeficiency population is 30-95%. Although fungal infections have posed a great threat to humans, there are still very limited drugs available clinically to treat fungal infections.
The current clinical antifungal medicines can be divided into azole medicines for inhibiting ergosterol synthesis according to different action mechanisms; echinocandins antifungal agents that disrupt cell walls, polyenes that cause cell membrane leakage, and antimetabolites that act on nucleic acids. Wherein, the azole drug blocks the important constituent components of fungal cell membranes, namely the synthesis of ergosterol by inhibiting the activity of lanosterol 14 alpha-demethylase (CYP 51), and is the most active and mature target in the field of antifungal drugs. At present, clinical azole antifungal drugs are mainly divided into two categories: imidazoles such as miconazole (Miconazole), clotrimazole (Clotrimazole), ketoconazole (Ketoconazole); triazole drugs such as fluconazole (Fluconazole), itraconazole (Itraconazole), voriconazole (Voriconazole) and posaconazole (Posaconazole). Although azole drugs play an irreplaceable role in clinic, the serious toxic and side effects of the drugs and the generation of drug-resistant strains urge pharmaceutical chemists to develop antifungal drugs with more structure types, high efficiency, low toxicity and various administration modes. Thus, finding new ways to cope with the development of fungal resistance has become a current research focus.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, provides 4, 6-biphenol derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the derivatives, a preparation method of the derivatives and application of the derivatives; also provided are pharmaceutical compositions containing the 4, 6-biphenol derivatives.
In order to achieve the above purpose, the invention adopts the following technical scheme:
4, 6-biphenol derivative: a compound of formula (I), and stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:
Wherein:
x, Y, Z, W, which may be identical or different, are selected from N, O, S or C;
L is selected from amino, substituted with at least one substituent selected from (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkoxy, (C 1-C6) alkyl, (C 1-C6) alkanoyl, carbamoyl, (C 1-C3) alkylenedioxy; the following substituents are hydroxy, (C 1-C6) haloalkyl, (C 1-C6) alkoxy, (C 1-C6) alkyl;
m is selected from (-CH 2 -) n, carbonyl, amide, thiocarbonyl; wherein n=1-6;
A is selected from
R 1 and R 2 are identical or different and are selected from the group consisting of hydrogen, halogen, nitro, cyano, amino which is unsubstituted or substituted by 1 to 3 of the following groups, hydroxy, (C 1-C6) alkyl, (C 2-C6) alkenyl, (C 2-C6) alkynyl, (C 1-C6) alkoxy, (C 1-C6) haloalkoxy, (C 1-C6) alkylthio, (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkanoyl, Carbamoyl, (C 1-C3) alkylenedioxy; the following groups may be (C 1-C6) haloalkyl, (C 1-C6) alkoxy, (C 1-C6) alkylthio, C 1-C6 alkyl; a 5-10 membered heterocyclyl, C 6-C12 aryl or C 5-C12 heteroaryl, unsubstituted or substituted with 1-3 identical or different R 3 groups, said heterocyclyl and heteroaryl containing 1-3 heteroatoms selected from O, N and S;
(p in R 1)p is an integer of 1 to 5, (q in R 2)q is an integer of 1 to 4;
R 3 is selected from hydrogen, halogen, nitro, cyano, (C 1-C6) alkyl, which is unsubstituted or substituted by 1-3, (C 2-C6) alkenyl, (C 2-C6) alkynyl, (C 1-C6) alkoxy, (C 1-C6) alkylthio, (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkanoyl, carbamoyl, (C 1-C3) alkylenedioxy; the following groups are (C 1-C6) haloalkyl, (C 1-C6) alkoxy, (C 1-C6) alkylthio, and C 1-C6 alkyl.
Preferably, the compound of formula (I), and stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
Wherein,
X, Y, W, which may be identical or different, are selected from N, O or S;
z is selected from C or S;
L is selected from amino, (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkoxy, (C 1-C6) alkyl, (C 1-C6) alkanoyl, carbamoyl, (C 1-C3) alkylenedioxy;
M is selected from (-CH 2 -) n, n=1-6;
A is selected from
R 1 and R 2 are identical or different and are selected from the group consisting of hydrogen, halogen, nitro, cyano, amino which is unsubstituted or substituted by 1 to 3 of the following groups, hydroxy, (C 1-C6) alkyl, (C 2-C6) alkenyl, (C 2-C6) alkynyl, (C 1-C6) alkoxy, (C 1-C6) haloalkoxy, (C 1-C6) alkylthio, (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkanoyl, Carbamoyl, (C 1-C3) alkylenedioxy; the following groups may be (C 1-C6) haloalkyl, (C 1-C6) alkoxy, (C 1-C6) alkylthio, C 1-C6 alkyl; a 5-10 membered heterocyclyl, C 6-C12 aryl or C 5-C12 heteroaryl, unsubstituted or substituted with 1-3 identical or different R 3 groups, said heterocyclyl and heteroaryl containing 1-3 heteroatoms selected from O, N and S;
(p in R 1)p is an integer of 1 to 5, (q in R 2)q is an integer of 1 to 4;
Further preferred are compounds of the general formula (I), stereoisomers thereof or salts thereof with 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 or benzoic acid;
Wherein,
X, Y, W, which may be identical or different, are selected from N or O;
Z is selected from C;
L is selected from (C 1-C6) alkoxy or (C 1-C6) alkyl;
M is selected from (-CH 2 -) n, n=1-6;
A is selected from
R 1 and R 2 are identical or different and are selected from the group consisting of hydrogen, halogen, nitro, cyano, amino which is unsubstituted or substituted by 1 to 3 of the following groups, hydroxy, (C 1-C6) alkyl, (C 2-C6) alkenyl, (C 2-C6) alkynyl, (C 1-C6) alkoxy, (C 1-C6) haloalkoxy, (C 1-C6) alkylthio, (C 1-C6) alkylamido, (C 1-C6) alkylsulfinyl, sulfonyl, (C 1-C6) alkanoyl, Carbamoyl, (C 1-C3) alkylenedioxy; the following groups may be (C 1-C6) haloalkyl, (C 1-C6) alkoxy, (C 1-C6) alkylthio, C 1-C6 alkyl; a 5-10 membered heterocyclyl, C 6-C12 aryl or C 5-C12 heteroaryl, unsubstituted or substituted with 1-3 identical or different R 3 groups, said heterocyclyl and heteroaryl containing 1-3 heteroatoms selected from O, N and S;
(p in R 1)p is an integer of 1 to 5, (q in R 2)q is an integer of 1 to 4;
the compounds are described below, and meanwhile, the corresponding structural formulas are detailed in examples, and specifically are as follows:
5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (3 '- (Tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (methoxymethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (3 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (4 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (3 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-methoxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (3 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-2 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (2 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (2 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4 '- (Tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (4 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (2 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-2 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- ((1, 1-thiomorpholino) methyl) phenyl) -N-ethylisoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (piperidin-1-ylmethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (4-methylpiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (((1-methylpiperidin-4-yl) amino) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) -N-ethylisoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-methyl-1, 4-diaza-1-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((3-oxopiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (2-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (3-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (2-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
4- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) -5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl) -isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-morpholinopiperidin-1-yl) methyl) phenyl) isoxazole-3-carboxamide.
A preparation method of 4, 6-biphenol derivatives comprises the following steps:
Step a: heating and refluxing the raw material 1 (1 eq) and bromobenzyl (2 eq) under alkaline conditions to obtain an intermediate 2;
step b: intermediate 2 (1 eq) and N-bromosuccinimide (1 eq) undergo bromination reaction to obtain intermediate 3;
step c: the intermediate 3 (1 eq) and diethyl oxalate (1.2 eq) are subjected to condensation reaction under alkaline conditions to obtain an intermediate 4;
Step d: cyclizing the intermediate 4 (1 eq) with hydroxylamine hydrochloride or hydrazine hydrate and the like (1.1 eq) to obtain an intermediate 5;
step e: intermediate 5 is subjected to ammonolysis or hydrolysis, condensation and other reactions to obtain intermediate 6;
Step f: performing suzuki coupling reaction on the intermediate 6 (1 eq) and different substituted phenylboronic acids (1.1 eq) under alkaline conditions to obtain an intermediate 7;
Step g: intermediate 7 (1 eq) and N-bromosuccinimide (1.1 eq) undergo bromination reaction to obtain intermediate 8;
Step h: performing suzuki coupling reaction on the intermediate 8 (1 eq) and different substituted p-formylphenylboronic acid (1.1) to obtain an intermediate 9;
step i: the intermediate 9 undergoes reductive amination reaction under acidic conditions to obtain an intermediate 10;
step j: intermediate 10 provides the target compound of formula I under hydrogen palladium carbon reduction conditions.
The preferred conditions are as follows:
In step a, raw material 1 (0.263 mol) was dissolved in acetonitrile, potassium carbonate (0.657 mol) was added, stirred at room temperature, bromobenzyl (0.657 mol) was added dropwise over 5min, and the mixture was heated under reflux for 18h, cooled to room temperature, filtered, washed and dried to give intermediate 2. Wherein the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc., and the reaction solvent is acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably potassium carbonate is used as an acid binding agent and acetonitrile is used as a solvent.
In step b, intermediate 2 (0.255 mol) was dissolved in N, N-dimethylformamide (250 mL), N-bromosuccinimide (0.255 mol) was added in portions with stirring at room temperature, and after stirring at room temperature for 5 hours, the suspension was poured into water (1L), filtered, washed and dried to give intermediate 3. The reaction solvent may be acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc., preferably N, N-dimethylformamide.
In step c, sodium (364.71 mmol) was added in portions to absolute ethanol (350 mL) and stirred at room temperature under nitrogen for 18h to give a fresh sodium ethoxide solution. Intermediate 3 (119.9 mol) was added in portions to sodium ethoxide solution, diethyl oxalate (24.77 ml,119.9 mmol) was added, and the mixture was heated to reflux for 3h, cooled to room temperature, filtered, washed and dried to give intermediate 4.
In step d, intermediate 4 (17 mmol) was dissolved in ethanol solution (170 mL), hydroxylamine hydrochloride (20.4 mmol) was added in portions and heated to reflux for 1.5h, cooled to room temperature, filtered and washed with water and ethanol, and dried to give intermediate 5. The reaction solvent may be acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethanol.
In step e, intermediate 5 (15.5 mmol) was dissolved in ethanol (80 mL), a methanolic solution of ethylamine (2.0M, 65mL,130 mmol) was added thereto, and after refluxing for 18h, it was cooled to room temperature, filtered, washed and dried to give intermediate 6. The reaction solvent may be acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethanol.
In step f, intermediate 6 (2.13 mmol), substituted arylphenylboronic acid (2.13 mmol) and sodium bicarbonate (6.39 mmol) were dissolved in N, N-dimethylformamide (30 mL), 3mL of water was added, and after adding thereto the palladium complex (2 mol%), the reaction was stirred under nitrogen at 80℃for 5 hours, cooled, and the organic solvent was distilled off, followed by purification by column chromatography to obtain intermediate 7. The palladium complex can be Pd (PPh 3)4、PdCl2、PdCl2 (dppf), pd (PPh 3)2Cl2, etc.), preferably Pd (PPh 3)4; the inorganic base can be sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc.), the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water, ethylene glycol dimethyl ether, etc., or a mixed solvent composed of two solvents, preferably N, N-dimethylformamide.
In step g, intermediate 7 (9.73 mmol) was dissolved in acetonitrile (60 mL), N-bromosuccinimide (10.07 mmol) and ceric ammonium nitrate (4.86 mmol) were added thereto, heated under reflux for 4h, cooled to room temperature, the solvent was distilled off, extracted with ethyl acetate, dried, and the solvent was distilled off to give intermediate 8. The reaction solvent may be acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc., preferably acetonitrile.
In step h, intermediate 8 (2.42 mmol), 4-formylphenylboronic acid (3.63 mmol) and sodium bicarbonate (4.84 mmol) were dissolved in tetrahydrofuran (20 mL), 4mL of water was added, and after the addition of palladium complex (2 mol%), the reaction was stirred under nitrogen at 80℃for 5h, cooled to room temperature and subjected to column chromatography to give intermediate 9. The palladium complex can be Pd (PPh 3)4、PdCl2、PdCl2(dppf)、Pd(OAc)2, pd (PPh 3)2Cl2, etc.), preferably Pd (PPh 3)4; the inorganic base can be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride, etc., preferably sodium bicarbonate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water, ethylene glycol dimethyl ether, etc., or a mixed solvent composed of two solvents, preferably a mixed solvent of tetrahydrofuran and water (5:1).
In step i, intermediate 9 (0.133 mmol) and the corresponding amine (0.265 mmol) were dissolved in methanol (10 mL), catalytic amounts of acetic acid and sodium cyanoborohydride (0.2 mmol) were added, stirred at room temperature for 3h, the solvent was distilled off, and the intermediate 10 was obtained by column chromatography. The solvent may be acetonitrile, methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc., preferably methanol, and the acid may be trifluoroacetic acid, hydrochloric acid/ethanol, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, etc., preferably acetic acid.
In step j, intermediate 10 (0.122 mmol) obtained by reductive amination was dissolved in acetic acid (5 mL), palladium on carbon catalyst (10%) was added, hydrogenation was carried out for 16h with stirring, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo, and finally the target compound of formula I was obtained by column chromatography.
An application of a4, 6-biphenol derivative in preparing a medicament for resisting fungal infection diseases, wherein the compound is shown in a general formula I and a geometric isomer thereof or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
A pharmaceutical composition, which is an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises a compound shown in a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.
Use of a pharmaceutical composition for the preparation of a medicament for the treatment of a fungal infection disease.
In addition, prodrugs of the derivatives of the invention are also encompassed by the invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have a relatively weak or even no activity, but are converted to the corresponding biologically active form after administration under physiological conditions (e.g. by metabolism, solvolysis or otherwise).
The compounds of formula I may be in unsolvated forms as well as solvated forms which include pharmaceutically acceptable solvents such as water, ethanol, and the like. The compounds of formula I may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the invention.
The compounds of formula I may exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconverted via a low energy barrier.
"Halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "alkylene" refers to a straight or branched chain alkylene group; "aryl" refers to an organic group obtained by removing two hydrogen atoms at one or different positions in an aromatic hydrocarbon, such as phenyl, naphthyl; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which ring system is aromatic and is an organic radical obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, furanyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like. "Heterocyclylalkyl" refers to a heteroatom, such as N, O, S, cyclic alkyl, such as tetrahydrofuranyl, piperidinyl, piperazinyl.
The invention can contain the derivative of the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and can be mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluent, auxiliary agent and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The pharmaceutical compositions of the present invention may be formulated in several dosage forms, containing some excipients commonly used in the pharmaceutical arts. The above-mentioned several dosage forms can be made into injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment and ointment.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmenting agents, flavoring agents, preservatives, solubilizing agents, matrices and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drugs are unstable in gastric conditions, they may be formulated as enteric coated tablets.
Wherein said fungal infection disease is associated with one or more of the following pathogenic fungi:
Absidia umbrella (Absidia corymbifera), abrus capsulifera Luo Jun (Ajellomyces capsulatus), abrus dermatitis Luo Jun ((Ajellomyces dermatitidis), alternaria benzoguanensis (Arthroderma benhamiae), alternaria farinacea (Arthroderma fulvum), alternaria gypsum (Arthroderma gypseum), alternaria endonudus (Arthroderma incurvatum), The fungus is selected from the group consisting of Aspergillus tai Tian Jiepi (Arthroderma otae), pelaromyces Mo Bojie (Arthroderma vanbreuseghemii), aspergillus flavus (Aspergillus flavus), aspergillus fumigatus (Aspergillus fumigatus), aspergillus niger (Aspergillus niger), acidoptera dermatitis (Blastomyces dermatitidis), candida albicans (Candida albicans), candida glabrata (Candida glabra), Candida quaternary (Candida guilliermondii), candida krusei (Candida krusei), candida parapsilosis (Candida parapsilosis), candida tropicalis (Candida tropicalis), candida mycota (Candida pelliculosa), calicheamicin californica (Cladophialophora carrionii), coccidioidosporum (Coccidioides immitis), Cryptococcus neoformans (Cryptococcus neoformans), han dynasty (Cunninghamella sp.), epidermomyces floccosum (Epidermophyton floccosum), exophiala dermatitis (Exophiala dermatitidis), leuconostoc mesenteroides (Filobasidiella neoformans), sporotrichum petersonii (Fonsecaea pedrosoi), fusarium solani (Fusarium solani), Geotrichum candidum (Geotrichum candidum), histoplasmosis capsulatum (Histoplasma capsulatum), exophiala venenum (Hortaea werneckii), issatchenkia orientalis (Gong SSATSCHENKIA ORIENTALIS), mycobacterium griseus (Madurella grisae), malassezia furfur (Malassezia fur fur), malassezia globosa (Malassezia globosa), malassezia dulcis (Malassezia obtusa), Moraxella (Malassezia pachydermatis), moraxella restricta (Malassezia restricta), moraxella (Malassezia slooffiae), moraxella (Malassezia sympodialis), moraxella microsporopsis canis (Microsporum cams), microsporopsis flavescens (Microsporum fulvum), microsporopsis gypseum (Microsporum gypseum), Mucor circinelloides (Mucor circinelloides), sclerotinia reddish shell (Nectria haematococca), paecilomyces variotii (Paecilomyces variotii), paracoccus Brazil (Paracoccidioides brasiliensis), penicillium marneffei (Peniciliium marneffei), pichia anomala (Pichia anomala), pichia guilliermondii (Pichia guilliermondii), Pneumosporosis californica (Pneumocystis carinii), false A Li Shenjun (Pseudallescheria boydii), rhizopus oryzae (Rhizopus oryzae), rhodotorula rubra (Rhodotorula rubra), saprolegnia cuspidata (Scedosporium apiospernium), schizophyllum (Schizophyllum commune), sporotrichosis lanuginose (Sporothrix schenckii), trichophyton mentagrophytes (Trichophyton mentagrophytes), Trichophyton rubrum (Trichophyton rubrum), trichophyton palmatum (Trichophyton verrucosum), trichophyton purple (Trichophyton violaceum), trichosporon assamicum (Trichosporon asahii), trichosporon cutaneum (Trichosporon cutaneum), trichosporon Mo Mao (Trichosporon inkin), trichosporon viscosus (Trichosporon mucoides), Candida otophylla (Candida auris).
The invention has the positive progress effects that: the serial compounds related to the invention have biphenyl parent nucleus structures different from the prior Hsp90 inhibitor; the series of compounds can realize the inhibition effect on the drug-resistant deep fungal infection by a combined drug mode, and aims to solve the problem that the prior deep fungal infection caused by drug-resistant bacteria is increasingly serious and has no effective drug for treatment; the synthesis route of the series of compounds is simple and easy to operate, the conditions are mild, the yield is high, and the large-scale preparation of target compounds can be realized; the 4, 6-biphenol derivative has good antifungal activity on various superficial and deep fungi and drug-resistant bacteria, has the advantages of high efficiency, low toxicity, wide antifungal spectrum, strong drug-resistant activity and the like, and can be used for preparing drug-resistant fungi drugs.
Detailed Description
The examples and preparations provided herein further illustrate and exemplify the compounds of the invention and methods of preparing the same. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way. The compounds of the general formula I according to the invention can be prepared by the process of scheme 1, all the variable factors used in these schemes being as defined in the claims.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The examples provided below are therefore intended to illustrate, but not limit the scope of the invention.
The starting materials may generally be obtained from commercial sources or prepared using methods well known to those skilled in the art or according to the methods described herein. The reagents used are analytically pure or chemically pure, unless otherwise specified.
Mass spectra used for structural confirmation of compounds were determined using Agilent 1100 LC/MSD. The column chromatography purified product is 100-200 mesh or 200-300 mesh silica gel produced by Qingdao ocean chemical plant.
Example 1:5- (2 '-chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
In step a, raw material 1 (0.263 mol) was dissolved in acetonitrile, potassium carbonate (0.657 mol) was added, stirred at room temperature, bromobenzyl (0.657 mol) was added dropwise over 5min, the mixture was heated to reflux for 18h, the reaction was complete by tlc detection, cooled to room temperature, filtered and the filter cake was washed with water and ethanol, respectively, and dried at 45 ℃ to give intermediate 2.
In step b, intermediate 2 (0.255 mol) was dissolved in N, N-dimethylformamide (250 mL), N-bromosuccinimide (0.255 mol) was added in portions with stirring at room temperature, stirred at room temperature for 5h, TLC detection reaction was complete, the suspension was poured into water (1L), stirred for 1h, and then filtered, washed and dried to give intermediate 3.
In step c, sodium (364.71 mmol) was added in portions to absolute ethanol (350 mL) and stirred at room temperature under nitrogen for 18h to give a fresh sodium ethoxide solution. Intermediate 3 (119.9 mol) was added in portions to sodium ethoxide solution, diethyl oxalate (24.77 ml,119.9 mmol) was added, the mixture was heated to reflux for 3h, after completion of the reaction by tlc, cooled to room temperature, filtered, washed and dried to give intermediate 4.
In step d, intermediate 4 (17 mmol) was dissolved in ethanol solution (170 mL), hydroxylamine hydrochloride (20.4 mmol) was added in portions and heated to reflux for 1.5h, TLC detection was complete, cooled to room temperature, filtered and the filter cake was washed with water and ethanol and dried at 45℃to afford intermediate 5.
In step e, intermediate 5 (15.5 mmol) was dissolved in ethanol (80 mL), a methanolic solution of ethylamine (2.0M, 65mL,130 mmol) was added thereto, after refluxing for 18h with heating, TLC detection was complete, cooled to room temperature, filtered, washed and dried to give intermediate 6.
In step f, intermediate 6 (2.13 mmol), o-chlorobenzeneboronic acid (2.13 mmol) and sodium bicarbonate (6.39 mmol) were dissolved in N, N-dimethylformamide (30 mL), water 3mL was added, pd (PPh 3)4 (2 mol%) was added thereto, the reaction was stirred at 80℃under nitrogen protection for 5h, TLC detection was complete, after cooling, the organic solvent was distilled off, and intermediate 7 was purified by column chromatography.
In step g, intermediate 7 (9.73 mmol) was dissolved in acetonitrile (60 mL), N-bromosuccinimide (10.07 mmol) and ceric ammonium nitrate (4.86 mmol) were added thereto, heated to reflux for 4h, TLC detection reaction was complete, cooled to room temperature, the solvent was distilled off, extracted with ethyl acetate, dried over night over anhydrous sodium sulfate, the desiccant was filtered off, and concentrated under reduced pressure to give intermediate 8.
In step h, intermediate 8 (2.42 mmol), 4-formylphenylboronic acid (3.63 mmol) and sodium bicarbonate (4.84 mmol) were dissolved in tetrahydrofuran (20 mL), 4mL of water was added, pd (PPh 3)4 (2 mol%) was added, the reaction was stirred under nitrogen at 80℃for 5h, the reaction was complete by TLC detection, cooled to room temperature, concentrated under reduced pressure, and column chromatography was performed to give intermediate 9.
In step i, intermediate 9 (0.133 mmol) and ethylamine (0.265 mmol) were dissolved in methanol (10 mL), a catalytic amount of acetic acid and sodium cyanoborohydride (0.2 mmol) were added, and after stirring at room temperature for 3h, TLC detection reaction was complete, the solvent was distilled off, and intermediate 10 was obtained by column chromatography.
In step j, intermediate 10 (0.122 mmol) obtained by reductive amination was dissolved in acetic acid (5 mL), palladium on carbon catalyst (10%) was added, hydrogen was introduced under stirring for 16h, after tlc detection reaction was complete, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo, and finally column chromatography was performed to give example 1.
5- (2 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
ESI-MS[M+H]+(m/z):533.17
1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),10.00(s,1H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
Other compounds of formula I were prepared following the procedure of example 1, using the corresponding reagents, respectively.
Example 2:5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
the target compound was obtained by substituting o-chlorobenzoic acid in step f with other substituted boric acid fragments as described in example 1 above.
ESI-MS[M+H]+(m/z):541.65。
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
Example 3:5- (3 '- (tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):555.27
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.24(s,9H),1.07(t,J＝7.2Hz,3H).
Example 4: n-ethyl-5- (3 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):517.20
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 5:5- (4, 6-dihydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):567.20
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 6:5- (3 '-chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):533.17
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 7: n-ethyl-5- (3 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):527.24
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.55(q,J＝7.6Hz,2H),2.33(s,4H),1.15(t,J＝7.6Hz,3H),1.07(t,J＝7.2Hz,3H).
example 8:5- (4, 6-dihydroxy-3 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):583.19
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 9:5- (4, 6-dihydroxy-4 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):513.23
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.27(s,3H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 10: n-ethyl-5- (4 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):517.20
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 11:5- (4, 6-dihydroxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):567.20
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
Example 12:5- (4 '-chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):533.17
1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),10.00(s,1H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
example 13:5- (4, 6-dihydroxy-4 '-methoxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):529.22
1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),10.00(s,1H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.73(s,3H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
Example 14:5- (4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):499.21
1H NMR(600MHz,DMSO-d6)δ10.07(s,1H),10.04(s,1H),7.28(s,2H),7.27(d,J＝2.8Hz,2H),7.26(s,2H),7.23(d,J＝8.0Hz,2H),7.20(m,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
Example 15:5- (4, 6-dihydroxy-4 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):541.26
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
Example 16:5- (4 '- (tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):555.27
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.24(s,9H),1.07(t,J＝7.2Hz,3H).
example 17: n-ethyl-5- (4 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):527.24
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.55(q,J＝7.6Hz,2H),2.33(s,4H),1.15(t,J＝7.6Hz,3H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 18 5- (4, 6-dihydroxy-4 '-trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):583.19
1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),10.00(s,1H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 19 5- (4, 6-dihydroxy-2 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):513.23
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.27(s,3H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 20N-ethyl-5- (2 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):527.24
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.55(q,J＝7.6Hz,2H),2.33(s,4H),1.15(t,J＝7.6Hz,3H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 21 5- (4, 6-dihydroxy-2 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):541.26
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 22N-ethyl-5- (2 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):517.20
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.33(s,4H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 23 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (thiomorpholino) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):557.23。
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 24 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- ((1, 1-thiomorpholino) methyl) phenyl) -N-ethylisoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):589.22
1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),10.00(s,1H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,4H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 25 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):554.29
1H NMR(600MHz,DMSO-d6)δ10.03(s,2H),8.86(t,J＝5.7Hz,1H),7.24(s,4H),7.18(t,J＝7.5Hz,1H),7.11(d,J＝9.0Hz,2H),7.08(d,J＝7.6Hz,1H),6.96(s,1H),6.60(s,1H),3.45(s,2H),3.32(s,2H),3.27–3.19(m,2H),2.82(m,1H),2.38(s,4H),2.23(s,3H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 26 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- (4- (dimethylamino) piperidin-1-yl) methyl) phenyl-N-ethylisoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):582.75
1H NMR(600MHz,DMSO-d6)δ10.02(s,2H),8.85(t,J＝5.7Hz,1H),7.24(s,4H),7.18(t,J＝7.6Hz,1H),7.14–7.09(m,2H),7.07(d,J＝7.6Hz,1H),6.96(s,1H),6.59(s,1H),3.42(s,2H),3.26–3.19(m,2H),2.86–2.77(m,3H),2.24(s,6H),1.91(t,J＝11.5Hz,2H),1.71(d,J＝12.1Hz,2H),1.44–1.33(m,2H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 27 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-methyl-1, 4-diazepin-1-yl) methyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):568.30
1H NMR(600MHz,DMSO-d6)δ10.11–10.08(m,1H),10.08–10.06(m,1H),8.88(t,J＝5.7Hz,1H),7.33–7.28(m,2H),7.27–7.25(m,2H),7.20(t,J＝7.6Hz,1H),7.15–7.11(m,2H),7.08(dt,J＝7.6,1.5Hz,1H),6.97(s,1H),6.65(d,J＝2.0Hz,1H),3.66(s,2H),3.23(m,2H),3.17(d,J＝2.5Hz,3H),2.88–2.81(m,1H),2.79(t,J＝5.0Hz,2H),2.66(q,J＝6.2,4.4Hz,6H),1.93–1.87(m,2H),1.17(d,J＝6.9Hz,6H),1.08(t,J＝7.2Hz,3H).
EXAMPLE 28 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((3-oxopiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):554.25
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.86(t,J＝5.7Hz,1H),7.74(d,J＝2.3Hz,1H),7.29–7.24(m,4H),7.22–7.19(m,1H),7.14–7.11(m,2H),7.08(m,1H),6.99(s,1H),6.58(s,1H),3.52(s,2H),3.23(m,2H),3.13(m,2H),2.91(s,2H),2.88–2.79(m,J＝6.9Hz,1H),2.56–2.51(m,2H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 29 4- (3, 5-difluoro-4- (morpholinomethyl) phenyl) -5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethylisoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):577.24
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,2H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 30 5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (3-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):559.25
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,3H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
EXAMPLE 31 4- (3-chloro-4- (morpholinomethyl) phenyl) -5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethylisoxazole-3-carboxamide:
ESI-MS[M+H]+(m/z):575.22
1H NMR(600MHz,DMSO-d6)δ10.01(s,2H),8.85(t,J＝5.7Hz,1H),7.27–7.23(m,3H),7.18(t,J＝7.9Hz,1H),7.12(dd,J＝7.1,1.5Hz,2H),7.08(d,J＝7.6Hz,1H),6.97(s,1H),6.59(s,1H),3.55(s,4H),3.44(s,2H),3.26–3.20(m,2H),2.85–2.79(m,1H),2.33(s,4H),1.17(d,J＝6.9Hz,6H),1.07(t,J＝7.2Hz,3H).
Pharmacological studies of part of the products of the invention.
Experimental methods reference to conventional in vitro bacteriostasis test methods (Reference method for brothdilution antifungal susceptibility testing of yeasts and filamentous fungi;Approved Standard M27-A3 and M38-A2).
Experimental materials and methods:
(1) Experimental strains:
In the experiment, 5 pathogenic fungi which are clinically verified to be resistant to fluconazole are selected, the strain numbers are 901, 904, 632, 100 and 101, and all the strains are presented by navy medical university; meanwhile pathogenic fungi are well documented in the literature (Zhao L,Sun N,Tian L,et al.Combating fluconazole-resistant fungi with novelβ-azole-phenylacetone derivatives[J].European Journal of Medicinal Chemistry,2019,183:111689.).
(2) The test method comprises the following steps:
Preparation of RPMI-1640 medium: RPMI-1640.0 g, naHCO 3 2.0.0 g, triazomorph propane sulfonic acid (sigma) 34.5g, adding 800mL sterile distilled water for dissolution, lmol/L NaOH adjusting pH to 7.0, then fixing volume to 1000mL, adding fluconazole with specific concentration into the culture medium, filtering and sterilizing by a 0.22 mu m microporous filter membrane, and then standing at 4 ℃ for later use.
Preparation of fluconazole resistant suspension of the above-mentioned spherical fungi: inoculating the activated strain on a plate of a Saussureae solid culture medium by partition streaking, culturing for 2-3 days at a constant temperature of 32 ℃, taking a proper amount of single colony, inoculating into a triangular flask containing l 0mL 0.85% sterile physiological saline, oscillating for 15 minutes, taking a small amount of bacterial liquid on a blood cell counting plate by using a sterilizing gun head, and counting under a microscope. The final bacterial suspension was diluted with RPMI-1640 medium to a concentration of 1X10 6/mL.
Preparing a liquid medicine: 6.40mg of each of the chemicals obtained in the above example was weighed, and then l.0mL of dimethyl sulfoxide (DMSO), l.0mL of Tween-20 and 8.0mL of sterilized distilled water were added in order and mixed well. The concentration of the prepared medicinal liquid is 0.64mg/mL. Fluconazole and a positive control radicicol were formulated in the same manner.
Inoculating: in the first step, RPMI-1640 medium is added: mu. LRPMI-1640 medium was added to well 1, 100. Mu.L RPMI-1640 medium was added to well 2-11, and 200. Mu.L RPMI-1640 medium was added to well 12 of each row. Secondly, adding a medicine sample: to the 1 st well, 20. Mu.L of the drug solution to be measured (i.e., the compound obtained in each example) was added, and 100. Mu.L to 2 wells were aspirated after mixing with a pipette, diluted 2-fold sequentially to the 10 th well, and 100. Mu.L was discarded after mixing. Thirdly, adding bacterial suspension: to each of the 1-11 wells, 100. Mu.L of the inoculum suspension (i.e., fluconazole resistant pathogenic fungus) was added. Wells 11 were growth controls and wells 12 were blank medium controls. Positive control drug was not given a blank drug control, i.e. a multiple gradient dilution was made from well 1 to well 10, with test concentrations (μg/mL) ranging from 32, 16, 8, 4, 2, 1,0, 5, 0.25, 0.125, 0.0625.
Culturing and detecting: the blank control is used for sterile growth, and the good growth of the fluconazole administration group is used as a standard for judging whether the test operation is qualified. Each plate was tested for 8 samples and each bacteria was provided with a positive drug control (fluconazole in combination with radicicol). The minimum inhibitory concentration test is carried out by the drug dilution method to be tested in the same way and by adopting a combined drug mode.
Table 1 example minimum inhibitory concentration (MIC, μg/ml) in combination with fluconazole
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From the test results, the compounds of the general formula I and salts thereof to be protected by the invention have good antifungal activity, and after being combined with fluconazole, most biphenyl compounds have good inhibition effects on various drug-resistant bacteria, wherein the inhibition activity of examples 27 and 29 is equivalent to that of a positive control, and is 0.125 mug/mL, and the antifungal activity of the compounds is stronger than that of a control drug, so that the inhibition effect on drug-resistant fungi is realized. Compared with the existing antifungal medicines, the compound has the advantages of novel structure, low toxicity, high efficiency, drug resistance and the like after combined use, so that the compound has good application prospect.
The compounds of the general formula I according to the invention can be administered alone, but are generally administered in admixture with a pharmaceutically acceptable carrier, which is selected according to the desired route of administration and standard pharmaceutical practice, and the novel use thereof in the pharmaceutical field is indicated below by the preparation of various pharmaceutical dosage forms of such compounds, for example tablets, capsules, injections, aerosols, suppositories, films, drops, topical liniments and ointments, respectively.
Example 31: a tablet.
10G of the compound containing the compound of claim 1 (for example, the compound of example 30) was mixed with 20g of an auxiliary material according to a general pharmaceutical tabletting method, and then compressed into 100 tablets each having a weight of 300mg.
Example 32: and (5) preparing a capsule.
10G of the compound containing the compound of claim 1 (for example, the compound of example 30) and 20g of auxiliary materials are uniformly mixed according to the requirement of a pharmaceutical capsule, and the mixture is filled into hollow capsules, wherein each capsule weighs 300mg.
Example 33: an injection.
10G of the compound containing the compound according to claim 1 (exemplified by the compound of example 30) was subjected to activated carbon adsorption by a conventional pharmaceutical method, filtered through a 0.65 μm microporous membrane, and filled into nitrogen tanks to prepare water needle preparations each containing 2mL and 100 bottles in total.
Example 34: an aerosol.
10G of the compound containing the compound according to claim 1 (for example, the compound according to example 30) was dissolved in a suitable amount of propylene glycol, and distilled water and other radiation materials were added to prepare 500mL of a clear solution.
Example 35: a suppository.
10G of the compound containing the compound according to claim 1 (for example, the compound according to example 30) was ground, added with an appropriate amount of glycerin, ground uniformly, added with melted glycerogelatin, ground uniformly, and poured into a lubricant-coated mold to prepare 50 suppositories.
Example 36: and (3) a film agent.
10G of the compound of claim 1 (exemplified by the compound of example 30) was used, polyvinyl alcohol, glycerin for medical use, water and the like were stirred and expanded, then heated and dissolved, filtered through a 80-mesh screen, and then the compound of example 18 was added to the filtrate and stirred and dissolved, and film was applied to the film 100 sheets.
Example 37: dripping pill.
10G of the compound of claim 1 (example 30) and 50g of matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare the dripping pill 1000.
Example 38: a topical liniment.
10G of the compound containing the compound of claim 1 (for example, the compound of example 30) is mixed and ground with 2.5g of auxiliary materials such as an emulsifier according to a conventional pharmaceutical method, and distilled water is added to 200 mL.
Example 39: an ointment.
10G of the compound containing the compound according to claim 1 (exemplified by the compound of example 30), grinding, and mixing with 500g of an oily base such as vaseline.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (7)

1. A4, 6-biphenol derivative characterized by: a compound of formula (I), or a pharmaceutically acceptable salt thereof:
Wherein,
X is selected from NH or O;
Y is selected from N;
W is selected from NH or O;
Z is selected from C;
L is selected from (C 1-C6) alkyl;
M is selected from (-CH 2 -) n, n=1-6;
A is selected from
R 1 is selected from unsubstituted (C 1-C6) alkyl, (C 1-C6) alkoxy, (C 1-C6) haloalkoxy;
R 2 is selected from hydrogen, halogen;
(p in R 1)p is an integer of 1-5, (q in R 2)q is an integer of 1-4).
2. The 4, 6-biphenol derivative according to claim 1, wherein: the pharmaceutically acceptable salt is a salt formed by a compound of the general formula I and the following acid;
the following are 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 or benzoic acid.
3. A4, 6-biphenol derivative characterized by: the compound is
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (3 '- (Tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (methoxymethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (3 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (4 '-fluoro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (3 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-methoxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (3 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-2 '-methyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (2 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (2 '-Chloro-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4 '- (Tert-butyl) -4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
N-ethyl-5- (4 '-ethyl-4, 6-dihydroxy- [1,1' -biphenyl ] -3-yl) -4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-2 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- ((1, 1-thiomorpholino) methyl) phenyl) -N-ethylisoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (piperidin-1-ylmethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (4-methylpiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- (((1-methylpiperidin-4-yl) amino) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -4- (4- ((4- (dimethylamino) piperidin-1-yl) methyl) phenyl) -N-ethylisoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-methyl-1, 4-diaza-1-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((3-oxopiperazin-1-yl) methyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (2-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (3-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (2-fluoro-4- (morpholinomethyl) phenyl) isoxazole-3-carboxamide
4- (3, 5-Difluoro-4- (morpholinomethyl) phenyl) -5- (4, 6-dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl) -isoxazole-3-carboxamide
5- (4, 6-Dihydroxy-3 '-isopropyl- [1,1' -biphenyl ] -3-yl) -N-ethyl-4- (4- ((4-morpholinopiperidin-1-yl) methyl) phenyl) isoxazole-3-carboxamide.
4.A process for the preparation of 4, 6-biphenol derivatives according to claim 1, characterized in that:
Step a: heating and refluxing the raw material 1 and bromobenzyl under alkaline conditions to obtain an intermediate 2;
Step b: intermediate 2 and N-bromosuccinimide undergo bromination reaction to obtain intermediate 3;
step c: the intermediate 3 and diethyl oxalate undergo condensation reaction under alkaline conditions to obtain an intermediate 4;
step d: the intermediate 4 and hydroxylamine hydrochloride or hydrazine hydrate undergo a cyclization reaction to obtain an intermediate 5;
Step e: intermediate 5 is subjected to ammonolysis or hydrolysis and condensation reaction to obtain intermediate 6;
Step f: the intermediate 6 and different substituted phenylboronic acids undergo Suzuki coupling reaction under alkaline conditions to obtain an intermediate 7;
step g: intermediate 7 and N-bromosuccinimide undergo bromination reaction to obtain intermediate 8;
step h: performing suzuki coupling reaction on the intermediate 8 and different substituted p-formylphenylboronic acids to obtain an intermediate 9;
step i: the intermediate 9 undergoes reductive amination reaction under acidic conditions to obtain an intermediate 10;
step j: intermediate 10 provides the target compound of formula I under hydrogen palladium carbon reduction conditions.
5. Use of the 4, 6-biphenol derivative according to claim 1 or 3, characterized in that: use of a compound as defined in claim 1 or 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a fungal infection disorder; the fungal infection is a deep fungal infection caused by drug-resistant bacteria.
6. A pharmaceutical composition characterized by: the composition is an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises a compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof.
7. Use of a pharmaceutical composition according to claim 6, wherein: the application of the composition in preparing medicines for resisting fungal infection diseases is that the fungal infection is deep fungal infection caused by drug-resistant bacteria.
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