CN-118994102-B - Efluorconazole derivatives and antifungal activity thereof

CN118994102BCN 118994102 BCN118994102 BCN 118994102BCN-118994102-B

Abstract

The invention discloses a series of efroconazole derivatives or pharmaceutically acceptable inorganic salts, organic salts and solvates thereof. Also discloses a preparation method of the derivatives and application of the derivatives in preparing medicines for treating or preventing fungal infection. The experimental results show that the initial in vitro antifungal activity of a plurality of target compounds is obviously better than that of a lead compound, namely, iferoconazole and other azole antifungal drugs (such as miconazole, fluconazole, octreonazole and the like) widely used clinically at present, and the compound has the advantages of better water solubility, broad antibacterial spectrum, high activity, good pharmacokinetic property and further development potential.

Inventors

ZHANG XIAOYU
ZHANG HONG

Assignees

张小宇
张宏

Dates

Publication Date: 20260508
Application Date: 20240827

Claims (4)

1. An ifetroconazole derivative, wherein said derivative is: 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N-phenylacetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N-4-methoxyphenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (4-methylphenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (4-fluorophenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (4-chlorophenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (4-bromophenyl) acetamide; methyl 4- (2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene)) acetamido) benzoate; Ethyl 4- (2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene)) acetamido) benzoate; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (3-methoxyphenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (3-methylphenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (3-fluorophenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-methylene) -N- (3-chlorophenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N- (3-bromophenyl) acetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N-hydroxyacetamide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (2-hydroxyphenylmethylene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-methylene) -N' - (3-hydroxyphenylmethylene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-methylene) -N' - (4-hydroxyphenylmethylene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (2-methylbenzylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (3-methylbenzylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (4-methylbenzylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (2-bromobenzylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (3-bromobenzylidene) acethydrazide; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -N' - (4-bromobenzylidene) acethydrazide; methyl 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) acetate; Ethyl 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) acetate; phenyl 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) acetate; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -O- (4-methoxyphenyl) acetic acid ester; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -O- (4-methylphenyl) acetate; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -O- (4-fluorophenyl) acetate; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -O- (4-chlorophenyl) acetic acid ester; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) -O- (4-bromophenyl) acetic acid ester; selenium 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) - (Se-phenyl) acetate; Selenium 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) - (Se-methyl) acetate; selenium 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) piperidin-4-ylidene) - (Se- (4-trifluoromethoxy) phenyl) acetate; 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -N- (4-fluorophenyl) acetamide 2- (1- ((2 R,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -N- (4-chlorophenyl) acetamide 2- (1- ((2R, 3R) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -O- (4-methoxyphenyl) acetic acid ester 2- (1- ((2R, 3R) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -O- (4-methylphenyl) acetic acid ester 2- (1- ((2R, 3R) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -O- (4-fluorophenyl) acetic acid ester 2- (1- ((2R, 3R) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -O- (4-chlorophenyl) acetic acid ester 2- (1- ((2R, 3R) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) -O- (4-bromophenyl) acetic acid ester Selenium 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) - (Se-phenyl) acetate Selenium 2- (1- ((2 r,3 r) -3- (2, 4-difluorophenyl) -3-hydroxy-4- (1H-1, 2, 4-triazol-1-yl) -2-butyl) -4-piperidinyl) - (Se-methyl) acetate.
2. A medicament having antifungal effect, characterized by comprising the efonazole derivative according to claim 1.
3. The preparation method of the efonazole derivative according to claim 1, which is characterized in that the preparation method of the derivative comprises the following steps: Synthesis method 1 of target compound: N-Boc-4-piperidone (2) and diethyl (2-amino-2-oxo-ethyl) phosphonate (3) are used as starting materials, and a target compound A01 is obtained through Wittig-Horner reaction and Boc protecting group removal intermediate 2- (piperidine-4-subunit) acetamide (4), (4) and an efaconazole intermediate (1) through hydrocarbylation reaction; ; The structure of the efroconazole intermediate (1) is as follows: CA accession number 127000-90-2; Synthesis method 2 of target compound: N-Boc-4-piperidone (2) and 2-diethoxyphosphonoacetic acid ethyl ester (5) are used as starting materials, N-Boc-2- (piperidine-4-subunit) acetic acid (7) is obtained through Wittig-Horner reaction and ester hydrolysis reaction, amidation reaction is carried out on the N-Boc-2- (piperidine-4-subunit) acetic acid (7) and various substituted anilines under the catalysis of HATU-DIPEA to obtain an intermediate (8) or (9), and the intermediate (8) or (9) and the efaconazole intermediate (1) are subjected to hydrocarbylation reaction to obtain a target compound A02-A14; ; Synthesis method 3 of target compound: 2- (piperidine-4-subunit) ethyl acetate (10) and an efaconazole intermediate (1) are used as raw materials, A28 is obtained through alkylation reaction, A28 reacts with hydroxylamine hydrochloride or hydrazine hydrate to obtain a target compound A15 or A16, and the compound A16 reacts with various substituted benzaldehydes to form Schiff bases to obtain target compounds A17-A25; ; synthesis method 4 of target compound: The A28 prepared in the prior art is taken as a raw material, free acid A26 and free acid A26 are obtained through hydrolysis of lithium hydroxide, esterification reaction is carried out on the free acid A26 and various substituted phenols to obtain target compounds A29-A34, and the target compounds A26 and various alkyl diselenide or substituted phenyl diselenide are subjected to Se-acylation reaction under the catalysis of sodium borohydride in the presence of isobutyl chloroformate to obtain target compounds A35-A37; ; Synthesis method 5 of target compound: The preparation method comprises the steps of taking 2- (piperidine-4-yl) methyl acetate hydrochloride (12) as a starting material, carrying out alkylation reaction with an efaconazole intermediate (1) to obtain B05, hydrolyzing the B05 by lithium hydroxide to obtain free acid B04, and carrying out amidation reaction on the free acid B04 and various substituted anilines under the catalysis of HATU to obtain B02, B03, B04 and various substituted phenols are subjected to esterification reaction to prepare target compounds B6-B10; ; synthesis method 6 of target compound: Taking the B04 prepared above as a raw material, and carrying out Se-acylation reaction with various alkyl diselenide or substituted phenyl diselenide under the catalysis of sodium borohydride in the presence of isobutyl chloroformate to obtain target compounds B11-B13; 。
4. use of an efaconazole derivative according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of a fungal infection.

Description

Efluorconazole derivatives and antifungal activity thereof Technical Field The invention relates to the technical field of medicines, in particular to an epoxiconazole derivative with antifungal activity or pharmaceutically acceptable inorganic salt, organic salt, solvate or polymorph thereof. Background Mycoses are multiple and refractory disorders. In recent years, the incidence and death rate of fungal infection are all in an increasing trend year by year, but clinically used antifungal medicines are relatively deficient, and azole antifungal medicines are still preferred, and the antifungal medicines have certain curative effects, but have poor curative effects on deep fungi due to toxic and side effects, and particularly have the azole drug-resistant fungi in recent years, so that the clinical application of the antifungal medicines is limited. Therefore, the development of antifungal drugs with high efficiency, low toxicity and novel structure is still a very urgent task. Efaconazole (Efinaconazole) was co-developed by scientific pharmaceutical co-produced and Valeant, first approved by canadian department of health on 10, 2, 2013, then approved by the united states Food and Drug Administration (FDA) on 6, 2014, and approved by the japan medical instruments and devices (PMDA) on 7, 4 for the topical treatment of toenail mycosis caused by trichophyton rubrum and trichophyton mentagrophytes. Although the efucaconazole has better antibacterial effect in the aspect of treating superficial fungal infection, the efucaconazole still has the defects of poor water solubility, unsatisfactory pharmacokinetic property, only external use, single dosage form, narrow antibacterial spectrum and the like. Although there are few studies on derivatives of efroconazole which are structurally modified in the prior art, better antifungal effects and pharmacokinetic properties cannot be obtained. Disclosure of Invention In order to overcome the defects of the prior art, the invention is based on the molecular docking research result of a lead compound, namely, iferoconazole, and target enzyme (CYP 51), and modifies 4-methylenepiperidine in the structure, and the number of hydrogen bond acceptors and hydrogen bond donors of target molecules is increased by introducing amide, ester or selenate into the methylene or reducing the methylene into methyl and then introducing the amide, ester or selenate and other structures, so that more interactions between the target molecules and amino acid residues of the target enzyme are increased. Meanwhile, the water solubility of the epoxiconazole derivatives is improved by increasing the molecular polarity, so that a series of epoxiconazole derivatives are designed and obtained. The in vitro antifungal activity of the designed target compounds is tested by adopting a two-fold concentration dilution method, and the initial in vitro antifungal activity of a plurality of target compounds is found to be obviously better than that of a lead compound, namely, iferoconazole and other azole antifungal drugs (such as miconazole, fluconazole and the like) widely used clinically at present, and the compound has better water solubility, broad antibacterial spectrum, high activity, good pharmacokinetic property and further development potential. To achieve the above object, the present invention discloses the following technical matters An efroconazole derivative shown in a formula I or pharmaceutically acceptable inorganic salt, organic salt and solvate thereof: Wherein: Y=NH;O;Se H;OH;NH2;N＝CHAr;(CH2)nCH3 R1,R2＝H;CH3;CF3;OCH3;OCF3;C2H5;OC2H5;OH;NH2;F;Cl;Br;I;CO2H;CO2CH3;CO2C2H5;NO2;CN n=0~7。 Wherein the method comprises the steps of Is thatY is NH, O, se, preferably Y is NH and O group, R is substituted benzene ring, hydrogen atom, hydroxy and amino, preferably R is substituted ring; r 1,R2 is H atom, halogen, nitro, trifluoromethyl, alkyl and alkoxy, R 1,R2 can be the same or different, R 1,R2 is preferably H atom, halogen, alkyl and trifluoromethyl, R 1,R2 can be the same or different, R 1,R2 is preferably halogen and alkyl, and R 1,R2 can be the same or different. Preferred R 1,R2 is halogen and R 1,R2 may be the same or different. The invention further discloses a medicine with antifungal effect, which comprises an active ingredient of the efroconazole derivative shown in the formula I or pharmaceutically acceptable inorganic salt, organic salt, solvate or polymorph thereof, wherein each unit preparation amount of the medicine contains 10-500 mg of the efroconazole derivative shown in the formula I or pharmaceutically acceptable inorganic salt, organic salt, solvate or polymorph thereof. Preferably, each unit preparation of the medicine contains 50-300 mg of the efroconazole derivative shown in the formula I or pharmaceutically acceptable inorganic salt, organic salt, solvate or polymorph thereof. The invention further discloses a preparation method of an efroconazole derivative or pharmaceutic