CN116041322B - N-substituted fluorine-containing piperidine derivative, preparation method and application thereof - Google Patents
N-substituted fluorine-containing piperidine derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN116041322B CN116041322B CN202210162822.4A CN202210162822A CN116041322B CN 116041322 B CN116041322 B CN 116041322B CN 202210162822 A CN202210162822 A CN 202210162822A CN 116041322 B CN116041322 B CN 116041322B
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- pharmaceutically acceptable
- application
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
Abstract
The application provides a compound shown as a formula (I) or (II) or a stereoisomer or a pharmaceutically acceptable salt thereof,
Description
Technical Field
The application relates to the field of drug synthesis. More particularly, the application relates to a preparation method and application of N-substituted fluorine-containing piperidine derivatives, and the compounds can be used as antifungal medicines.
Background
In recent years, with the widespread use of broad-spectrum antibiotics, antitumor drugs and immunosuppressants, the prevalence of organ transplantation surgery, radioactive quality and the prevalence of some immunodeficiency diseases (e.g., aids), the incidence of deep fungal infections caused by opportunistic pathogens such as candida albicans, cryptococcus and aspergillus has been greatly increased. Deep fungal infection has now become one of the major infectious diseases clinically, severely threatening the life and health of the patient. There are relatively few antifungal agents currently available on the market for the treatment of deep fungal infections, but these agents have inhibitory effects on only a small fraction of fungi, and there is a growing problem of fungal resistance. Therefore, the development of broad-spectrum, low-toxicity, highly effective and resistant antifungal agents has been a focus of attention of pharmaceutical chemists.
Currently, more anti-deep fungus drugs are clinically used, mainly including triazole drugs, and representative drugs include fluconazole (GB 2099818), itraconazole (US 4267179), voriconazole (EP 440372), posaconazole (WO 9517407) and the like. The action mechanism of the medicine is to inhibit lanosterol-14 alpha-demethylase (CYP 51) in the biological synthesis process of the fungal ergosterol, so that lanosterol is accumulated, thereby destroying fungal cell membranes and playing a bacteriostatic role. However, fluconazole has a narrow antimicrobial spectrum and has increasingly serious fungal resistance problems. Even though itraconazole, voriconazole and posaconazole have an enlarged antibacterial spectrum, the metabolism and physicochemical properties of these drugs are not ideal, resulting in low bioavailability. Therefore, the search for antifungal drugs with broad spectrum, low toxicity, high efficiency and drug resistance has important research value and practical significance.
Piperidine is a very important class of heterocyclic compounds for drug molecules and is widely used in the backbones of many drugs on the market and in research. Thus, the development of piperidine derivatives and methods for their preparation can provide more options for finding broad-spectrum, low-toxicity, highly potent and resistant antifungal agents.
Disclosure of Invention
Aiming at the problems of antibacterial activity, drug resistance, metabolism and physicochemical properties of triazole drugs, the application provides a series of preparation methods of N-substituted fluorine-containing piperidine derivatives and application thereof in antifungal aspect based on N-alkylation of fluorine-containing piperidine derivatives and triazole drug frameworks.
It is an object of the present application to provide a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein R is selected from H, F, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl, said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl groups are optionally substituted with halogen;
x, Y is independently selected from H or F;
R 1 selected from F or C substituted by F 1 -C 6 Alkyl or C 2 -C 6 Alkenyl groups;
n is selected from 0, 1,2,3, 4, 5 or 6.
In some embodiments, when n is selected from 0, at least one of X, Y is selected from F.
The application aims at providing a compound shown as a formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein R is selected from H, F, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl, said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl groups are optionally substituted with halogen;
represents a single bond or a double bond;
R 1 selected from F or C substituted by F 1 -C 6 Alkyl or C 2 -C 6 Alkenyl groups;
n is selected from 1,2,3, 4, 5 or 6.
In some embodiments, R is selected from H, F, C 1 -C 6 Alkyl or C 2 -C 6 Alkenyl group, the C 1 -C 6 Alkyl or C 2 -C 6 Alkenyl groups are optionally substituted with substituted halogen.
In some embodiments, R 1 Selected from F or C substituted by F 1 -C 6 An alkyl group.
In some embodiments, R 1 Selected from F or CF 3 。
In some embodiments, n is selected from 1,2,3, 4, 5, or 6.
In some embodiments, n is selected from 1,2,3, or 4.
In some embodiments, the compound of formula (II) or stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II-1) or stereoisomers or pharmaceutically acceptable salts thereof,
wherein R is 1 R, n are as defined above.
In some embodiments, the compound of formula (II) or stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II-2) or stereoisomers or pharmaceutically acceptable salts thereof,
wherein R is 1 R, n are as defined above.
In some embodiments, the pharmaceutically acceptable salt is selected from any one of salts formed from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, tartaric acid, citric acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid; preferably, the pharmaceutically acceptable salt is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.
In some embodiments, the compound of formula (I) or formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or stereoisomers or pharmaceutically acceptable salts thereof,
further, the application also provides a pharmaceutical composition, which comprises a compound shown in a formula (I) or a formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
Furthermore, the application also provides application of the compound shown in the formula (I) or the formula (II) or the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in medicines for treating fungal infectious diseases.
Another object of the present application is to provide a process for preparing a compound of formula (i) or formula (ii) or a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises:
or alternatively
Or alternatively
Or alternatively
Wherein R is 1 R, X, Y, n are as defined above.
In some embodiments, the base is an inorganic base or an organic base, wherein the inorganic base is selected from any one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or potassium bicarbonate; the organic base is selected from any one or more of triethylamine, diisopropylethylamine, N-methylmorpholine, 1, 8-diazabicyclo undec-7-ene (DBU), triethylenediamine (DABCO), pyridine or substituted pyridine; the solvent is selected from any one of tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide or N, N-dimethylformamide; the additive is selected from potassium iodide or lithium iodide.
The N-substituted fluorine-containing piperidine derivative provided by the application is used as an antifungal drug, has stronger antifungal activity than the existing drug, and meanwhile, the introduction of fluorine atoms enables the compound shown in the general formula (I) or the general formula (II) to have better cell or skin penetrability, so that the N-substituted fluorine-containing piperidine derivative has better treatment effect on deep fungal infectious diseases. Due to the uniqueness of fluorine atoms, the metabolic stability of the drug can be improved, the fat solubility of the drug can be improved, the penetrating power of the drug to cell membranes can be increased, the acid-base property of related functional groups can be regulated, and the binding degree of drug molecules and targets can be improved after the fluorine atoms are introduced.
Definition and description of terms
Unless otherwise indicated, the terms used in the present application have the following meanings, and the groups and term definitions recited in the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may be deuterium and a variant of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl group"optionally" substituted with halogen means that the ethyl group may be unsubstituted (CH 2 CH 3 ) Monosubstituted (CH) 2 CH 2 F、CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F、CH 2 CHF 2 、CHFCH 2 Cl、CH 2 CHCl 2 Etc.) or fully substituted (CF) 2 CF 3 、CF 2 CCl 3 、CCl 2 CCl 3 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "alkyl" refers to a compound of the formula C n H 2n+1 The alkyl group may be linear or branched. The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1,2,3, 4, 5 or 6 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl and the like.
The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, straight or branched chain, and having at least one double bond. The term "C 2 -C 6 Alkenyl "is understood to mean a straight-chain or branched unsaturated hydrocarbon radical which contains one or more double bonds and has 2,3, 4, 5 or 6 carbon atoms, more preferably" C " 2 -C 4 Alkenyl ", more preferably C 2 Or C 3 Alkenyl groups. It will be appreciated that where the alkenyl group comprises more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, isopropenylEtc.
The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
The pharmaceutical composition of the application is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions of the application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula I described herein, the daily dosage is from 0.01 to 200mg/kg body weight, either alone or in divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
Detailed Description
The above-described aspects of the present application will be described in further detail with reference to the following embodiments. The application is not limited to these specific embodiments only. All techniques implemented based on the above description of the application are within the scope of the application.
The raw materials used in the preparation process of the compound are not specially marked, and are all the prior art. The compound of the present application can be produced by a method, but the conditions of the method, such as a solvent, a base, the amount of the compound used, a reaction temperature, a reaction time, etc., are not limited to the following description.
Example 1 Compounds (3) and (4)
Compound (1) (20.00 g,79.61mmol,1.05 eq.) compound (2) (11.50 g,75.85mmol,1.0 eq.) lithium iodide (10.15 g,75.84mmol,1.0 eq.) and potassium carbonate (12.58 g,91.03mmol,1.2 eq.) are added sequentially to 250mL dry acetonitrile (250 mL) and the resulting mixture heated to 130 ℃ and reacted at this temperature for 50 hours. Cooled to room temperature, diluted with 1L of water, extracted with ethyl acetate (3X 350 mL), and the organic phases were combined, washed successively with deionized water (3X 150 mL), saturated brine (1X 150 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography, and the obtained product was slurried with petroleum ether (1X 50 mL), and filtered to obtain a white solid, which was resolved by chiral column to obtain Compound 3 and Compound 4 (total 3.29g,11% yield).
1 H NMR(400MHz,CDCl 3 )δ8.28(s，1H)，7.68(s，1H)，7.35–7.28(m，1H)，7.15–7.08(m，1H)，6.94–6.89(m，1H)，5.54(s，1H)，5.14–4.76(m，5H)，3.37–3.19(m，2H)，2.98–2.27(m，5H)，0.75(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–105.9，–112.3，–186.6。
1 H NMR(400MHz,CDCl 3 )δ8.29(s，1H)，7.65(s，1H)，7.33–7.29(m，1H)，7.13–7.06(m，1H)，6.92–6.87(m，1H)，5.55(s，1H)，5.14–4.75(m，5H)，3.35–3.16(m，2H)，2.74–2.28(m，5H)，0.72(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–106.2，–112.4，–186.3。
EXAMPLE 3 Compound (5)
The preparation was the same as in example 1 except that compound (2) was replaced with 4- (difluoromethylene) piperidine hydrochloride to give product (5):
1 H NMR(400MHz,CDCl 3 )δ7.99(s，1H)，7.80(s，1H)，7.52–7.46(m，1H)，6.82–6.72(m，2H)，4.92–4.82(m，3H)，2.97–2.78(m，2H)，2.38–2.17(m，3H)，1.91–1.83(m，4H)，0.94(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–96.5，–105.9，–112.1。
EXAMPLE 4 Compound (6)
The preparation method was the same as in example 1 except that compound (2) was replaced with 1,2,3, 6-tetrahydro-4- (trifluoromethyl) pyridine to prepare product (6):
1 H NMR(400MHz,CDCl 3 )δ8.27(s，1H)，7.69(s，1H)，7.58–7.45(m，1H)，6.82–6.72(m，2H)，6.33–6.30(m，1H)，6.00–5.85(m,1H)，5.18–4.87(m，2H)，3.45–3.12(m，3H)，2.86–2.51(m，4H)，0.97(t，J＝7.2Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–67.1，–105.9，–112.3。
EXAMPLE 5 Compound (7)
The preparation method is the same as in example 1, except that compound (2) is replaced with 1,2,3, 6-tetrahydro-4-fluoropyridine to prepare product (7):
1 H NMR(400MHz,CDCl 3 )δ8.24(s，1H)，7.68(s，1H)，7.56–7.41(m，1H)，6.80–6.70(m，2H)，6.34–6.30(m，1H)，5.98–5.82(m，1H)，4.82–4.59(m，2H)，3.46–3.12(m，5H)，2.56–2.27(m，2H)，0.97(t，J＝7.2Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–106.0，–112.1，–135.2。
EXAMPLE 6 Compound (8)
The preparation method is the same as in example 1, except that compound (2) is replaced with 3-fluoropyridine to prepare product (8):
1 H NMR(400MHz,CDCl 3 )δ8.00(s，1H)，7.70(s，1H)，7.58–7.45(m，1H)，6.80–6.74(m，2H)，4.94–4.60(m，4H)，2.86–2.16(m，5H)，1.52–1.22(m，4H)，0.94(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–105.9，–112.3，–186.0。
EXAMPLE 7 Compound (9)
The preparation method is the same as in example 1, except that compound (2) is replaced with 4-fluoropyridine hydrochloride to prepare product (9):
1 H NMR(400MHz,CDCl 3 )δ8.00(s，1H)，7.72(s，1H)，7.55–7.49(m，1H)，6.80–6.72(m，2H)，5.45–4.84(m，4H)，2.98–2.18(m，5H)，2.01–1.77(m，4H)，0.92(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–106.0，–112.2，–175.3。
EXAMPLE 8 Compound (10)
The preparation method is the same as in example 1, except that compound (2) is replaced with 4, 4-difluoropyridine hydrochloride to prepare product (10):
1 H NMR(400MHz,CDCl 3 )δ7.93(s，1H)，7.80(s，1H)，7.48–7.44(m，1H)，6.80–6.70(m，2H)，5.35–4.88(m，3H)，3.16–2.88(m，3H)，2.52–2.38(m，2H)，2.06–1.99(m，4H)，0.93(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–100.5，–106.0，–112.2。
EXAMPLE 9 Compound (11)
The preparation method is the same as in example 1, except that compound (2) is replaced with 3, 3-difluoropyridine hydrochloride to prepare product (11):
1 H NMR(400MHz,CDCl 3 )δ8.26(s，1H)，7.67(s，1H)，7.37–7.30(m，1H)，7.18–7.10(m，1H)，6.98–6.87(m，1H)，5.61(s,1H)，4.82–4.78(m，2H)，5.44(d，J＝19.2Hz，1H)，3.48–3.30(m，3H)，2.64–2.54(m，2H)，1.99–1.80(m，2H)，1.58–1.52(m，2H)，0.77(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–105.9，–110.8，–112.3。
EXAMPLE 10 Synthesis of Compound (12)
The preparation was the same as in example 1 except that compound (2) was replaced with 4- (trifluoromethyl) pyridine hydrochloride to prepare product (12):
1 H NMR(400MHz,CDCl 3 )δ7.99(s，1H)，7.80(s，1H)，7.52–7.48(m，1H)，6.82–6.72(m，2H)，4.90–4.80(m，3H)，3.00–2.93(m，2H)，2.65–2.58(m，2H)，2.38–2.24(m，1H)，1.91–1.83(m，4H)，0.97(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–73.3，–106.1，–112.3。
EXAMPLE 11 Compound (13)
/>
The preparation method is the same as in example 1, except that compound (2) is replaced with 3, 3-difluoro-4-methylenepiperidine hydrochloride to prepare product (13):
1 H NMR(400MHz,CDCl 3 )δ8.22(s，1H)，7.67(s，1H)，7.31–7.25(m，1H)，7.12–7.07(m，1H)，6.93–6.88(m，1H)，5.57(s，1H)，5.29(s,1H)，5.16(m，1H)，4.86–4.78(m，2H)，3.35–3.24(m，2H)，2.97–2.94(m，1H)，2.81–2.75(m，1H)，2.57–2.45(m，3H)，0.73(t，J＝6.8Hz，3H)； 19 F NMR(376MHz,CDCl 3 )δ–94.6，–109.9，–112.2。
experimental example 1 biological Activity test
The N-substituted fluorine-containing piperidine derivatives synthesized by the application have antibacterial activity, and the following evaluation and test methods for the antifungal activity are as follows: minimum Inhibitory Concentration (MIC)
1. Materials and methods
(1) Experimental strains
Candida albicans (ATCC 10231); trichophyton rubrum (ATCCYA-4438); trichophyton mentagrophytes (ATCCYA-4439)
(2) Experimental method
i) The concentration of the candida albicans strain to be tested is adjusted to be 2-3 multiplied by 10 by using an RPMI1640 culture medium 3 The spore concentration of cfu/mL, trichophyton mentagrophytes and trichophyton rubrum is adjusted to 2000-6000 spores/mL;
ii) adding RPMI1640 medium containing the experimental strain to a 96-well plate; the compound to be tested is set into different concentration gradients by adopting a 2-time dilution method, is added into bacterial liquid of a 96-well plate, and is selected as a reference by Voriconazole (Voriconazole);
iii) 96-well plates were incubated at 35 ℃ + -2deg.C for 24 hours (Candida albicans) or 96 hours (Trichophyton mentagrophytes and Trichophyton rubrum) in incubator and three replicates were performed for each compound.
iv) after 24 hours of incubation of candida albicans, the lowest drug concentration that inhibits cell growth by 50% compared to the growth control is the MIC value of the drug by visual inspection of the test plate. After 96 hours of culture of Trichophyton mentagrophytes, the lowest drug concentration that inhibited cell growth by 80% compared to the growth control was the MIC value for the drug by visual inspection of the test plate. After 96 hours of trichophyton rubrum incubation, the test plate was visually inspected and the lowest drug concentration that inhibited cell growth by 80% compared to the growth control was the MIC value of the drug.
2. Experimental results
The results of in vitro bacteriostasis experiments are shown in Table 1
TABLE 1 minimum in vitro antifungal concentration values (ug/mL) for compounds of the application
/>
(Candida albicans, MIC) 50 ug/mL; trichophyton mentagrophytes, MIC 80 ug/mL; trichophyton rubrum, MIC 80 ，ug/mL)
The experimental results show that most of the N-substituted fluorine-containing piperidine derivatives synthesized by the application have better antibacterial activity, and the antibacterial activity in vitro is obviously stronger than that of voriconazole.
In a word, the N-substituted fluorine-containing piperidine derivative prepared by the application has better inhibition activity on candida albicans, trichophyton mentagrophytes and trichophyton rubrum. Thus, the N-substituted haloperidol derivatives of the application can be used for the preparation of a medicament for the treatment of fungal infectious diseases.
While the present application has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the application. Many modifications and alternatives to the present application will be apparent to those of skill in the art upon reading the foregoing description. The scope of the application should therefore be determined by the following claims.
Claims (4)
1. A compound of the structure or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:
or (b)。
2. The compound as set forth in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, tartaric acid, citric acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; preferably, the pharmaceutically acceptable salt is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.
3. A pharmaceutical composition characterized by: the pharmaceutical composition comprises the compound of any one of claims 1 or 2 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
4. Use of a compound as set forth in any one of claims 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as set forth in claim 3, for the manufacture of a medicament for the treatment of an infectious disease of a fungus selected from candida albicans or trichophyton mentagrophytes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210162822.4A CN116041322B (en) | 2022-02-22 | 2022-02-22 | N-substituted fluorine-containing piperidine derivative, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210162822.4A CN116041322B (en) | 2022-02-22 | 2022-02-22 | N-substituted fluorine-containing piperidine derivative, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116041322A CN116041322A (en) | 2023-05-02 |
| CN116041322B true CN116041322B (en) | 2023-10-10 |
Family
ID=86112047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210162822.4A Active CN116041322B (en) | 2022-02-22 | 2022-02-22 | N-substituted fluorine-containing piperidine derivative, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116041322B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810534A (en) * | 2015-11-30 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | Chinese mugwort Fluconazole crystal formation and preparation method thereof |
-
2022
- 2022-02-22 CN CN202210162822.4A patent/CN116041322B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810534A (en) * | 2015-11-30 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | Chinese mugwort Fluconazole crystal formation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Hironobu OGURA等.Synthesis and Antifungal Activities of (2R, 3R)-2-Aryl-1-azolyl-3-(substituted amino)-2-butanol Derivatives as Topical Antifungal Agents.《Chemical and Pharmaceutical Bulletin》.1999,第47卷(第10期),1417-1425. * |
| Synthesis and Antifungal Activities of (2R, 3R)-2-Aryl-1-azolyl-3-(substituted amino)-2-butanol Derivatives as Topical Antifungal Agents;Hironobu OGURA等;《Chemical and Pharmaceutical Bulletin》;第47卷(第10期);1417-1425 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116041322A (en) | 2023-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2609803T3 (en) | New antifungal triazole derivatives | |
| US20100234599A1 (en) | Method for preparing acid addition salts of polyacidic basic compounds | |
| JP6752283B2 (en) | EGFR kinase inhibitor and its production method and use | |
| JP5268902B2 (en) | Salt of pyrrolopyrimidinone derivative and process for producing the same | |
| EP3022209B1 (en) | Dolutegravir potassium salt | |
| EP3430004B1 (en) | Solid state forms of nilotinib salts | |
| EP2455368A1 (en) | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof | |
| EP2626355B1 (en) | Process for the preparation of nilotinib hydrochloride | |
| AU2018234306B2 (en) | Salts of antiviral phosphonate analogues and process for preparation thereof | |
| CN116041322B (en) | N-substituted fluorine-containing piperidine derivative, preparation method and application thereof | |
| CN109796455B (en) | Salt of aminopyrane derivative, crystal form of salt, preparation method and application of salt | |
| CN110950845B (en) | Formylacetamide azole derivative and application thereof | |
| TW202227445A (en) | Use of inhibiting genetically defective hiv virus | |
| CN109485607B (en) | Beta-azole-phenyl ketone derivative and application thereof | |
| WO2017004537A1 (en) | (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate | |
| JP2022517396A (en) | EGFR inhibitor salt, crystalline form and method for producing it | |
| US11884627B2 (en) | Compounds and compositions for treating conditions associated with LPA receptor activity | |
| CN114634453B (en) | Quinazoline derivative preparation method and application thereof | |
| BRPI0709709A2 (en) | compound, pharmaceutical composition, method of treating cell B cancer or malignancies, use of a compound, and process for preparing a compound | |
| CN114105753A (en) | Fisetin derivative and application thereof in preparation of anti-inflammatory drugs | |
| CN114426535A (en) | N-substituted fluorine-containing pyrrolidine derivative, preparation method and application thereof | |
| JPS63119442A (en) | Amine compound | |
| CN115477637A (en) | Application of 2, 4-disubstituted benzimidazole compound in tumor resistance | |
| CN112010820A (en) | Tricyclic derivative containing benzamide and application thereof in antitumor drugs | |
| CN115368354A (en) | Pharmaceutical salts of ATX inhibitors, compositions and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |