CN111892573A - Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof - Google Patents
Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN111892573A CN111892573A CN202010872079.2A CN202010872079A CN111892573A CN 111892573 A CN111892573 A CN 111892573A CN 202010872079 A CN202010872079 A CN 202010872079A CN 111892573 A CN111892573 A CN 111892573A
- Authority
- CN
- China
- Prior art keywords
- formula
- heterocyclic compound
- aromatic heterocyclic
- compound
- hydrogen
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a sulfur aromatic heterocyclic compound shown as a formula I and an optical isomer thereof,
wherein, Y‑Is an anion; r1Is NR4R5Hydrogen, halogen, C1‑C4Alkyl radical, C1‑C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1‑C4Alkanoylamino, cyano, C1‑C4Alcoxyl acyl radical, C3‑C6Cycloalkyl or C1‑C4An alkylsulfonyl group; r4And R5Each independently selected from hydrogen or C1‑C4An alkyl group; r2And R3Each independently selected from hydrogen, halogen, C1‑C4Alkyl radical, C1‑C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1‑C4Alkanoylamino, cyano, C1‑C4Alcoxyl acyl radical, C3‑C6Cycloalkyl or C1‑C4An alkylsulfonyl group; the sulfur aromatic heterocyclic compound has good inhibition effect on various fungi such as saccharomycetes, candida albicans, cryptococcus neoformans, aspergillus fumigatus and the like.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a substituted sulfur aromatic heterocyclic compound, and a preparation method and application thereof.
Background
In recent years, with the large application of broad-spectrum antibiotics, the spread of AIDS, the increase of immunosuppressive agents caused by cancer chemotherapy and organ transplantation, the morbidity and mortality of clinical fungal infection are increased year by year, the proportion of drug-resistant bacteria is also remarkably increased, and more serious challenges are provided for the treatment of fungal infection. At present, the standard drugs clinically used for treating invasive fungal infection, namely amphotericin B, have high toxicity, weak bactericidal activity of azole drugs and serious drug resistance, and the clinical application of echinocandin drugs is limited due to short half-life and low oral bioavailability. On the other hand, the development of antifungal drugs has progressed slowly, and since 2006, no new antifungal drug has been approved for clinical use. Therefore, the development of new antifungal drugs is still of great significance.
The cell wall is an important structure of fungal cells, which can protect them from intracellular osmotic pressure, provide mechanical protection and maintain cell shape, and disruption of the cell wall structure can lead to plasma membrane disruption and cell lysis. In addition, the cell wall is also closely related to cell growth and division. Inhibiting the synthesis of cell wall components or destroying their structures can reach the aim of inhibiting and killing fungi. Glucan is an important component of fungal cell walls, echinocandin drugs, such as caspofungin, which target the fungal cell walls are used for treating clinical fungal infection at present, and the cell walls do not exist in mammalian cells, so that the development of new drugs using glucan as a target is always an important strategy for developing antifungal drugs.
Disclosure of Invention
In order to solve the problems of few antifungal drugs, drug resistance of fungi and the like in the prior art, the invention researches a novel compound with antifungal activity.
One technical scheme of the invention provides a sulfur aromatic heterocyclic compound shown as a formula I and an optical isomer thereof,
wherein the content of the first and second substances,
Y-is an anion;
R1is NR4R5Hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group;
R4and R5Each independently selected from hydrogen or C1-C4An alkyl group;
R2and R3Each independently selected from hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group.
In a further development, Y-Is tetrafluoroborate.
In a further development, R1Is NR4R5，R4And R5Are all C2An alkyl group.
In a further development, R2And R3Are all made ofAnd (3) hydrogen.
In a further improved scheme, the structure of the sulfur aromatic heterocyclic compound shown in the formula I is as follows:
interpretation of terms:
the term "anion" as used herein includes, but is not limited to, tetrafluoroborate, periodate, iodide, perchlorate, bromide, bicarbonate, permanganate, phosphate, and the like.
The term "halogen" as used herein includes, but is not limited to, fluorine, chlorine, bromine, and the like.
The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon radical, e.g. C1-C4An alkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and the like.
The term "alkoxy" as used herein refers to a group having the structure "W-O-", wherein W is an alkyl group, e.g., C1-C4Alkoxy, non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy and the like.
The term "alkanoylamino" as used herein refers to a group having the structure "W-C (O) NH-" wherein W is alkyl and said alkanoylamino may be C1-C4Alkanoylamino and the like, non-limiting examples of alkanoylamino include formylamino, acetylamino and the like.
The term "alkylsulfonyl" as used herein means having the meaning of "W-S (O)2- "where W is alkyl, the alkylsulfonyl group may be C1-C4Alkylsulfonyl and the like, non-limiting examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl and the like.
The term "alkoxyacyl" as used herein refers to a group having the structure "W-C (O) -", wherein W is an alkyl group and the alkoxyacyl group may be C1-C4Alkoxyacyl groups and the like, non-limiting examples of the alkoxyacyl group include methoxyacyl group, ethoxyacyl group and the like;
the term "cycloalkyl" as used herein refers to a saturated or partially saturated cyclic hydrocarbon group, and the number of carbon atoms constituting the cycloalkyl group may be 3 to 15, for example 3 to 6. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The invention also provides a preparation method of the sulfur aromatic heterocyclic compound shown as the formula I and an optical isomer thereof, wherein the preparation method comprises the following steps:
1) the compound 1 and sodium sulfide generate a compound 2 under the action of alkali;
2) carrying out oxidation reaction on the compound 2 to generate a compound 3;
3) reacting compound 3 with a grignard reagent to produce compound 4;
4) carrying out condensation reaction on the compound 4 and a compound 5 to generate a sulfur aromatic heterocyclic compound shown as a formula I;
the reaction equation is as follows:
the invention also provides a pharmaceutical composition, which comprises the sulfur aromatic heterocyclic compound shown as the formula I, an optical isomer thereof and a pharmaceutically acceptable carrier or excipient.
The prepared pharmaceutical composition can be administered orally, transdermally, intramuscularly, subcutaneously, etc.
When administered orally, the thio-aryl heterocyclic compound of formula one provided by the present invention can be made into any orally acceptable dosage form, including but not limited to tablets, capsules, and the like. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents for use in capsules typically include lactose and dried corn starch. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When applied topically to the skin, the thioaromatic heterocyclic compounds of formula one provided herein can be formulated in the form of suitable ointments or creams, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; creams carriers that may be used include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The sulfur heterocyclic compound shown in the formula I can also be used in the form of sterile injection preparations, including sterile injection water, oil suspension or sterile injection solution, and also can be in a freeze-dried form. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
The invention also provides a sulfur aromatic heterocyclic compound shown as the formula I and application of an optical isomer thereof in preparing antifungal medicaments, wherein the sulfur aromatic heterocyclic compound shown as the formula I has the following structure:
wherein the content of the first and second substances,
Y-is an anion;
R1is NR4R5Hydrogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group;
R4and R5Each independently selected from hydrogen or C1-C4An alkyl group;
R2and R3Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group.
In a further development, Y-Is tetrafluoroborate.
In a further improved scheme, the structure of the sulfur aromatic heterocyclic compound shown in the formula I is as follows:
the invention has the beneficial effects that: the sulfur aromatic heterocyclic compound shown in the formula I has a very good inhibition effect on various fungi such as saccharomycetes, candida albicans, cryptococcus neoformans, aspergillus fumigatus and the like.
Detailed Description
Example 1 Synthesis of (E) -4- (4- (dimethylamino) styryl) -2, 6-diphenylthiopyridinium tetrafluoroborate (Compound G3)
1) Synthesis of 2, 6-diphenyltetrahydro-4H-thiopyran-4-one (Compound G3-1)
In a 500mL round bottom flask, (1E, 4E) -1, 5-diphenyl penta-1, 4-dien-3-one (4.68g, 20mmol) and methyl trioctyl ammonium chloride (0.85g, 2.1mmol) were added to methyl tert-butyl ether (210mL) and 1.2M dipotassium hydrogen phosphate (70mL), followed by sodium sulfide (3.3g, 42 mmol). The mixture was then stirred at 55 ℃ overnight, and after completion of the reaction was checked by LCMS, 100mL of cold 1N hydrochloric acid and 100mL of saturated ammonium chloride solution were slowly added to the reaction after cooling to room temperature. Then, the mixture was extracted three times with 100mL of methyl t-butyl ether, and the organic phases were combined and washed three times with 200mL of saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating, mixing a sample with silica gel, separating by column chromatography, and mixing petroleum ether: ethyl acetate eluted as a mobile phase to give the intermediate compound 2, 6-diphenyltetrahydro-4H-thiopyran-4-one as a yellow solid, 4.4g, yield: 82.1 percent.
LCMS:268.9[M+H+].
1H NMR(400MHz,CDCl3)：7.42-7.29(m,10H),4.34-4.30(m,2H),3.09-2.90(m,4H).
2) Synthesis of 2, 6-diphenyl-4H-thiopyran-4-one (Compound G3-2)
In a 250mL round bottom flask, 2, 6-diphenyltetrahydro-4H-thiopyran-4-one (4.3g, 16mmol) and DDQ (2, 3-dichloro-5, 6-dicyan-p-benzoquinone, 9.31g, 41mmol) were added to toluene (100mL), and then heated to 100 ℃ for 2 hours. After completion of the reaction by LCMS, cool to room temperature and add ethyl acetate (200 mL). The mixture was washed once with 200mL of a saturated aqueous sodium bicarbonate solution and 200mL of a saturated brine, and dried over anhydrous sodium sulfate. Filtering and concentrating, mixing a sample with silica gel, separating by column chromatography, and mixing petroleum ether: ethyl acetate eluted as a mobile phase to give the intermediate compound 2, 6-diphenyl-4H-thiopyran-4-one as a brown solid, 3.5g, yield: 82.9 percent.
LCMS：265[M+H+].
1H NMR(400MHz,CDCl3)：7.69-7.65(m,4H),7.55-7.50(m,6H),7.34(s,2H).
3) Synthesis of 4-methyl-2, 6-diphenylthiopyridinium tetrafluoroborate (Compound G3-3)
In a dry 100mL three-necked round bottom flask, 2, 6-diphenyl-4H-thiopyran-4-one (1g, 3.8mmol) was added to anhydrous tetrahydrofuran (20mL), cooled to 0 deg.C, 3N MeMgBr (3.8mL, 11.3mmol) was slowly added, and then reacted at room temperature for 3 hours. After completion of the reaction by LCMS, the reaction was poured into 10% fluoroboric acid (40mL), and then stirred for 2 hours. The emerging solid was filtered, washed with water and dried under vacuum to give the intermediate compoundThe substance 4-methyl-2, 6-diphenylthiopyridinium tetrafluoroborate was a brown solid 1.3g, yield: 97.7 percent. LCMS: 263[ M ]+]。
4) Synthesis of (E) -4- (4- (dimethylamino) styryl) -2, 6-diphenylthiopyridinium tetrafluoroborate (Compound G3)
In a 100mL round-bottom flask, 4-methyl-2, 6-diphenylthiopyridinium tetrafluoroborate (1.6g, 4.56mmol) and 4- (diethylamino) benzaldehyde (0.97g, 5.47mmol) were added to acetic anhydride (20mL), followed by heating to 120 ℃ for 2 hours. After completion of the reaction by LCMS, cool to room temperature and add methyl tert-butyl ether (50 mL). The solid which appeared was filtered, washed with a mixed solution of ethanol and methyl tert-butyl ether (1/2) (20mL) and dried in vacuo to give the product (E) -4- (4- (dimethylamino) styryl) -2, 6-diphenylthiopyridinium tetrafluoroborate as a green solid in 1.3g, yield: 56 percent.
LCMS：421.8[M+]。
1H NMR(400MHz,DMSO)：8.71-8.63(m,3H),8.05(d,J＝6Hz,4H),7.81(d,J＝7.6Hz,2H),7.73-7.70(m,6H),7.56(d,J＝14.8Hz,1H),7.00(d,J＝8.8Hz,2H),3.59(q,J＝6.8Hz,4H),1.20(t,J＝6.8Hz,6H).
Experimental example 1 evaluation of antifungal Activity
The Minimum Inhibitory Concentrations (MICs) of compound G3 against yeasts BY4741, Candida albicans ATCC10231, Cryptococcus neoformans ATCC208821 and Aspergillus fumigatus ATCC204305 were tested according to the method M27-A recommended BY the American national Committee for standardization of clinical trials.
Inoculating the frozen yeast to YPD solid culture medium, inoculating to primary culture medium, culturing at 35 deg.C for 24 hr, inoculating Candida albicans and Cryptococcus neoformans to agar culture medium, inoculating to primary culture medium, and culturing at 35 deg.C for 24 hr and 48 hr, respectively. The three strains were adjusted to 1-5X 106cfu/mL with physiological saline and diluted 1000-fold with RPMI 1640. Diluting the compound from 256 mu g/mL to 0.0625 mu g/mL by RPMI, adding 100 mu L of bacterial liquid and compound liquid into a 96-well plate, making two multiple wells simultaneously, placing the plate at 35 ℃, observing for 24h, 48h and 72h respectively, and judging the concentration at which no thallus growth is seen by naked eyes as MIC; aspergillus fumigatus was inoculated in PDA medium, cultured at 30 ℃ for 7-10 days after one transfer, and then eluted with physiological saline to 0.4-5X 106cfu/mL, diluted 50-fold with RPMI 1640. The compound is diluted from 256 mug/mL to 0.0625 mug/mL by RPMI, 100 mug liquid and compound liquid are respectively added into a 96-well plate, two multiple wells are simultaneously made, the growth condition of the bacteria is observed, the concentration at which the bacteria can not grow by naked eyes is judged as MIC, and the result is shown in Table 1.
TABLE 1 minimal inhibitory Activity of the Compounds on fungi (MIC, μ g/mL)
As can be seen from table 1, the compound G3 provided by the present invention has better bacteriostatic effect on yeast, candida albicans, cryptococcus neoformans and aspergillus fumigatus than the positive control drug fluconazole, and has equivalent curative effect with the positive control drug Amb (amphotericin B).
Claims (10)
1. A sulfur-aromatic heterocyclic compound shown in the formula I,
wherein the content of the first and second substances,
Y-is an anion;
R1is NR4R5Hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group;
R4and R5Each independently selected from hydrogen or C1-C4An alkyl group;
R2and R3Each independently selected from hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoyl radicalAmino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group.
2. A thio-aromatic heterocyclic compound of formula (la) as claimed in claim 1, wherein Y is-Is tetrafluoroborate.
3. A thio-aromatic heterocyclic compound of formula I according to claim 1 wherein R is1Is NR4R5，R4And R5Are all C2An alkyl group.
4. A thio-aromatic heterocyclic compound of formula I according to claim 3 wherein R is2And R3Are all hydrogen.
5. The thio-aromatic heterocyclic compound of formula I as claimed in claim 4, wherein the thio-aromatic heterocyclic compound of formula I has the following structure:
6. a preparation method of a sulfur aromatic heterocyclic compound shown as the formula I is characterized by comprising the following steps:
1) the compound 1 and sodium sulfide generate a compound 2 under the action of alkali;
2) carrying out oxidation reaction on the compound 2 to generate a compound 3;
3) reacting compound 3 with a grignard reagent to produce compound 4;
4) carrying out condensation reaction on the compound 4 and a compound 5 to generate a sulfur aromatic heterocyclic compound shown as a formula I;
the reaction equation is as follows:
7. a pharmaceutical composition comprising a thiaaromatic heterocyclic compound of formula one as described in any of claims 1-5 and a pharmaceutically acceptable carrier or excipient.
8. The application of the sulfur-aromatic heterocyclic compound shown as the formula I in preparing antifungal medicines is characterized in that the structure of the sulfur-aromatic heterocyclic compound shown as the formula I is as follows:
wherein the content of the first and second substances,
Y-is an anion;
R1is NR4R5Hydrogen, C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group;
R4and R5Each independently selected from hydrogen or C1-C4An alkyl group;
R2and R3Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Alkoxy, trifluoromethoxy, trifluoromethyl, nitro, hydroxy, C1-C4Alkanoylamino, cyano, C1-C4Alcoxyl acyl radical, C3-C6Cycloalkyl or C1-C4An alkylsulfonyl group.
9. Use according to claim 8, wherein Y is-Is tetrafluoroborate.
10. The use of claim 8, wherein the thiaaromatic heterocyclic compound of formula one has the following structure:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010872079.2A CN111892573B (en) | 2020-08-26 | 2020-08-26 | Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010872079.2A CN111892573B (en) | 2020-08-26 | 2020-08-26 | Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111892573A true CN111892573A (en) | 2020-11-06 |
| CN111892573B CN111892573B (en) | 2021-05-11 |
Family
ID=73225640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010872079.2A Active CN111892573B (en) | 2020-08-26 | 2020-08-26 | Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111892573B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07250680A (en) * | 1994-03-16 | 1995-10-03 | Canon Inc | Method for inducing mutation |
-
2020
- 2020-08-26 CN CN202010872079.2A patent/CN111892573B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07250680A (en) * | 1994-03-16 | 1995-10-03 | Canon Inc | Method for inducing mutation |
Non-Patent Citations (3)
| Title |
|---|
| CAS CLIENT SERVICES: "STN Files", 《REGISTRY DATABASE》 * |
| I. N. KLOCHKOVA: "SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF COMPOUNDS CONTAINING BOTH THIOPYRAN (THIAPYRYLIUM) AND PYRROLIDONE CYCLES", 《PHARMACEUTICAL CHEMISTRY JOURNAL》 * |
| N.I.YASTREBOVA: "Ion Associate Formation of Some Chalcogen Pyrylium Cyanine Dyes with Anionic Surfactants and Their Use in Spectrophotometric and Test Methods of Analysis", 《JOURNAL OF ANALYTICAL CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111892573B (en) | 2021-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101463707B1 (en) | Topical antifungal agent | |
| Xu et al. | Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections | |
| WO2011006061A1 (en) | Diyne compositions | |
| Xu et al. | Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51 | |
| JPS6330308B2 (en) | ||
| CN111892573B (en) | Substituted sulfur aromatic heterocyclic compound and preparation method and application thereof | |
| CA2664915A1 (en) | Pharmaceutical composition comprising phenylamidine derivative and method of using the pharmaceutical composition in combination with antifungal agent | |
| FI85701B (en) | FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA TRIAZOLDERIVAT. | |
| KR102517368B1 (en) | Salts of novel imidazole derivatives with antifungal activity and uses thereof | |
| IE56611B1 (en) | Triazole antifungal agents | |
| JPH02243673A (en) | Cyclopropyl-substituted azolymethylcarbinol derivative, preparation thereof,and use thereof as medicine | |
| EP0427242B1 (en) | Azole derivatives and antifungal drugs containing the same as an active component | |
| FI89595C (en) | FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE 2- (THIOALKYLAMINO) EECL-1H-IMIDAZOLDERIVAT | |
| KR100344853B1 (en) | 6,7-Substituted-5,8-quinolinedione derivatives as an antifungal agent | |
| US5183824A (en) | Azole derivatives and antifungal drugs containing the same as an active component | |
| EP0102727B1 (en) | Chloropyridyl antifungal agents | |
| US11292776B2 (en) | Small molecule inhibitors of fungal hyphae and biofilm formation | |
| BG108032A (en) | Azole compounds as anti-fungals agents | |
| CN108440538B (en) | Novel pyrroloimidazole derivative and preparation method and application thereof | |
| JPS6346073B2 (en) | ||
| CN114736164A (en) | 1, 2, 4-triazole benzophenone compound or pharmaceutically acceptable salt thereof and application thereof | |
| JPS6345676B2 (en) | ||
| CN102503954B (en) | Imidazole derivative and preparation method and application thereof | |
| CN115028585A (en) | Arylalkanazole derivatives and use thereof | |
| JPS63215670A (en) | Imidazole derivative, manufacture and pharmaceutical composition |
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 |