CN115215850A - Tetrazole alcohol compound, preparation method and antifungal drug - Google Patents
Tetrazole alcohol compound, preparation method and antifungal drug Download PDFInfo
- Publication number
- CN115215850A CN115215850A CN202110416875.XA CN202110416875A CN115215850A CN 115215850 A CN115215850 A CN 115215850A CN 202110416875 A CN202110416875 A CN 202110416875A CN 115215850 A CN115215850 A CN 115215850A
- Authority
- CN
- China
- Prior art keywords
- difluorophenyl
- tetrazol
- butan
- isoxazol
- compound
- 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.)
- Pending
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- -1 Tetrazole alcohol compound Chemical class 0.000 title claims abstract description 128
- 239000003429 antifungal agent Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 241000222122 Candida albicans Species 0.000 claims abstract description 8
- 229940095731 candida albicans Drugs 0.000 claims abstract description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 229940121375 antifungal agent Drugs 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 241000233866 Fungi Species 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 201000007336 Cryptococcosis Diseases 0.000 claims description 5
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 5
- 206010017533 Fungal infection Diseases 0.000 claims description 4
- 208000031888 Mycoses Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 2
- 241000222173 Candida parapsilosis Species 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000004150 EU approved colour Substances 0.000 claims description 2
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
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- 241000893976 Nannizzia gypsea Species 0.000 claims description 2
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- 230000000843 anti-fungal effect Effects 0.000 abstract description 13
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Images
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides a tetrazolyl alcohol compound, a preparation method and an antifungal drug, and belongs to the field of organic chemistry. The structural formula of the tetrazole alcohol compound provided by the invention is shown as the following formula:
wherein, in the formula I, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from any one of H, cyano, nitro, mesyl, C1-C4 alkyl substituted by halogen, C1-C4 alkoxy and C1-C4 alkoxy substituted by halogen, R 6 Is H or methyl. The compound has obvious in-vitro effect on human pathogenic fungi candida albicans and cryptococcus neoformansAnd the in-vivo antifungal activity is stronger than that of the conventional antifungal drug fluconazole, and the tetrazolium alcohol compound has low inhibition effect on human liver drug enzyme CYP3A 4.
Description
Technical Field
The invention belongs to the field of organic matters, and particularly relates to a tetrazolyl alcohol compound, a preparation method and an antifungal drug.
Background
In recent years, with the extensive application of broad-spectrum antibiotics, anti-tumor drugs and immunosuppressive agents, the wide implementation of radiotherapy and organ transplantation, the general development of catheters and cannulas, and the rapid increase of patients with immunodeficiency, especially AIDS patients, the fungal infection, especially deep fungal infection, has become a major cause of death of serious diseases such as AIDS, tumors and the like. The existing antifungal drugs are mainly allylamines acting as squalene epoxidase, azoles acting as lanosterol 14a demethylase, lipopeptides acting as cell wall b- (1, 3) -glucan synthase, and the like. However, the current antifungal drugs applied clinically have the problems of large side effect, narrow antibacterial spectrum, easy generation of drug resistance and the like, and effective antifungal drugs, particularly deep antifungal drugs, are very lack and far fail to meet the treatment requirements. Therefore, the development of more effective antifungal drugs is necessary.
Disclosure of Invention
The present invention is made to solve the above problems, and an object of the present invention is to provide a tetrazolyl alcohol compound having an antifungal effect, a preparation method thereof, and an antifungal agent containing the tetrazolyl alcohol compound.
The invention provides a tetrazolyl alcohol compound which has the characteristics that the structural formula is shown as the formula I:
wherein, in the formula I, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from any one of H, halogen, cyano, nitro, mesyl, C1-C4 alkyl substituted by halogen, C1-C4 alkoxy and C1-C4 alkoxy substituted by halogen, R 6 Is H or methyl.
The tetrazolyl alcohol compound provided by the invention also has the following characteristics: wherein, the alkyl of C1-C4 is methyl or ethyl, the alkyl of C1-C4 substituted by halogen is trifluoromethyl, the alkoxy of C1-C4 is methoxy, and the alkoxy of C1-C4 substituted by halogen is trifluoromethoxy and trifluoroethoxy.
The tetrazolyl alcohol compound provided by the invention can also have the following characteristics: the structural formula is shown as formula II:
the tetrazolyl alcohol compound provided by the invention can also be characterized by being any one of the following compounds:
(2R, 3R) -3- (3- (4-trifluoromethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetraazazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 6-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 3-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 4-dichlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butane-2-ol,
(2R, 3R) -3- (3-phenylisoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-methylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluoro-3-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-cyanophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluoro-2-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chloro-3-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-trifluoromethylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chloro-2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butane-2-ol,
(2R, 3R) -3- (3- (pentafluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3, 5-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-trifluoroethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetraazazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol.
The invention also provides a preparation method of the tetrazolol compound, which is used for preparing any one of the tetrazolol compounds and has the following characteristics: the reaction formula is as follows:
the preparation method of the tetrazolyl alcohol compound provided by the invention can also have the characteristics that the preparation method comprises the following steps: dissolving the compound 2 and the compound 3 in an organic solvent, adding Lewis base, reacting for 6-12 hours, and purifying to obtain the compound.
The preparation method of the tetrazolyl alcohol compound provided by the invention can also have the characteristic that R 6 In the case of methyl, the general reaction scheme for the preparation of compound 2 is as follows:
the method comprises the following specific steps:
s1, dissolving a compound 4 in dichloromethane, adding triethylamine, and dropwise adding MsCl at a low temperature (preferably-80-60 ℃, more preferably-78 ℃) to obtain a compound 5;
s2, mixing Pd (CH) 3 CN) 2 Cl 2 Dissolving in anhydrous THF, adding PPh 3 Reacting at room temperature for 10 minutes, adding the compound 5 and the compound 6, and dropwise adding ZnEt under the condition of ice dissolution 2 Reacting at room temperature to generate a compound 7;
and S3, dissolving tetrazole (namely the compound 8) in DMF, adding potassium carbonate, stirring until the mixture is dissolved, adding the compound 7, and reacting for 3-5 hours at the temperature of 60-80 ℃ to obtain the compound 2.
The preparation method of the tetrazolyl alcohol compound provided by the invention can also have the characteristics that the reaction general formula for preparing the compound 3 is as follows:
the method comprises the following specific steps:
s1, dissolving the compound 9 in MeOH, adding hydroxylamine hydrochloride and NaHCO 3 Reacting with water at room temperature for 1-3 hours to obtain a compound 10;
and S2, dissolving the compound 10 in DMF, adding NCS, and reacting at 20-40 ℃ for 1-4 hours to obtain a compound 3.
The present invention also provides an antifungal agent for treating or preventing a disease caused by fungal infection, comprising: at least one of the above tetrazolol compounds or pharmaceutically acceptable salts thereof.
In an antifungal agent provided by the present invention, the pharmaceutically acceptable salt may be any one of hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, nitrate, maleate, fumarate, tartrate, succinate, lactate, methanesulfonate, p-toluenesulfonate, salicylate, or oxalate.
The antifungal medicine provided by the invention can also have the characteristics of being any one of tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained-release tablets, capsules, soft capsules, dropping pills, granules, injections, powder injections or aerosol.
In the antifungal drug provided by the present invention, the antifungal drug may further include: a pharmaceutically acceptable carrier or adjuvant.
In the antifungal drug provided by the present invention, the antifungal drug may further include: one or more of pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preservatives, salts for influencing osmotic pressure, buffers, sweetening agents, flavouring agents or colouring agents.
In the antifungal drug provided by the invention, the antifungal drug can also have the following characteristics: wherein the fungus is any one or more of Candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, aspergillus fumigatus, trichophyton rubrum or microsporum gypseum.
Action and Effect of the invention
According to the tetrazolium alcohol compounds related by the invention, the compounds have remarkable in-vitro and in-vivo antifungal activities on human pathogenic fungi candida albicans and cryptococcus neoformans, are both stronger than the traditional antifungal drug fluconazole, and simultaneously have low inhibition effect on human liver drug enzymes.
Drawings
FIG. 1 is a single crystal diagram of a compound of the present invention, 2R, 3S-2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazol-1-yl) -4-pentyn-2-ol;
FIG. 2 is a graph showing the survival of mice treated with systemic Candida albicans SC5314 infection at different doses in the test example of the present invention; and
FIG. 3 is a graph showing the survival of treated mice with systemic cryptococcus neoformans H99 infection at various doses in the examples of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.
Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. The reagents used in the examples were all commercially available analytical grade.
< example 1>
The reaction formula for the synthesis of (2R, 3S) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazol-1-yl) -4-pentyn-2-ol is as follows:
the method comprises the following specific steps:
s1, (R) -3-butyn-2-ol (50 mmol, namely a compound R-4) is dissolved in dichloromethane, triethylamine (100 mmol) is added, methanesulfonyl chloride (55 mmol) is added dropwise at-78 ℃, after complete reaction, the mixture is poured into an aqueous solution of sodium bicarbonate, extraction is carried out twice by dichloromethane, an organic phase is washed twice by water, and after drying by anhydrous sodium sulfate, concentration is carried out by a rotary evaporator. The compound R-5 is obtained and is directly used in the next step without further purification;
the hydrogen spectrum of compound R-5 is as follows:
1 H NMR(300MHz,CDCl 3 )δ5.29(q,1H),3.13(s,3H),2.71(s,1H),1.66(d, 3H).
s2, mixing Pd (CH) 3 CN) 2 Cl 2 (5 mmol) in tetrahydrofuran and triphenylphosphine(12.5 mmol), after reacting for 10 minutes, adding 2-chloro-2 ',4' -difluoroacetophenone (50 mmol, i.e., compound 6) and (R) -3-butyn-2-ol methanesulfonate (50 mmol, i.e., compound R-5), then slowly adding dropwise a 1M toluene solution of diethyl zinc (100 mmol), reacting at room temperature for 1 hour, pouring into a 2M hydrochloric acid solution, extracting with ethyl acetate for 3 times, washing the organic phase twice with a saturated aqueous solution of sodium chloride, drying with anhydrous sodium sulfate, and concentrating by a rotary evaporator to obtain a crude product of (2R, 3S) -1-chloro-2- (2, 4-difluorophenyl) -3-methyl-4-pentyn 2-ol (i.e., compound (2R, 3S) -7);
s3, dissolving 1H-tetrazole (150 mmol, namely the compound 8) in DMF, adding potassium carbonate (150 mmol) and (2R, 3S) -1-chloro-2- (2, 4-difluorophenyl) -3-methyl-4-pentyn-2-ol crude product (50 mmol, namely the compound (2R, 3S) -7), reacting at 70 ℃ for 4 hours, pouring into ice water, extracting for 3 times by ethyl acetate, washing the organic phase twice by saturated sodium chloride water solution, drying the organic phase by anhydrous sodium sulfate, concentrating by a rotary evaporator, performing column chromatography to obtain (2R, 3S) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazole-1-yl) -4-pentyn-2-ol crude product (namely the compound (2R, 3S) -2, and crystallizing by ethyl acetate and petroleum ether to obtain (2R, 3S) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazole) -4-pentyn-2-ol pure product.
A single crystal of (2R, 3S) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazol-1-yl) -4-pentyn-2-ol is shown in FIG. 1, and the compound has the configuration 2R,3S as shown in FIG. 1 without any doubt.
The hydrogen spectrum of (2R, 3S) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazol-1-yl) -4-pentyn-2-ol is as follows:
1 H NMR(300MHz,DMSO)δ9.15(s,1H),7.13–7.27(m,2H),6.90(td,J＝ 9.0,3.0Hz,1H),6.12(s,1H),5.08(d,J＝15Hz,1H),4.97(d,J＝15Hz,1H),3.22– 3.28(m,2H),0.89(d,J＝6.0Hz,3H).
< example 2>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (4-trifluoromethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthetic reaction formula is shown below:
the specific reaction operation is as follows:
step S1: 4-trifluoromethoxybenzaldehyde (1 mmol, compound 9 a) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 Stirring OH & HCl (1.1 mmoL) water solution (10 mL) at room temperature for 2h, adding water until white solid is separated out, filtering, and drying to obtain compound 4-trifluoromethoxy benzaldehyde oxime (compound 10 a);
step S2: dissolving compound 4-trifluoromethoxybenzaldehyde oxime (1 mmol, i.e. compound 10 a) in 10mL DMF, adding NCS (1.1 mmol), stirring at 35 deg.C for 3h, monitoring reaction completion by TCL, extracting with ethyl acetate three times, combining organic phases, washing twice with saturated NaCl, anhydrous Na 2 SO 4 Drying, concentrating by a rotary evaporator to obtain a compound 4-trifluoro-methoxy benzaldehyde oxime chloride (namely a compound 3 a);
and step S3: the compounds 4-trifluoromethoxybenzaldehyde oxime chloride (1 mmoL, i.e. compound 3 a) and (2r, 3s) -2- (2, 4-difluorophenyl) -3-methyl-1- (1H-tetrazol-1-yl) -4-pentyn-2-ol (1 mmoL, i.e. compound (2r, 3s) -2, prepared as in example 1) were dissolved in THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. After the reaction was monitored by TCL, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, concentrating by rotary evaporator, and performing column chromatography to obtain target compound (2R, 3R) -1a.
The hydrogen spectrum of the target compound (2R, 3R) -1a is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),8.04(d,J＝9.0Hz,2H),7.54(d,J＝ 9.0Hz,2H),7.13–7.33(m,3H),6.93(td,J＝9.0,3.0Hz,1H),6.19(s,1H),5.21(d, J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.89(q,J＝9.0Hz,1H),1.11(d,J＝9.0Hz, 3H).
< example 3>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and the synthetic reaction formula thereof is shown as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1b is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.93–7.98(m,1H),7.54–7.62(m, 1H),7.15–7.45(m,4H),6.90–6.96(m,2H),6.22(s,1H),5.22(d,J＝15Hz,1H), 4.56(d,J＝15Hz,1H),3.93(q,J＝9.0Hz,1H),1.11(d,J＝9.0Hz,3H).
< example 4>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (2, 6-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1c is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.97–8.05(m,1H),7.46–7.54(m, 1H),7.14–7.33(m,3H),6.90–6.95(m,2H),6.22(s,1H),5.22(d,J＝15Hz,1H), 4.56(d,J＝15Hz,1H),3.93(q,J＝6.0Hz,1H),1.10(d,J＝6.0Hz,3H).
< example 5>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (2, 3-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1d is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.76(t,J＝7.0Hz,1H),7.58–7.67 (m,1H),7.15–7.42(m,3H),6.90–7.02(m,2H),6.24(s,1H),5.22(d,J＝15Hz, 1H),4.57(d,J＝15Hz,1H),3.95(q,J＝6.0Hz,1H),1.11(d,J＝6.0Hz,3H).
< example 6>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (2, 4-dichlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butane-2-ol, and the synthetic reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1e is as follows:
1 H NMR(300MHz,DMSO)δ9.05(s,1H),7.85(d,J＝3.0Hz,1H),7.79(d,J＝ 9.0Hz,1H),7.60(dd,J＝9.0,3.0Hz,1H),7.15–7.32(m,2H),6.90–6.98(m,2H), 6.27(s,1H),5.23(d,J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.92(q,J＝6.0Hz,1H), 1.12(d,J＝6.0Hz,3H).
< example 7>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3-phenylisoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1f is as follows:
1 H NMR(300MHz,DMSO)δ9.06(s,1H),7.91(dd,J＝6.0,3.0Hz,2H),7.52 –7.55(m,3H),7.16–7.34(m,2H),7.09(s,1H),6.93(td,J＝9.0,3.0Hz,1H),6.18 (s,1H),5.22(d,J＝12Hz,1H),4.59(d,J＝12Hz,1H),3.89(q,J＝6.0Hz,1H), 1.10(d,J＝6.0Hz,3H).
< example 8>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-methylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and the synthetic reaction formula thereof is shown as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1g was as follows:
1 H NMR(300MHz,DMSO)δ9.05(s,1H),7.80(d,J＝9.0Hz,2H),7.34(d,J＝ 9.0Hz,2H),7.15–7.29(m,2H),7.04(s,1H),6.92(td,J＝9.0,3.0Hz,1H),6.15(s, 1H),5.21(d,J＝12Hz,1H),4.58(d,J＝12Hz,1H),3.87(q,J＝6.0Hz,1H),2.36(s, 3H),1.09(d,J＝6.0Hz,3H).
< example 9>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-fluoro-3-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butane-2-ol, and the synthetic reaction formula thereof is shown as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1h was as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.94–7.98(m,1H),7.74–7.82(m, 2H),7.15–7.33(m,3H),6.93(td,J＝9.0,3.0Hz,1H),6.20(s,1H),5.20(d,J＝15 Hz,1H),4.59(d,J＝15Hz,1H),3.88(q,J＝6.0Hz,1H),1.10(d,J＝6.0Hz,3H).
< example 10>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-cyanophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown below:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1i was as follows:
1 H NMR(300MHz,DMSO)δ9.03(s,1H),8.11(d,J＝6.0Hz,2H),8.02(d,J＝ 6.0Hz,2H),7.82–7.91(m,1H),7.15–7.33(m,3H),6.93(td,J＝9.0,3.0Hz,1H), 6.19(s,1H),5.20(d,J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.91(q,J＝6.0Hz,1H), 1.11(d,J＝6.0Hz,3H).
< example 11>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (4-fluoro-2-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown below:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1j is as follows:
1 H NMR(300MHz,DMSO)δ9.06(s,1H),7.79–7.84(m,1H),7.68(dd,J＝ 9.0,3.0Hz,1H),7.40(td,J＝9.0,3.0Hz,1H),7.16–7.32(m,2H),6.90–6.95(m, 2H),6.27(s,1H),5.23(d,J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.92(q,J＝6.0Hz, 1H),1.12(d,J＝6.0Hz,3H).
< example 12>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and the synthesis reaction formula is as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1k is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.94–7.99(m,2H),7.09–7.41(m, 4H),7.09(s,1H),6.93(td,J＝9.0,3.0Hz,1H),6.17(s,1H),5.20(d,J＝15Hz,1H), 4.58(d,J＝15Hz,1H),3.88(q,J＝6.0Hz,1H),1.10(d,J＝6.0Hz,3H).
< example 13>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (2, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown below:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1l is as follows:
1 H NMR(300MHz,DMSO)δ9.06(s,1H),7.59–7.69(m,1H),7.14–7.35(m, 4H),6.87–6.96(m,2H),6.29(s,1H),5.24(d,J＝15Hz,1H),4.58(d,J＝15Hz, 1H),3.95(q,J＝6.0Hz,1H),1.12(d,J＝6.0Hz,3H).
< example 14>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (4-chloro-3-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthetic reaction formula is shown below:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1m is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),8.13(dd,J＝9.0,3.0Hz,1H),7.91 –7.97(m,1H),7.60(t,J＝9.0Hz,1H),7.15–7.32(m,3H),6.93(td,J＝9.0,3.0Hz, 1H),6.18(s,1H),5.20(d,J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.88(q,J＝6.0Hz, 1H),1.10(d,J＝6.0Hz,4H).
< example 15>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-trifluoromethylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and the synthesis reaction formula is as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1n is as follows:
1 H NMR(300MHz,DMSO)δ9.05(s,1H),8.14(d,J＝9.0Hz,2H),7.91(d,J＝ 9.0Hz,3H),7.15–7.32(m,3H),6.93(td,J＝9.0,3.0Hz,1H),6.22(s,1H),5.22(d, J＝15Hz,1H),4.60(d,J＝15Hz,1H),3.91(q,J＝9.0Hz,1H),1.11(d,J＝9.0Hz, 3H).
< example 16>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (4-chloro-2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthetic reaction formula is shown below:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1o is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.98(t,J＝9.0Hz,1H),7.70(dd,J ＝12,3.0Hz,1H),7.48(dd,J＝9.0,3.0Hz,1H),7.14–7.33(m,2H),6.90–6.98(m, 2H),6.23(s,1H),5.22(d,J＝15Hz,1H),4.56(d,J＝15Hz,1H),3.93(q,J＝6.0Hz, 1H),1.10(d,J＝6.0Hz,3H).
< example 17>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (pentafluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and the synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1p is as follows:
1 H NMR(300MHz,DMSO)δ9.05(s,1H),7.15–7.32(m,2H),6.90–6.97(m, 2H),6.33(s,1H),5.24(d,J＝15Hz,1H),4.58(d,J＝15Hz,1H),3.98(q,J＝6.0Hz, 1H),1.13(d,J＝6.0Hz,3H).
< example 18>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3, 5-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2, and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1q was as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.62–7.69(m,2H),7.41–7.47(m, 1H),7.15–7.33(m,3H),6.93(td,J＝9.0,3.0Hz,1H),6.20(s,1H),5.20(d,J＝15 Hz,1H),4.59(d,J＝15Hz,1H),3.88(q,J＝6.0Hz,1H),1.12(d,J＝6.0Hz,3H).
< example 19>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown as follows:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1r is as follows:
1 H NMR(300MHz,DMSO)δ9.06(s,1H),7.95–8.02(m,1H),7.78–7.82(m, 1H),7.57–7.67(m,1H),7.15–7.33(m,3H),6.93(td,J＝9.0,3.0Hz,1H),6.23(s, 1H),5.20(d,J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.87(q,J＝6.0Hz,1H),1.10(d, J＝6.0Hz,3H).
< example 20>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this example is (2r, 3r) -3- (3- (4-trifluoroethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthetic reaction formula is shown below:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1s is as follows:
1 H NMR(300MHz,DMSO)δ9.04(s,1H),7.89(d,J＝9.0Hz,2H),7.15–7.33 (m,4H),7.06(s,1H),6.93(td,J＝9.0,3.0Hz,1H),6.15(s,1H),5.21(d,J＝15Hz, 1H),4.85(q,J＝9.0Hz,2H),4.58(d,J＝15Hz,1H),3.86(q,J＝6.0Hz,1H),1.09 (d,J＝6.0Hz,3H).
< example 21>
Synthesis of tetrazole alcohol compound
The tetrazolyl alcohol compound provided in this embodiment is (2r, 3r) -3- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol, and its synthesis reaction formula is shown below:
the specific reaction operation is similar to that of example 2 and is not repeated herein.
The hydrogen spectrum of the target compound (2R, 3R) -1t is as follows:
1 H NMR(300MHz,DMSO)δ9.06(s,1H),7.95(d,J＝9.0Hz,2H),7.62(d,J＝ 9.0Hz,2H),7.14–7.35(m,3H),6.94(td,J＝9.0,3.0Hz,1H),6.19(s,1H),5.22(d, J＝15Hz,1H),4.59(d,J＝15Hz,1H),3.90(q,J＝6.0Hz,1H),1.11(d,J＝6.0Hz, 3H).
< example 21>
Synthesis of tetrazole alcohol compound
Step S1: dissolving 1H-tetrazole (150 mmol, namely compound 8) in DMF, adding potassium carbonate (150 mmol) and compound 6 (150 mmol), reacting at 70 ℃ for 4 hours, pouring into ice water, extracting with ethyl acetate for 3 times, washing an organic phase twice with saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating by a rotary evaporator, and performing column chromatography to obtain compound 11.
Step S2: compound 11 (20 mmol) and propargyl bromide (12, 40 mmol) were dissolved in a mixed solvent (DMF-THF, volume ratio 1. Zinc powder (60 mmol, 2% HCl wash, water wash and vacuum dry) was added to the well stirred solution. The exothermic reaction self-refluxed after 2-5 minutes. The entire reaction mixture was stirred at 60 ℃ for 7 hours until TLC indicated completion of the reaction. Adding 4M HCl to the mixture, extracting twice with ethyl acetate, combining the organic layers, washing several times with water until the pH of the organic layer is adjusted to about 7, and adding anhydrous Na 2 SO 4 Drying, concentrating by rotary evaporator, and performing column chromatography to obtain compound 13.
The hydrogen spectrum of the target compound 13 is as follows:
1 H NMR(300MHz,DMSO)δ9.12(s,1H),7.20–7.33(m,2H),6.96(td,J＝ 9.0,3.0Hz,1H),6.38(s,1H),4.90(d,J＝15Hz,1H),4.78(d,J＝15Hz,1H),2.75– 2.95(m,3H).
and step S3: dissolving compound 4-chlorobenzaldehyde oxime chloride (1 mmoL, i.e. compound 3 t) and compound 13 in THF (10 mL), vacuumizing under nitrogen protection, slowly adding TEA (1 mmoL) dropwise, stirring at 35 deg.C for 12h. After the reaction was monitored by TCL, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, concentrating by a rotary evaporator, and performing column chromatography to obtain the target compound 14.
The hydrogen spectrum of target compound 14 is as follows:
1 H NMR(300MHz,DMSO)δ9.13(s,1H),7.78(d,J＝9.0Hz,2H),7.53(d,J＝ 9.0Hz,2H),7.12–7.32(m,2H),6.88(td,J＝9.0,3.0Hz,1H),6.66(s,1H),6.53(s, 1H),5.05(d,J＝15Hz,1H),4.84(d,J＝15Hz,1H),3.61(d,J＝15Hz,1H),3.41(d, J＝15Hz,1H).
< test example 1>
In vitro bacteriostasis test
Experimental strains: the experiment selects the following two common human body pathogenic standard fungus strains as screening objects, wherein the fungus strains are provided by a fungus room (or purchased from a pharmaceutical institute of Chinese academy of sciences) in Shanghai Yangzhong Hospital.
Candida albicans (Candida albicans, standard strain SC 5314),
the experimental procedure used was a conventional in vitro antibacterial assay (see: antimicrobiorobAgents Chemother 1995,39 (5): 1169).
Specifically, the steps are as follows:
preparing a bacterial suspension: culturing the above fungi in YEPD liquid culture medium at 35 deg.C for 16 hr, activating twice, counting with blood cell counting plate, and adjusting bacteria concentration to 1 × 10 with RPM1640 liquid culture medium 4 ～1×10 5 one/mL.
Preparing a liquid medicine: the compounds prepared in examples 2-21 were dissolved in dimethyl sulfoxide to prepare 0.8mg/mL drug stock solutions, which were diluted to 8. Mu.g/mL with RPM1640 before the experiment.
Inoculation: adding RPM1640100 mu L to No. 1 well of a 96-well plate as blank control; the drug concentration of each hole is diluted by 10-grade times, wherein 100 mu L of bacterial suspension is added into each hole from No. 3 to No. 12, 200 mu L of bacterial suspension is added into each hole from No. 2, and the drug concentration of each hole is 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 mu g/mL in sequence. No. 12 wells were not filled with drug solution and served as positive control. The drug control is fluconazole.
The results of the experiment are shown in table 1.
TABLE 1 minimum antifungal inhibitory concentration values (MIC, μ g/mL) for target compounds in vitro
As shown in Table 1, the tetrazolium alcohol compounds provided in examples 2-21 have better antifungal activity against Candida albicans and Cryptococcus neoformans, and the antifungal activity is mostly higher than that of the control drug fluconazole.
< test example 2>
Human liver drug enzyme inhibition assay
The test compounds were co-incubated with human liver microsomes and five mixed probe substrates (phenacetin for CYP1A2, diclofenac for CYP2C9, mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam for CYP3 A4) (see table below). The reaction will be initiated by the addition of the coenzyme NADPH. The reaction was terminated by adding glacial acetonitrile containing an internal standard to the incubation system. After protein precipitation, the supernatant was centrifuged. Characteristic metabolites in the supernatant (paracetamol versus CYP1A2, 4-hydroxydiclofenac versus CYP2C9, 4-hydroxymephenytoin versus CYP2C19, dexrazoxane versus CYP2D6, 1-hydroxy-midazolam versus CYP3A 4) were analyzed by LC-MS/MS method. The effect of the test compound on the production of these characteristic metabolites was finally investigated on the basis of the data obtained. The selective inhibitor ketoconazole served as a positive control. All incubations were performed in parallel with 2.
TABLE 2 incubation conditions
TABLE 3 inhibition of human CYP enzymes by compounds
As shown in tables 2 to 3, the tetrazolyl alcohol compounds provided in examples 2 to 21 also have the advantage of low inhibitory activity on human liver enzymes.
< test example 3>
Mouse systemic candida albicans SC5314 infection survival experiment
The experimental method comprises the following steps: 100 mice were divided into 5 groups of 10 mice each, and 200 μ L of 5 × 10 rat tail vein was administered to each group 6 Candida albicans SC 5314/ml, test compound, was formulated into a suspension of a certain concentration with sodium carboxymethylcellulose aqueous solution, and administered by gavage (200. Mu.L) after 2 hours, 5 groups of gavage drugs and gavage amounts are shown in Table 3, and the administration was continued for 7 days, and the death of mice was observed daily and recorded for 20 days.
TABLE 4 mouse systemic Candida albicans SC5314 infection survival experiment grouping
| Group of | Blank group | Contrast light | Group 1 | Group 2 | Group 3 | ||
| Stomach-filling medicine | - | | 1a | 1a | 1a | ||
| Dosage (mg/kg) | - | 0.5 | 0.5 | 1 | 5 |
The results of the experiment are shown in FIG. 2.
As shown in FIG. 2, compound 1a is superior to the control drug fluconazole at the administration condition of 0.5mg/kg, and the mice can achieve complete protection at the administration condition of 5 mg/kg.
< test example 3>
Mouse systemic cryptococcus neoformans H99 infection survival experiment
The experimental method comprises the following steps: dividing 100 mice into 5 groups of 10 mice, and administering 200 μ L of 9 × 10 venules from the tail of the rat 6 The cryptococcus neoformans H99/ml and the tested compound are prepared into a suspension with a certain concentration by using a sodium carboxymethylcellulose aqueous solution, and are subjected to intragastric administration (200 mu L) after 2 hours, the intragastric administration and the intragastric administration amount of 5 groups are shown in a table 4, the continuous administration is carried out for 7 days, the death condition of the mice is observed every day, and the recording is carried out for 20 days.
TABLE 5 groups of mouse systemic Candida albicans SC5314 infection survival experiments
| Group of | Blank group | Contrast light | Group 1 | Group 2 | Group 3 | ||
| Stomach-filling medicine | - | | 1a | 1a | 1a | ||
| Dosage (mg/kg) | - | 8 | 1 | 4 | 8 |
The results of the experiment are shown in FIG. 3.
As shown in FIG. 3, compound 1a showed no significant protection at 1mg/kg, which was comparable to fluconazole at 4mg/kg and superior to the control drug fluconazole at 8 mg/kg.
Effects and effects of the embodiments
According to the tetrazolium alcohol compounds related in the embodiments, the compounds have significant in-vitro and in-vivo antifungal activities on human pathogenic fungi candida albicans and cryptococcus neoformans, are both stronger than that of the conventional antifungal drug fluconazole, and have low inhibition effect on human liver drug enzymes.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. The tetrazole alcohol compound is characterized in that the structural formula is shown as formula I:
wherein, in the formula I, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from any one of H, cyano, nitro, methylsulfonyl, C1-C4 alkyl substituted by halogen, C1-C4 alkoxy and C1-C4 alkoxy substituted by halogen,
R 6 is H or methyl.
2. The tetrazolyl alcohol compound of claim 1, wherein the structural formula is represented by formula II:
3. the tetrazolyl alcohol compound according to claim 1, which is any one of the following compounds:
(2R, 3R) -3- (3- (4-trifluoromethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 6-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 3-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 4-dichlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3-phenylisoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-methylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluoro-3-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-cyanophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluoro-2-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (2, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chloro-3-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-trifluoromethylphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chloro-2-fluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (pentafluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3, 5-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3, 4-difluorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-trifluoroethoxyphenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
(2R, 3R) -3- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol,
1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (2, 4-difluorophenyl) -1- (1H-tetrazol-1-yl) butan-2-ol.
4. A preparation method of tetrazole alcohol compounds is used for preparing the tetrazole alcohol compounds of any one of claims 1 to 3, and is characterized in that the reaction general formula is as follows:
5. the preparation method of tetrazole alcohol compounds according to claim 4, comprising the following steps:
dissolving the compound 2 and the compound 3 in an organic solvent, adding Lewis base, reacting for 6-12 hours, and purifying to obtain the compound.
6. An antifungal agent for treating or preventing a fungal infection disease, comprising:
at least one tetrazolol compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
7. The antifungal agent in accordance with claim 6,
wherein the pharmaceutically acceptable salt is any one of hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, nitrate, maleate, fumarate, tartrate, succinate, lactate, methanesulfonate, p-toluenesulfonate, salicylate or oxalate.
8. The antifungal agent of claim 6, further comprising:
a pharmaceutically acceptable carrier or adjuvant.
9. The antifungal agent of claim 6, further comprising:
pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preservatives, salts for influencing osmotic pressure, buffers, sweetening agents, flavouring agents or colouring agents.
10. The antifungal agent of claim 6, wherein:
wherein the fungus is any one or more of Candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, aspergillus fumigatus, trichophyton rubrum or microsporum gypseum.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6300353B1 (en) * | 1998-03-06 | 2001-10-09 | Basilea Pharmaceutica Ag, A Swiss Company | Azoles for treatment of fungal infections |
| CN106336383A (en) * | 2016-08-24 | 2017-01-18 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6300353B1 (en) * | 1998-03-06 | 2001-10-09 | Basilea Pharmaceutica Ag, A Swiss Company | Azoles for treatment of fungal infections |
| CN106336383A (en) * | 2016-08-24 | 2017-01-18 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| FEI XIE 等: "Design, synthesis, and in vitro evaluation of novel antifungal triazoles", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, pages 2171 - 2173 * |
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