CN102796087B - Coumarin triadimenol, and preparation method and application thereof - Google Patents
Coumarin triadimenol, and preparation method and application thereof Download PDFInfo
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- CN102796087B CN102796087B CN201210322800.6A CN201210322800A CN102796087B CN 102796087 B CN102796087 B CN 102796087B CN 201210322800 A CN201210322800 A CN 201210322800A CN 102796087 B CN102796087 B CN 102796087B
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Abstract
The invention discloses coumarin triadimenol shown in a structural formula I and a preparation method thereof. The preparation method comprises the following step: under the catalytic effect of inorganic base, reacting 5,7-di((epoxyethyl-2-)methoxy)-4-methyl coumarin and 1H-1,2,4-triazole at 60-80 DEG C in an organic solvent while stirring. In-vitro antimicrobial activity detection discovers that the compound has a certain activity inhibition effect on gram positive bacteria (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Micrococcus luteus and Bacillus subtilis), gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Bacillus proteus and Salmonella typhosa) and fungi (Candida albicans and Candida krusei). The compound can be used for preparing antibacterial and/or antifungal drugs.
Description
Technical field
The invention belongs to chemical field, relate to a kind of new organic compound, also relate to preparation method and the medicinal use thereof of this compound.
Background technology
Natural and synthesizing coumarin is the important lactone compound of a class, all have a wide range of applications potentiality with the benzo of its uniqueness α-pyrone structure in fields such as medical science, agricultural, Materials science, synthetic perfume, ion and Supramolecular Recognition, correlative study becomes increasingly active and develops very rapid.Coumarin kind compound has larger conjugated system and strong cyclic voltammetry method ability, this special rigidity condensed cyclic structure makes it easily be had an effect by the bioactive molecule in the multiple non covalent bond effects such as hydrogen bond, hydrophobic interaction, pi-pi accumulation and electrostatic interaction and organism and active binding site and be shown the biologic activity of wide spectrum, especially shows wide application prospect at medicinal chemistry art.In recent years, coumarin kind compound, because having wider antimicrobial spectrum and good anti-microbial activity, receives much concern antibacterium and antimycotic field, and shows great Development volue.Extensive work is devoted to take tonka bean camphor as the research and development of lead compound, expects to obtain the coumarins medicine that pharmacokinetic property is good, toxic side effect is low and biological activity is high.
Fluconazole be world health organisation recommendations be widely used in clinical antibacterial triazole alcohols medicine, its toxic side effect is little, and pharmacokinetics is good, especially to treatment deep fungal infection Be very effective.Lot of documents research shows, and the triadimenol fragment in fluconazole structure plays very important effect in the pharmacological properties of fluconazole, and wherein hydroxyl forms hydrogen bond by the crystal water of target enzyme active sites and active-site residues H310, increases water-soluble; Triazole ring nitrogen and cytochrome p450 protein prosthetic heme group Fe
2+in conjunction with, make oxyphorase lose with oxygen in conjunction with chance, thus suppress lanosterol 14 α position demethylation, and then Antifungi growth reaches fungistatic effect.
Summary of the invention
In view of this, an object of the present invention is the tonka bean camphor triadimenol providing a kind of novel structure, and two of object is the preparation method providing this compound, and three of object is to provide the application of this compound in pharmacy field.
Through research, the invention provides following technical scheme:
1. structural formula
1shown tonka bean camphor triadimenol and pharmacologically acceptable salt thereof:
2. structural formula
1the preparation method of shown tonka bean camphor triadimenol: by structural formula
25,7-bis-shown ((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin and structural formulas
3shown 1H-1,2,4-triazole in organic solvent, under mineral alkali catalysis, temperature 60 ~ 80 DEG C of stirring reactions, i.e. obtained structural formula
1shown tonka bean camphor triadimenol; Chemical equation is as follows:
。
Further, described organic solvent is any one or more mixing in methyl alcohol, ethanol and acetonitrile, and described mineral alkali is any one or more mixing in salt of wormwood, sodium carbonate, sodium bicarbonate and sodium hydroxide.
Further, described organic solvent is dehydrated alcohol, and described mineral alkali is salt of wormwood.
Further, the mol ratio of described 5,7-bis-((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin, 1H-1,2,4-triazole and salt of wormwood is 10:15:15.
3. structural formula
1shown tonka bean camphor triadimenol or the application of its pharmacologically acceptable salt in preparation antibacterium and/or antifungal drug.
Described antibacterium and/or antifungal drug both can be the single preparationss of ephedrine of tonka bean camphor triadimenol or its pharmacologically acceptable salt, also can be tonka bean camphor triazole or its pharmacologically acceptable salt and other there is the compound preparation of the compound of pharmacologically active.Described preparation type includes but not limited to the formulations such as tablet, capsule, powder, granule, pill, injection, powder injection, solution, suspensoid, emulsion, suppository, ointment, gelifying agent, film, aerosol, percutaneous absorption patch, and various slowly-releasing, controlled release preparation and nanometer formulation.
Further, described bacterium is any one or more mixing in streptococcus aureus, methicillin-resistant staphylococcus aureus (MASR), Bacillus subtilus, micrococcus luteus, intestinal bacteria, Bacillus proteus, Pseudomonas aeruginosa and Salmonella typhi; Described fungi is Candida albicans and/or candidiasis.
Beneficial effect of the present invention is: the present invention has designed and synthesized a kind of tonka bean camphor triadimenol of novel structure, this compound detects through in vitro anti-microbial activity, find gram-positive microorganism (streptococcus aureus, MASR, Bacillus subtilus, micrococcus luteus), Gram-negative bacteria (intestinal bacteria, Bacillus proteus, Pseudomonas aeruginosa, Salmonella typhi) and fungi (Candida albicans, candidiasis) there is certain inhibit activities, may be used for preparation antibacterium and/or antifungal drug, thus for clinical antimicrobial treatment provide more how efficient, the drug candidate of safety, contribute to solving the resistance be on the rise, the clinical treatment problems such as obstinate invasive organism and emerging harmful microorganism.In addition, the synthetic route of this compound is short, preparation method simple, and raw material is easy to get, and cost is lower.
Embodiment
In order to make the object, technical solutions and advantages of the present invention clearly, below the preferred embodiments of the present invention are described in detail.
the preparation of the tonka bean camphor triadimenol shown in embodiment 1 structural formula 1
Raw material 5,7-bis-((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin is reference literature method (Shi Y., Zhou C. H. Synthesis and evaluation for a class of new coumarin triazole derivatives as potential antimicrobial agents. Bioorganic Medicianl Chemistry Letter. 2011,21,956-960), obtained by 4-methylcoumarin and epoxy chloropropane generation nucleophilic substitution reaction.
In 100 mL round-bottomed flasks, add 1H-1, 2, 4-triazole (1.03 g, 15 mmol), salt of wormwood (2.07 g, 15 mmol) and dehydrated alcohol (20 mL), temperature control 50 DEG C stirs 0.5 hour, add 5 again, 7-bis-((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin (2.32 g, 10 mmol), temperature control 70 DEG C reaction, thin-layer chromatography tracks to reaction to be terminated, be cooled to room temperature, underpressure distillation removing ethanol obtains crude product, with purification by silica gel column chromatography the chloroform-methanol mixed solution of 100:7 (be with volume ratio be eluent), dry, obtain tonka bean camphor triadimenol 1.68 g shown in structural formula 1, yield 56 %, white solid, fusing point 144-146 DEG C,
1h NMR (300 MHz, DMSO-d6) δ: 8.49 (s, 1H, triazole 3-H), 7.99 (s, 1H, triazole 5-H), 7.72-7.69 (d, 1H,
j=9 Hz, coumarin 5-H), 7.00-6.98 (m, 2H, coumarin 6,8-H), 6.23 (s, 1H, coumarin 3-H), 5.60-5.58 (d, 1H,
j=6 Hz, OH), 4.38-4.31 (m, 2H, phenyl-OCH
2), 4.18 (bs, 1H, CHOH), 4.09-4.04 (m, 2H, triazole-CH
2), 2.40 (s, 3H, coumarin 4-CH
3) ppm,
13c NMR (75 MHz, DMSO-d6) δ: 161.9 (coumarin 2-C), 160.5 (coumarin 7-C), 155.1 (coumarin 9-C), 153.8 (coumarin 4-C), 151.8 (triazole 3-C), 145.4 (triazole 5-C), 126.9 (coumarin 5-C), 113.7 (coumarin 3-C), 112.8 (coumarin 10-C), 111.7 (coumarin 6-C), 101.7 (coumarin 8-C), 70.7 (coumarin 7-OCH
2), 67.6 (CHOH), 52.2 (triazole-CH
2), 18.6 (coumarin-CH
3) ppm.
the antimicrobial acivity of the tonka bean camphor triadimenol shown in embodiment 2 structural formula 1
Adopt clinical experiment standard (the National Committee for Clinical Laboratory Standards meeting United States National Committee's formulations in 1993, NCCLS) 96 hole micro-dilution methods, detect the minimum inhibitory concentration (MIC) of the obtained tonka bean camphor triadimenol of embodiment 1 to streptococcus aureus, MASR, Bacillus subtilus, micrococcus luteus, intestinal bacteria, Bacillus proteus, Pseudomonas aeruginosa, Salmonella typhi, Candida albicans and candidiasis.Dissolved by a small amount of methyl-sulphoxide of testing compound, thin up makes the solution that concentration is 1.28 mg/mL, then is diluted to 128 μ g/mL with bacteria culture fluid, cultivates 24 ~ 72 hours for 35 DEG C, after vibration mixing, measures MIC at wavelength 490nm place.The results are shown in Table 1, the tonka bean camphor triadimenol shown in structural formula 1 all shows certain restraining effect to bacteria tested and fungi.
The antimicrobial acivity (MIC, μ g/mL) of the tonka bean camphor triadimenol shown in table 1 structural formula 1
the preparation of embodiment 3 tonka bean camphor triadimenol tablet
Prescription: structural formula
1shown tonka bean camphor triadimenol 10g, starch 50 g, Microcrystalline Cellulose 90 g, Magnesium Stearate 2.0 g, 40% (w/w) Vltra tears (E-30) solution in right amount, make 1000.
Method for making: get 10 g starch, 105 DEG C of dryings 5 hours, obtain dry starch; Separately get tonka bean camphor triadimenol and the Microcrystalline Cellulose of 40 g starch and recipe quantity, mixing, pulverized 80 mesh sieves, with 40% (w/w) Gonak softwood, 20 mesh sieves are granulated, 50 ~ 60 DEG C are dried to pellet moisture about 3%, the whole grain of 20 mesh sieve, adds the Magnesium Stearate of aforementioned dry starch and recipe quantity, mixing, compressing tablet, i.e. obtained tonka bean camphor triadimenol tablet.
the preparation of embodiment 4 tonka bean camphor triadimenol injection liquid
Prescription: the tonka bean camphor triadimenol 10g shown in structural formula 1, propylene glycol 300 mL, water for injection 700 mL, makes 1000 mL.
Method for making: tonka bean camphor triadimenol and the propylene glycol of getting recipe quantity, add water for injection 700 mL, be stirred to dissolve, then to add gac to final concentration be 0.1% (g/mL), stir, leave standstill 30 minutes, with 5 μm of de-charcoals of titanium rod, then be the millipore filtration essence filter of 0.45 μm and 0.22 μm successively with aperture, filtrate is filling in 10 mL amperes, 100 DEG C of circulation vapor sterilizations 1 hour, i.e. obtained tonka bean camphor triadimenol injection liquid.
Finally illustrate, above embodiment, only for illustration of technical scheme of the present invention, does not form the restriction to content of the present invention.Although by above-described embodiment to invention has been comparatively detailed exemplifying, but those of ordinary skill in the art is to be understood that, various change can be made to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (2)
1. structural formula
1shown tonka bean camphor triadimenol and pharmacologically acceptable salt thereof:
。
2. structural formula
1the preparation method of shown tonka bean camphor triadimenol, is characterized in that, by structural formula
25,7-bis-shown ((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin and structural formulas
3shown 1H-1,2,4-triazole in organic solvent, under mineral alkali catalysis, temperature 60 ~ 80 DEG C of stirring reactions, i.e. obtained structural formula
1shown tonka bean camphor triadimenol; Chemical equation is as follows:
。
3. preparation method according to claim 2, it is characterized in that, described organic solvent is any one or more mixing in methyl alcohol, ethanol and acetonitrile, and described mineral alkali is any one or more mixing in salt of wormwood, sodium carbonate, sodium bicarbonate and sodium hydroxide.
4. preparation method according to claim 3, is characterized in that, described organic solvent is dehydrated alcohol, and described mineral alkali is salt of wormwood.
5. preparation method according to claim 4, is characterized in that, the mol ratio of described 5,7-bis-((epoxy ethyl-2-) methoxyl group)-4-methylcoumarin, 1H-1,2,4-triazole and salt of wormwood is 10:15:15.
6. structural formula
1shown tonka bean camphor triadimenol or the application of its pharmacologically acceptable salt in preparation antibacterium and/or antifungal drug,
。
7. application according to claim 6, is characterized in that, described bacterium is any one or more mixing in streptococcus aureus, Bacillus subtilus, micrococcus luteus, intestinal bacteria, Bacillus proteus, Pseudomonas aeruginosa and Salmonella typhi; Described fungi is Candida albicans and/or candidiasis.
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| CN106588892B (en) * | 2015-10-14 | 2021-11-02 | 西南大学 | Coumarin derived fluconazole analogue and preparation method and application thereof |
| CN105693705B (en) * | 2016-03-04 | 2018-12-28 | 西南大学 | Azoles alcohol compound based on cumarin and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4652579A (en) * | 1980-05-16 | 1987-03-24 | Bayer Aktiengesellschaft | Antimicrobial azoles |
| CN1040795A (en) * | 1988-08-13 | 1990-03-28 | 美国辉瑞有限公司 | The preparation method of triazole species antimycotic agent |
| CN1760193A (en) * | 2005-10-27 | 2006-04-19 | 中国人民解放军第二军医大学 | Antifungal compound of alkyl substitutional triazole class |
-
2012
- 2012-09-04 CN CN201210322800.6A patent/CN102796087B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4652579A (en) * | 1980-05-16 | 1987-03-24 | Bayer Aktiengesellschaft | Antimicrobial azoles |
| CN1040795A (en) * | 1988-08-13 | 1990-03-28 | 美国辉瑞有限公司 | The preparation method of triazole species antimycotic agent |
| CN1760193A (en) * | 2005-10-27 | 2006-04-19 | 中国人民解放军第二军医大学 | Antifungal compound of alkyl substitutional triazole class |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents;Yuan Shi,et al;《Bioorganic ＆ Medicinal Chemistry Letters》;20101216;第21卷(第3期);第957页方案1 * |
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