Antifungal compounds based on 3,5,8-trioxabicyclo[5,1,0]octane derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to antifungal compounds based on 3,5,8-trioxabicyclo[5,1,0]octane derivatives, obtained by trans-opening of its epoxide cycle, namely 6-(arylthio)-1,3-dioxepan-5-ols in racemic and enantiopure form of the general formula Ia and Ib , where at R1=F, R2=H, R3=H; at R1=Br, R2=H, R3=H; at R1=H, R2=Br, R3=H; at R1=H, R2=H, R3=Br.

EFFECT: compounds of formula Ia and Ib possess low toxicity and high antifungal activity with respect to fungi Candida albicans, Aspergillus fumigatus, Epidermophyton floccosum, Mucor pusilos, Saccharomyces cerevisiae and can be applied in medicine and veterinary.

2 tbl, 13 ex

 

The invention relates to synthetic biologically active substances heterocyclic series, with high antifungal activity, and representing the products of TRANS-opening epoxy cycle 3,5,8-dioxabicyclo[5.1.0]octane, 6-(arieti)-1,3-dioxan-5-Ola in racemic and anunciacion a General formula Ia and Ib:

where:

when R1=F, R2=H, R3=H

when R1=Br, R2=H, R3=H

when R1=H, R2=Br, R3=H

when R1=H, R2=H, R3=Br

The compounds of formula Ia and Ib have high antifungal activity against the background of low toxicity and can be used in medicine and veterinary medicine.

Mycosis - urgent medical problem. The increase in population immunocompromising patients with a high risk of severe fungal infections caused by the introduction into clinical practice of new medical technologies (e.g., transplantation of organs and tissues, high-dose immunosuppressive therapy, invasive diagnostic and therapeutic procedures, etc.), the HIV pandemic, as well as for success in the treatment of bacterial complications. The number of invasive mycoses progressive increase, with associated mortality remains very high (40-90%). Basically the treatment of fungal infections today is chemical-therapeutic method, based on the use of various drugs that have anti-fungal properties.

An important feature of fungal infections is currently a high frequency of pathogens that are resistant to the use of antimycotics, such as Fusarium spp., Scedosporium spp., Rhizopus spp., Mucor spp.and others Besides, are increasingly common causative agents of invasive candidiasis, in particular, Candida glabrata and Candida krusei, characterized by resistance to triazolam first generation and reduced susceptibility to amphotericin Century Marked the emergence of Aspergillus spp., resistant to amphotericin b and Itraconazole [Klimko N. N. Invasive fungal infections: new treatment options // Infection and antimicrobial therapy 2004. - So 6, No..2. - S. 71-74]. Development of new effective and safe antimycotics, acting on a previously unknown biological target, providing new opportunities for clinicians in the fight against these serious diseases [Lee Yu-Ting, Cui Chang-Jun, Chow Eve W. L., Pue Nason, Lonhienne Thierry, Wang Jian-Guo, James A. Fraser, Luke Guddat W. Sulfonylureas Have Antifungal Activity and Are Potent Inhibitors of Candida albicans Acetohydroxyacid Synthase // J. Med. Chem. - 2013. - V. 56. - P. 210-219].

Studied by the applicant of the prior art is not revealed equivalents of the claimed technical solution with similar structural formula, however, revealed equivalents by function - drugs that have a high antimycotic activity.

The most common in clinical practice, the antibiotic is mi on purpose are fluconazole and terbinafine.

Fluconazole exhibits high antimycotic activity and has low toxicity [patent US 4404216. Antifungal 1,3-bis-triazolyl-2-propanol derivative (I Pfizer. Inc. - Publ. - 13.09.1983].

However, as already noted, in recent years the number of fluconazole-resistant strains has increased dramatically [Vanden Bossche H., P. Marichal, Odds, F. Molecular mechanisms of drug resistance in fungi // Trends Environ - 1994. -V 2. - P. 393-400].

Of the investigated prior art identified no less significant antimycotic terbinafine [patent US 5231183. Antifungal 1,3-bis-triazolyl-2-propanol derivative / Banyu Pharmaceutical Co., Ltd. - Publ. - 27.07.1993]. It should be noted that resistance to this drug in microorganisms produced significantly less than the means of the class triazoles, however, the toxicity of the latter is much lower.

Of the investigated prior art, the applicant identified the products tialize thiophenols disubstituted when acetaldol the carbon atom 3,5,8-dioxabicyclo[5.1.0]octane, namely 2,2-dimethyl-3,5,8-dioxabicyclo[5.1.0] octane, which were described by Japanese authors in 1995 [O. Yamada, K. Ogasawara Lipase-mediated preparation of optically pure four-carbon di - and triols from meso-precursor // Synthesis. - 1995. - N. 10. - P. 1291-1294]. In this work to separate the obtained racemic alcohol on their enantiomers was used lipase PS (Amano). However, the biological properties of the synthesized enantiomers have not been studied at all.

The prior art identified known the awn disclosure thiophenols another disubstituted derivative 3,5,8-dioxabicyclo[5.1.0]octane namely, 3,5,8-dioxaspiro[bicyclo[5.1.0]octane-4,1-cyclohexane] obtained by the applicant [Pavelyev R. S., Klimovitsky E. N., Nikitina L. E. Synthesis of isomeric hydroxysulfates (sulfones) based 3,5,8-dioxaspiro[bicyclo[5.1.0]octane-4,1'-cyclohexane] // Chemistry for sustainable development. - 2010. - So 18, No..6. - S. 775-781].

Thus, the obtained 3,5,8-dioxaspiro[bicyclo[5.1.0]octane-4,1-cyclohexane] was not investigated by the applicant for the presence of antifungal activity.

Besides this, the applicant also identified their own work to study the reaction of cialisa thiophenols monopolization when acetaldol the carbon atom isomeric 3,5,8-dioxabicyclo[5.1.0]octanol [Pavelyev R. S., Gnevashev S. G., Vafina R. M., Gnezdilov O. I., A. Dobrynin Century, Lisovskaya S. A., Nikitina L. E., Klimovitsckii E. N. Synthesis and Antimycotic Properties of Hydroxy Sulfides Derived from exo - and endo-4-phenyl-3,5,8-trioxabicyclo[5.1.0]octanes // Mendeleev communications. - 2012. - V. 12, no. 3. - P. 127-128].

The obtained isomeric beta-hydroxysulfate (including anunciacion) were investigated for the presence of antifungal activity, which was strongly dependent on the structure of the synthesized compounds. However, the minimum inhibiting concentrations of these compounds were very high and was not of practical interest from the point of view of availability of perspectives in the development of new antifungal funds.

Himself 3,5,8-dioxabicyclo[5.1.0]octane would be the subjected to tialize thiophenols in the presence of potash reaction without solvent, in the course of which was obtained 6-(phenylthio)-1,3-dioxan-5-ol, which differs from the claimed compounds in the absence of the halogen atom in the aromatic ring [Pavelyev R. S. Synthesis of β-hydroxy (acetoxy) sulfides and sulfones based 3,5,8-dioxabicyclo[5.1.0]octanol: Dis. ... candles. chem. Sciences: 02.00.03: protected 22.04.2011: appr. 08.07.2011 / Pavelyev Roman Sergeevich. - Kazan, 2011. - 142 S. - Bibliogr.: S. 127-142].

This spirit showed antimycotic activity, completely inhibiting the growth of the studied fungi (Candida albicans, Aspergillus fumigatus, Epidermophyton floccosum) in concentrations less than 1 mg/ml, but more than 0.5 mg/ml

Alternatively, the racemic alcohol was separated into the enantiomers by using lipase PS (Amano). Antifungal properties of enantiomers studied were not.

It should be noted that the above-described compounds in General, according to the applicant, can be regarded as structural analogues to the claimed technical solution due to the fact that they belong to the same class of compounds - 1,3-diasepam and do not coincide with the proposed technical solution according to the nature of substituents in discepola cycle, which define the antimycotic properties of the claimed technical solution.

The objective of the claimed technical solution is to create a new non-lethal biologically active compounds with high anti-fungal activity of the Yu both mizelialnah, yeast and yeast fungi.

The problem is solved by the synthesis of antifungal substances of General formula Ia and Ib:

where

when R1=F, R2=H, R3=H

when R1=Br, R2=H, R3=H

when R1=H, R2=Br, R3=H

when R1=H, R2=H, R3=Br

In modern medicine are not used antimycotics with similar structures.

The claimed substance on the background of low toxicity showed high antifungal activity against strains of Candida albicans, Aspergillus fumigatus, Epidermophyton floccosum, Mucor pusilos, Saccharomyces cerevisiae and can find application in medicine and veterinary medicine.

The applicant has not identified the sources, which would contain information about the impact of the distinctive features of invention technical result achieved. Specified a new property of the object determines, according to the applicant, according to the invention, the criterion of "inventive step".

Presented in the claimed technical solution of the compounds of formula Ia and Ib were obtained according to the scheme below:

where

R1R2R3
Ia-1FHH
Ib-1FHH
Ia-2BrSH
Ib-2BrHH
Ia-3HBrH
Ib-3HBrH
Ia-4HHBr
Ib-4HIIBr
III-1FHH
III-2BrHH
III-3HBr H
III-4HIIBr

Characteristics of the new compounds are given in the examples of specific performance. The structure of the obtained compounds were confirmed by mass spectrometry,1H and13C NMR spectroscopy. NMR spectra were recorded on a device Bruker AVANCE-400. The chemical shift was determined relative to the signals of the residual protons of the deuterated solvents (1H and13C). Monitoring the progress of reactions and the purity of the compounds was performed by TLC on plates Sorbfil Plates. Mass MALDI spectra were recorded on a wall-mounted device III Bruker equipped with a solid-state laser and a time-of-flight mass analyzer. Accelerating voltage of 25 kV. Samples were applied to the target Anchor Chip. The recording of the spectra was carried out in positive ion mode. The resulting spectrum was the sum of 300 spectra obtained at different points of the sample. As the matrices used 2,5-dihydroxybenzoic acid (DHB) (Acros, 99%) and n-nitroaniline (PNA). For preparation of matrices used chloroform. Application of samples to the target was performed by the method of "dried droplet".

The rotation angles of the beam of polarized light optically active compounds was determined on the polarimeter ADP-440 (B+S) (Britain).

Temperature p is Alenia crystalline substances were determined using an instrument MPA-100 OptiMelt (Stanford Research Systems).

To determine the enantiomeric excess (EE) used the NMR method1N-spectroscopy in the presence of shift-reagent (Tris[3-(heptafluoropropoxy)-(+)-comfort] europium (III) the firm ALDRICH CHEMISTRY), comparing painterly area (intensity) of the signals of the hydrogen atoms at the carbon atom With2enantiomers.

Examples of specific performance of the claimed technical solution

Example 1. Synthesis 3,5,8-dioxabicyclo[5.1.0]octane (II). To 22.35 g (223 mmol) of 1,3-dioxocyclohex-5-ene and 89 g (1061 mmol) and NaHCO3in 400 ml of fifty percent aqueous acetone at room temperature was added in portions with stirring 178 g (290 mmol) oxone. The reaction mass was further stirred for 1.5 hours the reaction Course was monitored by TLC. The product was extracted with methylene chloride (3×70 ml). Water saturated with sodium chloride and re-made extraction. The organic phases were combined and dried over magnesium sulfate. The solvent was evaporated. Received 19.18 g of colorless crystals with so pl. 56-57°C (yield 74%) [lit. Gianni M., Cody R., Asthana, M. R. The role of The generalized anomeric effect in the conformational analysis of 1,3-dioxacycloalkanes. Conformational analysis of 3,5-dioxabicyclo[5.1.0]octanes and 3,5,8-trioxabicyclo[5.1.0]octanes // J. Org. Chem. - 1977. - V. 42, N. 2. - P. 365-368].

Example 2. Synthesis of racemic 6-((2-forfair)thio)-1,3-dioxan-5-ol (Ia-1+Ib-1). A mixture of 0.22 g (1.72 mmol) of 2-portifino, 0.023 g (0.17 mmol) of K2CO3and 0.2 is (1.72 mmol) of epoxide II was heated until the first bubbles next, heating was stopped. There were intermittent (<1 min) boil the mixture with a sharp increase in temperature. The mass was cooled, the product was purified by the method of column chromatography (eluent is a mixture of petroleum ether and ethyl acetate in the ratio 4:1). Obtained 0.38 g of colorless oily liquid (yield 90%).

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 3.07 ush. s (1H, OH), 3.17 m (1H, H6,3J(N6N5)=5.4 Hz,3J(H6H7A)=5.8 Hz,3J(H6H7B)=6.3 Hz), 3.65 m (1H, H5,3J(H5H4A)=2.7 Hz,3J(H5H4B)=1.9 Hz), 3.74 m (1H, H4A,2J(H4AN4In)=-12.0 Hz), 3.83 DD (1H, H7A), 4.04 DD (1H, H7A,2J(H7AH7B)=-12.4 Hz), 4.09 DD (1H, H4B), 4.72 (1H, H2A,2J(H2AH2B)=-4.4 Hz), 4.73 (1H, H2B,), 7.04-7.51 m (4H, 2-FC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 54.61 (C6,4J(FC6)=-1.2 Hz), 65.41 (C7), 66.44 (C4), 71.63 (C5), 94.20 (C2), 116.20 (CAr,2J=-23.1 Hz), 120.02 (CAr,2J=-18.0 Hz), 124.75 (CAr,3J=3.8 Hz), 130.38 (CAr,3J=8.1 Hz), 135.49 (CAr), 162.59 (CAr,1J=246.0 Hz). Mass spectrum MALDI: 267 [M+Na]+, 283 [M+K]+.

Example 3. Synthesis of racemic 6((2-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-2+Ib-2). Synthesize and purify similar to compound (Ia-1+Ib-1) from 0.2 g (1.72 mmol) of epoxide II. Obtained 0.44 g of colorless oily liquid (yield 83%).

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 3.01 ush. s (1H, OH), 3.31 m (1H, H6,3J(H6H5)=5.5 Hz,3J(H6H7A)=5.7 Hz,3J(H6H7B)=2.7 Hz,4J(H6H4A)=-1.2 Hz), 3.72 TD (1H, H5,3J(H5H4A)=5.3 Hz,3J(H5H4B)=1.5 Hz), 3.78 DDD (1H, H4A,2J(H4AH4B)=-12.1 Hz), 3.93 DD (1H, H7A,2J(H7AH7B)=-12.6 Hz), 4.14 DD (1H, H7B), 4.14 DD (1H, H4B), 4.75 (1H, H2A,2J(H2AH2B)=-4.6 Hz), 4.76 (1H, H2B,), 7.07-7.60 m (4H, 2-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 54.17 (C6), 65.21 (C7), 66.51 (C4), 71.51 (C5), 94.42 (C2), 126.70 (CAr), 128.12 (CAr), 128.50 (CAr), 132.03 (CAr), 133.59 (CAr), 135.14 (CAr). Mass spectrum MALDI: 328 [M+Na]+, 344 [M+K]+.

Example 4. Synthesis of racemic 6-((3-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-3+Ib-3). Synthesize and purify similar to compound (Ia-1+Ib-1) from 0.2 g (1.72 mmol) of epoxide II. Obtained 0.47 g of colorless oily liquid (yield 89%).

An NMR spectrum1H (400 MHz, CDCl3) δ, memorial plaques: 2.96 ush. s (1H, OH), 3.24 m (1H, H6,3J(H6H5)=5.4 Hz,3J(H6H7A)=5.8 Hz,3J(H6H7B)=2.7 Hz), 3.69 TD (1H, H5,3J(H5H4A)=5.5 Hz,3J(H5H4B)=1.5 Hz), 3.76 DD (1H, H4A,2J(H4AH4B)=-12.0 Hz), 3.84 DD (1H, H7A,3J(H7AH7B)=-12.5 Hz), 4.04 DD (1H, H7B), 4.06 DD (1H, H4B), 4.73 (1H, H2A,2J(H2AH2B)=-4.6 Hz), 4.74 (1H, H2B,), 7.13-7.56 m (4H, 3-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 54.75 (C6), 65.22 (C7), 66.39 (C4), 71.50 (C5), 94.27 (C2), 122.98 (CAr), 129.86 (CAr), 130.44 (CAr), 130.53 (CAr), at 133.86 (CAr). 136.13 (CAr). Mass spectrum MALDI: 328 [M+Na]+, 344 [M+K]+.

Example 5. Synthesis of racemic 6-((4-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-4+Ib-4). Synthesize and purify similar to compound (Ia-1+Ib-1) from 0.2 g (1.72 mmol) of epoxide II. Obtained 0.48 g of a colorless crystalline substance TPL=58°C (yield 91%).

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 3.00 ush. d (1H, OH,3J(OHH5)=3.5 Hz), 3.20 m (1H, H6,3J(H6H5)=5.5 Hz,3J(H6H7A)=5.9 Hz,3J(H6H7B)=2.7 Hz,4J(H6H4A)=0.8 Hz), 3.75 ush. m (1H, H5,3J(H5H4A)=5.7 Hz), 3.76 m (1H, H4A,2J(H4AH4B)=-12.1 Hz), 3.83 DD (1H, H7A,2J(H7AH7B)=-12.5 Hz), 4.05 t (1H, H7B), 4.06 t (1H, H4B), 4.73 (1H, H2A,2J(H2AH2B)=-4.6 Hz), 4.75 (1H, H2B,), 7.27-7.44 m (4H, 4-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: at 54.91 (C6), 65.28 (C7), 66.39 (C4), 71.46 (C5), 94.30 (C2), 121.66 (CAr), 132.36 (CAr), 132.74 (CAr). 133.30 (CAr). Mass spectrum MALDI: 328 [M+Na]+, 344 [M+K]+.

Example 6. Separation of racemic 6-((2-forfinal)thio)-1,3-dioxan-5-ol (Ia-1+Ib-1) enantiomers by enzymatic acylation using lipase PS (Amano).

To a solution of 1.00 g (4.09 mmol) of racemic 6-((2-forfinal)thio)-1,3-dioxan-5-ol (Ia-1+Ib-1) in 30 ml of tetrahydrofuran or toluene was added 0.76 ml (8.19 mmol) of vinyl acetate and 0.5 g of lipase PS, immobilized on diatomite. The mixture was stirred at 30-40°C for two days. The lipase was filtered, the solvent removed in vacuo. The products were separated by the method of column chromatography (eluent is a mixture of petroleum ether and ethyl acetate in the ratio 7:1).

(5S,6S)-6-((2-forfinal)thio)-1,3-dioxan-5-ol (Ia-1).

Obtained 0.45 g of a transparent oily substance is (yield 45%) with the rotation angle of the beam of polarized light [α] 24D=1.2°; ee>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

(5R,6R)-6-((2-forfinal)thio)-1,3-dioxan-5-yl acetate (III-1).

Obtained 0.54 g of a colorless crystalline substance TPL=51-52°C (yield 46%) with the rotation angle of the beam of polarized light α=-0.4°; ee>99%.

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 2.06 (3H, CH3); 3.36 m (1H, H6,3J(H6H5)=5.5 Hz,3J(H6H7A)=6.5 Hz,3J(H6H7B)=2.1 Hz); 3.87 DD (1H, H7A,2J(H7AH7B)=-12.3 Hz); 3.89 DD (1H, H4A,2J(H4AH4B)=-12.7 Hz3J(H4AH5)=5.6 Hz); 4.08 DD (1H, H4B,3J(H4BH5)=2.1 Hz); 4.15 m (1H, H7B); 4.75 (1H, H2A,2J(H2AH2B)=-4.4 Hz); 4.80 (1H, H2B); TD 4.87 (1H, H5); 7.08-7.54 m (4H, 2-FC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 21.15 (CH3), at 51.89 (C6), 65.23 (C7(4)), 65.34 (C4(7)), 73.82 (C5), 94.49 (C2), 116.18 (CAr,2J=-23.1 Hz), 120.09 (CAr,2J=-17.8 Hz), 124.76 (CAr,3J=3.7 Hz), 130.49 (CAr,3J=8.0 Hz), 135.60 (CAr), 162.69 (CAr,1J=246.4 Hz), 170.19 (CO). Mass spectrum MALDI: 309 [M+Na]+, 328 [M+K]+.

Note the p 7. Synthesis of (5R,6R)-6-((2-forfinal)thio)-1,3-dioxan-5-ol (Ib-1).

To a solution of 0.5 g (1.75 mmol) of optically active acetate (III-1) in 20 ml of methanol was added 0.72 g (5.25 mmol) of potash (K2CO3). The mixture was stirred 5 hours at room temperature, then potash, and the solvent was removed. The product was purified by the method of column chromatography (eluent is a mixture of petroleum ether and ethyl acetate in the ratio 1:1). Obtained 0.40 g of a transparent oily substance (yield 93%) with the rotation angle of the beam of polarized light [α]24D=-1.2°; her>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

Example 8. Separation of racemic 6-((2-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-2+Ib-2) enantiomers by enzymatic acylation using lipase PS (Amano).

(5S,6S)-6-((2-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-2).

Synthesize and purify similar to compound (Ia-1) of 1 g (3.28 mmol) of racemic 6-((2-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-2+Ib-2). Obtained 0.41 g of a transparent oily substance (yield 41%) with the rotation angle of the beam of polarized light [α]24D=1.0°; her>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

(5R,6R)-6-((2-bromophenyl)thio)-1,3-dioxan-5-ol acetate (III-2).

Obtained 0.51 g of clear oil is shaped substance (yield 45%) with the rotation angle of the beam of polarized light α=0.2°; it>99%.

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 2.08 (3H, CH3); 3.46 m (1H, H6,3J(H6H5)=4.6 Hz,3J(H6H7A)=5.3 Hz,3J(H6H7B)=2.2 Hz,4J(H6H4A)=-1.2 Hz); 3.92 DDD (1H, H4A,2J(H4AH4B)=-12.8 Hz3J(C4AH5)=4.7 Hz); 3.96 DDD (1H, H7A,2J(H7AH7B)=-12.3 Hz4J(H7AH5)=-0.8 Hz); 4.13 DD (1H, H4B,3J(H4BH5)=2.0 Hz); 4.18 DD (1H, H7B); 4.77 (1H, H2A,2J(H2AH2B)=-4.4 Hz); 4.82 (1H, H2B); 4.92 m (1H, H5); 7.09-7.60 m (4H, 2-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 21.13 (CH3), 51.72 (C6), 64.87 (C7(4)), 65.47 (C4(7)), 73.65 (C5), 94.47 (C2), 126.64 (CAr), 128.05 (CAr), 128.55 (CAr), 132.40 (CAr), 133.49 (CAr), 134.97 (CAr), 170.10 (CO). Mass spectrum MALDI: 370 [M+Na]+, 386 [M+K]+.

Example 9. Synthesis of (5R,6R)-6-((2-bromophenyl)thio)-1,3-dioxan-5-ol (Ib-2).

Synthesize and purify similar to compound (Ib-1) from 0.5 g (1.44 mmol) of optically active acetate (III-2). Obtained 0.43 g of a transparent oily substance (yield 98%) with the rotation angle of the beam of polarized light [α]24D=-1.0°; ee>99%.

Spectra PITS the 1H and NMR13C the compounds obtained are fully consistent racemic sample.

Example 10. Separation of racemic 6-((3-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-3+Ib-3) enantiomers by enzymatic acylation using lipase PS (Amano).

(5S,6S)-6-((3-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-3).

Synthesize and purify similar to compound (Ia-1) of 1 g (3.28 mmol) of racemic 6-((3-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-3+Ib-3). Obtained 0.40 g of a colorless crystalline substance TPL=69°C (yield 40%) with the rotation angle of the beam of polarized light [α]24D=1.2°; ee>99%.

The NMR spectra of1H and NMR13With the compounds obtained are fully consistent racemic sample.

(5R,6R)-6-((3-bromophenyl)thio)-1,3-dioxan-5-ol acetate (III-3).

Obtained 0.45 g of a transparent oily substance (yield 40%) with the rotation angle of the beam of polarized light α=-0.1°; ee>99%.

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 2.09 (3H, CH3); 3.45 TD (1H, H6,3J(H6H5)=5.4 Hz,3J(H6H7A)=6.2 Hz,3J(H6H7B)=2.3 Hz); 3.84 DD (1H, H7A,2J(H7AH7B)=-12.3 Hz); 3.87 DD (1H, H4A,2J(H4AH4B)=-12.3 Hz3J(H4AH5)=5.4 Hz); 4.03 DD (1H, H4B,3J(H4 BH5)=2.3 Hz); 4.13 DD (1H, H7B); 4.74 (1H, H2A,2J(H2AH2B)=-4.6 Hz); 4.80 (1H, H2B); 4.92 TD (1H, H5); 7.15-7.63 m (4H, 3-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 21.07 (CH3), 52.06 (C6), 65.08 (C7(4)), 65.40 (C4(7)). 73.65 (C5), 94.38 (C2), 122.84 (CAr), 129.85 (CAr), 130.37 (CAr), 130.42 (CAr), 133.81 (CAr), 136.07 (CAr), 170.04 (CO). Mass spectrum MALDI: 370 [M+Na]+, 386 [M+K]+.

Example 11. Synthesis of (5R,6R)-6-((3-bromophenyl)thio)-1,3-dioxan-5-ol (Ib-3).

Synthesize and purify similar to compound (Ib-1) from 0.5 g (1.44 mmol) of optically active acetate (III-3). Obtained 0.40 g of a colorless crystalline substance TPL=69°C (yield 98%) with the rotation angle of the beam of polarized light [α]24D=-1.2°; ee>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

Example 12. Separation of racemic 6-((4-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-4+Ib-4) enantiomers by enzymatic acylation using lipase PS (Amano).

(5S,6S)-6-((4-bromophenyl)thio)-1,3-dioxan-5-ol (IA-4).

Synthesize and purify similar to compound (Ia-1) of 1 g (3.28 mmol) of racemic 6-((4-bromophenyl)thio)-1,3-dioxan-5-ol (Ia-4+Ib-4). Received 0.39 g of a colorless crystalline substance TPL=68°C (yield 39%) is the rotation angle of the beam of polarized light [α] 24D=1.0°; ee>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

(5R,6R)-6-((4-bromophenyl)thio)-1,3-dioxan-5-ol acetate (III-4).

Obtained 0.45 g of a transparent oily substance (yield 40%) with the rotation angle of the beam of polarized light α=-0.9°; ee>99%.

An NMR spectrum1H (400 MHz, CDCl3) δ, M. D.: 2.09 (3H, CH3); 3.32 TD (1H, H6,3J(H6H5)=5.4 Hz,3J(H6H7A)=6.1 Hz,3J(H6H7B)=2.4 Hz); 3.82 DD (1H, H7A,2J(H7AH7B)=-12.3 Hz); 3.86 DD (1H, H4A,2J(H4AH4B)=-12.5 Hz3J(H4AH5)=5.3 Hz); 4.03 DD (1H, H4B,,3J(H4BH5)=2.3 Hz); 4.13 DD (1H, H7B); 4.73 (1H, H2A,2J(H2AH2B)=-4.6 Hz); 4.80 (1H, H2B); 4.91 TD (1H, H5); 7.32-7.44 m (4H, 4-BrC6H4). NMR13C {H} (100 MHz, CDCl3) δ, M. D.: 21.13 (CH3), 52.26 (C6), 65.23 (C7(4)), 65.45 (C4(7)), 73.66 (C5), 94.46 (C2), 121.75 (CAr), 132.27 (CAr), 132.68 (CAr), 133.48 (CAr), 170.11 (CO). Mass spectrum MALDI: 370 [M+Na]+, 386 [M+K]+.

Example 13. Synthesis of (5R,6R)- 6-((4-bromophenyl)thio)-1,3-dioxan-5-ol (Ib-4).

Synthesize and purify similar to compound (Ib-1) of 0.5 is (1.44 mmol) of optically active acetate (III-4). Received 0.37 g of a colorless crystalline substance TPL=68°C (yield 91%) with the rotation angle of the beam of polarized light [α]24D=-1.0°; ee>99%.

The NMR spectra of1H and NMR13C the compounds obtained are fully consistent racemic sample.

The methodology for the study of antifungal activity

Due to the variety of properties of microscopic fungi and their differences in adaptive capacities, including the existence of fungi in vivo, the representatives of the other kingdoms of living beings, including man, you must use the test strains of fungi, as belonging to different classes, and to consider their potential ability to be pathogens. For a more complete evaluation of the investigated substances with regard to their antifungal properties, prediction of consequences from their use and identify areas for practical use, we have proposed the most important group of fungi with different physiological and biochemical activity related departments: Zygomycota - fungi (Mucor pusilos), Ascomycota higher fungi. In addition, since in the laboratory often reveal vegetative forms of fungi Ascomycota, they use the work classification, in accordance with which this group of fungi called deuteromycete, which in turn also divided into Blastomyces (yeast Candia albicans) and hyphomycetes (with the septate hyphae - Aspergillus fumigatus, Epidermophyton floccosum). Data on antifungal activity relative to the mushrooms can be extrapolated to the other representatives of the relevant taxa due to similarity of their structure and life processes.

Based on the above facts, the study of antifungal activity was carried out on strains of Candida albicans, Aspergillus fumigatus, Epidermophyton floccosum, Mucor pusilos, which were isolated from patients with mycosis. Cultivation of fungi was carried out in the liquid nutrient medium Saburo.

Evaluation of antifungal activity was performed in vitro by serial dilution method based on the determination of the minimum inhibitory concentration (MIC).

To study the antifungal activity took physiologically active two-day culture of yeast fungi and shestitochiya culture of filamentous fungi. Next was preparing a suspension of fungi at a concentration of 1-2 million/ml Suspension of vegetative cell or spore suspension was made in a test tube with media containing a set of concentrations of the studied compounds: from 160 mg/ml to 0.1 mg/ml were Incubated at a temperature of 28-30°C for 9 days. As control was used environment in the absence of drugs. MIC (minimum inhibitory concentration) was estimated using fotoelektrokalorimetry at a wavelength of 530 nm. The warranty is if compared with the figures of absorption in the control tubes.

Also used a strain of the yeast Saccharomyces cerevisiae No. Y-830. Yeast cells of S. cerevisiae were grown on YPD medium until the stationary phase of growth within days at 37°C and 250 rpm/min determination of the minimum inhibitory concentration of the substances was performed by standard methods of microdesmidae culture [I. Wiegand, Hilpert K., Hancock, R. E. W. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances / Nature Protocols. - 2008. - V. 3. - pp.163-175]. The culture was diluted to 106 cells/ml Stock concentration was 90 mg/ml, which was then diluted 10 times and consistently got divorced dmocrate to 20480 time, initial concentration. Cultivation of the substance was added in the amount of 100 μl to 100 μl of nutrient medium YPD in 96-well plate. As controls were used nutrient medium and untreated cells. Incubation occurred at 37°C for 24 hours and 250 rpm data Obtained optical density of the culture at a wavelength of 600 nm were compared with controls and were expressed as the ordinate axis polynomial graph, the abscissa is expressed in decimal logarithm of the concentration of the substance. According to the schedule found minimum inhibitory concentration.

As a reference (connection to compare the antifungal activity of the compounds were selected known modern antifungals, fluconazole and terbinafine.

Table 1.
The minimum inhibiting concentration (mg/ml) of compounds of General formula Ia and Ib in relation to the strains studied mushrooms
SampleSaccharomyces cercvisiaeCandida albicansAspergillus fumigatusEpidermophyton floccosumMucor pusilos
Ia-10,161,51,51,51,5
Ib-11,132,52,52,52,5
Ia-20,10,50,50,90,9
Ib-20,930,711,51,5
Ia-30,040,150,150,3
Ib-30,260,60,70,70,9
Ia-40,1511,51,50,3
Ib-40,961,52,52,50,9
Fluconazole0,241,52,52,52
Terbinafine0,260,10,120,150,5

From the presented data in table 1 it follows that the claimed compounds have antifungal activity, in this connection, Ia-3, Ia-4 inhibit the growth of fungi at the level of terbinafina - one of the most powerful systemic antimycotics, identified by the applicant on the date of submission of application materials, you must specify its high CIT is toxicity.

Table 2 summarizes spookiest the most active compounds Ia-2 and Ia-3 in normal cells, dog kidney (MDCK) in comparison with known antifungal drugs fluconazole and terbinafine. The experiment was performed according to the following method.

Cells of the kidney dogs Maiden-Derby (line MDCK) were cultured in polystyrene flasks in DMEM with addition of 10% fetal serum of calves, 2 mm L-glutamine, 100 µg/ml streptomycin and 100 units/ml penicillin in CO2-incubator at 37°C, 5% CO2. Cells were grown until reaching monolayer and dissociatively using a solution of trypsin-EDTA. The density of cells in the suspension was estimated at hemocytometer. Cytotoxicity were determined using proliferative MTT-test. Cells were dissipated in a 96-well plate with a density of 1000 cells per well and has precultural 12 hours under standard conditions. In the culture medium was made of the sample solutions of the investigated substances in phosphate-buffered saline (FSB) in various concentrations and cultured cells 3 days. After incubation the wells were made in 20 μl of MTT reagent concentration of 5 mg/ml in DMEM, and the mixture was stirred for 2 h, then the culture medium was replaced with DMSO and then measured the absorption in the wells at 550 on the tablet analyzer Infinite 200 PRO (Tecan). Cell viability is proportional to the absorption solution, exp is tight relative to the control (FSB), 100%. Cytotoxicity was assessed by the magnitude of the concentrations of these substances, inhibiting cell growth by 50% (inhibitory concentration, IC50).

Table 2.
The results of the study of cytotoxicity of compounds Ia-2 and Ia-3 on normal cells of the kidney of the dog MDCK (IC50, µg/ml)
ConnectionIC50, µg/ml
Ia-232.2±5.6
Ia-339.7±4.3
Fluconazole57.2±6.9
Terbinafine9.8±1.0

Presented in table 2 data shows that the analyte and a half to two times more toxic fluconazole and three-four times less toxic terbinafine. Thus, the synthesized 6-(arieti)-1,3-dioxan-5-Ola interest in the development of new low-toxic antifungal agents, because the claimed technical solution is more acceptable therapeutic latitude of action.

The claimed technical solution meets the criterion of "novelty", presented to the invention, since the home is built, the set of actions performed leading to the realization of this goal could not be identified from the studied technology.

The claimed technical solution meets the criterion of "inventive step", presented to the invention, because it allows one to resolve not resolved prior to the filing date of the present application materials the problem of creating effective and safe antimycotics.

The claimed technical solution meets the criterion of "industrial applicability", presented to the invention, since the performed experiments showed the possibility of industrial applications to obtain in the industry antimycotic funds, based on the claimed technical solution.

Antifungal compounds derived 3,5,8-dioxabicyclo[5.1.0]octane, obtained TRANS-disclosure of epoxy cycle, namely 6-(arieti)-1,3-dioxan-5-Ola in racemic and anunciacion a General formula Ia and Ib
where
when R1=F, R2=H, R3=H
when R1=Br, R2=H, R3=H
when R1=H, R2=Br, R3=H
when R1=H, R2=H, R3=Br



 

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