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    • 专利摘要:
    Compounds with structure of drimenyloxarenes and derivatives, and their use for the treatment of infections produced by phytopathogenic fungi, as fungistatic agents with low ecological impact. The present invention comprises compounds with the general formulas 1 (Figure 1), 2 (Figure 2), 3 (Figure 3) and 4 (Figure 4), where R1 , R2 and R3 are hydrogen atoms or chains or cycles that may contain carbon, hydrogen or other hetero atoms atoms. These compounds can be used as plant protection agents to control diseases caused by fungi of the genus Botrytis and other phytopathogenic fungi. The claimed compounds are equally applicable to inhibit fungal growth in various non-agricultural applications. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2696903A1
    申请号:ES201700660
    申请日:2017-07-14
    公开日:2019-01-18
    发明作者:Collado Isidro Gonzalez；Sanchez Antonio José Macias；Gonzalez Antonio Ruano；Ana Andreina Pinto
    申请人:Universidad de Cadiz；
    IPC主号:
    专利说明:

    [0001]
    [0002] Compounds with drimenyloxyane structures and derivatives and their use for the treatment of infections caused by phytopathogenic fungi, as fungistatic agents with low ecological impact.
    [0003]
    [0004] Sector of the technique
    [0005]
    [0006] The invention belongs to the field of agricultural fungicides.
    [0007]
    [0008] State of the art
    [0009]
    [0010] Numerous species of fungi are capable of causing infections and act as pathogens on commercial crops with great economic impact in agriculture. At present, a large number of fungicides have been developed in order to prevent and reduce the diseases caused by these pathogenic fungi.
    [0011]
    [0012] Among the phytopathogenic fungi that affect commercial crops of economic importance are the fungi of the genus Botrytis, which are widely distributed throughout the world (from cold areas to tropical areas). Botrytis is an imperfect fungus of the monilinial order, polyphagous, which can act as a saprophyte or as a necrotroph on more than 200 different plants. The genus Botrytis includes several species such as: B. cinerea, B. there, B. squamosa. Among them, B. cinerea presents a special interest due to the considerable economic losses it produces. This pathogen attacks fruits such as grapes and strawberries, vegetables such as beans, carrots and cucumbers and ornamental plants such as begonias, chrysanthemums, geraniums, roses and tulips.
    [0013]
    [0014] The development of tolerance by species of the genus Botrytis to various commercial fungicides has led to the loss of effectiveness of these or the need to use larger quantities of them. This fact, together with the increase in public concern about the environmental impact of the excessive use of pesticides and the development of populations resistant to fungicides, has led to a growing interest in the search for and development of new fungal control chemicals. reduced persistence in the ecosphere and, therefore, I do not know how to incorporate into the food chain.
    [0015]
    [0016] Therefore, it is interesting to obtain new fungicides and fungistatic agents of low ecological impact and methods to treat or prevent fungal infections. Previous examples of compounds for treating fungal infections are the 2-O, 9-substituted clove derivatives (ES2154185 A1), the 2-N, 9-substituted clovanic derivatives (ES 2241482 A1), the phenylethanol skeleton derivatives (ES 2221805 A1 ), the (phenylhydroxyethylamino) benzoic derivatives (ES 2325513 A1) and the 2N, 9-substituted derivatives (Admitted for processing 201700028).
    [0017]
    [0018] Explanation of the invention
    [0019]
    [0020] The invention comprises compounds with the general formula 1 (Figure 1) where R1, R2 and R3 are hydrogen atoms or chains or rings that may contain carbon, hydrogen or other heteroatoms atoms.
    [0021]
    [0022] The invention comprises compounds with the general formula 2 (Figure 2) wherein R1, R2 and R3 are hydrogen atoms or chains or rings which may contain carbon, hydrogen or other hetero atoms atoms.
    [0023] The invention comprises compounds with the general formula 3 (Figure 3) where R1, R2 and R3 are hydrogen atoms or chains or rings which may contain carbon, hydrogen or other hetero atoms atoms.
    [0024] The invention comprises compounds with the general formula 4 (Figure 4) where R1, R2 and R3 are hydrogen atoms or chains or rings which may contain carbon, hydrogen or other heteroatoms atoms.
    [0025] To prepare compounds of general formula 1-4 with R1, R2 and R3 as previously defined, the following procedure can be used:
    [0026] Starting from the corresponding epoxypharnesiloxiderivative, compounds 19-24, it is possible to obtain derivatives of drimenyloxarenes of general formula 1-4, by rearrangement catalyzed by monochloride of titanocene, Cp2Ti (III) CI, using manganese (0) as reducing agent (Barrero, AF, Quílez , F., Sanchez, EM & Arteaga, JF Titanocene-Mediated Radical Cyclization: An Emergent Method Towards the Synthesis of Natural Products, European J. Org. Chem. 2, 1627-1641 (2006)).
    [0027] These compounds, of general formula 1-4 are able to reduce the growth of a fungus by application of a sufficient amount thereof.
    [0028] These derivatives can be used to reduce the growth of the fungus prophylactically, or to reduce the growth of a fungus already present in the area to be treated. Preferably, the disclosed compounds are used to reduce or prevent the growth of plant pathogenic fungi; however, these compounds can be used to inhibit fungal growth in various non-agricultural applications (for example, to reduce moisture damage on wood, paints, etc.).
    [0029] Brief description of the figures
    [0030] For a better understanding of what is described in this report, a series of figures describing the compounds referred to throughout the text are attached.
    [0031] Figure 1. Compounds of general formula 1, wherein R1, R2 and R3 are chains or rings that may contain carbon, hydrogen or other heteroatoms.
    [0032] Figure 2.- Compounds of general formula 2, wherein R1, R2 and R3 are hydrogen atoms or chains or cycles which may contain carbon, hydrogen or other heteroatoms atoms.
    [0033] Figure 3.-. Compounds of general formula 3, wherein R 1, R 2 and R 3 are hydrogen atoms or chains or rings which may contain carbon, hydrogen or other hetero atoms atoms.
    [0034] Figure 4 .- Compounds of general formula 4, wherein R 1, R 2 and R 3 are hydrogen atoms or chains or cycles that may contain carbon atoms, hydrogen or other heteroatoms.
    [0035] Figure 5.- Compounds 5-10 of general formula 1.
    [0036] Figure 6.- Compounds 11-14 of general formula 2.
    [0037] Figure 7.- Compounds 15 and 16 of general formula 3.
    [0038] Figure 8. Compounds 17 and 18 of general formula 4.
    [0039] Figure 9.- Compounds 19-24, precursors of the drimanyloxyacenes.
    [0040] Figure 10.- Table 1 describing the 1 H-NMR data for compounds 5, 7, 9 and 10.
    [0041] Figure 11.- Table 2 describing 13C-NMR data for compounds 5, 7, 9 and 10.
    [0042] Figure 12.-Table 3 that describes the 1H-NMR data for compounds 11-14.
    [0043] Figure 13.- Table 4 describing 13C-NMR data for compounds 11-14.
    [0044] Figure 14.- Table 5 describing the 1 H-NMR data for compounds 15-18.
    [0045] Figure 15.- Table 6 describing 13C-NMR data for compounds 15-18.
    [0046] Figure 16.- Percentages of inhibition of the growth of the mycelium of the fungus B. cinerea by compounds 7, 10 and 14, depending on the concentration. Control: irgasan (5-chloro-2- (2,4-dichlorophenoxy) phenol).
    [0047] Figure 17. Percentages of inhibition of mycelial growth of the fungus B. cinerea by compounds 5, 9 and 13, depending on the concentration. Control: irgasan (5-chloro-2- (2,4-dichlorophenoxy) phenol).
    [0048] Figure 18.- Table describing the minimum inhibitory concentration of compounds 5, 7, 9-18 and irgasan, to reduce 50% (MIC50), the growth of the treated colony of the fungus B. cinerea.
    [0049] Embodiment of the invention. Examples of synthesized compounds and fungicidal activity shown
    [0050] Example 1. Preparation of drimanyloxycoumarins (5, 7, 9 and 10) (Figure 5).
    [0051] Starting from the epoxifarnesiloxicumarinas (19, 20). A mixture of Cp2TiCl2 (0.51 mmol) and manganese powder (10.2 mmol) dissolved in dry and deoxygenated THF (100 ml) was stirred in a round-bottomed flask, when the initially red solution acquired a green coloration was added the corresponding epoxide derivative (19. 20) that had previously been dissolved in dry and deoxygenated THF (0.1 g in 5 ml of THF). The reaction was maintained under stirring under inert atmosphere conditions for 4 h. After the marked time, the reaction was stopped by adding a volume of 5 ml HCl (2N), filtered, extracted with ethyl acetate (AcOEt), dried with anhydrous Na 2 SO 4 and concentrated in vacuo. The reaction crude was purified by column chromatography (AcOEt / Hexane 1: 4) obtaining the corresponding mixture of exocyclic and endocyclic isomers (5, 7 and 9, 10) which was subsequently purified by HPLC chromatography.
    [0052] Physical and spectroscopic data for compound 5.
    [0053] White solid. , MP, 159 ° C-160 ° C.
    [0054] IR Vmax (film): 3446, 2927, 2871, 1710, 1620, 1504, 1258, 1174, 989 cm'1
    [0055] UV Amax (nm): 270, 260.
    [0056] 1 H-NMR; Table 1-1H (see Figure 10)
    [0057] 13C-NMR; Table 2-13C (see Figure 11)
    [0058] HRMS (ESI +): Calculated for C 24 H 31 O 4 [M + H] + 383.2222, observed in 383.2219.
    [0059] Physical and spectroscopic data for compound 7.
    [0060] Amorphous solid,
    [0061] IR Vmax (film): 3446, 2927, 2871, 1710, 1620, 1504, 1258, 1174, 989 cm-1.
    [0062] UV Amax (nm): 270, 260.
    [0063] 1 H-NMR; Table 1-1H (see Figure 10)
    [0064] 13C-NMR; Table 2-13C (see Figure 11)
    [0065] HRMS (ESI +): Calculated for C 24 H 31 O 4 [M + H] + 383.2222, observed in 383.2222.
    [0066] Physical and spectroscopic data for compound 9.
    [0067] Amorphous solid,
    [0068] IR Vmax (film): 3476, 2940, 2870, 2446, 1714, 1600, 1511, 1470, 1389, 1146, 1071, 851, 754 cm-1.
    [0069] UV Amax (nm): 270, 250.
    [0070] 1 H-NMR; Table 1-1H (see Figure 10)
    [0071] 13C-NMR; Table 2-13C (see Figure 11)
    [0072] HRMS (ESI +): Calculated for C25H33O4 [M + H] + 397.2379, observed at 397.2375.
    [0073] Physical and spectroscopic data for compound 10.
    [0074] Amorphous solid,
    [0075] IR Vmax (film): 3456, 2929, 2852, 1713, 162, 1530, 1455, 1390, 1283, 1145, 1071, 1016, 850, 758 cm-1.
    [0076] UV Amax (nm): 270, 250.
    [0077] 1 H-NMR; Table 1-1H (see Figure 10)
    [0078] 13C-NMR; Table 2-13C (see Figure 11)
    [0079] HRMS (ESI +): Calculated for C25H33O4 [M + H] + 397.2379, observed at 397.2365;
    [0080] Example 2. Preparation of drimanyloxarenes (11-18)
    [0081] Starting from the corresponding epoxypharnesiloxyrene (21-24) and following the same procedure as that indicated in example 1, drimanyloxyacenes 11-18 were obtained. The following is the spectroscopic data of some of the synthesized compounds.
    [0082] Physical and spectroscopic data for compound 11.
    [0083] Amorphous solid,
    [0084] IR Vmax (film): 2917, 2849, 1732, 1485, 1391, 1250, 1035, 906, 871, 759 cm-1.
    [0085] UV Amax (nm): 275, 240.
    [0086] 1 H-NMR; Table 3-1H (see Figure 12)
    [0087] 13C-NMR; Table 4-13C (see Figure 13)
    [0088] HRMS (ESM-): Calculated for C23H33O3 [M + H] + 357.2430, observed at 357.2428.
    [0089] Physical and spectroscopic data for compound 13.
    [0090] Amorphous solid,
    [0091] IR Vmax (film): 3476, 2967, 2940, 2868, 1640, 1622, 1505, 1472, 1371, 1256, 1135, 1032, 804, 754 crn-1.
    [0092] UV Amax (nm): 260.
    [0093] 1 H-NMR; Table 3-1H (see Figure 12)
    [0094] 13C-NMR; Table 4-13C (see Figure 13)
    [0095] HRMS (ESI +): Calculated for C23H33O4 [M + H] + 373.2379, observed in 373.2365.
    [0096] Physical and spectroscopic data for compound 15.
    [0097] Amorphous solid,
    [0098] IR Vmax (film): 3395, 2965, 2939, 2871, 1716, 1696, 1651, 1596, 1455, 1442, 1263, 1226, 1029, 1009, 753 cm-1.
    [0099] UV Amax (nm): 260.
    [0100] 1 H-NMR; Table 5-1H (see Figure 14)
    [0101] 13C-NMR; Table 6-13C (see Figure 15)
    [0102] HRMS (ESI +): Calculated for C27H34O3Na [M + Na] + 429.2406, observed at 429.2396; calculated for C27H35O3 [M + H] + 407.2586, observed at 407.2575.
    [0103] Physical and spectroscopic data for compound 17.
    [0104] Amorphous solid,
    [0105] IR Vmax (film): 3450, 2969, 2941, 2870, 1599, 1496, 1472, 1408, 1390, 1268, 1230, 1191, 1115, 1110, 864, 808, 798, 757 cm'1.
    [0106] UV Amax (nm): 260.
    [0107] 1 H-NMR; Table 5-1H (see Figure 14)
    [0108]
    [0109] 13C-NMR; Table 6-13C (see Figure 15)
    [0110]
    [0111] HRMS (ESI +): Calculated for C27H31O3NaCl3 [M + Na] + 531.1236, observed at 531.1238.
    [0112]
    [0113] Physical and spectroscopic data for compound 18.
    [0114]
    [0115] IR Vmax (film) 3421, 2964, 2928, 2853, 1598, 1497, 1473, 1408, 1389, 1267, 1231, 1191, 1114, 1099, 809, 800, 756 cm-1.
    [0116]
    [0117] UV Amax (nm) 280, 250.
    [0118]
    [0119] 1 H-NMR; Table 5-1H (see Figure 14)
    [0120]
    [0121] 13C-NMR; Table 6-13C (see Figure 15)
    [0122]
    [0123] HRMS (ESI +): Calculated for C27H31O3NaCI3 [M + Na] + 531.1236, observed at 531.1243.
    [0124]
    [0125] Example 3. Assay of growth inhibition of B. cinerea mycelium by compounds 5-18. Microdilution method.
    [0126]
    [0127] The lowest concentration that inhibits mycelial growth by 50%, compared to the positive control (MIC50) was evaluated in triplicate, using the microdilution method, using 96-well microplates. Solutions of compounds 5-18 were prepared in DMSO (12.5 mg / mL). From these stock solutions, solutions of the compounds in the range 125-0'06 pg / mL were prepared using Sabourad-glucose medium, so that the final concentration of DMSO does not exceed 2%. Both solutions inoculated with the fungus (Compound Medium Fungus, MCH) and solutions without inoculation were prepared (Compound Medium, MC). On the other hand, control solutions containing the inoculated microorganism were prepared in the culture medium (positive control, Fungus Medium, MH) and sterile culture medium without inoculation (Medium, M). The final concentration of spores in the inoculated solutions is 5 x 103 spores / mL.
    [0128]
    [0129] The plates were incubated for 72 hours at a temperature of 28 ° C to 30 ° C together with a fungus control plate (MFI) and another control medium (M). Irgasan (5-chloro-2- (2,4-dichlorophenoxy) phenol) was used as a negative control (inhibition of the fungus over a wide range of concentrations). The tests were carried out in triplicate. After the aforementioned time the absorbance reading was performed at 492 nm in an absorbance reader in 96-well ELISA plates and the inhibition percentages (l%) were calculated, using the means / standard deviation to construct the curves which represent the percentage of inhibition (%) against the concentration (Percentage of inhibition (l%) = 100-100 * (Abs492MCH-Abs492MC) / (Abs492MH-Abs492M)). Estimates of MIC50 values for each compound were obtained from these curves, by fitting to a dose-response curve.
    权利要求:
    Claims (8)
    [1]
    1. Compounds 7-drimeniloxicumarinas, with the general formula 1 (Figure 1), where R1, R2 and R3 are hydrogen atoms or chains or cycles that can contain carbon atoms, hydrogen or other heteroatoms.

    [2]
    2. Compounds derived from substituted drimenyloxyacetophenones, with the general formula 2 (Figure 2), where R2 and R3 are hydrogen atoms or chains or cycles which may contain carbon, hydrogen or other heteroatoms atoms.

    [3]
    3. Compounds derived from substituted drimenyloxybiphenyls, with the general formula 3 (Figure 3), wherein R1, R2 and R3 are hydrogen atoms or chains or cycles which may contain carbon, hydrogen or other heteroatoms atoms.

    [4]
    4. Compounds derived from 2,4-dichloro-1- (4'-chloro-2- (3 "-hydroxydrimenyloxy) phenoxy) benzene substituted, with the general formula 4 (Figure 4), where R1, R2 and R3 are atoms of hydrogen or well chains or cycles that may contain carbon, hydrogen or other heteroatom atoms.

    [5]
    5. Use of the compounds to which claims 1-4 refer for the treatment of infections caused by phytopathogenic fungi, as fungistatic agents of low ecological impact.
    [6]
    6. Use of the compounds to which claims 1-4 refer to control infections caused by phytopathogenic fungi, especially of the genus Botrytis.
    [7]
    7. Use of the compounds to which claims 1-4 refer to inhibit fungal growth in various non-agricultural applications.
    [8]
    8. Use of the compounds to which claims 1-4 refer to reduce the damage that fungal growth produces on wood and paints.
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    ES2696903B2|2019-05-24|
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    优先权:
    申请号 | 申请日 | 专利标题
    ES201700660A|ES2696903B2|2017-07-14|2017-07-14|Composed with structures of drimenyloxyacenes and derivatives and their use for the treatment of infections caused by phytopathogenic fungi, as fungistatic agents of low ecological impact|ES201700660A| ES2696903B2|2017-07-14|2017-07-14|Composed with structures of drimenyloxyacenes and derivatives and their use for the treatment of infections caused by phytopathogenic fungi, as fungistatic agents of low ecological impact|
    PCT/ES2018/000060| WO2019012166A1|2017-07-14|2018-07-13|Compounds with drimenyloxyarene structures and derivatives, and the use thereof to treat infections caused by phytopathogenic fungi, as fungistatic agents with a low ecological impact|
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