CN104961686B - The synthetic method and its application in five kinds of common causative fungi growth activities suppress of 1,6 dihydrogen dazins and pyridazine compound - Google Patents

The synthetic method and its application in five kinds of common causative fungi growth activities suppress of 1,6 dihydrogen dazins and pyridazine compound Download PDF

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CN104961686B
CN104961686B CN201510252977.7A CN201510252977A CN104961686B CN 104961686 B CN104961686 B CN 104961686B CN 201510252977 A CN201510252977 A CN 201510252977A CN 104961686 B CN104961686 B CN 104961686B
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chlorphenyls
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CN104961686A (en
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陈加荣
胡小强
肖文精
严冬梅
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Huazhong Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention provides 1, the synthetic method and its application in five kinds of common causative fungi growth activities suppress of 6 dihydrogen dazins and pyridazine compound, the compound is compound shown in Formulas I and its pyridazine salt compounds shown in formula III or its enantiomter, diastereoisomer, racemic modification, pharmaceutically acceptable salt, crystalline hydrate or solvate.Wherein, R1For the aromatic radical optionally substituted, the benzyl optionally substituted or the alkyl optionally substituted；R2For the aromatic radical optionally substituted；R3For p-toluenesulfonyl.The compound can be used in treating fungus-caused relevant disease.

Description

The synthetic method of 1,6- dihydrogen dazins and pyridazine compound and its in five kinds of common causes Application in sick fungi growth activity suppression
Technical field
The present invention relates to chemical field, specifically, the present invention relates to compound and its preparation method and application, more specifically , the present invention relates to compound and derivative and its preparation method and application shown in formula Ι.
Background technology
Pyridazine and its derivative are as a kind of important hexa-atomic nitrogen heterocyclic ring, the organic bases being derived from living nature Compound, is widely present in many bioactive natural products, and functional material has with some in the drug molecule of important biomolecule activity.Cause Its extensive bioactivity, pyridazine and its derivative are considered as " dominance structure " for finding newtype drug molecule, and it is efficiently high The synthesis of selectivity attracts the research interest of many chemists and medicine scholars always.
Tradition is very deficient on the synthetic method of 1,6- dihydrogen dazin class compounds, mainly passes through α, β-insatiable hunger Realized with the intramolecular cyclization reaction of halo hydrazone, but this method has higher reaction temperature, and relatively low yield and substrate are applicable The shortcomings of scope is narrower.And on the classical synthesis of pyridazine compound, to depend primarily on beta-unsaturated carbonyl compounds straight with hydrazine Connect cyclodehydration to react to obtain, but the regioselectivity of the reaction is poor.Therefore more efficient, high selectivity side is developed Method builds 1,6- dihydrogen dazins and pyridazine compound is that tool is of great significance.By the access to known method, We have found that using visible light catalytic strategy, by the intramolecular free radical cyclization of beta, gamma-unsaturated hydrazone come direct construction 1,6- dihydrogen dazin class compound, method is simple, mild condition, there is not yet document report.
Analyzed based on more than, the intramolecular that applicant sends out beta, gamma-unsaturated hydrazone of exhibition visible light catalytic is freely cyclization Reaction is next efficiently, synthesis has polysubstituted 1,6- dihydrogen dazins class compound with high selectivity.Herein on basis, Wo Menyou Develop the de- Ts protection groups aromatization of 1,6- dihydrogen dazins class compound under alkalescence condition, simply efficiently synthesize one Class pyridazine compound, and this kind of compound is used successfully in the synthesis of the pyridazine salt compounds with antibacterial activity Conversion.
In recent years, widely using due to antibiotic and immunodepressant, cause fungal infection that the trend risen is presented, because This clinical demand to novel antifungal drugs is continuously increased, the results showed that the pyridazine salt compounds pair that we design and synthesize Five kinds of common causative fungies such as candida albicans bacterium, Candida glabrata, Candida parapsilosis bacterium show good suppression System activity, there is the development prospect of the active ingredient as wide-spectrum bactericide.
The content of the invention
It is contemplated that at least solves one of technical problem in correlation technique to a certain extent.Therefore, the present invention Purpose is to propose a kind of compound with antibacterial activity.
In the first aspect of the present invention, there is provided a kind of compound.According to an embodiment of the invention, the compound is Formulas I The enantiomter of compound shown in shown compound or Formulas I, diastereoisomer, racemic modification, pharmaceutically acceptable salt, Crystalline hydrate or solvate,
Wherein,
R1For the aromatic radical optionally substituted, the benzyl optionally substituted or the alkyl optionally substituted；
R2For the aromatic radical optionally substituted；
R3For p-toluenesulfonyl.
It is surprisingly found by the inventors that compound according to embodiments of the present invention has effectively antibiotic bioactive
According to an embodiment of the invention, above-claimed cpd can also have following additional technical feature：
According to one embodiment of present invention, R1For the alkyl containing 1~10 carbon atom, the phenyl optionally substituted, The benzyl that optionally substitutes, phenylethyl, phenyl vinyl, 3- (N-Ts) indyl, 2- naphthyls, 3- pyrazinyls, 2- thienyls, 2- pyrrole radicals, 1,2,4- triazol radicals, 1,2,4- triazole methyl bases；
According to one embodiment of present invention, R2For phenyl, 2- aminomethyl phenyls, 3- methoxyphenyls, 4- chlorphenyls, 2- Chlorphenyl, 3- chlorphenyls, 4- chlorphenyls, 2,4 dichloro benzene base, 3- bromophenyls, 4- bromophenyls, 4- fluorophenyls, 3- fluorophenyls, 2, 4- difluorophenyls, 4- trifluoromethyls, the trifluoromethyls of 2,4- bis- or 1- methyl-benzyls, 2- pyrrole radicals, ortho position pyridine Base, meta pyridine radicals, contraposition pyridine radicals, 1,2,4- triazol radicals, 1,2,4- triazole methyl bases.
According to one embodiment of present invention, R1For isopropyl, the tert-butyl group, 3- amyl groups, cyclopropyl, cyclopenta, hexamethylene Base, phenyl, 2- aminomethyl phenyls, 3- methoxyphenyls, 4- chlorphenyls, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2,4- dichloros Phenyl, 3- bromophenyls, 4- bromophenyls, 4- fluorophenyls, 3- fluorophenyls, 2,4- difluorophenyls, 4- trifluoromethyls, 2,4- bis- Trifluoromethyl, 1- methyl-benzyls, 2- pyrrole radicals, ortho position pyridine radicals, meta pyridine radicals, contraposition pyridine radicals, benzyl, phenyl second Base, phenyl vinyl, 3- (N-Ts) indyl, 2- naphthyls, 3- pyrazinyls, 2- thienyls, 2- pyrrole radicals, 1,2,4- triazoles Base, 1,2,4- triazole methyl bases.
According to one embodiment of present invention, the compound is pair of following compounds or the following compounds Reflect isomers, diastereoisomer, racemic modification, pharmaceutically acceptable salt, crystalline hydrate or solvate：
In the second aspect of the present invention, there is provided a kind of pyridazine salt compounds of above-claimed cpd.According to the present invention's Embodiment, the compound is the enantiomter of compound shown in compound shown in formula III or formula III, diastereoisomer, outer Raceme, pharmaceutically acceptable salt, crystalline hydrate or solvate,
Wherein R1And R2It is as previously described in this way.
According to one embodiment of present invention, the pyridazine salt compounds are following compounds or followingization Enantiomter, diastereoisomer, racemic modification, pharmaceutically acceptable salt, crystalline hydrate or the solvate of compound：
In the third aspect of the present invention, the invention provides a kind of method for preparing compound shown in Formulas I noted earlier, root According to embodiments of the invention, this method includes：
Compound shown in formula A is set to be contacted with 2,2,6,6- tetramethyl piperidine oxides in the first organic solvent, with Just compound shown in Formulas I is obtained,
Wherein R1、R2、R3It is as defined in any one of Claims 1 to 4.
Optional, the first organic solvent is at least one of chloroform, toluene, methanol, tetrahydrofuran and acetonitrile；
Optionally, the contact is compound, 2 shown in formula A, and 2,6,6- tetramethyl piperidine oxides, inorganic base and light are urged Agent is dissolved in the first organic solvent, under the protection of argon gas, is reacted under the conditions of the irradiation of 3W blue LED lamp, TLC detections Reaction；
Optionally, the inorganic base is at least one of potassium carbonate, saleratus, potassium dihydrogen phosphate and sodium hydroxide.
Optionally, the photochemical catalyst is EosinY, Ru (bpy)3Cl2·6H2O、Ru(bpy)3(PF6)2With Ir (ppy)2 (dt-ppy)PF6At least one of；
Optionally, compound, 2 shown in the formula A, 2,6,6- tetramethyl piperidine oxides, the equivalent proportion of inorganic base are 1: 1:1.5；
Optionally, the reaction temperature is 25 degrees Celsius；
Optionally, silica gel column chromatography purifies, and separates compound shown in the Formulas I, wherein, the column chromatography uses petroleum ether It is used as with the mixture of ethyl acetate and separates phase, and the volume ratio of petroleum ether and ethyl acetate is 10:1~20：1.
Thus, according to an embodiment of the invention, the present invention proposes a synthetic route, can be used for shown in formula I Compound
In above-mentioned reaction, at room temperature, raw material beta, gamma-unsaturated hydrazone A, the 2 of 1.0 equivalents, 2,6,6- tetramethyl piperidine oxygen Compound B, the inorganic base potassium carbonate and 2mol% photochemical catalysts of 1.5 equivalents are dissolved in anhydrous chloroform, removed under the protection of argon gas Micro oxygen in solvent.Then room temperature reaction has been reacted until TLC is detected under the conditions of the irradiation of 3W blue LED lamp Entirely, with V petroleum ethers/V ethyl acetate=20:1-10:1 column chromatography directly obtains compound shown in Formulas I.
In the fourth aspect of the present invention, the invention provides a kind of method for preparing compound shown in formula III noted earlier, According to an embodiment of the invention, this method includes：
(1) compound shown in Formulas I is made to be contacted with sodium hydroxide, to obtain compound shown in Formula II,
(2) compound shown in Formula II is made to be contacted in a second organic solvent with compound shown in formula B, to obtain formula Compound shown in III,
Wherein R1、R2、R3It is as defined in any one of Claims 1 to 4.
Optional, contact described in step (1) is dissolved in acetonitrile for compound shown in Formulas I with sodium hydroxide, at 80 degrees Celsius Reaction is complete until TLC detection reactions, and silica gel column chromatography purification, the column chromatography is using petroleum ether and the mixture of ethyl acetate As separation phase, and the volume ratio of petroleum ether and ethyl acetate is 20:1~3:1；
Optionally, compound shown in Formulas I described in step (1) and the equivalent proportion of sodium hydroxide are 1:3；
Optionally, the second organic solvent is at least one of acetone, methanol, ethanol and acetonitrile in step (2)；
Optionally, it is organic molten to be that compound shown in compound shown in Formulas I and formula B is dissolved in first for contact described in step (2) In agent, react until there is linen solid；
Optionally, the reaction temperature is 100 degrees Celsius；
Optionally, filter, ether elution is pure, and reaction solution described in step (2) pours into bottle,suction, and suction filtration obtains solid, uses Ether washs to obtain compound shown in formula III.
Thus, according to an embodiment of the invention, the present invention proposes a synthetic route, can be used for formula III institutes Show compound
(1)
In above-mentioned reaction, raw material 1, the inorganic base sodium hydroxide of 6- dihydrogen dazins I and 3.0 equivalents is dissolved in acetonitrile, 80 Degree Celsius reaction is complete until TLC detection reactions, with V petroleum ethers/V ethyl acetate=20:1-3:1 column chromatography directly obtains formula Compound shown in II.
(2)
In above-mentioned reaction, 3, the 4- dihydroxy chloroacetophenones B of raw material pyridazine II and 2.0 equivalents is dissolved in anhydrous propanone, Under 100 degrees Celsius, tube sealing reaction directly filters until there is linen solid to separate out and obtains solid, wash to obtain with ether Formula III target product.
The fifth aspect of the present invention, the invention provides purposes of the compound noted earlier in medicine is prepared, the medicine Thing is used to treat disease, and optionally, the disease is as caused by least one following：Candida albicans bacterium, candida albicans Bacterium, Candida parapsilosis bacterium, Candida glabrata, neogenesis cryptococcus.
Embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair It is bright, and be not considered as limiting the invention.
Embodiment 1
Compound I-1
Preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone A-1 (117.0mg, 0.3mmol), the 2 of 1.0 equivalents, 2,6,6- tetramethyls Phenylpiperidines oxide (46.9mg, 0.3mmol), the inorganic base potassium carbonate (62.2mg, 0.3 mmol) and 2mol% light of 1.5 equivalents Catalyst Ru (bpy)3Cl2·6H2O (4.5mg, 0.006mmol) is dissolved in anhydrous chloroform, and solvent is removed under the protection of argon gas In micro oxygen.Then room temperature reaction reacts complete until TLC is detected under the conditions of the irradiation of 3W blue LED lamp, with VPetroleum ether/VEthyl acetate=20:1-10:1 column chromatography directly obtains the target product of Formulas I -1, yield 84%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=7.95 (d, J=8.2Hz, 2H), 7.81-7.81 (m, 2H), 7.57 (d, J=7.0Hz, 2H), 7.47-7.44 (m, 3H), 7.43-7.42 (m, 3H), 7.38 (d, J=8.1Hz, 2H), 6.81 (s, 1H),4.36(s,2H),2.45(s,3H)。
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.71,144.27,139.73,135.21,134.91, 131.95,129.79,129.58,129.48,128.79,128.66,128.36,125.75,125.38,112.43, 43.26, 21.44。
High-resolution：Calculated value：[M+H]+:389.1318；Measured value：389.1340.
Following compound is prepared according to compound I-1 method, and its Structural Identification data is as follows：
Embodiment 2
Compound I-2
Preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone A-2 (121.2mg, 0.3mmol), the 2 of 1.0 equivalents, 2,6,6- tetramethyls Phenylpiperidines oxide (46.9mg, 0.3mmol), the inorganic base potassium carbonate (62.2mg, 0.3 mmol) and 2mol% light of 1.5 equivalents Catalyst (4.5mg, 0.006mmol) is dissolved in anhydrous chloroform, and the micro oxygen in solvent is removed under the protection of argon gas.With Room temperature reaction reacts complete until TLC is detected under the conditions of the irradiation of 3W blue LED lamp afterwards, with V petroleum ethers/V ethyl acetate =20:1-10:1 column chromatography directly obtains the target product of Formulas I -2, yield 85%.1H NMR(600MHz,CDCl3)δ(ppm)δ =7.91 (d, J=8.1Hz, 2H), 7.66 (d, J=8.0Hz, 2H), 7.52 (d, J=7.7Hz, 2H), 7.40-7.33 (m, 3H), 7.33 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 6.76 (s, 1H), 4.30 (s, 2H), 2.40 (s, 3H),2.37(s,3H)。
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.77,144.26,139.82,139.75,135.42, 132.26,132.07,129.83,129.53,129.16,128.88,128.79,125.77,125.48,112.66, 43.39, 21.56,21.30。
High-resolution：Calculated value：[M+H]+:403.1475, measured value：403.1475.
Embodiment 3
Compound I-3
Preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone A-3 (127.2mg, 0.3mmol), the 2 of 1.0 equivalents, 2,6,6- tetramethyls Phenylpiperidines oxide (46.9mg, 0.3mmol), the inorganic base potassium carbonate (62.2mg, 0.3 mmol) and 2mol% light of 1.5 equivalents Catalyst (4.5mg, 0.006mmol) is dissolved in anhydrous chloroform, and the micro oxygen in solvent is removed under the protection of argon gas.With Room temperature reaction reacts complete until TLC is detected under the conditions of the irradiation of 3W blue LED lamp afterwards, with V petroleum ethers/V ethyl acetate =20:1-10:1 column chromatography directly obtains the target product of Formulas I -3, yield 74%.
1H NMR (600MHz, CDCl3) δ (ppm) δ=7.93 (d, J=7.9Hz, 2H), 7.73 (d, J=8.2Hz, 2H), 7.56 (d, J=6.7Hz, 2H), 7.48-7.45 (m, 3H), 7.39 (t, J=9.1Hz, 4H), 4.36 (s, 2H), 2.45 (s,3H)。
13C NMR (100MHz, CDCl3) δ (ppm) δ=149.67,144.42,140.09,135.60,135.18, 133.47,131.95,129.98,129.56,128.89,128.68,128.63,127.07,125.46,112.05, 43.29, 21.53。
High-resolution：Calculated value：[M+H]+:423.0929, measured value：423.0929.
Embodiment 4
Compound I-4
Preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone A-4 (118.8mg, 0.3mmol), the 2 of 1.0 equivalents, 2,6,6- tetramethyls Phenylpiperidines oxide B (46.9mg, 0.3mmol), the inorganic base potassium carbonate (62.2mg, 0.3 mmol) and 2mol% of 1.5 equivalents Photochemical catalyst (4.5mg, 0.006mmol) is dissolved in anhydrous chloroform, and the micro oxygen in solvent is removed under the protection of argon gas. Then room temperature reaction reacts complete until TLC is detected under the conditions of the irradiation of 3W blue LED lamp, with V petroleum ethers/V acetic acid second Ester=20:1-10:1 column chromatography directly obtains the compound of Formulas I -4, yield 59%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=7.95 (d, J=8.1Hz, 2H), 7.55 (d, J=7.9Hz, 2H), 7.48–7.44(m,3H),7.39–7.37(m,4H),7.08–7.03(m,1H),6.73(s,1H),4.34 (s,2H),2.45 (s,3H)。
13C NMR (100MHz, CDCl3) δ (ppm) δ=146.78,144.40,140.14,139.87,135.22, 131.91,130.02,129.52,128.94,127.92,127.26,125.89,125.54,112.09,43.72,21.60. M.P.:163.7–164.5℃。
High-resolution：Calculated value：[M+H]+:395.0882, measured value：395.0884.
Embodiment 5
Compound I-5
Preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone A-5 (106.8mg, 0.3mmol), the 2 of 1.0 equivalents, 2,6,6- tetramethyls Phenylpiperidines oxide (46.9mg, 0.3mmol), the inorganic base potassium carbonate (62.2mg, 0.3 mmol) and 2mol% light of 1.5 equivalents Catalyst (4.5mg, 0.006mmol) is dissolved in anhydrous chloroform, and the micro oxygen in solvent is removed under the protection of argon gas.With Room temperature reaction reacts complete until TLC is detected under the conditions of the irradiation of 3W blue LED lamp afterwards, with V petroleum ethers/V ethyl acetate =20:1-10:1 column chromatography directly obtains the target product of Formulas I -5, yield 72%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=7.92 (d, J=8.1Hz, 2H), 7.51 (d, J=6.6Hz, 2H), 7.47-7.43 (m, 3H), 7.40 (d, J=8.0Hz, 2H), 6.27 (s, 1H), 4.21 (s, 2H), 2.69-2.65 (m, 1H), 2.49(s,3H),1.19(s,3H),1.18(s,3H).
13C NMR (100MHz, CDCl3) δ (ppm) δ=159.09,143.98,139.62,135.27,131.83, 129.58,129.21,128.79,128.72,125.24,113.11,43.32,33.72,21.47,19.98.
High-resolution：Calculated value：[M+H]+:355.1475, measured value：355.1475.
Embodiment 6
Compound I-6
Yield is 63%.
1H NMR(400MHz,CDCl3) δ (ppm) δ=7.90 (d, J=8.3Hz, 2H), 7.50-7.48 (m, 2H), 7.46-7.43 (m, 3H), 7.37 (d, J=8.2Hz, 2H), 6.40 (t, J=1.2Hz, 1H), 4.15 (d, J=1.3Hz, 2H), 2.47(s,3H),1.19(s,9H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=160.97,144.08,139.56,135.65,131.87, 129.58,129.24,128.99,128.81,125.37,112.30,43.21,36.51,27.86,21.57.
High-resolution：Calculated value：[M+H]+:369.1631, measured value：369.1642.
Embodiment 7
Compound I-7
Yield is 71%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=7.89 (d, J=8.2Hz, 2H), 7.50-7.46 (m, 2H), 7.42 (q, J=6.1Hz, 3H), 7.35 (d, J=8.1Hz, 2H), 6.18 (s, 1H), 4.19 (s, 2H), 2.45 (s, 3H), 2.27- 2.22 (m, 1H), 1.58-1.48 (m, 4H), 0.79 (t, J=7.4Hz, 6H)
13C NMR(100MHz,CDCl3) δ (ppm) δ=157.18,144.03,139.82,135.34,131.91, 129.71,129.26,128.85,128.82,125.33,112.74,48.11,43.62,25.42,21.56,11.64.
High-resolution：Calculated value：[M+H]+:383.1788, measured value：383.1783.
Embodiment 8
Compound I-8
Yield is 83%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=7.87 (d, J=8.2Hz, 2H), 7.37-7.35 (m, 7H), 7.25 (s, 2H), 7.23-7.22 (m, 1H), 7.15 (d, J=7.1Hz, 2H), 6.08 (s, 1H), 4.20 (s, 2H), 3.68 (s, 2H), 2.46(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=153.51,144.06,139.60,136.33,134.78, 131.77,129.66,129.30,128.74,128.68,128.60,128.38,126.60,125.19,113.95, 43.17, 41.51,21.45.
High-resolution：Calculated value：[M+H]+:403.1475, measured value：403.1474.
Embodiment 9
Compound I-9
Yield is 70%.
1H NMR(400MHz,CDCl3) δ (ppm) δ=7.88 (d, J=8.2Hz, 2H), 7.49-7.43 (m, 5H), 7.38 (d, J=8.0Hz, 2H), 7.28-7.26 (m, 2H), 7.22-7.20 (m, 1H), 7.18 (d, J=7.1Hz, 2H), 6.17 (s, 1H),4.20(s,2H),2.96–2.93(m,2H),2.75–2.72(m,2H),2.50 (s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=154.36,144.08,140.74,139.68,135.06, 131.94,129.81,129.44,128.83,128.76,128.32,128.29,125.94,125.41,114.67, 43.26, 36.87,32.70,21.59.
High-resolution：Calculated value：[M+H]+:417.1631, measured value：417.1632.
Embodiment 10
Compound I-10
Yield is 70%.
1H NMR(400MHz,CDCl3) δ=7.83 (d, J=8.1Hz, 2H), 7.46 (d, J=6.4Hz, 2H), 7.40 (d, J=7.5Hz, 2H), 7.36 (d, J=6.9Hz, 3H), 7.29 (d, J=7.4Hz, 4H), 7.23 (d, J=7.1Hz, 1H), 6.95–6.82(m,2H),6.63(s,1H),4.23(s,2H),2.35(s,3H).
13C NMR(100MHz,CDCl3) δ=150.85,144.42,139.41,135.94,135.44,133.02, 132.06,129.91,129.63,128.93,128.77,128.73,128.69,126.94,125.73,125.51, 111.10,43.90,21.60.
High-resolution：Calculated value：[M+H]+:415.1475, measured value：415.1480.
Embodiment 11
Compound I-11
Yield is 84%.
1H NMR(600MHz,CDCl3) δ=7.97 (d, J=8.2Hz, 2H), 7.58-7.56 (m, 2H), 7.54-7.52 (m, 3H), 7.48 (d, J=8.0Hz, 2H), 6.17 (s, 1H), 4.28 (s, 2H), 2.57 (s, 3H), 1.81-1.79 (m, 1H), 0.98–0.94(m,4H).
13C NMR(100MHz,CDCl3) δ=156.09,143.96,139.69,135.07,131.75,129.61, 129.24,128.68,128.67,125.26,112.81,43.35,21.43,15.10,6.93.
High-resolution：Calculated value：[M+H]+:353.1318, measured value：353.1319.
Embodiment 12
Compound I-12
Yield is 86%.
1H NMR(600MHz,CDCl3) δ=7.88 (d, J=8.1Hz, 2H), 7.47 (d, J=6.9Hz, 2H), 7.42- 7.36 (m, 3H), 7.36 (d, J=8.0Hz, 2H), 6.22 (s, 1H), 4.18 (s, 2H), 2.83-2.80 (m, 1H), 2.46 (s, 3H),1.88–1.87(m,2H),1.70–1.61(m,6H).
13C NMR(100MHz,CDCl3) δ=157.78,144.04,139.64,135.31,131.90,129.63, 129.30,128.82,128.77,125.30,113.87,44.80,43.40,30.18,25.28,21.53
High-resolution：Calculated value：[M+H]+:381.1631, measured value：381.1639.
Embodiment 13
Compound I-13
Yield is 96%.
1H NMR(600MHz,CDCl3) δ=7.87 (d, J=8.1Hz, 2H), 7.45 (d, J=6.7Hz, 2H), 7.41- 7.38 (m, 3H), 7.35 (d, J=8.0Hz, 2H), 6.23 (s, 1H), 4.15 (s, 2H), 2.44 (s, 3H), 2.30-2.27 (s, 1H), 1.83-1.79 (m, 4H), 1.70 (d, J=12.9Hz, 1H), 1.36-1.27 (m, 5H)
13C NMR(100MHz,CDCl3) δ (ppm) δ=158.54,144.01,139.50,135.33,131.90, 129.60,129.29,128.81,128.76,125.29,113.49,43.48,43.35,30.25,25.85,25.80, 21.53.
High-resolution：Calculated value：[M+H]+:395.1788, measured value：395.1788.
Embodiment 14
Compound I-14
Yield is 61%.
1H NMR(600MHz,CDCl3) δ=7.93 (d, J=7.7Hz, 2H), 7.90 (d, J=8.0Hz, 2H), 7.68 (d, J=7.9Hz, 2H), 7.57 (d, J=7.4Hz, 2H), 7.47 (d, J=6.6Hz, 3H), 7.39 (d, J=7.8Hz, 2H), 6.78(s,1H),4.40(s,2H),2.45(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=149.37,144.61,140.22,138.40,135.12, 132.02,131.72,131.40,131.08,130.76,130.15,129.67,128.98,128.72,127.94, 126.13,125.52,125.45,125.41,125.23,122.53,119.82,111.93,43.37,21.57.
High-resolution：Calculated value：[M+H]+:457.1192, measured value：457.1190.
Embodiment 15
Compound I-15
Yield is 86%.
1H NMR(600MHz,CDCl3) δ=8.11 (s, 1H), 8.05 (d, J=8.7Hz, 1H), 7.96 (d, J= 8.3Hz, 2H), 7.88-7.84 (m, 3H), 7.59 (d, J=7.0Hz, 2H), 7.53-7.47 (m, 2H), 7.46-7.43 (m, 3H), 7.36 (d, J=8.1Hz, 2H), 6.96 (s, 1H), 4.38 (s, 2H), 2.41 (s, 3H)
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.59,144.42,139.89,135.50,133.88, 132.88,132.53,132.11,129.96,129.62,128.97,128.85,128.47,128.36,127.69, 126.89,126.46,125.59,123.31,112.56,43.57,21.62.
High-resolution：Calculated value：[M+H]+:439.1475, measured value：439.1475.
Embodiment 16
Compound I-16
Yield is 70%.
1H NMR(600MHz,CDCl3) δ=7.93 (d, J=8.2Hz, 2H), 7.67 (d, J=8.4Hz, 2H), 7.56 (d, J=7.1Hz, 4H), 7.49-7.44 (m, 3H), 7.38 (d, J=8.1Hz, 2H), 6.74 (s, 1H), 4.36 (s, 2H), 2.45(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=149.77,144.49,140.13,135.20,133.97, 132.00,131.62,130.04,129.62,128.93,128.73,127.38,125.51,124.01,112.01, 43.34, 21.58.
High-resolution：Calculated value：[M+H]+:467.0423, measured value：467.0418.
Embodiment 17
Compound I-17
Yield is 53%.
1H NMR(600MHz,CDCl3) δ=8.44 (d, J=7.3Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.93 (d, J=7.9Hz, 2H), 7.87 (s, 1H), 7.78 (d, J=7.8Hz, 2H), 7.58 (d, J=7.6Hz, 2H), 7.49-7.45 (m, 3H), 7.41-7.36 (m, 2H), 7.33 (s, 2H), 7.23 (d, J=7.9Hz, 2H), 4.39 (s, 2H), 2.39 (s, 3H), 2.35(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=146.60,145.33,144.37,139.96,135.21, 135.11,134.54,132.01,130.00,129.92,129.59,129.58,128.91,128.60,127.50, 126.78,125.46,125.42,124.15,123.86,118.67,113.01,112.42,43.42,21.49.
High-resolution：Calculated value：[M+H]+:582.1516, measured value：582.1528.
Embodiment 18
Compound I-18
Yield is 81%.
1H NMR(600MHz,CDCl3) δ=7.90 (d, J=8.2Hz, 2H), 7.75-7.73 (m, 2H), 7.56 (d, J= 8.5Hz, 2H), 7.40-7.39 (m, 5H), 7.34 (d, J=8.2Hz, 2H), 6.76 (s, 1H), 4.28 (s, 2H), 2.41 (s, 3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.59,144.44,138.51,134.81,134.22, 132.05,131.97,129.75,129.59,128.75,128.48,126.98,125.82,124.01,112.91, 43.07, 21.57.
High-resolution：Calculated value：[M+H]+:489.0243, measured value：489.0250.
Embodiment 19
Compound I-19
Yield is 51%.
1H NMR(600MHz,CDCl3) δ=7.88 (d, J=8.1Hz, 2H), 7.75-7.73 (m, 2H), 7.39-7.38 (m, 3H), 7.33 (d, J=8.0Hz, 2H), 7.29-7.26 (m, 2H), 7.22 (t, J=7.3Hz, 1H), 7.18 (d, J= 7.5Hz,1H),6.43(s,1H),4.08(s,2H),2.41(s,3H),2.40(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=151.14,144.24,142.21,137.16,135.16, 134.82,131.98,130.79,129.66,129.47,128.85,128.69,128.40,127.98,126.03, 125.77,116.33,45.11,21.48,20.37.
High-resolution：Calculated value：[M+H]+:403.1475, measured value：403.1476.
Embodiment 20
Compound I-20
Yield is 76%.
1H NMR(600MHz,CDCl3) δ=7.93 (d, J=8.2Hz, 2H), 7.78-7.77 (m, 2H), 7.51 (d, J= 8.8Hz, 2H), 7.41-7.39 (m, 3H), 7.35 (d, J=8.1Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 6.71 (s, 1H),4.30(s,2H),3.86(s,3H),2.42(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=160.92,151.04,144.27,139.45,135.26, 132.13,129.57,129.53,128.79,128.42,127.62,126.97,125.89,114.26,110.56, 55.35, 43.30,21.54.
High-resolution：Calculated value：[M+H]+:419.1424, measured value：419.1424.
Embodiment 21
Compound I-21
Yield is 78%.
1H NMR(400MHz,CDCl3) δ=7.96 (d, J=8.2Hz, 2H), 7.77 (s, 1H), 7.68 (d, J= 7.1Hz,1H),7.58–7.56(m,2H),7.49-7.47(m,3H),7.39–7.35(m,4H),6.75(s, 1H),4.38(s, 2H),2.46(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=149.50,144.53,140.15,136.88,135.18, 134.55,132.04,130.09,129.75,129.65,129.61,128.96,128.76,125.97,125.53, 124.00,112.08,43.37,21.59.
High-resolution：Calculated value：[M+H]+:423.0929, measured value：423.0936.
Embodiment 22
Compound I-22
Yield is 57%.
1H NMR(600MHz,CDCl3) δ=7.92 (d, J=8.0Hz, 2H), 7.77-7.76 (m, 2H), 7.49 (s, 1H), 7.43-7.42 (m, 3H), 7.38 (d, J=8.0Hz, 2H), 7.34-7.31 (m, 2H), 6.60 (s, 1H), 4.20 (s, 2H),2.45(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.69,144.48,138.36,135.61,134.85, 134.54,133.06,132.03,130.88,129.98,129.88,129.63,128.74,128.53,127.57, 125.83,117.86,44.41,21.58.
High-resolution：Calculated value：[M+H]+:457.0539, measured value：457.0541.
Embodiment 23
Compound I-23
Yield is 75%.
1H NMR(600MHz,CDCl3) δ=7.94 (d, J=8.2Hz, 2H), 7.79-7.77 (m, 2H), 7.50 (d, J= 8.5Hz,2H),7.45–7.42(m,5H),7.39(s,2H),6.79(s,1H),4.32(s,2H),2.45(s, 3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=150.54,144.38,138.40,135.65,134.77, 133.71,131.92,129.68,129.53,129.04,128.70,128.42,126.70,125.76,112.81, 43.08, 21.48.
High-resolution：Calculated value：[M+H]+:423.0929, measured value：423.0929.
Embodiment 24
Compound I-24
Yield is 72%.
1H NMR(600MHz,CDCl3) δ=7.93 (d, J=8.2Hz, 2H), 7.77-7.76 (m, 2H), 7.55-7.52 (m, 2H), 7.42-7.40 (m, 3H), 7.36 (d, J=8.1Hz, 2H), 7.14 (t, J=8.5Hz, 2H), 6.74 (s, 1H), 4.30(s,2H),2.43(s,3H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=164.63,162.14,150.65,144.36,138.64, 134.88,131.96,131.54,131.51,129.67,129.54,128.72,128.43,127.46,127.38, 125.80,116.07,115.86,112.38,43.27,21.51.
High-resolution：Calculated value：[M+H]+:407.1224, measured value：407.1224.
Embodiment 25
Compound II-1
Preparation
By raw material 1, the inorganic base sodium hydroxide of 6- dihydrogen dazins I-1 (116.4mg, 0.3mmol) and 3.0 equivalents (36.0mg, 0.9mmol) is dissolved in acetonitrile, in 80 DEG C of reactions until TLC detections are reacted completely, with VPetroleum ether/VEthyl acetate=20:1- 3:1 column chromatography directly obtains the target product of Formula II -1, yield 90%.
1H NMR(400MHz,CDCl3) δ (ppm) δ=9.45 (d, J=2.0Hz, 1H), 8.17 (d, J=6.8Hz, 2H), 8.04 (d, J=2.0Hz, 1H), 7.77 (d, J=6.8Hz, 2H), 7.61-7.55 (m, 6H)
13C NMR(100MHz,CDCl3) δ (ppm) δ=159.38,148.40,139.03,136.41,134.84, 130.06,130.04,129.50,128.99,127.20,127.12,120.99.
High-resolution：Calculated value：[M+H]+:233.1073, measured value：233.1068.
Following compound is prepared according to compound II-1 method, and its Structural Identification data is as follows：
Embodiment 26
Compound II-2
Yield is 91%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=9.31 (s, 1H), 7.92 (s, 1H), 7.77 (d, J=3.2 Hz, 1H), 7.72 (d, J=7.1Hz, 2H), 7.59-7.53 (m, 4H), 7.20 (t, J=4.2Hz, 1H)
13C NMR (100MHz, CDCl3) δ (ppm) δ=154.98,148.32,140.61,139.03,134.62, 130.20,129.56,129.41,128.15,127.14,126.41,119.20。
High-resolution：Calculated value：[M+H]+:239.0637, measured value：239.0646.
Embodiment 27
Compound II-3
Yield is 86%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=9.37 (d, J=1.9Hz, 1H), 8.03 (d, J=8.1Hz, 2H), 7.96 (d, J=1.9Hz, 1H), 7.71 (d, J=6.6Hz, 2H), 7.56-7.51 (m, 3H), 7.34 (d, J=8.0Hz, 2H), 2.43(s,3H)。
13C NMR(100MHz,CDCl3) δ (ppm) δ=159.25,148.16,140.28,138.94,134.88, 133.49,129.96,129.71,129.44,127.09,127.01,120.67,21.32。
High-resolution：Calculated value：[M+H]+:247.1230, measured value：247.1230.
Embodiment 28
Compound II-4
Yield is 89%.
1H NMR(600MHz,CDCl3) δ (ppm) δ=9.44 (s, 1H), 8.12 (d, J=7.2Hz, 2H), 7.99 (s, 1H), 7.75 (d, J=7.6Hz, 2H), 7.61-7.54 (m, 5H).
13C NMR(100MHz,CDCl3) δ (ppm) δ=158.28,148.55,139.20,136.42,134.77, 134.61,130.18,129.54,129.24,128.44,127.13,120.72。
High-resolution：Calculated value：[M+H]+:267.0684, measured value：267.0677.
Embodiment 29
Compound III-1
Preparation
Raw material pyridazine II-3 (73.8mg, 0.3mmol) and 2.0 equivalents 3,4- dihydroxy chloroacetophenones C (111.6mg, 0.6mmol) is dissolved in anhydrous propanone, and at 100 DEG C, tube sealing reaction is until there is linen solid to separate out, directly Suction filtration obtains solid, washs to obtain compound shown in formula III -1, yield 85% with ether.
1H NMR (400MHz, DMSO) δ (ppm) δ=10.62 (s, 1H), 10.55 (s, 1H), 9.78 (s, 1H), 9.48 (s, 1H), 8.31 (d, J=7.0Hz, 4H), 7.77 (s, 3H), 7.62 (d, J=8.3Hz, 1H), 7.55 (s, 2H), 7.52 (s, 1H), 7.07 (d, J=8.3Hz, 1H), 6.76 (s, 2H), 2.48 (s, 3H)
13C NMR (100MHz, DMSO) δ (ppm) δ=187.98,160.80,152.69,147.72,145.87, 142.97,132.47,130.66,130.03,129.68,129.16,128.65,128.28,128.13,125.01, 122.12,115.68,115.18,69.95,21.09.
High-resolution：Calculated value：[M-Cl-]+:397.1547, measured value：397.1547.
Following compound is prepared according to compound III-1 method, and its Structural Identification data is as follows：
Embodiment 30
Compound III-2
By corresponding raw material pyridazine (73.8mg, 0.3mmol) and the 3,4- dihydroxy chloroacetophenones C of 2.0 equivalents (111.6mg, 0.6mmol) is dissolved in anhydrous propanone, and at 100 DEG C, tube sealing reaction is until there is linen solid to separate out, directly Suction filtration obtains solid, is washed to obtain the target product of formula III -2, yield 82% with ether.
1H NMR (400MHz, DMSO) δ (ppm) δ=10.69 (s, 1H), 10.55 (s, 1H), 9.76 (s, 1H), 9.41 (d, J=10.9Hz, 1H), 8.32 (d, J=7.7Hz, 2H), 8.20 (d, J=8.1Hz, 2H), 7.65 (t, J=8.0Hz, 3H), 7.55 (d, J=8.4Hz, 1H), 7.49 (d, J=8.3Hz, 3H), 7.03 (d, J=8.3Hz, 1H), 6.74 (s, 2H), 2.40(s,3H)。
13C NMR (100MHz, DMSO) δ (ppm) δ=187.97,160.84,152.66,147.77,145.88, 145.84,143.14,132.47,132.09,130.35,129.42,128.39,128.20,128.16,127.76, 125.00,122.11,115.64,115.11,69.96,21.09。
High-resolution：Calculated value：[M-Cl-]+:397.1547, measured value：397.1546.
Embodiment 31
Compound III-3
By corresponding raw material pyridazine (79.8mg, 0.3mmol) and the 3,4- dihydroxy chloroacetophenones C of 2.0 equivalents (111.6mg, 0.6mmol) is dissolved in anhydrous propanone, and at 100 DEG C, tube sealing reaction is until there is linen solid to separate out, directly Suction filtration obtains solid, is washed to obtain the target product of formula III -3, yield 76% with ether.
1H NMR (600MHz, DMSO) δ (ppm) δ=10.78 (s, 1H), 10.60 (s, 1H), 9.81 (s, 1H), 9.54 (s, 1H), 8.39 (t, J=8.4Hz, 4H), 7.85 (d, J=8.4Hz, 2H), 7.75-7.70 (m, 3H), 7.61 (d, J= 8.3Hz, 1H), 7.56 (s, 1H), 7.08 (d, J=8.3Hz, 1H), 6.81 (s, 2H)
13C NMR (100MHz, DMSO) δ (ppm) δ=192.85,166.06,157.74,153.05,150.91, 149.95,142.68,137.61,137.07,135.20,134.82,134.69,134.48,133.31,130.14, 127.14,120.77,120.31,75.02。
High-resolution：Calculated value：[M-Cl-]+:417.1000, measured value：417.1001.
Embodiment 32
Compound III-4
Yield is 76%.
1H NMR (600MHz, DMSO) δ (ppm) δ=10.51 (s, 1H), 10.45 (s, 1H), 9.71 (s, 1H), 9.47 (s, 1H), 8.35 (d, J=8.0Hz, 4H), 7.75-7.67 (m, 3H), 7.62 (t, J=8.7Hz, 2H), 7.58 (d, J= 8.2Hz, 1H), 7.48 (s, 1H), 7.00 (d, J=8.3Hz, 1H), 6.69 (s, 2H)
13C NMR (100MHz, DMSO) δ (ppm) δ=187.74,165.88,163.37,160.84,152.57, 147.88,145.76,144.94,132.43,131.96,131.03,130.96,129.33,129.13,128.14, 127.21,124.98,122.01,116.91,116.69,115.60,115.12,69.87.
Embodiment 33
Compound III-5
Yield is 69%.
1H NMR (600MHz, DMSO) δ (ppm) δ=10.43 (s, 1H), 10.22 (s, 1H), 9.69 (s, 1H), 9.44 (s, 1H), 8.29 (d, J=7.4Hz, 2H), 8.05 (s, 1H), 7.95 (d, J=8.3Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.73 (t, J=7.4Hz, 1H), 7.68 (t, J=7.5Hz, 2H), 7.57 (d, J=7.8Hz, 1H), 7.47 (s, 1H), 6.98 (d, J=8.2Hz, 1H), 6.71 (s, 2H)
13C NMR (100MHz, DMSO) δ (ppm) δ=187.66,160.91,152.58,149.75,145.74, 144.04,136.97,133.90,133.54,132.74,132.57,131.61,129.94,129.73,129.52, 128.52,128.10,124.92,122.14,115.53,115.06,70.13.
According to prepare compound III-1 method, inventor is also prepared for compound as follows：
Embodiment 34
Pharmacological Activity Screening is tested
(1) pyridazine and its salt compounds common manifestation go out certain antibacterial activity, and we enter to synthesized compound Following 5 plants clinical common causative fungi activities of having gone are tested：
Candida albicans bacterium (Candida albicans, strain number-Y0109), candida albicans bacterium (Candida Albicans, strain number-SC5314), Candida parapsilosis bacterium (Candida parapsilosis, strain number- ATCC 22019), Candida glabrata (Candida glabrata, strain number -537), neogenesis cryptococcus (cryptococcus neoformans, strain number -32609).
(2) test material
Fungi culture medium:RPMI 1640 culture mediums, YEPD nutrient solutions, husky fort glucose agar medium, potato grape Sugared agar medium (PDA culture medium).
(3) method of testing
This experiment uses U.S. clinical Laboratory Standard association (Clinical and Laboratory Standards Institute, CLSI) Herbs By Broth Microdilution (Broth that is recommended of CLSI-M27A3 and M38A2 files Microdilution compound to be screened) is detected to candidiasis and filamentous fungi minimum inhibitory concentration (minimal Inhibitory concentration, MIC), carry out antifungal activity screening.
(4) quality control
Every piece of drug sensitive plate H behaviors Quality-control strains and Quality Control compound, its object is to monitor drug sensitive test the degree of accuracy, Precision, agents useful for same, the situation of test condition and instrument, the operation of guarantee test person and result it is accurate objective.Matter Control compound uses Fluconazole, and Quality-control strains use Candida parapsilosis ATCC22019.Candida parapsilosis ATCC22019MIC reference values are as shown in table 1 below, only when its MIC value circle is in above range, just think test operation standard It is really reliable.As simultaneously test strain well-grown, then it is believed that success of the test, be as a result subjected to.
(5) test result
The Herbs By Broth Microdilution that this research is recommended using CLSI detects compound to be screened to 5 plants of common causative fungies Minimum inhibitory concentration (MIC) value, every piece of drug sensitive plate are equipped with Quality-control strains and Quality Control compound, Quality Control compound in experimentation Fluconazole MIC fluctuation ranges are no more than 1 medicine gradient concentration, the Quality Control announced in CLSI-M27A3 and CLSI-M38A2 In bacterial strain MIC critical fields, show that experimental result data is reliable in this research.
Our compounds to all synthesis have carried out biological activity test and all compounds all show obvious resist The activity of fungi, only list partial data in following table, as shown in table 2, compound III-1, III-2, III-3, III-4 and III-5 dialogues candidiasis (Candida albicans, strain number-Y0109), candida albicans bacterium (Candida Albicans, strain number-SC5314), Candida parapsilosis bacterium (Candida parapsilosis, strain number-ATCC 22019), Candida glabrata (Candida glabrata, strain number -537), neogenesis cryptococcus (cryptococcus Neoformans, strain number -32609) five kinds of pathomycetes show good inhibitory activity.
The series compound of table 2 is to common causative fungi external activity (MIC80, μ g/ml)
(6) measuring unit
Cellege of Pharmacy, No. 2 Military Medical Univ., PLA's new drug research center.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description Point is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term not Necessarily refer to identical embodiment or example.Moreover, specific features, structure, material or the feature of description can be any One or more embodiments or example in combine in an appropriate manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Not In the case of departing from the principle and objective of the present invention a variety of change, modification, replacement and modification can be carried out to these embodiments, this The scope of invention is limited by claim and its equivalent.

Claims (4)

1. the method for the pharmaceutically acceptable salt of compound, its feature exist shown in compound shown in a kind of formula I or Formulas I In, including：
Make compound shown in formula A, 2,2,6,6- tetramethyl piperidine oxides, inorganic base potassium carbonate and photochemical catalyst Ru (bpy)3Cl2·6H2O is dissolved in chloroform, under the protection of argon gas, is reacted under the conditions of the irradiation of 3W blue LED lamp, and TLC detections are anti- Should, to obtain compound shown in Formulas I,
Wherein,
R2For phenyl, 2- aminomethyl phenyls, 3- methoxyphenyls, 4- chlorphenyls, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2,4- Dichlorophenyl, 3- bromophenyls, 4- bromophenyls, 4- fluorophenyls, 3- fluorophenyls, 2,4- difluorophenyls, 4- trifluoromethyls, 2,4- Two trifluoromethyls or 1- methyl-benzyls, 2- pyrrole radicals, ortho position pyridine radicals, meta pyridine radicals, contraposition pyridine radicals, 1,2,4- Triazol radical, 1,2,4- triazole methyl；
R1For isopropyl, the tert-butyl group, 3- amyl groups, cyclopropyl, cyclopenta, cyclohexyl, phenyl, 2- aminomethyl phenyls, 3- methoxybenzenes Base, 4- chlorphenyls, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2,4 dichloro benzene base, 3- bromophenyls, 4- bromophenyls, 4- fluorobenzene Base, 3- fluorophenyls, 2,4- difluorophenyls, 4- trifluoromethyls, the trifluoromethyls of 2,4- bis-, 1- methyl-benzyls, 2- pyrroles Base, ortho position pyridine radicals, meta pyridine radicals, contraposition pyridine radicals, benzyl, phenylethyl, phenyl vinyl, 3- (N-Ts) indyl, 2- naphthyls, 3- pyrazinyls, 2- thienyls, 2- pyrrole radicals, 1,2,4- triazol radicals, 1,2,4- triazole methyl；
R3For p-toluenesulfonyl.
2. the preparation method of compound according to claim 1, it is characterised in that compound, 2,2,6,6- shown in the formula A Tetramethyl piperidine oxides, the equivalent proportion of inorganic base are 1:1:1.5.
3. the preparation method of compound according to claim 1, it is characterised in that the reaction temperature is 25 degrees Celsius.
4. the preparation method of compound according to claim 1, it is characterised in that silica gel column chromatography purifies, and separates the Formulas I Shown compound, wherein, the column chromatography using the mixture of petroleum ether and ethyl acetate as separating phase, and petroleum ether with The volume ratio of ethyl acetate is 10:1~20：1.
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