CN103819464B - Sulphur chroman compound and synthetic method thereof and prepare the application of antifungal drug - Google Patents
Sulphur chroman compound and synthetic method thereof and prepare the application of antifungal drug Download PDFInfo
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- CN103819464B CN103819464B CN201410087557.3A CN201410087557A CN103819464B CN 103819464 B CN103819464 B CN 103819464B CN 201410087557 A CN201410087557 A CN 201410087557A CN 103819464 B CN103819464 B CN 103819464B
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- 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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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
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Abstract
The present invention relates to a kind of sulphur chroman compound, it can be applicable to prepare antimycotic medicine, has structural formula:
wherein Z is sulphur, sulfinyl or alkylsulfonyl; Y is carbon or nitrogen; R5, R8 are selected from hydrogen, fluorine, chlorine, bromine or iodine respectively or simultaneously; R6 is selected from the alkyl of fluorine, chlorine, bromine, iodine, hydrogen, the-oxyl of C1-C3 or C1-C4, amino, five yuan or hexa-atomic nitrogen heterocyclic ring; Be particularly preferably: R7 is selected from fluorine or C
1-C
3-oxyl, R5, R6, R8 are hydrogen.This compound has antimycotic physiologically active widely, can be used for the bactericide preparing wide spectrum, low toxicity, efficient antifungal drug and agricultural, gardening.
Description
Technical field
The present invention relates to a kind of antimycotic sulphur chroman compound, this compound synthetic method and preparing the application in antifungal drug.
Background technology
The diseases such as the ringworm of the foot, ringworm, candidiasis and crypotococcal result from fungi infestation more.In recent years, due to widely using of Broad spectrum antibiotics, immunosuppressor and all kinds of hormone medicine, in addition the many reasons such as application and infected by HIV of the methods for the treatment of such as chemicotherapy, organ transplantation, cause human immune system's function reduction, the chance of fungal infection increases, and causes the M & M of fungal diseases constantly to rise.In addition, the problems such as the resistance existed in clinical treatment and narrow antimicrobial spectrum, also exacerbate the treatment difficulty of fungal infection disease.Therefore in the urgent need to develop wide spectrum, efficient, low toxicity novel antifungal drugs for clinical treatment.
Antifungal drug is divided into the classifications such as polyenoid class, nitrogen azole, allylamine and Thiourea usually, thiochromanone is the sulfur-bearing antifungal drug developed rapidly in recent years, research shows, it has stronger inhibit activities to several important pathogeny bacterium such as Cryptococcus neoformans, yeast, sporule silk bacterium, mould and trichophytons.The chemical structural formula of thiochromanone is:
For researching and developing the antifungal drug of high-efficiency low-toxicity, at present mainly 1,3,4 is concentrated to the structural modification of sulphur look (expiring) ketone.Wherein, modify for 1 and generate sulphur look (expire) ketone 1,1-dioxide, 3 modifiers comprise beta-amino ketones compound, 3-benzyl-6-chlorine thiochromanone and 3-benzyl-thiochromanone, and 4 modifications are more is at present the modification of heteroatoms and amido-containing group.Through modifying the thiochromone derivative obtained above, its anti-mycotic activity has raising in various degree, or has higher activity to certain class fungi.But sulphur look (expiring) ketone antifungal drug is far above in this, the present invention is according to the structure effect relation of sulphur look (expiring) ketone compounds, and further research acquisition anti-mycotic activity is more excellent, kind more sulphur look (expiring) ketone compounds.
Summary of the invention
The object of this invention is to provide a kind of sulphur chroman class antifungal compound, this compound all has stronger inhibit activities to common causative fungi and deep fungal, and has the features such as toxicity is low, good stability, anti-fungus spectra are wide, security is good.The present invention also provides the preparation method of this sulphur chroman class antifungal compound and the application in the medicine preparing transplantation in treating systemic fungi infestation thereof.
A kind of sulphur chroman compound, chemical structure is such as formula (I):
In formula (I):
Z is selected from sulphur (S), sulfinyl
or alkylsulfonyl
Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
Wherein:
W, V, M, G are separately selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can by C
1-C
4alkyl replaced;
L is selected from hydrogen, C
1-C
4alkyl, hydroxyl or C
1-C
4-oxyl.
In described formula (I) sulphur chroman compound, preferred scheme is: Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R7 is selected from fluorine or C
1-C
3-oxyl; R5, R6, R8 are hydrogen.
Sulphur chroman compound synthetic method of the present invention, press step:
With formula II compound for raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (Ia) solid chemical compound, namely Z is selected from formula (I) the sulphur chroman compound product of sulphur; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Wherein Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
W, V, M, G are separately selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can by C
1-C
4alkyl replaced.
By formula (Ia) the compound elder generation of gained and acetic anhydride, protection hydroxyl, then the oxygenant of 0.9-1.1 equivalent is added, oxidizing reaction is there is under the effect of oxygenant, obtain oxo sulphur chroman compound, last be hydrolyzed such as formula the oxo sulphur chroman compound of (Ib) in sodium hydroxide solution, it is formula (I) the sulphur chroman compound product that Z is selected from sulfinyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
By formula (Ia) the compound elder generation of step 1 gained and acetic anhydride, protection hydroxyl, then the oxygenant of more than 2 equivalents is added, oxidizing reaction obtains oxo sulphur chroman compound, finally be hydrolyzed such as formula (Ic) compound in sodium hydroxide solution, be formula (I) the sulphur chroman compound product that Z is selected from alkylsulfonyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
The invention provides the application of described sulphur chroman compound in people's medicine or medicine for animal of preparation treatment fungal infection disease.
Except containing except activeconstituents sulphur chroman compound in described medicine, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
The formulation of described medicine is solution, creme, suppository, ointment or solution.
The present invention also provides described sulphur chroman compound as application that is agriculture and horticultural bactericides.
Except containing except activeconstituents sulphur chroman compound in described sterilant, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
By measuring minimum inhibitory concentration MIC (i.e. the concentration of compound energy inhibition test microorganism growth), in-vitro evaluation is carried out to the anti-mycotic activity of sulphur chroman compound of the present invention.Test confirms, sulphur chroman compound of the present invention has broad-spectrum antifungal activity, in human body and animal (particularly Mammals) body, there is pharmacological activity, can mix mutually with the acceptable diluent or carrier of common chemotherapy, or with other vehicle, make the formulations such as solution, creme, suppository, ointment, solution, carry out partial smearing use with the form of medicine.Also can simultaneously with other antiseptic-germicide, as used in combination in amphotericin B, fungistatin, trichomycin, variotin or Mycosporin etc., for fungal infection disease, there is obvious curative effect.Except using or animal antifungal drug beyond the region of objective existence for the preparation of antimycotic people, sulphur chroman compound of the present invention also can be used for the bactericide of agricultural and gardening, to the rust of various phytopathogen disease as the powder mildew of the powder mildew of rice blast, barley and wheat and other various host plants (as cucumber, apple, grape), the rust of wheat, the hat rust of oat and other various hosts, the control that the pathogenicity bo of the late blight of tomato and other host plants is rotted etc. is very effective.
Embodiment
Below by embodiment, foregoing of the present invention is described in detail further.It should be noted that, scope of the present invention does not limit by embodiment, and is as the criterion with claim.
Embodiment 1:3-(1H-1,2,4-triazol-1-yl) the synthesis preparation feedback formula of-4-hydroxyl sulphur chroman (formula I a1) is as follows:
Press step preparation:
Get 2-ethylmercapto group-3-(1H-1,2,4-triazol-1-yl) thiochromone compound 22.4mmol, be dissolved in the 50mL ethanol of 50%; 89.6mmol sodium borohydride is added in batches in above-mentioned solution, in room temperature for overnight, underpressure distillation is except desolventizing, and solid 50mL ethyl acetate and the extraction of 50mL water, get ethyl acetate layer, wash with water twice (50mL × 2), reclaim organic layer and evaporate to dryness, obtain formula (I a1) product 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, yield 86%.
1H NMR(CDCl
3):8.77(s,1H),8.06(s,1H),7.26-7.32(m,3H),7.14(t,1H),5.17(d,1H),4.50(d,1H),4.42-4.44(m,1H),3.30-3.34(m,1H),3.06-3.08(m,1H).
Embodiment 2-embodiment 19: the formula (preparation of I a) sulphur chroman compound
With formula II compound for raw material, prepare product formula (I a) compound (target product is formula (I a2) ~ formula (I a19) each compound in table 1), reaction formula is as follows:
Preparation process is as follows:
Getting 22.4mmol formula II compound is dissolved in polar solvent, is added in solution by 89.6mmol reductive agent in batches, in room temperature for overnight, by the process of embodiment 1 method, obtains formula (I a2) ~ formula (I a19) each sulphur chroman compound.
In embodiment 2 ~ embodiment 19, product formula (I a) each group of sulphur chroman compound select and preparation reagent and detect data and all list in table 1.
Table 1
Embodiment 20:3-(1H-1,2,4-triazol-1-yl) synthesis of-4-hydroxyl-1-sulfur oxide chroman
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepares target product (I b1) sulphur chroman compound.
Preparation feedback formula is as follows:
Preparation process is as follows:
Get raw material 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, add in 35mL diacetyl oxide solvent, acetylization reaction protection hydroxyl occurs, and reaction terminates rear underpressure distillation and removes diacetyl oxide solvent.Add 30mL saturated sodium bicarbonate solution and 30mL ethyl acetate, isolate ethyl acetate layer; Organic layer is merged after water layer 20mL extraction into ethyl acetate, at room temperature drip the hydrogen peroxide 3.4g(20mmol of 30% concentration more wherein) there is oxidizing reaction, reaction terminates to use 10mL saturated sodium bisulfite solution and 30mL water washing respectively afterwards, separates organic layer and evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% concentration and the mixed solution of 20mL ethanol, heating hydrolysis at 50 DEG C, solvent evaporated after complete reaction, organic layer is got with after 20mL water and the washing of 20mL ethyl acetate, product sulfoxide compound 3-(1H-1 is obtained after evaporate to dryness, 2,4-triazol-1-yl)-4-hydroxyl-1-sulfur oxide chroman (13.8mmol), yield 72%.
1H NMR(CDCl
3):8.71(s,1H),8.03(s,1H),7.51-7.55(m,3H),7.38(t,1H),5.19(s,1H),4.55(d,1H),4.18-4.22(m,1H),3.30-3.34(m,1H),3.09-3.13(m,1H).
Embodiment 21-embodiment 38: sulfoxide type sulphur chroman (I synthesis b)
With formula (I a) sulphur chroman compound for raw material, prepare general formula (I b) sulphur chroman compound product (target product is formula I b2 ~ formula I b19 in table 2, and preparation process is with embodiment 20.Reaction formula is as follows:
The formula of embodiment 21 ~ embodiment 38 (I b) each group of sulphur chroman compound select and preparation reagent and detect data and all list in table 2.
Table 2
Embodiment 39:3-(1H-1,2,4-triazol-1-yl) synthesis of-4-hydroxyl-1,1-sulfurous gas chroman (formula I c1)
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepare target product (I c1) compound, reaction formula is as follows:
By 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman (19.3mmol) adds in 35mL diacetyl oxide solvent, and acetylization reaction protection hydroxyl occurs, and reaction terminates rear underpressure distillation and removes diacetyl oxide solvent.Add saturated sodium bicarbonate 30mL solution and ethyl acetate 30mL, separate ethyl acetate layer, organic layer is merged after water layer 20mL extraction into ethyl acetate, at room temperature drip 30% excessive hydrogen peroxide 13.6g(80mmol more wherein) there is oxidizing reaction, reaction terminates to use 10mL saturated sodium bisulfite solution and 30mL water washing respectively afterwards, separates organic layer and evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% and the mixed solution of 20mL ethanol, heating hydrolysis at 50 DEG C, solvent evaporated after complete reaction, organic layer is got with after 20mL water and the washing of 20mL ethyl acetate, sulfone compound 3-(1H-1 is obtained, 2,4-triazol-1-yl after evaporate to dryness)-4-hydroxyl-1,1-sulfurous gas chroman (14.1mmol), yield 73%.
1H NMR(CDCl
3):8.73(s,1H),8.09(s,1H),7.81(d,1H),7.68(d,1H),7.51(t,1H),7.35(t,1H),5.19(s,1H),4.45(d,1H),4.19-4.24(m,1H),3.96-4.01(m,1H),3.79-3.84(m,1H).
Embodiment 40 ~ embodiment 57: sulfone class sulphur chroman (formula I synthesis c)
With formula (I a) sulphur chroman compound for raw material, by embodiment 39 same procedure, prepare general formula (I c) sulphur chroman compound product (object product is formula I c2 ~ formula I c19 in table 3).Reaction formula is as follows:
The formula of embodiment 40 ~ embodiment 57 (I c) each group of sulphur chroman compound select and preparation reagent and detect data and all list in table 3.
Table 3
Embodiment 58: extracorporeal antifungal activity is tested
1, test bacterial strain
Candida parapsilosis, sporothrix, saccharomyces cerevisiae aspergillus tubigensis, Candida albicans, Candida glabrata, Oidium tropicale, trichophyton, Penicillium notatum, Trichophyton verrucosum, Trichophyton violaceum, cryptococcus neoformans, gram Rou Shi candidiasis, acrothesium floccosum, trichophyton gypseum.
2, reagent and material
Test material:
Improvement Martin substratum, 96 well culture plates, DMSO
Control drug: fluconazole
3, test method
(1) preparation of antibacterial liquid
Test medicine is dissolved with DMSO respectively, is made into the solution of 25.6g/L, saves backup in less than one 20 DEG C.Before test, the tested liquid of deepfreeze is taken out, melt in 35 DEG C of thermostat containers, dilute 10 times with RPMI1640, for subsequent use.
(2) preparation of inoculation liquid
Each tested beads bacterial strain (Candida albicans, Candida glabrata, Oidium tropicale, Candida parapsilosis) is transferred species on improvement Martin substratum, used massfraction be 0.85% Sterile Saline make suspension.Count spore with blood cell counting plate, adjustment bacteria containing amount, makes colony forming unit be 1 × 10
6~ 5 × 10
6cFU/mL.After being diluted 200 times with RPMI-1640 nutrient solution during inoculation, redilution 10 times, CFU value is adjusted to 0.5 × 10
3~ 6.0 × 10
3cFU/mL, for subsequent use.
(3) preparation of MIC plate
Under aseptic technique, add RPMI-1640 nutrient solution 100 μ L, as blank in No. 1 hole of 96 hole polystyrene plates of sterilizing.No. 2 hole adds bacterium liquid 190 μ L, and 3-12 hole adds the bacterium liquid 100 μ L configured.Then in No. 2 holes, add the tested liquid of 10 μ L, by the concentration in 10 grades of doubling dilution 2-11 holes, make the ultimate density in each hole be 128,64,32,16,8,4,2,1,0.5,0.25mg/L, No. 12 hole does not add tested liquid as growth control.Each MIC plate is airtight to be placed in 35 DEG C of normal air incubators, hatches full 24h judged result.
(4) result judges
The OD value in each hole is surveyed in 620nm, using the minimum concentration of OD value decline more than 80% as MIC value with enzyme micro-plate reader.When MIC value is higher than counting ﹥ 128mg/L during 128mg/L; When MIC value counts≤0.25mg/L lower than during 0.25mg/L.
(5) repeated observation and statistics
Above-mentioned test needs at least in triplicate, when there is the single jumping hole of MIC value, is then recorded as maximum anti-bacteria concentration, when two or more jumping holes appear in MIC value, then re-starts test.
4, antimycotic sensitivity test result
Measured by preliminary MIC and find, test-compound has broad-spectrum antifungal activity, wherein the sulphur chroman compound Antifungi activity of embodiment 1, embodiment 4, embodiment 5, example 9, embodiment 10, embodiment 11, embodiment 13, embodiment 14, embodiment 15, embodiment 20 ~ embodiment 57 is more remarkable, is all less than 2mg/L to the MIC value of above strain subject.
Claims (10)
1. a sulphur chroman compound, it is characterized in that chemical structure such as formula (
):
Formula (
) in:
Z be selected from sulphur (S), sulfinyl (
) or alkylsulfonyl (
);
Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
;
Wherein:
W, V, M, G are separately selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can by C
1-C
4alkyl replaced;
L is selected from hydrogen, C
1-C
4alkyl, hydroxyl or C
1-C
4-oxyl.
2. sulphur chroman compound according to claim 1, it is characterized in that described formula (
) in sulphur chroman compound, Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R
7be selected from fluorine or C
1-C
3-oxyl; R
5, R
6, R
8be hydrogen.
3. a sulphur chroman compound synthetic method for claim 1, is characterized in that according to the following steps:
With formula II compound for raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (
a) solid chemical compound, namely Z be selected from sulphur formula (
) sulphur chroman compound product; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Wherein, Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8separately be selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
,
W, V, M, G are separately selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can by C
1-C
4alkyl replaced.
4. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of gained (
a) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, oxidizing reaction occur, obtain oxo sulphur chroman compound, be finally hydrolyzed in sodium hydroxide solution such as formula (
b) oxo sulphur chroman compound, its be Z be selected from sulfinyl formula (
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
。
5. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of step 1 gained (
a) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, be finally hydrolyzed in sodium hydroxide solution such as formula (
c) compound, be Z be selected from alkylsulfonyl formula (
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
。
6. the application of sulphur chroman compound described in a claim 1 or 2 in people's medicine or medicine for animal of preparation treatment fungal infection disease.
7. application according to claim 6, is characterized in that except containing except activeconstituents sulphur chroman compound in described medicine, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, and composition composition.
8. application according to claim 7, is characterized in that the formulation of described medicine is solution, creme, suppository or ointment.
9. sulphur chroman compound described in a claim 1 or 2 is as application that is agriculture and horticultural bactericides.
10. application according to claim 9, is characterized in that except containing except activeconstituents sulphur chroman compound in described sterilant, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, and composition composition.
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CN107556296B (en) * | 2017-09-06 | 2020-10-02 | 南京工业大学 | 2-hydroxy-3-azacyclo chromone compound, synthetic method thereof and application thereof in antifungal drugs |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3682899A (en) * | 1969-06-20 | 1972-08-08 | Meiji Seika Kaisha | 1-oxo - 3-benzal-thiochromanone derivatives and a process for the production of these compounds |
US4007203A (en) * | 1973-12-04 | 1977-02-08 | Warner-Lambert Company | 4-(1-Pyrolidenyl)-2H-1-benzothiopyran-3-carboxanilide |
US4703057A (en) * | 1985-10-04 | 1987-10-27 | Adir Et Compagnie | Beta-blocking thiochroman derivatives, compositions and method of use therefor |
US5403842A (en) * | 1992-02-25 | 1995-04-04 | Recordati S.A., Chemical And Pharmaceutical Company | Benzopyran and benzothiopyran derivatives |
US6716834B2 (en) * | 2000-05-16 | 2004-04-06 | Astrazeneca Ab | Thiochromane derivatives and their use as thrombin inhibitors |
CN101519402A (en) * | 2009-04-13 | 2009-09-02 | 南京工业大学 | Thiochromone compound, synthetic method and application thereof in preparing antifungal medicaments |
-
2014
- 2014-03-11 CN CN201410087557.3A patent/CN103819464B/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3682899A (en) * | 1969-06-20 | 1972-08-08 | Meiji Seika Kaisha | 1-oxo - 3-benzal-thiochromanone derivatives and a process for the production of these compounds |
US4007203A (en) * | 1973-12-04 | 1977-02-08 | Warner-Lambert Company | 4-(1-Pyrolidenyl)-2H-1-benzothiopyran-3-carboxanilide |
US4703057A (en) * | 1985-10-04 | 1987-10-27 | Adir Et Compagnie | Beta-blocking thiochroman derivatives, compositions and method of use therefor |
US5403842A (en) * | 1992-02-25 | 1995-04-04 | Recordati S.A., Chemical And Pharmaceutical Company | Benzopyran and benzothiopyran derivatives |
US6716834B2 (en) * | 2000-05-16 | 2004-04-06 | Astrazeneca Ab | Thiochromane derivatives and their use as thrombin inhibitors |
CN101519402A (en) * | 2009-04-13 | 2009-09-02 | 南京工业大学 | Thiochromone compound, synthetic method and application thereof in preparing antifungal medicaments |
Non-Patent Citations (3)
Title |
---|
Stereoselective Synthesis and in Vitro Antifungal Evaluation of (E)- and (Z)-Imidazolylchromanone Oxime Ethers.;Saeed Emami, et al.,;《Arch. Pharm. Pharm. Med. Chem.》;20021231;第318-324页 * |
田欣,肖涛..色酮及硫色酮类化合物的合成进展..《化学试剂》.2014,第36卷(第2期),第125-130页. * |
马正月.硫色满酮衍生物的合成及其生物活性研究..《中国博士学位论文全文数据库 工程科技I辑》.2012,(第1期),绪论第8-10页. * |
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