CN1394858A - Cycermanone quaternary antifungal compound - Google Patents
Cycermanone quaternary antifungal compound Download PDFInfo
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- CN1394858A CN1394858A CN 02128936 CN02128936A CN1394858A CN 1394858 A CN1394858 A CN 1394858A CN 02128936 CN02128936 CN 02128936 CN 02128936 A CN02128936 A CN 02128936A CN 1394858 A CN1394858 A CN 1394858A
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Abstract
The present invention relates to a new cycermanketoqueternaries antifungal compound and its synthesis method. Its raw materials are easily available, its synthesis method is simple, yield rate is high, and its product has good activity for inhibiting fungi and killing bacteria, its toxicity is small or it is non-toxic. Said invented product can be used in antifungal medicines.
Description
Technical field
The present invention relates to the sulfur heterocyclic ring compound, particularly a kind of cycermanone Mannich antimycotic synthetic drugs of quaternary ammonium salt series of deriving.
Background technology
Fungi is the eucaryotic organism that a kind of and host cell have analog structure and physiological metabolism process, according to fungus-caused infection site difference, is divided into that the superficial part bacterium infects and the infection of deep bacterium.Mycotic infection of superficial part mainly causes by various tinea bacterium, as tinea manus and pedis, favus of the scalp, ringworm of the body etc., at present often with grisovin, nystatin, KETOKONAZOL etc. as medicine.Deep fungal infection harm is big; even threat to life; it is mainly caused by pathogenic fungus; comprise Candida albicans, Cryptococcus neoformans, aspergillus tubigensis, mucormycosis or the like; these fungies belong to flora member in the normal body; do not cause disease under the normal circumstances, still, long-term a large amount of Broad spectrum antibiotics, hormone and immunosuppressor etc. used can cause morbidity.In recent years, the sickness rate of deep fungal infection has the trend that rises year by year.
Because the biological nature of fungi, general antibacterials often destroying the fungal cell simultaneously, can be damaged host cell again, add the continuous appearance of Resistant strain, make the fungi infestation treatment of diseases sink into the border of facing a difficult choice.So far, can be applicable to clinical good effect, toxic side effect little, safety coefficient (Safety Index, LD
5/ ED
95) high medicine is very few.Amphotericin B and triazole species fluconazole class medicine are also big limited in application facet because of its toxic side effect.Therefore, developing and seek a kind of high-efficiency low-toxicity, the wide spectrum with treatment prevention double effects and narrow spectrum anti-mycotic activity new compound becomes when last significant research work.
Summary of the invention
The objective of the invention is to remedy above-mentioned weak point of the prior art, and simple, the effective cycermanone of the synthetic method antimycotic synthetic drugs of quaternary ammonium salt series of deriving is provided.
The object of the invention can reach by following measure: antimycotic cycermanone quaternary ammonium compound is characterized in that with general formula (I) expression compound:
Wherein:
1、n＝1、2
2、m＝0、2
3、x＝0，1/2，1，2，3
4、R
1＝H、-Me，-Et；
5, work as R
2, R
3, R
4In when having one or two to be H, two other or one are respectively:
R
2=X halogenic substituent ,-Me-OMe, OH
R
3=X halogenic substituent ,-Me;
R
4=X halogenic substituent ,-Me;
6, Y
1Or Y
2=-Me ,-Et, substituted-phenyl, amino acid based
7, A
-=HSO
4 -, H
2PO
4 -, Cl
-, Br
-, CH
3SO
3 -Methylsulfonic acid, CH
3CH
2SO
3 -Ethyl sulfonic acid
Halogenic substituent is meant fluorine, chlorine, bromine, iodine; Substituted-phenyl is meant rubigan, to fluorophenyl, to the sulfanilamide (SN) phenyl, to ethoxyl phenenyl, p-nitrophenyl, ortho-nitrophenyl base; Amino acid based glycine base, the L-glutamic acid base etc. of being meant.
The derive synthetic method of quaternary ammonium salt medicine series of cycermanone is that (for details see attached table 1) adds metallic zinc with benzene sulfonyl chloride (or substituted benzene SULPHURYL CHLORIDE), then to wherein dripping 4MH
2SO
4, to stir while dripping, separation and purification obtains thiophenol (or substituted benzene thiophenol), this product is dissolved in the 2MNaOH solution (can adding adequate amount of ethanol) again.In addition β-chloropropionic acid (or its methyl ester, ethyl ester) is dissolved in the Na of calculated amount
2CO
3In the solution, mix with above-mentioned solution then, ultrasonic, backflow 6-8 hour, eliminate alcohol back suction filtration, filtrate is used 4MH
2SO
4Acidifying, underpressure distillation, suction filtration, washing and drying gets β-(substituted benzene sulphur)-propionic acid, uses polyphosphoric acid (or vitriol oil) condensation again, and separation and purification obtains replacing cycermanone (Thiochromanone) crude product.In addition aminocompound (primary amine, secondary amine and amino acid) is dissolved in acidic medium and (removes sulfuric acid, outside the hydrochloric acid, methylsulfonic acid, ethyl sulfonic acid, L-glutamic acid, lactic acid, phosphoric acid, citric acid also has different good effects with substituted benzenesulfonic acid etc.), mix with simple alkanoic (formaldehyde, acetaldehyde) and above-mentioned replacement cycermanone, ultrasonic, heat back and heat up in a steamer 6-8 hour.Reaction product through ice separate, separation, purifying, synthesize II and III: if it is obtained product (II) with other aminocompounds, amino acid after reacting again; If will it with the part superoxide (as rare mistake lauric acid, H
2O
2) carry out amine exchange reaction with other aminocompound, amino acid again after the reaction, then reaction generates product (III).
R
1, R
2, R
3, R
4, n, Y
1, Y
2, A
-Define the same.
The derive synthetic method of quaternary ammonium salt II and III of subordinate list 1 match Kerman ketone Mannich
The present invention has following advantage compared to existing technology: the cycermanone quarternary ammonium salt compound of deriving is the heterogeneous ring compound that contains sulphur atom, has extensive bioactive beta-amino ketones compound stronger bacteriostatic activity is arranged, at 3 introducing-(CH
2)
nNy
1y
2Behind (n=1,2) group, its anti-microbial activity is significantly strengthened.From the molecular pharmacology level, the Fe on the heme in N nuclear power on the amine phenyl and fungi inner cell pigment P-450 molecule
2+Ion complexation, suppress the effect of P-450 hydroxylase, and the biosynthesizing of the ergosterol on the fungal cell membrane is obstructed, therefore, it not only has better inhibited activity to common superficial fungal infection, and deep fungal had good fungicidal activity, it is very little or nontoxic that pharmacological toxicology is learned this toxicity of compound of evidence.Raw material of the present invention is common to be easy to get, synthetic method is simple, yield is higher, has excellent research to be worth and application prospect.
Embodiment
Enumerate preparation example and embodiment below, 2 couples of the present invention are further specified in conjunction with subordinate list.
Preparation example 1
The preparation of compound 1 thiophenol in the subordinate list 2: get the 0.2mol benzene sulfonyl chloride and place three-necked bottle, other takes by weighing the adding of 27g metal zinc, stirs, and 0 ℃ of ice-water bath drips 4M H
2SO
4, stir while dripping, react after 6-8 hour filtering separation, washing, drying, recrystallization purifying.Productive rate is 89.8-92.1%, and fusing point is 70.7 ℃.
If synthesizing substituted thiophenol, available substituted benzene SULPHURYL CHLORIDE is synthetic, and method and above-mentioned steps are basic identical; For example halogeno-benzene SULPHURYL CHLORIDE yield is generally between 77%-89%.
Preparation example 2
Compound 2[6-fluoro-cycermanone in the subordinate list 2] preparation: the above-mentioned fluorobenzene thiophenol 0.05mol that makes is dissolved in the 2MNaOH solution (can adds adequate amount of ethanol).In addition 8.2g β-chloropropionic acid (or its methyl ester of 10g) is dissolved in the Na of calculated amount
2CO
3In the solution, mix with above-mentioned solution then, ultrasonic, return and heated up in a steamer 6-8 hour, eliminate alcohol back suction filtration, filtrate is used 4MH
2SO
4Suction filtration after 1-2 hour is stirred in acidifying, and washing and drying gets β-(substituted benzene sulphur)-propionic acid, uses polyphosphoric acid (or vitriol oil) condensation 24 hours again, and separation and purification obtains 6-fluoro-cycermanone.Productive rate 37.8-39.6%, fusing point 92-93 ℃.The physicochemical constant that records sees attached list 2.
Embodiment 1
Compound 3[6-fluoro-3-(dimethylamino) methyl cycermanone esilate in the subordinate list 1] preparation: the above-mentioned 6-fluoro-cycermanone 0.02mol, the formaldehyde 0.03mol (excessive) that obtain of producing is dissolved in the 50mL benzene, ultrasonic mixing, reflux 1 hour under induction stirring then.In addition dimethylamine 0.02mol is joined in the 0.2mol ethyl sulfonic acid, stir half an hour after, join in the middle of the above-mentioned reaction mixture, reflux is 8 hours once more.After reacting completely, suction filtration, filter cake is washed with benzene, gets white solid with the dehydrated alcohol recrystallization again, productive rate 48.2%.
Embodiment 2
Compound 4[6-chloro-3-(dimethylamino) methyl cycermanone esilate] preparation: will be to chlorothio-phenol 2.0 grams (0.014mol), β-chloropropionic acid 1.6 grams (0.014mol), 10 milliliters of 2M NaOH solution and 1.6g Na
2CO
3Add in the reaction flask, add an amount of ethanol, raw material is dissolved fully.100 ℃ backflow 6-8 hour, the cooling, the filtering crystallization.Filtrate decompression boils off ethanol, and it is 2-3 that concentrated solution is transferred PH with sulfuric acid, and the adularescent solid is separated out, suction filtration, and sherwood oil is washed, and drying adds 7 milliliters of vitriol oils then, stirring at room 6 hours, ice is separated, suction filtration, Na
2CO
3Solution is washed, washing, drying, get 2.1g 6-chlorine cycermanone, 1.2g (0.04mol) Paraformaldehyde 96,0.04mol dimethylamine and 0.2mol ethyl sulfonic acid, other gets 20 milliliters of benzene and adds in the reaction flask, stirring and adjusting PH is 3, refluxed 6 hours, cooling inclines benzene to go out, the anhydrous methanol recrystallization, productive rate 37.4%.
Compound 6[2-methyl-6-fluoro-3-(dimethylamino) methyl cycermanone vitriol] and 7[2-methyl-6-chloro-3-(dimethylamino) methyl cycermanone vitriol] synthetic method in use Alpha-Methyl-β-chloropropionic acid, and replacing ethyl sulfonic acid with sulfuric acid, basic synthesis step is also similar in aforesaid method.
Embodiment 3
Compound 5[6-methyl-3-(dimethylamino) methyl cycermanone esilate] synthetic method.Will be to methylbenzene thiophenol 0.02mol, β-chloropropionic acid 0.02mol, 10 milliliters of 2M NaOH solution and 1.6g Na
2CO
3Add in the reaction flask, add an amount of ethanol, raw material was dissolved back 100 ℃ of backflow 6-8 hours fully, it is 2-3 that concentrated solution is transferred PH with sulfuric acid, filtering and washing, drying, add the vitriol oil then, stirring at room 6 hours, 6-methyl cycermanone, add 1.2g (0.04mol) Paraformaldehyde 96,0.04mol dimethylamine and 0.2mol ethyl sulfonic acid, backflow 6-8 hour, cooling, the anhydrous methanol recrystallization, productive rate 40-42.4%.
Compound 21[8-methyl-3-(dimethylamino) methyl cycermanone esilate] synthetic method is identical with it.
Embodiment 4
Compound 8[6-fluoro-7-chloro-3-(dimethylamino) methyl cycermanone vitriol in the subordinate list 1] preparation: 6-fluoro-7-chloro-cycermanone 0.02mol, formaldehyde 0.03mol (excessive) be dissolved in heat back in the benzene heat up in a steamer 1 hour after, the mixing solutions that adds 0.02mol dimethylamine and 0.2mol ethyl sulfonic acid, mixing heats back and heats up in a steamer 8 hours together.Separation and purification gets white crystal 3.46g, productive rate 45.5%.
Embodiment 5
Compound 9[6-fluoro-3-(para-fluoroaniline base) methyl cycermanone vitriol in the subordinate list 2] preparation: the crystal 0.01mol that gets the compound 3 that makes obtains vitriol after with vitriolization again, be dissolved in the 50mL50% ethanolic soln, add the 0.01mol para-fluoroaniline again, 40 ℃ of water-baths 12 hours, cooling, suction filtration, crude product obtain yellow needle-like solid, yield 34.1% after with the dehydrated alcohol recrystallization.
Compound 10[6-fluoro-3-(p-Chlorobenzoic acid amide base) methyl cycermanone vitriol] synthetic method the same similar.Physicochemical constant separately is referring to subordinate list 2.
Embodiment 6
Compound 11[6-fluoro-3-(to the sulfabenz amido) methyl cycermanone vitriol in the subordinate list 2] preparation: the crystal 0.01mol that gets the compound 3 that makes, be dissolved in the 50mL50% ethanolic soln, 40 ℃ of water-baths slowly added 0.01mol benzene sulfanilamide (SN) in 0.5 hour more then and continue water-bath 24 hours, cooling, suction filtration, crude product obtains yellow needle-like solid, yield 63.1%, fusing point 189-191 ℃ after with dehydrated alcohol-acetone recrystallization.
Embodiment 7
The preparation of compound 12 in the subordinate list 2: get the compound 8 solid 0.01mol that make and join in 80 milliliter of 50% ethanol, 40 ℃ of water-baths 0.5 hour, slowly add 0.01mol then to monomethylaniline, continue water-bath 12 hours, the cooling back adds the ammoniacal liquor of 5mL 17%, leave standstill after fully stirring, suction filtration is washed to neutrality, gets the yellow solid crude product, use the dehydrated alcohol recrystallization, productive rate is 86.6%.
Synthesizing of compound 13 is similar with it, and productive rate is 69.4%.
Embodiment 8
Compound 14[6-fluoro-7-chloro-3-(to phenetidino) methyl cycermanone in the subordinate list 2] preparation: get compound 8 solid 0.01mol and join in 80 milliliter of 50% ethanol, 40 ℃ of water-baths 0.5 hour, slowly add the 0.01mol p-Phenetidine then, continue water-bath 12 hours, the cooling back adds the ammoniacal liquor of 5mL 17%, leaves standstill after fully stirring, suction filtration, be washed to neutrality, crude product gets yellow crystals with the dehydrated alcohol recrystallization, and productive rate is 63.6%.
Compound 15[6-fluoro-7-chloro-3-(ortho-nitrophenyl amino) methyl cycermanone] synthetic method is similar with it.
Utilize this amine exchange reaction, can also synthesize a series of substituted anilinic cycermanone Mannich quarternary ammonium salt compound, as 6-fluoro-7-chloro-3-(piperidyl) methyl cycermanone, 6-fluoro-7-chloro-3-(p-nitrophenyl amino) methyl cycermanone or the like.
Embodiment 9
Compound 16[6-fluoro-3-(glycine amino) methyl cycermanone in the subordinate list 2] preparation: get compound 3 crystal 0.01mol and 0.01mol glycine and join in 50 milliliter of 50% ethanol, 17% the ammoniacal liquor that adds 5mL, fully stir, 40 ℃ of water-baths 12 hours, cooling back suction filtration, be washed to neutrality, get the yellow solid crude product, productive rate is 42-48%.
Compound 17[6-fluoro-3-(L-glutamic acid amino) methyl cycermanone] adopt L-glutamic acid, add 7.5mL17% ammoniacal liquor, 40 ℃ of water-baths 24 hours, productive rate is 33-37%.
Embodiment 10
Compound 18[6-fluoro-3-(dimethylamino) methyl oxidation cycermanone vitriol in the subordinate list 2] preparation: in 40 milliliters of glacial acetic acids of compound 3 crystal 0.005mol dissolving, add mistake lauric acid (the perhaps 3.0g 30%H of 0.012mol
2O
2) 60-80 ℃ of reaction 4 hours, ice was separated, suction filtration, filter cake methanol-water recrystallization obtains yellow crystals, productive rate 44-50%.
Compound 19[6-chloro-3-(dimethylamino) methyl oxidation cycermanone vitriol] with 20[6-fluoro-3-(to chlorobenzene amino) methyl oxidation cycermanone vitriol] synthetic method similar to compound 18.Physicochemical constant separately is referring to subordinate list 2.
Embodiment 11
Compound 22[6-fluoro-3-(dimethylamino) ethyl cycermanone vitriol in the subordinate list 2] synthetic.Will be to fluoro thiophenol 0.05mol, β-chloropropionic acid 0.05mol is dissolved in 10 milliliters of 2M NaOH solution and 1.6g Na
2CO
3Add in the reaction flask, 100 ℃ backflow 6-8 hour, it is 2-3 that concentrated solution is transferred PH with sulfuric acid, filtering and washing, drying adds the vitriol oil then, stirring at room 6 hours, obtain 6-fluorine cycermanone, add 0.07mol acetaldehyde, 0.04mol dimethylamine and 4M sulfuric acid, backflow 6-8 hour, cooling, anhydrous methanol recrystallization, productive rate 36-40%.
Compound 23[6-chloro-3-(dimethylamino) ethyl cycermanone vitriol] synthetic method similar.
Embodiment 12
Compound 22[6-fluoro-3-(dimethylamino) ethyl cycermanone vitriol in the subordinate list 2] hydrate synthetic.Use methanol-water (80: 20) to carry out recrystallization again in 6-fluoro-3-(dimethylamino) the ethyl cycermanone vitriol that example 13 makes, separate the crystal of hydrate that obtains this compound.Productive rate is 94-96%.
The preparation method and the aforesaid method of the hydrate of compound 24,25,26 and other compound are similar.
Embodiment 13
Compound 27[6-methoxyl group-3-(dimethylamino) methyl cycermanone esilate in the subordinate list 2] synthetic method.Will be to methoxybenzenethiol 0.05mol, β-chloropropionic acid 0.05mol, 25 milliliters of 2M NaOH solution and 3.8g Na
2CO
3Add in the reaction flask, add an amount of ethanol, make raw material dissolve 90-100 ℃ of back fully backflow 6-8 hour, it is 2-3 that concentrated solution is transferred PH with sulfuric acid, filtering and washing, drying, add the vitriol oil then, stirring at room 6 hours obtains 6-methoxyl group cycermanone, add the 0.12mol Paraformaldehyde 96,0.1mol dimethylamine and 0.5mol ethyl sulfonic acid, backflow 6-8 hour, cooling, the anhydrous methanol recrystallization, productive rate 37-40%.
Embodiment 14
Compound 28[6-hydroxyl-3-(dimethylamino) methyl cycermanone vitriol in the subordinate list 2] synthetic method.With thiohydroquinone 0.01mol, β-chloropropionic acid 0.01mol is dissolved in the Na of 2M NaOH solution and calculated amount
2CO
3In the solution, add an amount of ethanol, make raw material dissolve fully the back 70-90 ℃ backflow 6-8 hour, it is 2 that concentrated solution is transferred PH with sulfuric acid, filtering and washing, drying, add the vitriol oil then, stirring at room 6 hours obtains 6-hydroxyl cycermanone, add the 0.02mol Paraformaldehyde 96,0.02mol the 2M sulfuric acid that dimethylamine is an amount of, backflow 6-8 hour, cooling, recrystallization, productive rate 47-50%.
The physicochemical constant of subordinate list 2 partial synthesis compounds
Bacteriostatic test
Cycermanone Mannich of the present invention derives the quaternary ammonium salt medicine series by to 10 genus, 18 kinds of l8 fungal strains, adopts two times of concentration dilution methods to carry out external bacteriostatic experiment, and the result is referring to subordinate list 3.
Strains tested: Candida albicans
(C.albicans), Oidium tropicale (C.tropicalis), saccharomyces cerevisiae
(S.cererisiae), cryptococcus neoformans
(C.neoformans), acrothesium floccosum
(E.floccosum), trichophyton gypseum
(T.gypsoum), trichophyton
(T.vubrum), trichophyton
(T.tonsurans), microsporon gypseum
(M.gypseum), Trichoderma
(Trichoderum), black-koji mould
(A.niger)Grayish green aspergillus
(A.glaucus), penicillium commune
(P.commune), Pei Shi Saksenaea vasiformis bacterium
(P.pedrosoi), the Cladosporium carrionii bacterium
(C.carionii), phialophora compacta
(P.comaitum), phialophora verrucosa
(P.verrucosa)And Sporothrix schenckii
(S.schenekn)
The preparation of bacterium liquid: what will reach full growth moves in the 5ml stroke-physiological saline solution for the examination bacterial classification, smashs the ultrasonic abundant concussion in back to pieces, removes block insoluble substance, mixing, and as original bacteria liquid, adjusting its concentration during test is 10
6Use behind individual cell/ml.
Experimental technique: test compound dissolves with an amount of methyl-sulphoxide, again with sterile distilled water dilution, adds death of monks or nuns and crosses in the proof agar substratum of 1% (heat) of bacterium, and sample concentration is 200,100,50,25,12.5,6.25,3.12,1.60mg/mL.Inoculation for the examination bacterium after, putting constant temperature oven, to cultivate 5-7 day be minimal inhibitory concentration MIC with the highly diluted concentration of no fungal growth.
From experimental result as can be seen, the cycermanone Mannich quaternary ammonium salt series compound of deriving all has in various degree inhibition activity to fungi, wherein compound (3), (5), (8), (11) etc. are the most remarkable to the deep fungal infection restraining effect, and are suitable with the reference substance clotrimazole.
In a word, the medicine that the present invention relates to all is synthesized as raw material with benzene sulfonyl chloride (or substituted benzene SULPHURYL CHLORIDE), the various chemical reagent of using in the synthetic reaction process all be common and be simple and easy to, the yield of reaction is also more satisfactory.
Learn experiment by pharmacological toxicology, show that the cycermanone Mannich quaternary ammonium salt series compound of deriving all has in various degree inhibition activity to fungi, the cycermanone Mannich of part ethyl sulfonic acid, amino acids very little of quaternary ammonium salt toxicity of deriving, in addition nontoxic.
The compounds of this invention is widely used in antimycotic field, and wide researching value and application prospect are arranged.
Subordinate list 3 external bacteriostatic experiments are table MIC (mgL as a result
-1)
| Clotrimazole DMSO 23456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 27 28 (gram certain kind of berries azoles) (20%) | ||
| ????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9 ????10 ????1l ????12 ????13 ????14 ????15 ????16 ????17 ????18 | A.glaucus A.niger C.albicans C.carrionii C.trcpicalis C.neoforma E.floccosum M.gypseum P.commune P.compaitu P.pedrosoi P.verrucosa S.cererisiae S.schenekn T.ferugineu T.gypsoum T.tongurans T.vubrum | 200??50????200???100???100???200???100???200???50???25???200??200??100??100??100???100??200??200??50???100??100??200??100??100??????25?????????????- 200??50????200???100???50????200???50????100???200??200??200??200??100??100??100???100??100??200??200??100??100??100??100??100??????25?????????????- 100??6.25??12.5??6.25??12.5??50????6.25??25????50???25???50???50???100??100??12.5??25???50???100??50???25???25???25???12.5?25???????12.5???????????- 50???6.25??12.5??6.25??6.25??50????12.5??50????200??100??50???100??100??100??25????50???50???100??200??25???25???25???25???25???????12.5???????????- 50???3.12??6.25??6.25??6.25??12.5??3.12??6.25??25???12.5?25???50???50???50???12.5??12.5?100??100??25???25???12.5?12.5?25???25???????2.12???????????- 100??25????6.25??6.25??25????50????3.12??6.25??6.25?6.25?50???100??100??100??50????50???50???50???12.5?6.25?50???100??50???50???????12.5???????????- 100??12.5??12.5??12.5??6.25??25????25????12.5??50???50???100??100??100??100??25????50???25???25???50???50???59???50???50???50???????12.5???????????- 25???6.25??50????25????6.25??50????3.12??12.5??100??100??100??100??100??50???25????25???50???100??100??25???25???25???100??25???????6.25???????????- 100??50????200???200???50????200???100???200???200??200??200??200??100??100??100???200??100??100??200??200??100??100??100??100??????50?????????????- 25???12.5??12.5??12.5??12.5??50????525???25????200??100??50???100??100??100??50????100??50???50???200??50???50???59???25???50???????12.5???????????- 25???6.25??12.5??25????12.5??50????12.5??50????100??100??50???100??50???100??25????25???50???100??100??50???25???25???25???25???????12.5???????????- 50???12.5??25????12.5??25????25????6.25??25????100??100??100??100??100??100??50????50???100??100??100??25???50???50???25???50???????12.5???????????- 50???3.12??6.25??6.25??6.25??12.5??3.12??6.25??12.5?12.5?50???100??50???50???25????50???50???50???25???12.5?25???12.5?12.5?25???????2.12???????????- 50???6.25??25????6.25??25????25????5.25??25????50???50???100??100??100??100??50????50???100??100??50???50???6.25?6.25?6.25?12.5?????25?????????????- 100??25????100???50????25????200???25????50????25???25???100??100??100??100??50????100??200??200??25???100??50???50???50???50???????25?????????????- 25???12.5??50????25????12.5??50????6.25??25????12.5?6.25?100??100??100??100??25????25???50???50???25???50???25???50???50???25???????12.5???????????- 100??12.5??25????25????12.5??50????12.5??50????25???50???100??100??100??50???50????50???100??100??50???25???50???25???25???50???????25?????????????- 100??6.25??25????12.5??25????25????6.25??50????100??50???100??100??100??100??50????25???50???50???100??12.5?25???25???12.5?25???????12.5???????????- |
Claims (1)
1, new cycermanone quaternary antifungal compound is characterized in that with general formula (I) expression compound:
Wherein:
1、n＝1、2
2、m＝0、2
3、x＝0，1/2，1，2，3，
4、R
1＝H、-Me，-Et；
5, work as R
2, R
3, R
4In when having one or two to be H, two other or one are respectively:
R
2=X halogenic substituent ,-Me-OMe, OH
R
3=X halogenic substituent ,-Me;
R
4=X halogenic substituent ,-Me;
6, Y
1Or Y
2=-Me ,-Et, substituted-phenyl, amino acid based
7, A
-=HSO
4 -, H
2PO
4 -, Cl
-, Br
-, CH
3SO
3 -Methylsulfonic acid, CH
3CH
2SO
3 -Ethyl sulfonic acid
Halogenic substituent is meant fluorine, chlorine, bromine, iodine; Substituted-phenyl is meant rubigan, to fluorophenyl, to the sulfanilamide (SN) phenyl, to ethoxyl phenenyl, p-nitrophenyl, ortho-nitrophenyl base; Amino acid based glycine base, the L-glutamic acid base etc. of being meant.
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|---|---|---|---|
| CNB021289360A CN1166664C (en) | 2002-08-22 | 2002-08-22 | Cycermanone quaternary antifungal compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021289360A CN1166664C (en) | 2002-08-22 | 2002-08-22 | Cycermanone quaternary antifungal compound |
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| Publication Number | Publication Date |
|---|---|
| CN1394858A true CN1394858A (en) | 2003-02-05 |
| CN1166664C CN1166664C (en) | 2004-09-15 |
Family
ID=4746075
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006122771A2 (en) * | 2005-05-20 | 2006-11-23 | Grünenthal GmbH | Substituted benzo-condensed cyclohexanone derivatives and the use thereof for medicament production |
-
2002
- 2002-08-22 CN CNB021289360A patent/CN1166664C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006122771A2 (en) * | 2005-05-20 | 2006-11-23 | Grünenthal GmbH | Substituted benzo-condensed cyclohexanone derivatives and the use thereof for medicament production |
| WO2006122771A3 (en) * | 2005-05-20 | 2007-04-26 | Gruenenthal Gmbh | Substituted benzo-condensed cyclohexanone derivatives and the use thereof for medicament production |
| US7973072B2 (en) | 2005-05-20 | 2011-07-05 | Gruenenthal Gmbh | Substituted benzo-condensed cyclohexanone derivatives and the use thereof for medicament production |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1166664C (en) | 2004-09-15 |
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