CN1861582A - Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof - Google Patents
Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof Download PDFInfo
- Publication number
- CN1861582A CN1861582A CN 200610027625 CN200610027625A CN1861582A CN 1861582 A CN1861582 A CN 1861582A CN 200610027625 CN200610027625 CN 200610027625 CN 200610027625 A CN200610027625 A CN 200610027625A CN 1861582 A CN1861582 A CN 1861582A
- Authority
- CN
- China
- Prior art keywords
- group
- cyclopropyl
- triazol
- butoxy
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
A cyclopropyl substituted triazole alcohol kind of antifungus compounds used for preparing antifungus medicines and its preparing process are disclosed. Its advantages are high curative effect, low poison and broad spectrum.
Description
Technical field:
The present invention relates to medical technical field, be specifically related to the new nitrogen azoles alcoholic antifungal compound of a class-cyclopropyl substituted 1,2,4-triazole alcohol compound, be 1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl-N-substituted-amino)-2-alcohol compound and its esters, and their preparation method and application.
Background technology:
In recent years, extensive application along with broad-spectrum antibiotics, antitumour drug, immunosuppressor, extensively carrying out of radiotherapy and organ transplantation, generally carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immune deficiency patient, cause fungi infestation particularly deep fungal infection rise significantly, deep fungal infection has now become major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.But with regard to the antifungal drug of present clinical application, have that side effect is big, narrow antimicrobial spectrum, easily produce problem such as resistance, effectively the particularly anti-deep fungal medicine of antifungal drug extremely lacks, and far can not satisfy the demand.Existing antifungal drug is mainly the propylamine that acts on the squalene cyclooxygenase, acts on the nitrogen azole of wool steroid 14a-demethylase and acts on cell walls and-1, the lipopeptid class of 3-beta glucan synthetic enzyme etc.But yet there are no the report of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-substituted amido)-2-alcohol compound and its esters anti-mycotic activity so far.
Summary of the invention:
The object of the present invention is to provide the novel nitrogen azoles alcoholic antifungal compound and preparation method thereof and application of a kind of efficient, low toxicity, wide spectrum.
The trinitrogenazole alcohol compounds that a class cyclopropyl provided by the invention replaces, its structure is shown in general formula:
Wherein X is the straight or branched ester group of hydroxyl or 1～5 carbon atom and the ester group with easy leavings group.Wherein said ester group is formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, tertiary butyl formic acid ester group, phenylformic acid ester group, toluylic acid ester group, N, N diethylamide ethylamino benzonitrile perester radical etc., preferably tertiary butyl formic acid ester group and N, N-diethylamide ethylamino benzonitrile perester radical.
Wherein Ar is for replacing aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from i or ii:
I. halogen is F, CI, Br, I;
Ii. aliphatic chain is methyl, ethyl, trifluoromethyl, trifluoromethoxy, the tertiary butyl.
Wherein M is hydrogen or methyl.Methyl preferably.
Wherein R is selected from i or ii or iii or iv:
I. acyl group, the fatty acyl group of 1-16 carbon atom straight chain or side chain; The benzoyl that replaces, phenylacetyl, hydrocinnamoyl, substituting group wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I, preferably 2,4-difluoro or 2, the 4-dichloro replaces; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
Ii. benzyl or substituted benzyl, the substituting group in the substituted benzyl wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido, preferred especially cyano group;
The straight or branched alkyl of iii.1-16 carbon atom;
Iv. the phenacylidene of Qu Daiing, substituting group wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido.
The straight or branched alkyl of a wherein said 1-6 carbon atom is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, tert-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl, the preferably tertiary butyl.
The trinitrogenazole alcohol compounds that cyclopropyl provided by the invention replaces can be its raceme, also can be its R type or S type isomer.
The present invention also provides the preparation method of above-claimed cpd, and it comprises following reaction scheme successively:
The first step, according to a) reaction scheme synthetic intermediate:
Second step is when R is selected from the i. acyl group, according to b) the reaction scheme synthesising target compound;
When R is selected from ii. benzyl or substituted benzyl, according to c) the reaction scheme synthesising target compound;
When R is selected from the straight or branched alkyl of iii.1-16 carbon atom, pass through e) the reaction scheme synthesising target compound;
When R is selected from the phenacylidene that iv. replaces, according to d) the reaction scheme synthesising target compound:
The present invention also provides the salt of above-claimed cpd, comprises hydrochloride, nitrate, hydrobromate and methane sulfonates, and salt is according to f on the basis of compound) the reaction scheme preparation:
HX wherein represents hydrochloride respectively, nitrate, hydrobromate or methane sulfonates.
Being prepared as follows of the particular compound that relates among the above-mentioned preparation method:
(1) preparation 2-chloro-2 ', 4 '-difluoro acetophenone (II)
Friedel-crafts reaction takes place and generates 2-chloro-2 ', 4 ' difluoro acetophenone (II) in m-difluorobenzene and chloroacetyl chloride under the condition that aluminum trichloride (anhydrous) exists.
(2) preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (III)
2-chloro-2 ', 4 '-difluoro acetophenone and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and salt of wormwood are at CH
2Cl
2In 0-5 ℃ of reaction 5 hours, then, generate 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (III) room temperature reaction 12 hours.
(3) preparation 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV)
2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone and iodate trimethylammonium oxygen sulphur, trimethylammonium hexadecyl brometo de amonio, reaction generates 1-[2-(2,4 difluorobenzene base)-2 in toluene and sodium hydroxide, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV).
(4) preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl amino)-2-alcohol (V)
1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate and cyclopropylamine, triethylamine generate 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl amino)-2-alcohol (V) in ethanol;
(6) preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-cyclopropyl-N-substituted acyl amino]-2-alcohol (VI)
The Benzoyl chloride of fat acyl chloride or replacement; phenyllacetyl chloride and 1-(1H-1; 2; the 4-triazol-1-yl)-2-(2; the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol (V) reacts in methylene dichloride, obtains 1-(1H-1,2; the 4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-cyclopropyl-N-substituted acyl amino]-2-alcohol (VI)
(6) preparation bromobenzyl
The toluene that replaces generates the bromobenzyl that replaces through the NBS bromination in tetracol phenixin;
(7) preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-cyclopropyl-N-substituted benzyl amino]-2-alcohol (VII)
1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol (V) and the benzyl that replaces be at acetonitrile, react in the yellow soda ash, generate 1-(1H-1,2, the 4-triazol-1-yl)-and 2-(2,4 difluorobenzene base)-3-[(N-cyclopropyl-N-substituted benzyl] amino)-2-alcohol (VII);
(7) alpha-chloro acetophenone of preparation replacement
Substituted benzene generates the alpha-chloro acetophenone that replaces with chloroacetyl chloride generation friedel-crafts reaction under the aluminum chloride existence condition;
(8) preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-cyclopropyl-N-(substituted benzene formyl methylene radical) amino]-2-alcohol (VIII)
1-(1H-1,2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol (V) and alpha-chloro acetophenone be at acetonitrile, react in the yellow soda ash, generate 1-(1H-1,2, the 4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[N-cyclopropyl-N-(substituted benzene formyl methylene radical) amino]-2-alcohol (VIII).
(9) preparation (IX) of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-substituted hydrocarbon radical amino)-2-alcohol
Halohydrocarbon and 1-(1H-1,2,4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-and 3-(N-cyclopropyl amino)-2-alcohol (V) back flow reaction in ethanol, get 1-(1H-1,2, the 4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-substituted hydrocarbon radical amino)-2-alcohol.(IX)
(10) target compound salt preparation
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-substituted-amino)-2-alcohol and excessive hydrochloric acid, nitric acid, Hydrogen bromide or methanesulfonic at room temperature reacted 2～3 hours, generated the salt of target compound.
The chemical structure of synthetic part preferred compound of the present invention (having following general formula), productive rate, fusing point and infrared, nuclear magnetic data is as shown in table 1.
Compound of the present invention has very strong anti-mycotic efficiency by pharmacological evaluation proof to deep fungal, compares with the antifungal drug of existing clinical application, has advantages such as efficient, hypotoxicity, antimycotic spectrum width, can be used for preparing new antifungal drug.
Chemical structure, productive rate, fusing point and the molecular formula of table 1 part preferred compound
| 20 | -(CH2) 4CH 3 -(CH2) 11CH 3 | 52.6％ 64.4％ | oil oil | 3200 2850 3350 3200 2850 | 3.55-3.7(m，2H，3-H)；4.42-4.46(d，1H，J＝14.7，1-H)； 4.53-4.58(d，1H，J＝14.7，1-H)；6.75-6.89(m，2H，Ar)；7.48-7.51(s，1H，Ar) 7.70(s，1H，triazole，3-H)；8.07(s，1H，triazole，5-H) 0.08-0.32(m，4H，Cyclopropane)；0.88-1.61(m，23H，-(CH2)10CH3)； 1.90-1.91(m，1H，Cyclopropane)；2.1-2.3(m.2H，N-CH2-C11H23) 3.55-3.7(m，2H，3-H)；4.57-4.59(s，2H，1-H)；6.75-6.89(m，2H，Ar)； 7.48-7.51(s，1H，Ar)7.79(s，1H，triazole，3-H)； 8.15(s，1H，triazole，5-H) |
Annotate: C, H, the measured value and the calculated value of three kinds of ultimate analyses of N differ less than 0.3%.
Embodiment:
Below in conjunction with embodiment the present invention is further described.
Embodiment 1:
According to a) reaction scheme synthetic intermediate.
(1), preparation 2-chloro-2 ', 4 '-difluoro acetophenone
Anhydrous alchlor 200g (1.494mol) and m-difluorobenzene 150g (1.30mol) place the 1000mL three-necked bottle, stir under the room temperature, slowly drip chloroacetyl chloride 150g (1.30mol), continue at after dropwising under the room temperature and stirred 30 minutes, slowly be warming up to 45 ℃, under this temperature, continue to stir 4.5 hours, routinely reaction solution is poured in the frozen water, separate out solid, filter; Filtrate is extracted at twice with methylene dichloride 800mL, the combined dichloromethane extracting solution, be washed to neutrality, anhydrous sodium sulfate drying filters, get solid after reclaiming solvent, merge gained solid ethyl alcohol recrystallization twice, get 2-chlorine 2 ', 4 '-difluoro acetophenone 215g, yield 88.2%, fusing point: 46-47 ℃.
(2), preparation 2-(1H-1,2,4-triazol-1-yl)--2 ', 4 '-difluoro acetophenone
Triazole 54g (0.4mol), TEBA0.8g, Anhydrous potassium carbonate 82g (0.3mol) are added 400mLCH
2Cl
2In suspension; 2-chloro-2 ', 4 '-difluoro acetophenone 76g (0.4mol) is dissolved in 60mL CH
2CI
2In, under condition of ice bath, it is added dropwise in the above-mentioned 400mL suspension, dripped off in about 2 hours, drip and finish the back in 0～5 ℃ of reaction 5 hours, normal-temperature reaction 24 hours.Filter filter cake CH then
2Cl
2Wash for several times, collect filtrate, filtrate water is washed 3 times, each 200mL, anhydrous Na
2SO
4Drying steams CH
2Cl
2Residue is dissolved in the 200mL anhydrous ethyl acetate, stirs down and drip concentrated nitric acid, till no longer separating out to yellow solid; Filter, filter cake is washed for several times with amount of ethyl acetate, and drying is dissolved in 200mL water with it, NaOH solution (w/w) adjust pH with 30% is 9, separate out solid, filter, the dry crude product that gets, use normal hexane: 1: 1 recrystallization of ethyl acetate (V/V), get compound 76g, yield 86.2%, fusing point: 104～105 ℃.
(3), preparation 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate
2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone 58g (0.23mol), trimethylammonium oxygen sulfuration iodine 50g (0.23mol), trimethylammonium hexadecyl brometo de amonio 3.2g, put into the 1000mL three-necked bottle, add toluene 400mL and 20% sodium hydroxide solution 450mL, 60 ℃ were heated 3 hours, after reaction finishes, isolate toluene layer, water layer is again with toluene extraction (200mL * 2), combining methylbenzene layer, be washed to neutrality, after reclaiming most toluene, debris adds the dilution of 240mL ethyl acetate, and 0 ℃ drips the ethyl acetate 5mL that is dissolved with the 16g methylsulfonic acid down, separate out faint yellow solid, filter, use ethyl alcohol recrystallization routinely, get compound 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate 44g, productive rate 57.6%, fusing point: 128～129 ℃.
(4), preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl amino)-2-alcohol
1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate 21g is with cyclopropylamine 10mL triethylamine 20mL, in 300mL ethanol reflux 6-8 hour, the reaction back that finishes was steamed and is desolventized, and uses the 200mL ethyl acetate extraction, 100mL * 2 washings, anhydrous sodium sulfate drying filters, steam and remove ethyl acetate, get oily 1-(1H-1,2, the 4-triazol-1-yl)-and 2-(2,4 difluorobenzene base)-3-(N-cyclopropyl amino)-2-alcohol 13.6, yield 68%;
(5), preparation is to the nitro bromobenzyl
In the 100mL round-bottomed flask, add para-nitrotoluene 13.7g (0.1mol) and tetracol phenixin 50mL, be warming up to 80 ℃, add N-bromo-succinimide 24g (0.11mol) and benzoyl peroxide 1.0g in batches, behind reinforced the finishing, reacting by heating 4 hours.After reaction finishes, filter, the filtrate evaporate to dryness gets gray solid 18.6g, and this is the nitro bromobenzyl, yield 85.5%, mp:98～100 ℃.
(6), preparation alpha-chloro acetophenone
Add benzene 20mL (0.23mol) in the 100mL three-necked bottle, aluminum chloride 50g slowly drips under the stirring at room situation, chloroacetyl chloride 18.2mL (0.23mol), the time is 0.5h, after dropwising, be warming up to 50 ℃ of reaction 6h gradually, after reaction finishes reactant be poured in the ice, add an amount of concentrated hydrochloric acid, filter washing, drying, re-crystallizing in ethyl acetate, get ashen solid crystal alpha-chloro acetophenone 26.8g, mp:(76-78 ℃ at last), yield 80%.
(7), preparation Benzoyl chloride
In the eggplant-shape bottle of 250mL, add phenylformic acid 25.2g (0.21mol), the 100mL sulfur oxychloride, zeolite is some, reflux 6h, the evaporate to dryness sulfur oxychloride gets tawny solid Benzoyl chloride 25g, yield 90% then.
Embodiment 2: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-benzylamino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol 0.55g (0.002mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol), bromobenzyl 0.54g (0.003mol), oil bath reflux 8 hours, solvent evaporated then, ethyl acetate 30mL extracts, and filters, ethyl acetate layer column chromatography (developping agent chloroform: methyl alcohol (60: 1), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-nitrobenzyl) amino)-2-alcohol 600mg, yield 62.4%.(concrete spectroscopic data sees Table compound 1 in 1)
Embodiment 3: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4-benzyl chloride base) amino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol 0.8g (0.003mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol), 4-chlorobenzyl chloride 0.8g (0.0048mol), oil bath reflux 8 hours, solvent evaporated then, ethyl acetate 30mL extracts, and filters, ethyl acetate layer column chromatography (developping agent chloroform: methyl alcohol (80: 1), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-benzyl chloride base) amino)-2-alcohol 950mg, yield 74.1%.(concrete spectroscopic data sees Table compound 2 in 1) compound 3,4,5,6 carries out according to the method described above.
Embodiment 4: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4-methyl-benzyl) amino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol 0.8g (0.003mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol) is to methyl benzyl chloride 0.68g (0.005mol), oil bath reflux 6 hours, solvent evaporated then, ethyl acetate 30mL extracts, and filters, ethyl acetate layer column chromatography (developping agent chloroform), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-methyl-benzyl) amino)-2-alcohol 800mg, yield 67.5%.(concrete spectroscopic data sees Table compound 7 in 1) compound 8 carries out according to the method described above.
Embodiment 5: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4 benzoyl benzyl) amino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL; 2; the 4-triazol-1-yl)-2-(2; the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol 0.5g (0.002mol); acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol) is to benzoyl bromobenzyl 0.9g (0.003mol); oil bath reflux 6 hours; solvent evaporated then, ethyl acetate 30mL extracts, and filters; ethyl acetate layer column chromatography (developping agent chloroform); get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last; the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-benzoyl benzyl) amino)-2-alcohol 600mg, yield 60.5%.(concrete spectroscopic data sees Table compound 9 in 1) compound 10,11,12.13 carries out according to the method described above.
Embodiment 6: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4-nitrobenzyl) amino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol (V) 0.8g (0.0027mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol) is to nitro bromobenzyl 0.8g (0.0035mol), oil bath reflux 8 hours, solvent evaporated then, ethyl acetate 30mL extracts, and filters, ethyl acetate layer column chromatography (developping agent chloroform: methyl alcohol (60: 1), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-nitrobenzyl) amino)-2-alcohol (VIII) 600mg, yield 60%.
Embodiment 7: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4-tertiary butyl benzyl) amino]-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-(N-cyclopropyl amino)-2-alcohol (V) 0.8g (0.003mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol) is to tertiary butyl bromobenzyl 1.46g (0.0035mol), oil bath reflux 8 hours, solvent evaporated then, ethyl acetate 30mL extracts, and filters, ethyl acetate layer column chromatography (developping agent chloroform), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, the 4-difluorophenyl)-3-[(N-cyclopropyl-N-(4-tertiary butyl benzyl) amino)-2-alcohol (VIII) 1g, yield 60%.
Embodiment 8: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-ethoxy acyl methylamino)-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100ml, 2, the 4-triazol-1-yl)-and 2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-benzylamino)-2-alcohol 0.8g (0.003mol), acetonitrile 40ml, anhydrous sodium carbonate 2g (0.019mol), ethyl bromoacetate 0.5 (0.004mol) g oil bath reflux 6 hours, solvent evaporated then, extract ethyl acetate 20ml * 3, tell ethyl acetate layer, use anhydrous sodium sulfate drying, filter the evaporate to dryness ethyl acetate, crude product column chromatography (developping agent chloroform), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, 4 difluorophenyls)-and 3-(N-cyclopropyl-N-ethoxy acyl methylamino)-2-alcohol 726mg, yield 68%.
Embodiment 9: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-phenacylidene amino)-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100ml, 2, the 4-triazol-1-yl)-and 2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-benzylamino)-2-alcohol 0.8g (0.003mol), acetonitrile 40ml, anhydrous sodium carbonate 2g (0.019mol), α chloroacetophenone 0.6g (0.004mol) oil bath reflux 6 hours, solvent evaporated then, extract ethyl acetate 20ml * 3, tell ethyl acetate layer, use anhydrous sodium sulfate drying, filter the evaporate to dryness ethyl acetate, crude product column chromatography (developping agent chloroform), get 1-(1H-1,2,4-triazol-1-yl)-2-(2 at last, 4 difluorophenyls)-and 3-(N-cyclopropyl-N-phenacylidene amino)-2-alcohol 700mg, yield 68%.
Embodiment 10: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-(N-cyclopropyl-N-benzoyl-amido)-2-alcohol
Add 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-benzylamino)-2-alcohol 0.8g (0.003mol) in the eggplant-shape bottle of 100mL, CH
2Cl
220mL, triethylamine 0.6g (0.005mol), the ice bath controlled temperature is about 0 ℃; slowly be added dropwise to Benzoyl chloride 0.38g (0.0027mol), dropwised the back room temperature reaction 6 hours, solvent evaporated after reaction finishes; washing; ethyl acetate extraction, (the developping agent chloroform: methyl alcohol (60: 1) gets 1-(1H-1 to column chromatography at last; 2; the 4-triazol-1-yl)-and 2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-benzoyl-amido)-2-alcohol 700mg, yield 85%.
The preparation of embodiment 11:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-methylamino)-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl)-2-alcohol 0.5g (0.002mol), dehydrated alcohol 40mL, anhydrous sodium carbonate 2g (0.019mol), methyl iodide 0.5g (0.003mol), oil bath reflux 8 hours, solvent evaporated then, extract ethyl acetate 20ml * 3, tells ethyl acetate layer, uses anhydrous sodium sulfate drying, filter, the evaporate to dryness ethyl acetate, (the developping agent chloroform gets oily matter 1-(1H-1 to the crude product column chromatography at last, 2, the 4-triazol-1-yl)-and 2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-methylamino)-2-alcohol 378mg, yield 71.2%.(spectroscopic data sees Table compound 16 in 1).Compound 17,18,19,20 is synthetic according to the method described above.
The preparation of embodiment 12:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-n-heptyl amino)-2-alcohol
Add 1-(1H-1 in the eggplant-shape bottle of 100mL, 2, the 4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl)-2-alcohol 0.8g (0.0027mol), acetonitrile 40mL, anhydrous sodium carbonate 2g (0.019mol), bromo pentane 0.864g, oil bath reflux 8 hours, solvent evaporated then, extract ethyl acetate 20ml * 3, tells ethyl acetate layer, uses anhydrous sodium sulfate drying, filter, the evaporate to dryness ethyl acetate, (the developping agent chloroform gets 1-(1H-1 to the crude product column chromatography at last, 2, the 4-triazol-1-yl)-and 2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-n-pentyl amino)-2-alcohol 678mg, yield 60%.
Embodiment 13: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-benzoyl-amido)--2-alcohol hydrochloride
Get 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene the base)-3-[N-cyclopropyl-N-(4-nitrobenzyl) that has prepared) amino]-2-alcohol 0.40g, (0.001mol), 5mLCH
2Cl
2Dissolving slowly drips concentrated hydrochloric acid 2mL, dropwises back room temperature reaction 4h, reacts the after-filtration that finishes, and the Virahol recrystallization gets white crystal 250mg, mp:110-172 ℃ of yield 62.5% at last.
Embodiment 14:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(4-tertiary butyl benzyl) amino]-the 2-alcohol hydrochloride
Get 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-(the 4-tertiary butyl benzyl) amino that has prepared]-2-alcohol 0.44g (0.001mol) 5mLCH
2Cl
2Dissolving slowly drips concentrated hydrochloric acid 2mL, dropwises back room temperature reaction 4h, reacts the after-filtration that finishes, and the Virahol recrystallization gets white crystal 300mg, mp:110-172 ℃ of yield 63.8% at last.
Embodiment 15:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-n-heptyl amino)-2-alcohol hydrochloride
Get 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-n-heptyl the amino)-2-alcohol 0.40g that has prepared, (0.0013mol), 5mLCH
2Cl
2Dissolving slowly drips concentrated hydrochloric acid 2mL, dropwises back room temperature reaction 4h, reacts the after-filtration that finishes, and the Virahol recrystallization gets white crystal 260mg, mp:110-172 ℃ of yield 60.5% at last.
Enforcement of the present invention is not limited to above embodiment, and all the other target compounds are with different halohydrocarbon, substituted benzyl, the substituted acetophenone of alpha-halogen, acyl chlorides is a synthesis material, repeats the step among the above embodiment, just can synthesize required trinitrogenazole alcohol antifungal compound or its esters.
Agents useful for same is commercially available analytical pure among the embodiment.
Embodiment 16:
The present invention synthesizes 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(N-cyclopropyl-N-substituted amido)-2-alcohol compound and has antifungic action, and its pharmacological evaluation is as follows:
(1) experimental technique: (see for details: AntimicrobAgents Chemother 1995,39 (5): 1169) to adopt conventional external bacteriostatic experiment method
1. materials and methods
(1) experimental strain
This experiment has selected for use following 8 kinds of common human body cause illness's standard fungal bacterial strains as screening object:
Deep fungal: Candida albicans, cryptococcus neoformans, Oidium tropicale, Candida parapsilosis;
Superficial mycosis: trichophyton;
Subcutaneous fungi: ulotrichy sporule silk bacterium, fonsecaea compacta, fumigation aspergillus tubigensis.
(2) test method
The bacteria suspension preparation: above-mentioned fungi was cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted bacteria concentration to 1 * 10 with the RPM1640 liquid nutrient medium
4～1 * 10
5Individual/mL.
Soup preparation: get testing compound of the present invention (compound of this sequence number in table 2 Chinese medicine number 1,3,4,5,6,16,17, the 18 difference correspondence table 1) and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 8.0mg/mL, be diluted to 640 μ g/mL with RPM1640 before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPM1640 100 μ l and makes blank, it is liquid 100 μ l that the 3-12 hole respectively adds bacterium, No. 2 the hole adds bacteria suspension 180 μ l and soup 20 μ l, 10 grades of doubling dilutions of the drug level in 2-11 hole, each hole drug level divide be 64,32,16,8,4,2,1 in addition, 0.0.5,0.25,0.125 μ l/mL.No. 12 the hole does not add soup, makes positive control.The medicine contrast is fluconazole (FLU.), itraconazole (ITR.) and special than naphthols (TRB.).
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest concentration of drug with optical density value than positive control hole is minimal inhibitory concentration value (MIC
80).
(2) experimental result
External bacteriostatic experiment the results are shown in Table 2.
The external antimycotic minimal inhibitory concentration value of table 2 part selected objective target compound (MIC, μ l/mL)
| Medicine number | Ca. | Cp. | Cn. | Ct. | Tr. | Af. | Mo. | Fc. |
| 1 2 5 7 16 17 18 FLU ITR TRB | ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 0.5 ≤0.125 2 | ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 0.25 ＜0.125 0.5 ≤0.125 8 | 0.125 0.5 ＜0.125 ＜0.125 ＜0.125 0.25 0.25 1 ≤0.125 ≤0.125 | ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 0.5 0.5 2 | ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125. 2 ≤0.125 ≤0.125 | 1 1 0.5 0.5 ＜0.125 ＜0.125 0.5 8 2 ≤0.125 | ＜0.125 ＜0.125 ＜0.125 0.5 1 ＜0.125 ＜0.125 2 ≤0.125 ≤0.125 | 0.25 0.5 ＜0.125 ＜0.125 0.25 ＜0.125 ＜0.125 16 ≤0.125 ≤0.125 |
Annotate: the Ca. Candida albicans, the Cp. Candida parapsilosis, the Cn. Cryptococcus neoformans, the Ct. Oidium tropicale, the Tr. trichophyton, Af. smokes aspergillus fumigatus, Mo. microsporum lanosum, Fc. fonsecaea compacta.
FLU. fluconazole, the ITR. itraconazole, TRB. spy compares naphthols.
Compound 1:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-cyclopropyl-N-benzylamino]-2-alcohol
Compound 2:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-(4-benzyl chloride base) amino]-2-alcohol
Compound 5:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-(4-cyano group benzyl) amino]-2-alcohol
Compound 7:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-(4-methyl-benzyl) amino]-2-alcohol
Compound 16:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-4-methylamino]-2-alcohol
Compound 17:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-4-ethylamino]-2-alcohol
Compound 18:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[N-ring third-N-allyl amino]-2-alcohol
Above-mentioned experimental result shows that compound of the present invention and its esters have good anti-mycotic activity, a plurality of compounds all far are better than fluconazole to the vitro inhibition activity of selected fungi, illustrate that The compounds of this invention and its esters can be used for preparing the medicine of anti-fungal infection.
Claims (10)
1, the trinitrogenazole alcohol compounds of class cyclopropyl replacement, its structure is shown in general formula:
Wherein X is the straight or branched ester group of hydroxyl or 1～5 carbon atom and the ester group with easy leavings group;
Wherein Ar is for replacing aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from i or ii:
I. halogen is F, CI, Br, I;
Ii. aliphatic chain is methyl, ethyl, trifluoromethyl, trifluoromethoxy, the tertiary butyl;
Wherein M is hydrogen or methyl;
Wherein R is selected from i or ii or iii or iv:
I. acyl group, the fatty acyl group of 1-16 carbon atom straight chain or side chain; The benzoyl that replaces, phenylacetyl, hydrocinnamoyl, substituting group wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
Ii. benzyl or substituted benzyl, the substituting group in the substituted benzyl wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
The straight or branched alkyl of iii.1-16 carbon atom;
Iv. the phenacylidene of Qu Daiing, substituting group wherein can be positioned at phenyl ring the neighbour,, contraposition, can be single replace or polysubstituted, substituting group is selected from (a) F, CI, Br, I; (b) the straight or branched alkyl of 1～6 carbon atom; (C) cyano group, nitro, trifluoromethyl, trichloromethyl, trifluoromethoxy, benzoyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, amido;
The straight or branched alkyl of a wherein said 1-6 carbon atom is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, tert-pentyl, sec.-amyl sec-pentyl secondary amyl or isopentyl.
2, the trinitrogenazole alcohol compounds of cyclopropyl replacement according to claim 1, it is characterized in that X wherein is formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, tertiary butyl formic acid ester group, phenylformic acid ester group, toluylic acid ester group or N, N diethylamide ethylamino benzonitrile perester radical.
3, the trinitrogenazole alcohol compounds of cyclopropyl replacement according to claim 1 is characterized in that Ar wherein is the 2,4 difluorobenzene base.
4, the trinitrogenazole alcohol compounds of cyclopropyl replacement according to claim 1 is characterized in that R wherein is 2,4-difluoro or 2, the benzoyl that the 4-dichloro replaces.
5, the trinitrogenazole alcohol compounds of cyclopropyl replacement according to claim 1 is characterized in that R wherein is methyl-benzyl, nitrobenzyl or cyano group benzyl.
6, the trinitrogenazole alcohol compounds that replaces according to claim 1,2,3,4 or 5 described cyclopropyl is characterized in that this compound is its raceme, or is its R type or S type isomer.
7, the preparation method of the trinitrogenazole alcohol compounds of cyclopropyl replacement as claimed in claim 1 is characterized in that it comprises following reaction scheme successively:
The first step, according to a) reaction scheme synthetic intermediate:
Second step is when R is selected from the i. acyl group, according to b) the reaction scheme synthesising target compound;
When R is selected from ii. benzyl or substituted benzyl, according to c) the reaction scheme synthesising target compound;
When R is selected from the straight or branched alkyl of iii.1-16 carbon atom, pass through e) the reaction scheme synthesising target compound;
When R is selected from the phenacylidene that iv. replaces, according to d) the reaction scheme synthesising target compound:
8, the salt of the trinitrogenazole alcohol compounds of cyclopropyl replacement as claimed in claim 1 is its hydrochloride, nitrate, hydrobromate or methane sulfonates.
9, the application of the trinitrogenazole alcohol compounds of cyclopropyl replacement as claimed in claim 1 in the preparation antifungal drug.
10, the application of the salt of the trinitrogenazole alcohol compounds of cyclopropyl replacement as claimed in claim 8 in the preparation antifungal drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610027625 CN1861582A (en) | 2006-06-13 | 2006-06-13 | Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610027625 CN1861582A (en) | 2006-06-13 | 2006-06-13 | Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1861582A true CN1861582A (en) | 2006-11-15 |
Family
ID=37389126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610027625 Pending CN1861582A (en) | 2006-06-13 | 2006-06-13 | Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1861582A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101798290A (en) * | 2010-04-02 | 2010-08-11 | 北京欧凯纳斯科技有限公司 | Method for synthesizing chiral cyproconazole |
| CN102276542A (en) * | 2011-05-27 | 2011-12-14 | 郑州大学 | Triazole alcohol compound, preparation method and application thereof |
| CN101768126B (en) * | 2009-12-10 | 2012-05-02 | 中国人民解放军第二军医大学 | Novel triazole antifungal compound and salt thereof |
| CN101575320B (en) * | 2008-05-08 | 2012-10-31 | 南京华威医药科技开发有限公司 | Water-soluble triazole antifungal compound |
| CN105308032A (en) * | 2013-04-12 | 2016-02-03 | 拜耳作物科学股份公司 | Novel triazole derivatives |
-
2006
- 2006-06-13 CN CN 200610027625 patent/CN1861582A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575320B (en) * | 2008-05-08 | 2012-10-31 | 南京华威医药科技开发有限公司 | Water-soluble triazole antifungal compound |
| CN101768126B (en) * | 2009-12-10 | 2012-05-02 | 中国人民解放军第二军医大学 | Novel triazole antifungal compound and salt thereof |
| CN101798290A (en) * | 2010-04-02 | 2010-08-11 | 北京欧凯纳斯科技有限公司 | Method for synthesizing chiral cyproconazole |
| CN101798290B (en) * | 2010-04-02 | 2012-03-07 | 北京欧凯纳斯科技有限公司 | Method for synthesizing chiral cyproconazole |
| CN102276542A (en) * | 2011-05-27 | 2011-12-14 | 郑州大学 | Triazole alcohol compound, preparation method and application thereof |
| CN105308032A (en) * | 2013-04-12 | 2016-02-03 | 拜耳作物科学股份公司 | Novel triazole derivatives |
| CN105308032B (en) * | 2013-04-12 | 2017-05-24 | 拜耳作物科学股份公司 | Novel triazole derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1181825C (en) | Use of colchinol derivatives as vascular damaging agents | |
| CN1138763C (en) | Di- or tri-fluoromethanesulfonyl anilide derivs., process for preparation of them and herbicides contg. them as active ingredient | |
| CN1426396A (en) | Substituted benzoic acid amides and use for inhibition of angiogenesis thereof | |
| CN1845917A (en) | 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicam | |
| CN101357906A (en) | Novel triazolols antifungal compound, preparation method and application thereof | |
| CN1861582A (en) | Cyclopropyl substituded triazol kind anti fungus compound and preparation process and use thereof | |
| CN1384816A (en) | Polymorphic forms of sertraline hydrochloride | |
| CN88100500A (en) | Novel polyamine derivatives | |
| CN101602738B (en) | Novel azole antifungal compound and preparation method thereof | |
| CN101402613A (en) | Substituted phenoxy oxygen alkylamine triazole alcohol antimycotic compounds and method of preparing the same | |
| CN85104471A (en) | Triazole antifungal agents | |
| CN1137102C (en) | Substituted propyl triazole as antifungal compound and its salts and their prepn. | |
| CN101781263A (en) | Nitrogen methyl side chain-substituted triadimenol antifungal compound and preparation method thereof | |
| CN1847240A (en) | Prazole derivative and its salt and use | |
| CN1483320A (en) | Heterocyclic ring contained methylamine cyanoacrylate compound and weeding activity | |
| CN1235884C (en) | Antifungal compound of substitution benzyl triazole alcohols | |
| CN1125819C (en) | Trinitrogenazole alcohol antifungal compound and its preparation method | |
| CN1303073C (en) | Substituted triazolone benzyl amine triazole antifungal compounds and method for preparing same | |
| CN1228330C (en) | Imidazole derivatives or their salts | |
| CN1103533A (en) | Biologically active ureido derivatives useful as antimetastatic agents | |
| CN1023223C (en) | Derivative of 1,5-diphenyl-1H-1,2,4-triazole-3-carboxamide and herbicidal composition containing same | |
| CN1405157A (en) | Novel diazo alcoholic antifungal compound and its salt | |
| CN1907971A (en) | Ciclopirox olamine crystal and method for preparing the same | |
| CN101054383A (en) | Bromodihydroartemisinin and preparation method thereof | |
| CN1020905C (en) | Method for preparation of azolyl-derivatives having fungicidal activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20061115 |