CN1405157A - Novel diazo alcoholic antifungal compound and its salt - Google Patents

Novel diazo alcoholic antifungal compound and its salt Download PDF

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CN1405157A
CN1405157A CN 02136947 CN02136947A CN1405157A CN 1405157 A CN1405157 A CN 1405157A CN 02136947 CN02136947 CN 02136947 CN 02136947 A CN02136947 A CN 02136947A CN 1405157 A CN1405157 A CN 1405157A
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hydroxyl
alcohol compounds
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CN1169798C (en
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张万年
盛春泉
季海涛
周有骏
吕加国
朱驹
余建鑫
宋云龙
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Second Military Medical University SMMU
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Abstract

The invention relates to the field of medicine, and it is new type triazoazole alcohol antimycotic compound-1-substituted piperazidyl-2-(2,4-difluorophenyl)-3-(1H-1,2,4- triazole-1-base)-2-propanol compound and its salts. Said invention provides its chemical structure general formula. Its salts comprises hydrochloride, hydrobromate and methane-sulfonate. The invented compounds have strong antimycotic activity, low toxicity and broad antimycotic spectrum, can be used for preparing antimycotic medicine.

Description

Novel diazo alcoholic antifungal compound and its esters
Technical field: the present invention relates to medical technical field, is a kind of novel trinitrogenazole alcohol antifungal compound--1-substituted piperazinyl-2-(2,4 difluorobenzene base)-3-(1H-1,2,4-triazol-1-yl)-2-propanol compound and its esters.
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 treatment needs.Existing antifungal drug is mainly the propylamine that acts on the squalene cyclooxygenase, acts on the nitrogen azole of lanosterol 14 α demethylases and act on lipopeptid class of cell walls β-(1,3)-glucan synthase etc.But yet there are no the report of 1-substituted piperazinyl-2-(2,4 difluorobenzene base)-3-(1H-1,2,4-triazol-1-yl)-2-propanol compound and anti-mycotic activity thereof so far.
Summary of the invention: the novel nitrogen azoles alcoholic antifungal compound that the invention provides a kind of efficient, low toxicity, wide spectrum, comprise 1-substituted piperazinyl-2-(2, the 4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol compound and hydrochloride, hydrobromate and methane sulfonates.
The general structure of The compounds of this invention is as follows:
Figure A0213694700051
Wherein: X group representation hydroxy or ester group
The ester group here refers to have the straight or branched ester group of 1～4 carbon atom, as formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, preferably has the ester group of 1～3 carbon atom, preferred especially acetate groups.
Y group is represented the various substituting groups on the aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition.Can be single replacement, also can be polysubstituted.Substituting group refers to:
(1) halogen, preferred especially 2 as F, Cl, Br, I, 4-difluoro or 2, the 4-dichloro replaces;
(2) aliphatic chain, as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., preferred trifluoromethyl replaces.
The M group is represented hydrogen or methyl, special preferable methyl.
The representative of R group
(1) heterocycle or substituted heterocycle
Heterocycle refers to common five yuan or hexa-member heterocycle, for example furans, thiophene, pyrroles, pyrazoles, imidazoles, oxazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine etc.Preferred hexa-member heterocycle, preferred especially pyridine or pyrimidine.Substituting group can be positioned at each position of heterocyclic on the heterocycle, can be single replacement, also can be polysubstituted.Substituting group refers to:
A. halogen, as F, Cl, Br, I, preferred especially chlorine atom;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., excellent especially
Select trifluoromethyl
C. electron-withdrawing substituent or push away electron substituent group, as cyano group, nitro, hydroxyl etc., preferred especially cyano group;
D. three-dimensional substituting group or hydrophobic substituent are as tertiary butyl etc.;
E. wetting ability substituting group is as hydroxyl etc.
(2) substituted benzoyl or substituted benzene ethanoyl
Substituting group in substituted benzoyl or the substituted benzene ethanoyl on the phenyl ring can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted.Substituting group is meant:
A. halogen is as F, Cl, Br, I; Preferred especially chlorine atom;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., excellent especially
Select trifluoromethyl;
C. electron-withdrawing substituent or push away electron substituent group, as cyano group, nitro, hydroxyl etc., preferred especially cyano group;
D. three-dimensional substituting group or hydrophobic substituent are as tertiary butyl etc.;
E. wetting ability substituting group is as hydroxyl etc.
(3) substituted benzyloxy phenyl
Substituted benzyloxy can be positioned at neighbour on the phenyl ring,, contraposition, can be single replacement, also can be polysubstituted, preferred especially para-orientation.Substituting group in the benzyloxy on the phenyl ring can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, preferred especially contraposition is single to be replaced, substituting group is meant:
A. halogen is as F, Cl, Br, I; Preferred especially chlorine atom;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., excellent especially
Select trifluoromethyl;
C. electron-withdrawing substituent or push away electron substituent group, as cyano group, nitro, hydroxyl etc., preferred especially cyano group;
D. three-dimensional substituting group or hydrophobic substituent are as tertiary butyl etc.;
E. wetting ability substituting group is as hydroxyl etc.
The salt of The compounds of this invention comprises hydrochloride, hydrobromate and methane sulfonates.
The building-up reactions flow process of The compounds of this invention is as follows:
The synthetic of The compounds of this invention salt is on the basis of above-mentioned reaction, further does following reaction:
Figure A0213694700072
Wherein HX represents hydrochloric acid, Hydrogen bromide or methanesulfonic.Concrete steps are: (1) preparation 2-chloro-2 ', 4 '-difluoro acetophenone (II)
M-difluorobenzene (I) and chloroacetyl chloride are at anhydrous AlCl 3Middle generation Friedel-Crafts reaction generation 2-chloro-2 ', 4 '-difluoro acetophenone (II); (2) preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (III)
2-chloro-2 ', 4 '-difluoro acetophenone (II) and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and K 2CO 3At CH 2Cl 2In 0～5 ℃ of reaction 5 hours, then, generate 2-(1H-1,2,4-triazol-1-yl)-2 ' room temperature reaction 12 hours, 4 '-difluoro acetophenone (III); (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 (III) 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 target compound (V)
1-substituted-piperazinyl and 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV) is in methyl alcohol, and under the sodium hydroxide existence condition, reaction generates 1-substituted piperazinyl-2-(2, the 4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol (V).(5) preparation target compound (VI)
1-substituted piperazinyl-2-(2,4 difluorobenzene base)-3-(1H-1,2,4-triazol-1-yl)-2-propyl alcohol (V) at room temperature reacted 2～3 hours with excessive acid, generated target compound (VI)
The present invention's chemical structure, productive rate, fusing point and molecular formula of synthetic part preferred compound sees Table 1.
Chemical constitution, productive rate, fusing point and the molecular formula of table 1 part preferred compoundCompound volume X group M radicals R group productive rate (%) fusing point (℃) molecular formula number 1 OH H 4-Pyridine 78.9 oil C20H 22F 2N 6O    2       OH      H       2-Pyridine          77.4        106～108    C 20H 22F 2N 6O    3       OH      H  4-CF 3-6-Cl-2-Pyridine   80.8        135～136    C 21H 20ClF 5N 6O    4       OH      H       3-pyridine          69.6        103～104    C 20H 22F 2N 6O    5       OH      H   4-C(CH 3) 3-2-pyridine 87.3        112～113    C 24H 30F 2N 6O    6       OH      H     4-CF 3-3-pyridine     85.4        98～99      C 21H 21F 5N 6O    7       OH      H     5-F-4-pyrimidine      91.8        105～106    C 19H 20F 3N 7O    8       OH      H     5-F-2-pyrimidine      93.1        95～96      C 19H 20F 3N 7O    9       OH      H    5-CF 3-4-pyrimidine    88.2        116～117    C 20H 20F 5N 7O    10      OH      H       2-pyrimidine        78.2        126～128    C 19H 21F 2N 7O    11      OH      H       4-pyrimidine        77.4        130～132    C 19H 21F 2N 7O    12      OH      H   4-Cl-benzyloxyphenyl    85.7           oil      C 28H 28ClF 2N 5O 2    13      OH      H    4-F-benzyloxyphenyl    91.4        118～119    C 28H 28F 3N 5O 2    14      OH      H     4-Br-benzyloxyphenyl         79.1        122～123    C 28H 28BrF 2N 5O 2    15      OH      H      4-I-benzyloxyphenyl         82.5        137～138    C 28H 28IF 2N 5O 2    16      OH      H     4-CF 3-benzyloxyphenyl       84.6        114～115    C 29H 28F 5N 5O 2    17      OH      H    4-OCH 3-benzyloxyphenyl       74.9        88～89      C 29H 31F 2N 5O 3    18      OH      H   4-C(CH 3) 3-benzyloxyphenyl    75.4        98～100     C 32H 37F 2N 5O 2    19      OH      H    2-F-4-Br-benzyloxyphenyl       76.5        83～85      C 28H 27BrF 3N 5O 2    20      OH      H    2-Br-4-F-benzyloxyphenyl       77.1        91～93      C 28H 27BrF 3N 5O 2    21      OH      H    2-Br-5-F-benzyloxyphenyl       96.5        127～129    C 28H 27BrF 3N 5O 2    22      OH      H    2，4-2Cl-benzyloxyphenyl       86.9        131～132    C 28H 27Cl 2F 2N 5O 2    23      OH      H    3，4-2Cl-benzyloxyphenyl       91.6        125～127    C 28H 27Cl 2F 2N 5O 2    24      OH      H           COC 6H 5p-Cl           78.6        136～138    C 22H 22ClF 2N 5O 2    25      OH      H           COC 6H 5p-F            74.3        115～117    C 22H 22F 3N 5O 2    26      OH      H           COC 6H 5o-Cl           87.9        110～111    C 22H 22ClF 2N 5O 2    27      OH      H           COC 6H 5p-NO 2         84.3        109～111    C 22H 22F 2N 6O 4    28      OH      H           COC 6H 5m-NO 2         72.8        91～93      C 22H 22F 2N 6O 4    29      OH      H           COC 6H 5p-CH 3         83.6        110～112    C 23H 25F 2N 5O 2    30      OH      H           COC 6H 5p-OCH 3        89.9        97～98      C 23H 25F 2N 5O 3    31      OH      H           COC 6H 5o-CH 3         81.7        oil         C 23H 25F 2N 5O 2    32      OH      H           COC 6H 5p-NH 2         91.4        106～109    C 22H 24F 2N 6O 2    33      OH      H           COCH 2C 6H 5           87.3        76～78      C 23H 25F 2N 5O 2    34      OH      H           COC 6H 5               88.2        oil         C 22H 23F 2N 5O 2    35      OH      H           COC 6H 5o-OCH 3        94.1        oil         C 23H 25F 2N 5O 3    36      OH      H           COC 6H 5p-tert-Butyl   81.6        145～146    C 26H 31F 2N 5O 2Annotate: C, H, measured value and the calculated value of three kinds of elementary analyses of N differ less than 0.3%.
Embodiment: embodiment 1:2-chloro-2 ', 4 '-preparation of difluoro acetophenone (II)
Anhydrous alchlor 100g (0.747mol) and m-difluorobenzene 75.33g (0.667mol) place the 500mol three-necked bottle, stir under the room temperature, slowly drip chloroacetyl chloride 75.33g (0.667mol), continue at after dropwising under the room temperature and stirred 30 minutes, slowly be warming up to 50 ℃, under this temperature, continue to stir 5 hours, reaction solution is poured in the frozen water, separate out crystallization, filter solid, filtrate is extracted at twice with methylene dichloride 400ml, and the combined dichloromethane extracting solution is washed to neutrality, anhydrous sodium sulfate drying, filter, reclaim solvent and get solid, merge gained solid recrystallizing methanol twice, 2-chloro-2 ', 4 '-difluoro acetophenone 107.38g, yield 87.2%, fusing point: 46--47 ℃.Embodiment 2:2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-preparation of difluoro acetophenone (III)
With triazole 27.2g (0.4mol), TEBA0.4g, anhydrous K 2CO 341.56g (0.3mol) add the CH of 180ml 2Cl 2In suspension; With 2-chloro-2 ', 4 '-difluoro acetophenone (II) 38.2g (0.2mol) is dissolved in 60ml CH 2Cl 2In, under condition of ice bath, it is added dropwise in the above-mentioned 180ml suspension, dripped off in about 1.5 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 100ml, anhydrous Na 2The SO4 drying steams CH 2Cl 2, residue is dissolved in the 100ml anhydrous ethyl acetate agitation and dropping concentrated nitric acid, till no longer separating out to yellow solid, filter, filter cake is washed for several times with amount of ethyl acetate, drying is dissolved in 100ml water with it, and it is 9 that the NaOH solution (w/w) with 30% is transferred pH value, separate out solid, filter, the dry crude product that gets, use normal hexane: ethyl acetate (v/v)=1: 1 recrystallization, get compound III 37.98g, yield 85.2%, fusing point: 104～105 ℃.Embodiment 3:1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2, the preparation of 4-triazole mesylate (IV)
Get 2-(1H-1,2, the 4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (III) 29.8g (0.115mol), trimethylammonium oxygen sulfuration iodine 25.3g (0.115mol), trimethylammonium hexadecyl brometo de amonio 1.6g puts into the 500ml three-necked bottle, add toluene 180ml and 20% sodium hydroxide solution (w/w) 225ml, 60 ℃ were heated 3 hours, and reaction is isolated toluene layer after finishing, water layer extracts (100ml * 2) with toluene, the combining methylbenzene layer is washed to neutrality, reclaim most toluene after, debris adds the dilution of 120ml ethyl acetate, 0 ℃ drips the ethyl acetate 2ml that is dissolved with the 8.3g methylsulfonic acid down, separates out faint yellow solid, filters, use recrystallizing methanol, get compound IV 21.71g, productive rate 56.7%, fusing point: 128～129 ℃.Embodiment 4:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-trifluoromethyl-6-chloro-2-pyridine) piperazine]-preparation of 2-propyl alcohol (compound 3 in the table 1)
In the round-bottomed flask of 50ml, add 1-[2-(2 under the room temperature, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV) 1.65g (0.005mol), 1-(4-trifluoromethyl-6-chloro-2-pyridine-1-yl) piperazine 1.27g (0.006mol), NaOH0.2g, methyl alcohol 30ml, 70～75 ℃ of oil bath heating, stirred 6 hours, the thin layer chromatography monitoring is finished until reaction.Reaction removes solvent under reduced pressure after finishing, and residue adds chloroform 50ml dissolving, filters, and filtrate water is washed (30ml * 3), anhydrous Na 2SO 4Dried overnight is filtered, and removal of solvent under reduced pressure gets crude product, and crude product is crossed silicagel column, and eluent is: CH 2Cl 2: CH 3OH=9.5: 0.5, get product 1.81g, yield 80.8%.This compound structure through proton nmr spectra ( 1HNMR) and infrared spectra (IR) identify that its data are as follows: 1HNMR (CDCl3, TMS) δ: 8.15 (1H, s, 1,2,4-Triazole C 3-H), 7.81 (1H, s, 1,2,4-Triazole C 5-H), 6.83～8.36 (5H, m, Ar-H), 4.57～4.61 (1H, d, J=14.4Hz triazole-CH a), 4.51～4.55 (1H, d, J=14.4Hz triazole-CH b), 3.37～3.40 (4H, m, N (CH 2) 4N), 3.12～3.16 (1H, d, J=13.6Hz, C-CH a-piperazine), 2.70～2.75 (1H, d, J=13.6z, C-CH b-piperazine), 2.48～2.55 (4H, m, N (CH 2) 4N) IR (cm -1, KBr): 3234,3077,2976; 2950,2863,2809; 1605,1499,1323; 1273,1249,1114; 1040,965,853 embodiment 5:1-(1H-1; 2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-methoxyl group-benzoyl) piperazine]-preparation of 2-propyl alcohol (compound 35 in the table 1)
In the round-bottomed flask of 50ml; add 1-[2-(2 under the room temperature; the 4-difluorophenyl)-2; the 3-epoxypropyl]-1H-1; 2,4-triazole mesylate (IV) 1.65g (0.005mol), 1-(4-methoxyl group-benzoyl) piperazine 1.32g (0.006mol), triethylamine 3ml, DMF30ml, 70～75 ℃ of oil bath heating; stirred 6 hours, the thin layer chromatography monitoring is finished until reaction.Reaction adds water 100ml after finishing, with ethyl acetate extraction (50ml * 3), and extracting solution washing (30ml * 3), anhydrous Na 2SO 4Dried overnight is filtered, and removal of solvent under reduced pressure gets crude product, and crude product is crossed silicagel column, and eluent is: CH 2Cl 2: CH 3OH=9.5: 0.5, get product 2.15g, yield 94.1%. 1HNMR (CDCl3, TMS) δ: 8.12 (1H, s, 1,2,4-Triazole C 3-H), 7.80 (1H, s, 1,2,4-Triazole C 5-H), 6.77～7.58 (7H, m, Ar-H), 5.03 (1H, s ,-OH), 4.56～4.60 (1H, d, J=14.4Hz triazole-CH a), 4.51～4.55 (1H, d, J=14.4Hztriazole-CH b), 3.81 (1H, s, CH 3), 3.48 (4H, s, N (CH 2) 4N), 3.08～3.12 (1H, d, J=13.2Hz, C-CH a-piperazine), 2.71～2.74 (1H, d, J=13.2Hz, C-CH b-piperazine), 2.35 (4H, s, N (CH 2) 4N) IR (cm -1, KBr): 3421,3133,3001,2921,2838,2807,1621,1450,1428,1174,1137,1024,969,853 embodiment 6:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-trifluoromethyl-6-chloro-2-pyridine) piperazine]-preparation of 2-propyl alcohol (compound 3 in the table 1) hydrochloride
Get 3 0.50g of compound shown in the table 1 (0.001mol) and be dissolved in the 5ml methylene dichloride, add 2ml hydrochloric acid, stirred 3 hours under the room temperature.Reaction finishes the back concentration of reaction solution, separates out precipitation, filter 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-trifluoromethyl-6-chloro-2-pyridine) piperazine]-2-propylate hydrochlorate 0.51g, productive rate 93.8%.
All the other target compounds are synthesis material with different substituted-piperazinyls, and are listed as table 1, repeat the step among the embodiment 4,5,6, just can synthesize required trinitrogenazole alcohol antifungal compound or its esters.Agents useful for same is commercially available analytical pure among the embodiment.
Synthetic 1-substituted piperazinyl-2-(2 of the present invention, the 4-difluorophenyl)-3-(1H-1,2, the 4-triazol-1-yl)-the 2-propanol compound has antifungic action, its The pharmacological results is as follows: (one) experimental technique: adopt conventional external bacteriostatic experiment method (to see for details: Antimicrob Agents Chemother1995,39 (5): 1169) 1. materials and methods (1) this experiment of experimental strain has selected for use following 6 kinds of common human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Shanghai Long March Hospital's Mycology Lab.The preparation of Candida albicans (Candida albicans) Oidium tropicale (Candida tropicalis) Candida parapsilosis (Candida parapsilosis) Cryptococcus neoformans (Cryptococcus neoformans) aspergillus fumigatus (Aspergillus fumigatus) fonsecaea pedrosoi (Fonsecaea pedrosoi) (2) test method bacteria suspension: above-mentioned fungi was cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, twice activation, with the blood cell counting plate counting, adjust 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 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; The 3-12 hole respectively adds bacteria suspension 100 μ l, and No. 2 the hole adds bacteria suspension 180 μ l and soup 20 μ l, and the drug level in 2-11 hole is made 10 grades of doubling dilutions, and each hole drug level is followed successively by 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.No. 12 the hole does not add soup, makes positive control.Fluconazole and KETOKONAZOL are selected in the medicine contrast for use.Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and the lowest concentration of drug that is lower than positive control hole 80% with optical density value is minimal inhibitory concentration value (MIC).(2) the external bacteriostatic experiment of experimental result the results are shown in Table 2
The external antimycotic minimal inhibitory concentration value of table 2 part selected objective target compound (MIC, μ g/ml) compound number Candida albicans Oidium tropicale Candida parapsilosis cryptococcus neoformans aspergillus fumigatus fonsecaea pedrosoi
3?????????≤0.125???????≤0.125???????≤0.125??????≤0.125????????64??????????≤0.125
2?????????≤0.125???????≤0.125?????????0.25???????????1??????????0.25??????????0.25
11????????≤0.125???????????1????????????0.5???????????8???????????4??????????????4
14≤0.125 2 0.5 16 64 16 fluconazoles, 0.25 0.5 0.5 16 32 64 KETOKONAZOL≤0.125≤0.125≤0.125≤0.125 1≤0.125
Above-mentioned experimental result shows that The compounds of this invention has anti-mycotic activity preferably, and for example the vitro inhibition activity of 3 pairs of selected fungies of compound all is better than fluconazole, with KETOKONAZOL quite or more excellent.It is low that The compounds of this invention also has toxicity, and advantages such as antimycotic spectrum width can be used for preparing antifungal drug.

Claims (18)

1. trinitrogenazole alcohol compounds is characterized in that such structural general formula is: Wherein: X group representation hydroxy or ester group;
The ester group here refers to have the straight or branched ester group of 1～4 carbon atom, as formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group;
Y group is represented the various substituting groups on the aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to:
(1) halogen is as F, Cl, Br, I;
(2) aliphatic chain is as methyl, ethyl, trifluoromethyl, the tertiary butyl;
The M group is represented hydrogen or methyl;
The representative of R group
(1) heterocycle or substituted heterocycle;
Heterocycle refers to common five yuan or hexa-member heterocycle, for example furans, thiophene, pyrroles, pyrazoles, imidazoles, oxazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine, substituting group can be positioned at each position of heterocyclic on the heterocycle, can be single replacement, also can be polysubstituted, substituting group refers to:
A. halogen is as F, Cl, Br, I;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl;
C. electron-withdrawing substituent or push away electron substituent group is as cyano group, nitro, hydroxyl;
D. three-dimensional substituting group or hydrophobic substituent are as the tertiary butyl;
E. wetting ability substituting group is as hydroxyl;
(2) substituted benzoyl or substituted benzene ethanoyl
Substituting group in substituted benzoyl or the substituted benzene ethanoyl on the phenyl ring can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group is meant;
A. halogen is as F, Cl, Br, I;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl;
C. electron-withdrawing substituent or push away electron substituent group is as cyano group, nitro, hydroxyl;
D. three-dimensional substituting group or hydrophobic substituent are as the tertiary butyl;
E. wetting ability substituting group is as hydroxyl;
(3) substituted benzyloxy phenyl
Substituted benzyloxy can be positioned at neighbour on the phenyl ring,, contraposition, can be single replacement, also can be polysubstituted; Substituting group in the benzyloxy on the phenyl ring can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group is meant:
A. halogen is as F, Cl, Br, I;
B.1～4 the aliphatic chain of a carbon atom is as methyl, ethyl, trifluoromethyl, the tertiary butyl;
C. electron-withdrawing substituent or push away electron substituent group is as cyano group, nitro, hydroxyl;
D. three-dimensional substituting group or hydrophobic substituent are as the tertiary butyl;
E. wetting ability substituting group is as hydroxyl.
2, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 4-trifluoromethyl-6-chloro-2-pyridyl.
3, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is an acetate groups, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is 4-trifluoromethyl-6-chloro-2-pyridyl.
4, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is the 4-tertiary butyl-2-pyridyl.
5, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 4-fluoro-3-pyridyl.
6, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 5-fluoro-4-pyrimidyl.
7, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is a 5-fluoro-2-pyrimidyl.
8, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is a methyl, and the R group is 5-trifluoromethyl-4-pyrimidyl.
9, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 4-methoxyl group-benzoyl.
10, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-benzyl chloride oxygen phenyl.
11, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-methoxyl group benzyloxy phenyl.
12, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-tertiary butyl benzyl oxy phenyl.
13, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 2-fluoro-4-bromobenzyl oxygen phenyl.
14, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is a 4-iodine benzyl oxy phenyl.
15, by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that the X group is a hydroxyl, Y group is 2, and 4-two is fluorine-based, and the M group is H, and the R group is 3,4-dichloro benzyl oxy phenyl.
16, the salt of the described trinitrogenazole alcohol compounds of claim 1～15 is characterized in that it is hydrochloride, hydrobromate or the methane sulfonates of this compound.
17, the described trinitrogenazole alcohol compounds of claim 1～15 is used to prepare the purposes of antifungal drug.
18, the salt of the described trinitrogenazole alcohol compounds of claim 16 is used to prepare the purposes of antifungal drug.
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