CN1760193A

CN1760193A - Antifungal compound of alkyl substitutional triazole class

Info

Publication number: CN1760193A
Application number: CN 200510030746
Authority: CN
Inventors: 刘超美; 何秋琴; 门秀峰; 曹永兵; 董玉环; 赵荔华; 姜远英; 赵靖霞
Original assignee: Second Military Medical University SMMU
Current assignee: Second Military Medical University SMMU
Priority date: 2005-10-27
Filing date: 2005-10-27
Publication date: 2006-04-19

Abstract

The present invention relates to alkyl-substituted triazole compounds of general formula (I), wherein R is tert-butyl, M is hydrogen or methyl, and Z is heterocycle or substituted heterocycle; substituted fused heterocycle; substituted Sulfone group, sulfoxide group and amino group, etc.; substituted piperazine, thiazole, hydrogenated imidazolinone, etc.; substituted piperazine phenoxy group. Substituents include alkyl, halogen, substituted benzene ring, benzyl, benzoyl, substituted heterocycle, heterocyclic methyl, heterocyclic formyl, substituted imidazolinone phenyl and substituted triazolone phenyl, etc., these benzene The substituents on rings and heterocycles refer to groups of 1-6 carbon atoms, halogens, electron-withdrawing groups or electron-donating groups. Any possible position on the benzene and heterocyclic rings, mono- or poly-substituted. The present invention also includes various enantiomers, diastereomers, nitrogen oxides and prodrugs of the above compounds, as well as common pharmaceutically acceptable salts. The compound of the invention has strong antifungal activity and can be used in the preparation of antifungal drugs.

Description

The triazole antifungal compound that alkyl replaces

Technical field

The present invention relates to medical technical field, is a kind of novel alkyl triazole antifungal compound, has replaced 2,4 difluorobenzene base in the common azole antifungal compound molecule with alkyl: 1-(1H-1,2,4-triazol-1-yl)-2-alkyl-3-replacement-2-propyl alcohol.

Background technology

In recent years, along with antibiotic a large amount of uses, the increase of the chemicotherapy of tumour patient and organ transplantation patient number, the generally employing of conduit and intubate, being extensive use of of cortin and immunosuppressor, and especially acquired immune deficiency syndrome (AIDS) patient's increase rapidly of immune deficiency patient, cause fungi infestation particularly the deep fungal infection sickness rate sharply increase.Deep fungal infection has risen to the third-largest communicable disease clinically, and human beings'health in serious threat.Statistical information shows that 60% the direct cause of death is a deep fungal infection among the AIDS patient.Therefore, press for efficient, low toxicity, novel deep antifungal drug that selectivity is high clinically.

At present, the medicine that is used for the treatment of deep fungal infection still has only amphotericin B (Amphotericin B), fluconazole (Fluconazole) and itraconazole (Itraconazole) to wait a few medicine.Amphotericin B is still the golden standard of antifungal drug, but side effect is serious, and as generating heat, shivering, especially serious renal toxicity has limited its clinical application.At present, fluconazole and itraconazole are most widely used, but the resistance problem that is on the rise and limited its clinical application to some bacterial strain curative effect is relatively poor.Find in the recent report of survey, exist the chemical sproof Candida albicans of fluconazole in 33% the AIDS patient oral cavity.

The mechanism of action of nitrogen azole drug is the ferrous atom complexing mutually on N atom and fungal cell's cytochrome p 450 14 α-sterol demethyl enzyme (CYP51) the protoheme porphyryl on the triazole ring, thereby interrupt the 14 α demethylations reaction of substrate lanosterol, make the ergosterol biosynthesis block, lanosterol is accumulated, cell flowability, membrane permeability and enzyme activity change, 26S Proteasome Structure and Function disappears, and finally causes fungi death.Since the nineties in last century, synthesized ten hundreds of triazole class compounds both at home and abroad, vivocon azoles (Voriconazole) has been got permission listing in 2002; Pressgang health azoles (Ravuconazole), general Saperconazole (Posaconazole) and TAK-187 etc. are carrying out clinical study.The structural difference of these compounds and fluconazole and itraconazole is all less, is easy to produce cross resistance, and all contains the 2,4 difluorobenzene base.Early stage structure activity study shows that phenyl is essential by anti-mycotic activity, and preferably 2,4-dichloro or 2, the phenyl that the 4-difluoro replaces, but the phenyl that halogen replaces in vivo during metabolism toxicity bigger.Compare with fluconazole, vivocon azoles and pressgang health azoles etc. are at present at clinical use or the s-generation triadimenol compounds has a broad antifungal spectrum that grinding, anti-microbial activity to the Eurotium fungi obviously strengthens, equally matched with itraconazole, and it is effective to the bacterial strain of anti-the fluconazole, its constitutional features is to have increased a methyl at 3, has increased a chiral carbon atom, and synthetic difficulty significantly increases.

Summary of the invention

For solving the deficiencies in the prior art, more provided by the invention with tertiary butyl replacement 2, the compound of 4-difluorophenyl, from external bacteriostatic activity, activity to deep fungal, superficial fungi, aspergillus tubigensis and the bacterial strain of anti-the fluconazole all can be compared with itraconazole, some in addition be better than itraconazole, illustrate that three methyl of the tertiary butyl have an effect of having played 3 methyl in vivocon azoles and the pressgang health azoles equimolecular, and do not increase the quantity of chiral carbon atom.The invention provides with the tertiary butyl and replace 2, the novel triazole antifungal agents of 4-difluorophenyl and efficient, low toxicity, wide spectrum, and common medicinal salts such as hydrochloride, phosphoric acid salt, methane sulfonates, oxalate, maleate, fumarate, tartrate, lactic acid salt and succinate.

The general structure of The compounds of this invention is as follows:

Wherein R representative:

Here a, b, c are respectively the group that contains 1-6 carbon atom, as methyl, ethyl, propyl group, butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.; Can be identical, also can be different.

In the Compound I: M represents hydrogen or has 1～4 carbon atom group, as methyl, ethyl, trifluoromethyl etc., preferable methyl.

The Z representative:

(1) heterocycle or substituted heterocycle:

The heterocycle here is meant five Yuans or six element heterocycles, be selected from furans, thiophene, pyrazoles, imidazoles, triazole, tetrazole, oxazole, thiazole, isoxazole, pyridine, pyrimidine, pyrazolone, hydrogenation pyrazolone, 2-imidazolone, 4,5-glyoxalidine quinoline ketone, 1,2,4-triazole-3-ketone, piperazine, morpholine and piperidines.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:

1) contains the group of 1-6 carbon atom, as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;

2) halogen is as F, Cl, Br, I;

3) electron-withdrawing group or electron-donating group, as methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group;

4) para-orientation styryl, the substituting group on the phenyl ring are F, Cl, Br, I; Methylsulfonyl, first sulfoxide group, methyl, ethyl, trifluoromethyl, trifluoromethoxy, tetrafluoro oxyethyl group, tetrafluoro propoxy-, methoxyl methyl, sec.-propyl and the tertiary butyl.

(2) substituted fused heterocycle:

The annelated heterocycles here is meant that phenyl ring and five Yuans or six element heterocycles condense, and five Yuans or six element heterocycles are selected from furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Substituting group can be positioned on the phenyl ring and heterocycle on, can be single replacement, also can be polysubstituted.Substituting group refers to:

2) halogen is as F, Cl, Br, I;

(3)

X-B

X is O, S, NH, SO, SO ₂Deng; B is:

1) contains the group of 1-6 carbon atom, as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, sec.-propyl, cyclopentyl and cyclohexyl etc.;

2) substituted-phenyl, the substituting group here are 1-3, can be the same or different, as F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

3) substituted heterocycle, the heterocycle here is meant five Yuans or six element heterocycles, be selected from furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, pyrazolone, hydrogenation pyrazolone, 2-imidazolone, 4,5-glyoxalidine quinoline ketone, 1,2,4-triazole-3-ketone, piperazine, morpholine and piperidines.Substituting group can be positioned at each position of heterocyclic on the heterocycle, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

4) substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, tetrazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N; N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.

(4)

X ₁-C

X ₁Be various heterocycles, as furans, thiophene, pyrazoles, imidazoles, triazole, tetrazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, piperazine, morpholine, piperidines, pyrazolone, hydrogenation pyrazolone, 2-imidazolone, 4,5-glyoxalidine quinoline ketone, 1,2,4-triazole-3-ketone etc.;

1) C is C ₁The time, C ₁Be

A. substituted-phenyl, the substituting group here can be 1-3, can be the same or different, as F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.; Substituting group can be positioned at each position of phenyl ring;

B. substituted heterocycle, the heterocycle here is meant five Yuans or six element heterocycles, is selected from furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines.Substituting group can be positioned at each position of heterocyclic on the heterocycle, can be single replacement, also can be polysubstituted.As F, Cl, Br, I methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

C. substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, tetrazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

D. replace ethanoyl, the substituting group here refers to substituted benzene ring and heterocycle again, and the heterocycle here is meant five Yuans or six element heterocycles, is selected from furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines.Substituting group is 1-3 on phenyl ring and the heterocycle, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N, N-dimethylamino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

E. substituted formyl methyl, the substituting group here refers to substituted aniline and heterocycle amido again, the heterocycle here is meant five Yuans or six element heterocycles, is selected from furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines.Substituting group is 1-3 on phenyl ring and the heterocycle, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N, N-dimethylamino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

2) C is C ₂The time, C ₂Be

X ₂Be S, O, NH.

E is: the substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

X ₂E can also be a substituted aroma ring formyl radical during for NH, and the fragrant fourth finger here common five Yuans or six Yuans fragrance (mixing) ring are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

3) C is C ₃The time, C ₃Be

Q is CH or N; G is:

A. the group that contains 1-6 carbon atom is as methyl, ethyl, trifluoromethyl, sec.-propyl, isobutyl-and the tertiary butyl, cyclopentyl and cyclohexyl etc.;

B. substituted aroma ring, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl and the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

C. substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

4) C is C ₄The time, C ₄Be

With

R ₂For: 1-3 F, Cl, Br can be the same or different.A and A ₁Can be O, S, N or NH.R ₃For:

1) contains the group of 1-6 carbon atom, as methyl, ethyl, propyl group, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.;

2) substituted aroma ring, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

3) substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N; N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.

(5)

R ₁For:

1) contains the group of 1-6 carbon atom, as methyl, ethyl, ethanoyl, sec.-propyl, propionyl and butyryl radicals etc.;

2) substituted aroma ring, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, formamido group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

3) substituted aroma cyclohexyl methyl, five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common are selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine.Fragrance (mixing) substitution in ring base can be positioned at each position, can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical, methoxy acyl group, ethoxy acyl group, amino, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

4) substituted aroma ring formyl radical; five Yuans or six Yuans fragrance (mixing) ring that the fragrant fourth finger here is common; be selected from phenyl ring, furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine and pyrimidine; fragrance (mixing) substitution in ring base can be positioned at each position; can be single replacement, also can be polysubstituted.As F, Cl, Br, I; Methyl, ethyl, trifluoromethyl, sec.-propyl, the tertiary butyl etc.; Methylsulfonyl, first sulfoxide group, nitro, cyano group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;

5)

Q is CH or N; Y is: contain the group of 1-6 carbon atom, as methyl, ethyl, trifluoromethyl, sec.-propyl, isobutyl-and isopentyl etc.

The compounds of this invention also comprises various enantiomers, diastereomer, oxynitride and the prodrug of above-claimed cpd, and common medicinal salts such as hydrochloride, phosphoric acid salt, methane sulfonates, acetate, oxalate, maleate, fumarate, grape hydrochlorate, tartrate, lactic acid salt and succinate.

The building-up reactions flow process of The compounds of this invention is as follows:

1. the preparation of intermediate (III):

1,2, a 4-triazole and a chloropinacolone (V) are at K ₂CO ₃Effect generates alpha-triazolyl pinacolone (VI) (reference US4486218) down; With the nucleophilic additions of sulphur Yi Lide (ylid) reagent trimethylammonium oxygen sulphur iodide at 60 ℃ of generation carbonyls, form epoxide, it can with the methanesulfonic salify, get intermediate 1-(the 2-tertiary butyl-2, the 3-epoxypropyl)-1H-1,2,4-triazole methane sulfonates (III) (reference US4499281).

2. intermediate (III) is at NaH, NaOH or K ₂CO ₃Effect in alkali just obtains target compound (I) with the nucleophilicity reagent react that contains oxygen, sulphur, nitrogen down; Target compound (I) just can make its salt with corresponding acid-respons.As:

Ring-opening reaction takes place with single substituted piperazine like compound and promptly generates the triadimenol compounds (I) that piperazine replaces in intermediate epoxide (III) under alkaline condition.(I) with the acid-respons of equivalent 1～2 hour, after reaction finished, concentration of reaction solution must precipitate, and filtered the precipitation that produces and was salt.

Embodiment:

Below the test of part example and bacteriostatic test are further illustrated alkyl triazole antifungal compound of the present invention and beneficial effect thereof by experiment.

Experimental section

Fusing point Yamato model MP-21 type melting point detector, capillary tube technique is measured, and temperature is not calibrated.Ultimate analysis is measured with MOD-1106 type elemental analyser, requires C, H, and the measured value and the calculated value of three kinds of ultimate analyses of N differ less than 0.3%.Infrared spectra Hitachi 270-50 type determination of infrared spectroscopy, the KBr pressed disc method.Nuclear magnetic resonance spectrum is with Bruke Spectrospin AC-P300 type nmr determination, with DMSO-d ₆Or CDCl ₃Be solvent, TMS is interior mark.It is synthetic that reference substance fluconazole and itraconazole are pharmaceutical college of The 2nd Army Medical College.Agents useful for same is commercial analytical pure.

Embodiment 1

Synthesizing of 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-(2-pyridine sulfydryl)-2-propyl alcohol

Get 1.78g (16mmol) 2-mercaptopyridine, 4.15g (15mmol) 1-(1H-1,2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates and 5.52g (40mmol) salt of wormwood is put into the 100ml three-necked bottle, add a little Tetrabutyl amonium bromide and 55ml DMF again, in 75 ℃ of stirring reaction 8h, filter, filtrate is transferred pH=2 with hydrochloric acid, ethyl acetate washing (30ml * 3), water is transferred pH=10 with 10% sodium hydroxide, filter out solid, use the dehydrated alcohol recrystallization, get pale yellow powder 1.4g, yield 31.96%, mp:68-70 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44 (1H, s, triazole C ₃-H), 7.91 (1H, s, triazole C ₅-H), 8.32 (1H, d, pyridine-C ₆-H), 7.62 (1H, m, pyridine-C ₄-H), 7.28 (1H, d, pyridine-C ₃-H), 7.12 (1H, m, pyridine-C ₅-H), 5.50 (1H, s, OH), 4.39 (1H, s ,-SCH ₂-), 3.28-3.54 (2H, AB system, triazole-CH ₂-), 0.97 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3341，3098，2970，2806，1615，1588，1559，1272，1102，1060

Embodiment 2

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-p-methoxy-phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.96g (5mmol) 1-[4-(4-methoxyl group) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, heated and stirred 7h in 90 ℃ of water-baths, in the impouring 100ml water, ethyl acetate extraction (30ml * 3), washing, anhydrous sodium sulfate drying reclaims solvent, gets solid, use re-crystallizing in ethyl acetate, white, needle-shaped crystals 0.83g, yield: 55.63%, mp:110～111 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 6.77～6.84 (4H, m, Ar-H), 4.53 (1H, s, OH), 4.32 (2H, s ,-CH ₂-), 3.67 (3H, s ,-OCH ₃), 2.29-2.88 (10H, m, piperazine-H ,-CH ₂-), 0.91 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3120，3042，2959，2910，2880，2833，1511，1242，1182，1140，1036，817

Embodiment 3

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-ethoxyl phenenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.03g (5mmol) 1-[4-(4-oxyethyl group) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.17g, yield: 60.5%, mp:78～80 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,848 (2H, s, s, triazole-H), 6.76～6.82 (4H, m, Ar-H), 4.52 (1H, s, OH), 4.32 (2H, s ,-CH ₂-), 3.93 (2H, q, J=7.0Hz ,-OCH ₂-), 2.27-2.88 (10H, m, piperazine-H ,-CH ₂-), 1.28 (3H, t, J=70Hz ,-CH ₃), 0.91 (9H, s ,-C (CH ₃) ₃)

Embodiment 4

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-pentyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.24g (5mmol) 1-[4-(4-pentyloxy) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.11g, yield: 51.7%, mp:120～123 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 6.75～6.81 (4H, m, Ar-H), 4.43 (1H, s, OH), 4.32 (2H, s ,-CH ₂-), 3.93 (2H, t, J=7.0Hz ,-OCH ₂-), 2.29-2.89 (10H, m, piperazine-H ,-CH ₂-), 1.20～1.22 (8H, m, 4X-CH ₂-), 0.91 (12H, s, s ,-CH ₃,-C (CH ₃) ₃)

Embodiment 5

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-isopropyl phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.10g (5mmol) 1-[4-(4-isopropoxy) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.98g, yield: 48.9%, mp:49～52 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.92,8.47 (2H, s, s, triazole-H), 6.76～6.82 (4H, m, Ar-H), 4.50 (1H, s, OH), 4.33 (2H, s ,-CH ₂-), 3.85～388 (1H, m ,-CH-), 2.30-2.89 (10H, m, piperazine-H ,-CH ₂-), 0.92 (15H, m, 2X-CH ₃,-C (CH ₃) ₃)

Embodiment 6

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.34g (5mmol) 1-[4-(4-benzyloxy) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.30g, yield: 57.9%, mp:139～141 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.92,8.46 (2H, s, s, triazole-H), 7.30～7.41 (5H, m, Ar-H), 6.81～6.89 (4H, m, Ar-H), 5.02 (2H, s ,-CH ₂-), 4.48 (1H, s, OH), 4.33 (2H, s ,-CH ₂-), 2.33-2.90 (10H, m, piperazine-H ,-CH ₂-), 0.92 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3124，2963，2880，2826，1510，1240，1180，1137，1020，818

Embodiment 7

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-is to methyl benzyloxy phenyl) piperazine-L-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.41g (5mmol) 1-[4-(4-is to the methyl benzyloxy) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.37g, yield: 59.2%, mp:133～135 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.16～7.30 (4H, d, d, J=8.0Hz, J=80Hz, Ar-H), 6.79～6.86 (4H, m, Ar-H), 496 (2H, s ,-CH ₂-), 4.52 (1H, s, OH), 4.32 (2H, s ,-CH ₂-), 2.30-2.89 (13H, m, piperazine-H ,-CH ₂-,-CH ₃), 0.91 (9H, s ,-C (CH ₃) ₃)

Embodiment 8

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-adjacent methyl benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.41g (5mmol) 1-[4-(the adjacent methyl benzyloxy of 4-) phenyl] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.02g, yield: 44.1%, mp:115～117 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 717～7.38 (4H, m, Ar-H), 6.82～6.90 (4H, m, Ar-H), 4.99 (2H, s ,-CH ₂-), 4.53 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.28-2.90 (13H, m, piperazine-H ,-CH ₂-,-CH ₃), 0.91 (9H, s ,-C (CH ₃) ₃)

Embodiment 9

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-(pyridine-4-methoxyl group) phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.35g (5mmol) 1-[4-(4-(pyridine-4-methoxyl group) phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.93g, yield: 41.3%, mp:84～86 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.39～7.40,8.55～8.56 (4H, m, m, Py-H), 6.81～6.89 (4H, m, Ar-H), 5.08 (2H, s ,-CH ₂-), 4.52 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.28-2.89 (10H, m, piperazine-H ,-CH ₂-), 0.91 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3121，2959，2878，2822，1605，1511，1247，1184，1137，1093，1054，817

Embodiment 10

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-(pyridine-2-methoxyl group) phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.35g (5mmol) 1-[4-(4-(pyridine-2-methoxyl group) phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.71g, yield: 31.6%, mp:122～124 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.31～8.56 (4H, m, Py-H), 6.81～6.89 (4H, m, Ar-H), 5.08 (2H, s ,-CH ₂-), 4.52 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.29-2.90 (10H, m, piperazine-H ,-CH ₂-), 0.91 (9H, s ,-C (CH ₃) ₃)

Embodiment 11

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-(pyridine-3-methoxyl group) phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.35g (5mmol) 1-[4-(4-(pyridine-3-methoxyl group) phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.70g, yield: 31.1%, mp:122～124 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.38～8.63 (4H, m, Py-H), 6.82～6.90 (4H, m, Ar-H), 5.06 (2H, s ,-CH ₂-), 4.52 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.29-2.90 (10H, m, piperazine-H ,-CH ₂-), 0.91 (9H, s ,-C (CH ₃) ₃)

Embodiment 12

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-is to fluorine benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.43g (5mmol) 1-[4-(4-is to fluorine benzyloxy phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.74g, yield: 31.6%, mp:110～112 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.44～7.48,7.17～7.21 (4H, m, Ar-H), 6.81～6.87 (4H, m, Ar-H), 4.99 (2H, s ,-CH ₂-), 4.53 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.28-2.89 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 13

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-adjacent fluorine benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.43g (5mmol) 1-[4-(the adjacent fluorine benzyloxy of 4-phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.75g, yield: 32.1%, mp:128～130 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.95,8.49 (2H, s, s, triazole-H), 7.52,7.39～7.40,7.20～7.23 (4H, m, Ar-H), 6.82～6.90 (4H, m, Ar-H), 5.05 (2H, s ,-CH ₂-), 4.53 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.29-2.90 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 14

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-is to chlorine benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.52g (5mmol) 1-[4-(4-is to chlorine benzyloxy phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.86g, yield: 35.6%, mp:143～145 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:794,848 (2H, s, s, triazole-H), 7.43 (4H, m, Ar-H), 6.80～6.87 (4H, m, Ar-H), 5.01 (2H, s ,-CH ₂-), 4.52 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.28-2.61 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 15

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-m-chloro benzyloxy phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.52g (5mmol) 1-[4-(4-m-chloro benzyloxy phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 0.76g, yield: 31.4%, mp:110～112 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.35～8.47 (4H, m, Ar-H), 6.82～6.88 (4H, m, Ar-H), 5.03 (2H, s ,-CH ₂-), 4.53 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.28-2.88 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 16

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-(2, the 4-dichloro-benzyloxy) phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.69g (5mmol) (4-(2 for 1-[4-, the 4-dichloro-benzyloxy) piperazine phenyl)], 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, press the operation steps of embodiment 2, white crystals 0.40g, yield: 15.4%, mp:102～105 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.94,8.48 (2H, s, s, triazole-H), 7.43～8.64 (4H, m, Ar-H), 6.82～6.90 (4H, m, Ar-H), 5.06 (2H, s ,-CH ₂-), 4.51 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 2.27-2.90 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 17

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-is to methoxyl group benzyloxy base phenyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.39g (5mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.49g (5mmol) 1-[4-(4-is to methoxyl group benzyloxy base phenyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, the operation steps of press embodiment 2 must white crystals 1.49g, yield: 62.2%, mp:139～141 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:7.95,8.49 (2H, s, s, triazole-H), 7.33,6.92 (4H, d, d, J=8.0Hz, J=80Hz, Ar-H), 6.83 (4H, d, d, J=8.6Hz, J=8.6Hz, Ar-H), 4.92 (2H, s ,-CH ₂-), 4.53 (1H, s ,-OH), 4.32 (2H, s ,-CH ₂-), 3.75 (3H, s ,-OCH ₃), 2.28-2.89 (10H, m, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 18

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(2, the 4-dichloro benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.18g (5mmol) 1-(2, the 4-dichloro benzyl) piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, heated and stirred 8h in 90 ℃ of water-baths filters, and reclaims ethanol, add water 50ml, filter,, get white crystals 0.42g with ethyl acetate-sherwood oil recrystallization, yield: 24.65%, mp:70～71 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.45,7.92 (2H, s, s, triazole-H), 7.37～7.54 (3H, m, Ar-H), 4.52 (1H, s ,-OH), 4.29 (2H, s ,-CH ₂-), 3.48 (2H, s ,-CH ₂-), 2.13-2.51 (10H, m, piperazine-H ,-CH ₂-), 0.89 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3429，3259，2982，1616，1545，1257，1234，1210

Embodiment 19

Synthesizing of 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-(4-benzyl diethylenediamine-1-yl)-2-propyl alcohol

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.88g (5mmol) 1-(4-benzyl) piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 1.05g, yield: 73.5%, mp:99～101 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.45,7.92 (2H, s, s, triazole-H), 7.22～7.30 (5H, m, Ar-H), 4.56 (1H, s ,-OH), 4.27 (2H, s ,-CH ₂-), 3.39 (2H, s ,-CH ₂-), 2.10-2.24 (10H, m, piperazine-H ,-CH ₂-), 0.87 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3398，3287，2946，1617，1548，1379，1266，1224

Embodiment 20

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(p-chlorobenzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.05g (5mmol) 1-(4-p-chlorobenzyl) piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 0.87g, yield: 55.6%, mp:130～133 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.24,7.82 (2H, s, s, triazole-H), 6.98～7.27 (4H, m, Ar-H), 5.27 (1H, s ,-OH), 4.58 (2H, s ,-CH ₂-), 3.62 (2H, s ,-CH ₂-), 2.22-2.53 (10H, m, piperazine-H ,-CH ₂-), 0.95 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3431，3148，2935，1621，1530，1340，1208，1148

Embodiment 21

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(to methyl-benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.95g (5mmol) 1-(4-is to methyl-benzyl) piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, press the operation steps of embodiment 18, get oily matter 1.16g, yield: 78.2%.

¹H-NMR (DMSO-d ₆) δ, ppm:8.05,7.87 (2H, s, s, triazole-H), 7.10～7.26 (4H, q, Ar-H), 4.65 (1H, s ,-OH), 4.47 (2H, s ,-CH ₂-), 3.46 (2H, s ,-CH ₂-), 2.54 (3H, s ,-CH ₃), 2.23-2.42 (10H, m, piperazine-H ,-CH ₂-), 0.99 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3410，3157，3086，1618，1591，1431，1268，1114

Embodiment 22

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(adjacent methyl-benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.95g (5mmol) 1-(the adjacent methyl-benzyl of 4-) piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 0.97g, yield: 65.4%, mp:84～88 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.27,7.84 (2H, s, s, triazole-H), 7.09～7.26 (4H, m, Ar-H), 5.13 (1H, s ,-OH), 426 (2H, s ,-CH ₂-), 335 (2H, s ,-CH ₂-), 2.54 (3H, s ,-CH ₃), 2.30 (10H, bs, piperazine-H ,-CH ₂-), 0.98 (9H, s ,-C (CH ₃) ₃)

IR(cm ^-1，KBr)：3425，3328，2941，1608，1540，1328，1286，1210

Embodiment 23

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(3, the 4-dichloro benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.16g (5mmol) 1-[4-(3, the 4-dichloro benzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, press the operation steps of embodiment 18, white crystals 1.08g, yield: 63.4%, mp:67～69 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44,7.91 (2H, s, s, triazole-H), 7.49～7.56 (2H, m, Ar-H), 7.24～7.27 (1H, m, Ar-H), 4.53 (1H, s ,-OH), 4.27 (2H, s ,-CH ₂-), 3.40 (2H, s ,-CH ₂-), 2.12～2.50 (10H, m, piperazine-H ,-CH ₂-), 0.98 (9H, s ,-C (CH ₃) ₃)

Embodiment 24

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(to luorobenzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.97g (5mmol) 1-[4-(4-luorobenzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 0.93g, yield: 62.0%, mp:101～101.7 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.45,7.92 (2H, s, s, triazole-H), 7.27～7.31 (2H, m, Ar-H), 7.09～7.14 (2H, m, Ar-H), 4.55 (1H, s ,-OH), 428 (2H, s ,-CH ₂-), 3.38 (2H, s ,-CH ₂-), 2.11～2.52 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 25

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(to methoxybenzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.03g (5mmol) 1-[4-(4-methoxybenzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 0.78g, yield: 50.4%, mp:88～93 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44,7.91 (2H, s, s, triazole-H), 7.15,6.85 (4H, d, d, J=8.4Hz, J=8.4Hz, Ar-H), 4.55 (1H, s ,-OH), 4.27 (2H, s ,-CH ₂-), 3.73 (3H, s ,-CH ₃), 3.32 (2H, s ,-CH ₂-), 2.09～2.51 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 26

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(m-chloro benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.06g (5mmol) 1-[4-(3-benzyl chloride base)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, press the operation steps of embodiment 18, get oily matter 1.03g, yield: 65.8%.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44,7.90 (2H, s, s, triazole-H), 7.20～7.33 (4H, m, Ar-H), 4.55 (1H, bs ,-OH), 4.27 (2H, s ,-CH ₂-), 3.39 (2H, s ,-CH ₂-), 2.10～2.50 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 27

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(adjacent luorobenzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 0.97g (5mmol) 1-[4-(2-luorobenzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, press the operation steps of embodiment 18, get oily matter 0.96g, yield: 64.0%.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44,7.90 (2H, s, s, triazole-H), 7.27～7.36 (2H, m, Ar-H), 7.09～7.16 (2H, m, Ar-H), 4.53 (1H, bs ,-OH), 4.27 (2H, s ,-CH ₂-), 3.45 (2H, s ,-CH ₂-), 2.09～2.50 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 28

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(2, the 6-dichloro benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.16g (5mmol) 1-[4-(2, the 6-dichloro benzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, press the operation steps of embodiment 18, white crystals 0.69g, yield: 40.5%, mp:73～77 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.45,7.91 (2H, s, s, triazole-H), 7.38～7.44 (2H, m, Ar-H), 7.25～7.31 (1H, m, Ar-H), 4.53 (1H, s ,-OH), 4.28 (2H, s ,-CH ₂-), 3.49 (2H, s ,-CH ₂-), 2.13～2.51 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 29

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(to nitrobenzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.11g (5mmol) 1-[4-(4-nitrobenzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 1.30g, yield: 80.8%, mp:100～102 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.42,7.89 (2H, s, s, triazole-H), 8.14,7.54 (4H, d, d, J=8.0Hz, J=8.0Hz, Ar-H), 4.48 (1H, bs ,-OH), 4.28 (2H, s ,-CH ₂-), 3.54 (2H, s ,-CH ₂-), 2.16～2.50 (10H, m, piperazine-H ,-CH ₂-), 0.89 (9H, s ,-C (CH ₃) ₃)

Embodiment 30

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(to the cyano group benzyl) piperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.01g (5mmol) 1-[4-(4-cyano group benzyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 1.26g, yield: 82.5%, mp:104～107 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.44,7.91 (2H, s, s, triazole-H), 7.75,7.46 (4H, d, d, J=8.0Hz, J=8.0Hz, Ar-H), 4.52 (1H, bs ,-OH), 4.28 (2H, s ,-CH ₂-), 3.49 (2H, s ,-CH ₂-), 2.13～2.50 (10H, m, piperazine-H ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 31

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(1-(benzimidazolyl-2 radicals-yl) methyl) piperazine-1-yl)-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 1.11g (4mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.08g (5mmol) 1-[4-(1-(benzimidazolyl-2 radicals-yl) methyl)] piperazine, 1.38g (10mmol) salt of wormwood, cetyl trimethylammonium bromide a little and anhydrous 30ml ethanol, the operation steps of press embodiment 18 must white crystals 1.43g, yield: 90.1%, mp:79～85 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.26,7.85 (3H, s, s, triazole-H, benzoglyoxaline-NH), 7.21～, 7.70 (4H, m, Ar-H), 4.62 (1H, bs ,-OH), 4.29 (2H, s ,-CH ₂-), 3.70 (2H, s ,-CH ₂-), 2.39～2.59 (10H, m, piperazine-H ,-CH ₂-), 0.98 (9H, s ,-C (CH ₃) ₃)

Embodiment 32

Synthesizing of 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-benzamido group-2-propyl alcohol

In the 100ml three-necked bottle, add 3.4g (12mmol) 1-(1H-1 successively, 2, the 4-triazol-1-yl)-and the 2-tertiary butyl-2,3-propylene oxide methane sulfonates, 1.1g (10mmol) benzylamine, 4.4g (32mmol) Anhydrous potassium carbonate, cetyl trimethylammonium bromide a little and 30ml dehydrated alcohol, heated and stirred 7h in 90 ℃ of water-baths filters, reclaim ethanol, add 50ml water, filter, with ethyl acetate extraction (50ml * 3), dry, reclaim solvent, column chromatography gets colorless oil, heavy 0.5g, yield: 17.65%.

¹H-NMR(DMSO-d ₆)δ，ppm：8.21，7.89(2H，s，s，triazole-H)，7.22～7.30(3H，m，Ar-H)，7.11～7.13(2H，m，Ar-H)，4.27(2H，s，-CH ₂-)，3.56(2H，s，-CH ₂-)，2.92，2.64(4H，d，d，J＝13.2Hz，J＝13.2Hz，-CH ₂-)，0.96(9H，s，-C(CH ₃) ₃)

Embodiment 33

Synthesizing of 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol

Get 2.7g (0.015mol) epoxide free alkali, it is 1-(1H-1,2,4-triazol-1-yl)-2-tertiary butyl-2, the 3-propylene oxide, 12.9g (0.15mol) Piperazine anhydrous and 40ml dehydrated alcohol are put into the 100ml three-necked bottle, reflux 6h reclaims ethanol, add 30ml water, piperazine is removed in underpressure distillation, adds 50ml chloroform, washing (20ml * 3) in residuum, anhydrous sodium sulfate drying, reclaim solvent, the adularescent solid is separated out, re-crystallizing in ethyl acetate, get the white powder solid, heavy 2.1g, yield 52.43%, mp:96～98 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.45,7.93 (2H, s, s, triazole-H), 4.63 (1H, bs ,-OH), 4.27 (2H, dd ,-CH ₂-), 2.34～2.54 (8H, m, piperazine-H), 1.97 (2H, dd ,-CH ₂-), 0.88 (9H, s ,-C (CH ₃) ₃)

Embodiment 34

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-anisole amido) formyl methylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.2g (11mmol) to the methoxychlor Acetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and has solid to separate out, and filters, dry, with ethyl acetate-sherwood oil recrystallization, get white solid, heavy 3.2g, yield 74.4%, mp:86～89 ℃.

¹H-NMR (DMS0-d ₆) δ, ppm:9.43 (1H, s ,-NH-), 8.47,7.94 (2H, s, s, triazole-H), 7.49～7.52 (2H, m, Ar-H), 6.86～6.88 (2H, m, Ar-H), 4.54 (1H, s ,-OH), 4.30 (2H, s ,-CH ₂-), 3.73 (3H, s ,-CH ₃), 3.03 (2H, s ,-CH ₂-), 2.21～2.53 (8H, piperazine-H), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 35

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(3-toluidine) formyl methylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2, the 4-triazol-1-yl)-the 2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.02g (11mmol) 3-methyl chloride Acetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, the operation steps of pressing embodiment 34, get white solid, heavy 2.70g, yield 65.2%, mp:141～143 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:9.50 (1H, bs ,-NH-), 8.48,7.95 (2H, s, s, triazole-H), 7.41～744,7.17～7.21,6.88～6.90 (4H, m, Ar-H), 4.55 (1H, s ,-OH), 4.31 (2H, s ,-CH ₂-), 3.06 (2H, s ,-CH ₂-), 2.23～2.55 (13H, piperazine-H ,-CH ₂-,-CH ₃), 0.92 (9H, s ,-C (CH ₃) ₃)

Embodiment 36

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-toluidine) formyl methylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2, the 4-triazol-1-yl)-the 2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.02g (11mmol) 4-methyl chloride Acetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, the operation steps of pressing embodiment 34, get white solid, heavy 2.72g, yield 65.7%, mp:84～88 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:9.46 (1H, bs ,-NH-), 8.45,7.92 (2H, s, s, triazole-H), 7.46,7.09 (4H, d, d, J=8.8Hz, J=8.8Hz, Ar-H), 4.53 (1H, s ,-OH), 4.29 (2H, s ,-CH ₂-), 3.02 (2H, s ,-CH ₂-), 2.21～2.52 (13H, piperazine-H ,-CH ₂-,-CH ₃), 0.89 (9H, s ,-C (CH ₃) ₃)

Embodiment 37

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(3-chloroanilino) formyl methylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2, the 4-triazol-1-yl)-the 2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.24g (11mmol) 3-chlorine chloroacetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, the operation steps of pressing embodiment 34, get white crystals, heavy 2.64g, yield 60.8%, mp:160～162 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:9.77 (1H, bs ,-NH-), 8.47,7.94 (2H, s, s, triazole-H), 7.51～7.53,7.30～7.34,7.09～7.11 (3H, m, Ar-H), 4.54 (1H, s ,-OH), 4.30 (2H, s ,-CH ₂-), 3.07 (2H, s ,-CH ₂-), 2.21～2.53 (10H, piperazine-H ,-CH ₂-), 0.90 (9H, s ,-C (CH ₃) ₃)

Embodiment 38

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-benzamido group formyl methylpiperazine-1-yl] 1-2-propyl alcohol nitrate synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.02g (11mmol) chloracetyl benzylamine, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and reclaims toluene, uses the 50ml acetic acid ethyl dissolution, under agitation drip the 1ml concentrated nitric acid, continue to stir 1h, filter out solid, drying is used the dehydrated alcohol recrystallization, gets white solid 3.2g, yield 75.3%, mp:127～129 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.71,8.18 (2H, s, s, triazole-H), 7.28～7.34 (5H, m, Ar-H), 4.94 (1H, bs ,-OH), 449 (2H, q ,-CH ₂-), 4.38 (2H, s ,-CH ₂-), 4.01 (2H, s ,-CH ₂-), 3.37～3.51 (10H, piperazine-H ,-CH ₂-), 0.93 (9H, s ,-C (CH ₃) ₃

Embodiment 39

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-anilino formyl methylpiperazine-1-yl]-2-propyl alcohol nitrate synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 1.87g (11mmol) chloroacetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and reclaims toluene, uses the 50ml acetic acid ethyl dissolution, under agitation drip the 1ml concentrated nitric acid, continue to stir 1h, filter out solid, drying is used the dehydrated alcohol recrystallization, gets white solid 3.1g, yield 65.0%, mp:130～132 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:10.52 (1H, bs ,-NH-), 8.75,8.18 (2H, s, s, triazole-H), 7.59～7.60,7.35～7.39,7.11～7.16 (5H, m, Ar-H), 494 (1H, bs ,-OH), 4.49 (2H, q ,-CH ₂-), 3.81 (2H, s ,-CH ₂-), 3.41～3.56 (10H, piperazine-H ,-CH ₂-), 0.92 (9H, s ,-C (CH ₃) ₃)

Embodiment 40

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-chloroanilino) formyl methylpiperazine-1-yl]-2-propyl alcohol nitrate synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.24g (11mmol) 4-chlorine chloroacetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and reclaims toluene, uses the 50ml acetic acid ethyl dissolution, under agitation drip the 1ml concentrated nitric acid, continue to stir 1h, filter the mountain solid, drying is used the dehydrated alcohol recrystallization, gets white solid 3.1g, yield 62.3%, mp:141～143 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.61,8.10 (2H, s, s, triazole-H), 7.58,7.39 (4H, d, d, J=8.8Hz, J=8.8Hz, Ar-H), 4.45 (2H, q ,-CH ₂-), 3.88 (2H, s ,-CH ₂-), 3.19～3.30 (10H, piperazine-H ,-CH ₂-), 0.92 (9H, s ,-C (CH ₃) ₃)

Embodiment 41

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-phenetole amido) formyl methylpiperazine-1-yl]-2-propyl alcohol nitrate synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.35g (11mmol) 4-oxyethyl group chloroacetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and reclaims toluene, uses the 50ml acetic acid ethyl dissolution, under agitation drip the 1ml concentrated nitric acid, continue to stir 1h, filter out solid, drying is used the dehydrated alcohol recrystallization, gets white solid 3.27g, yield 64.5%, mp: greater than 250 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:10.26 (1H, bs ,-NH-), 8.68,8.16 (2H, s, s, triazole-H), 7.47,6.92 (4H, d, d, J=8.8Hz, J=8.8Hz, Ar-H), 4.49 (2H, q ,-CH ₂-), 3.98～4.05 (4H, m, 2X-CH ₂-), 3.37～3.50 (10H, piperazine-H ,-CH ₂-), 1.31 (3H, t ,-CH ₃), 0.92 (9H, s ,-C (CH ₃) ₃)

Embodiment 42

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(2,4 dichloro benzene amido) formyl methylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add 2.8g (10mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, 2.62g (11mmol) 2,4-dichloro chloroacetanilide, 2.5g (18mmol) Anhydrous potassium carbonate and 50ml toluene, backflow 6h, placement is spent the night, and reclaims toluene, use the 50ml acetic acid ethyl dissolution, under agitation drip the 1ml concentrated nitric acid, continue to stir 1h, filter out solid, drying is used the dehydrated alcohol recrystallization, white solid 3.3g, yield 62.1%, mp:156～158 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:9.89 (1H, s ,-NH-), 8.49,7.96 (2H, s, s, triazole-H), 8.28～8.30,7.69,7.44～7.46 (3H, m, Ar-H), 4.51 (1H, s ,-OH), 4.33 (2H, s ,-CH ₂-), 3.17 (2H, s ,-CH ₂-), 2.28～2.60 (10H, piperazine-H ,-CH ₂-), 0.92 (9H, s ,-C (CH ₃) ₃)

Embodiment 43

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-chloracetyl piperazine-1-yl]-2-propyl alcohol synthetic

In the 50ml three-necked bottle, add 1.3g (5mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-piperazine-2-propyl alcohol, add the 10mlDMF dissolving, add 1g (10mml) triethylamine again, under condition of ice bath, slowly drip 1.1g (10mml) chloroacetyl chloride, stirring at room 1h pours in the 20ml frozen water, stirs, placement is spent the night, with ethyl acetate extraction (25ml * 3), saturated common salt washing, anhydrous sodium sulfate drying, filter, residue is directly used in next step reaction behind the recovery solvent.

Embodiment 44

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(2-1H-1,2,4-triazol-1-yl) acetylpiperazine-1-yl]-2-propyl alcohol synthetic

In the 50ml three-necked bottle, add 2.0g (6mmol) 1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-chloracetyl piperazine-1-yl]-the 2-propyl alcohol; 1.8g (18mmol) triethylamine; 1.2g (18mmol) 1,2,4-triazole and 25ml dehydrated alcohol; stirring at room 1h; reflux 7h reclaims ethanol, extracts (30ml * 3) with 5% hydrochloric acid soln; the acid layer alkalizes to pH10 with diluted sodium hydroxide solution; use ethyl acetate extraction (25ml * 3) again, anhydrous sodium sulfate drying filters; reclaim solvent and get solid; with ethyl acetate-sherwood oil recrystallization, get white solid, heavy 0.5g; yield 21.7%, mp:176～178 ℃.

¹H-NMR (DMSO-d ₆) δ, ppm:8.50,7.96; 8.39,7.91 (2H, s, s, triazole-H), 5.19 (2H, s ,-CH ₂-), 4.48 (1H, s ,-OH), 4.33 (2H, s ,-CH ₂-), 3.35 (2H, s ,-CH ₂-), 2.21～251 (8H, piperazine-H), 0.89 (9H, s ,-C (CH ₃) ₃)

Embodiment 45

1-(1H-1,2,4-the triazol-1-yl)-2-tertiary butyl-3-[4-(4-acetylpiperazine-1-yl) phenoxy group]-2-propyl alcohol synthetic

In the 100ml three-necked bottle, add the 25ml dehydrated alcohol; 0.5g sodium Metal 99.5; make pure sodium solution; added 4.0g (18.2mmol) 4-(4-ethanoyl piperazine-1-yl) phenol, stirring at room again 30 minutes; add 2.9g (16mmol) 1-(1H-1,2,4-triazol-1-yl)-2-tertiary butyl-2; the 3-propylene oxide is dissolved in the solution of 15ml dehydrated alcohol, reflux 3 days.Cooling adds 8% sodium hydroxide solution 50ml, and with ethyl acetate extraction (50ml * 3), anhydrous sodium sulfate drying spends the night, filter, and column chromatography behind the recovery solvent, developping agent is an ethyl acetate, gets oily matter, heavy 2.5g, yield 38.97%.

¹H-NMR (DMSO-d ₆) δ, ppm:8.36,7.89 (2H, s, s, triazole-H), 6.88～6.90 (2H, m, Ar-H), 6.77～6.79 (2H, m, Ar-H), 4.71 (1H, s ,-OH), 4.28 (2H, s ,-CH ₂-), 4.68,4.36 (2H, d, d, J=14.0Hz, J=14.0Hz ,-CH ₂-), 3.80,3.49 (2H, d, d, J=9.6Hz, J=9.6Hz ,-CH ₂-), 3.55～3.56,2.95～3.01 (8H, m, piperazine-H), 2.03 (3H, s ,-CH ₃), 1.03 (9H, s ,-C (CH ₃) ₃)

Bacteriostatic test

Synthetic triazole class compounds of the present invention and its esters have antifungic action, its bacteriostatic experiment method and result are as follows: the antimycotic susceptibility experimental technique of stdn that adopts American National standard committee of clinical labororatory (NCCLS) to recommend is tested its extracorporeal antifungal activity, the concentration that suppresses selected fungi 80% growth with target compound is as judging terminal point (MIC80, reference: Antimicrob Agents Chemother 45 (9): 2420,2001).

One, materials and methods

1, experiment fungal bacterial strain

Two kinds of ATCC type strains and six kinds of clinical strains are selected in this research for use, the ATCC type strain is given by Shanghai City Long March hospital bacterial classification preservation center, clinical strain is provided by Changhai Hospital, Shanghai City's Mycology Lab, picks up from different section office of Changhai hospital clinical sample respectively, and through morphology and biochemical evaluation.

8 kinds of fungies comprise 4 kinds of deep fungals: Candida albicans (Candida albicans) ATCC76615, cryptococcus neoformans (Cryptococcus neoformans) ATCC32609, Oidium tropicale (Candida tropicalis), Candida parapsilosis (Candida parapsilosis), 3 kinds of superficial mycosiss: trichophyton (Trichophytonrubrum), wool sample sporidiole bacteria (Microsporum lauosum), fonsecaea compacta (Fonsecaea compacta) and smoke aspergillus fumigatus (Aspergillus fumigatus).

2, nutrient solution

RPMI1640 nutrient solution: RPMI1640 (Gibco BRL) 10g, NaHCO ₃2.0g, morphine quinoline propanesulfonic acid (morpholinepropanesulfonic acid, MOPS) (Sigma) 34.5g (0.165M) adds tri-distilled water 900ml dissolving, and 1N NaOH transfers pH to 7.0 (25 ℃), and is fixed molten to 1000ml, filters sterilization, 4 ℃ of preservations.

Husky fort glucose agar medium (SDA): peptone 10g, glucose 40g, agar 18g adds tri-distilled water 900ml dissolving, adds 2mg/ml chloramphenicol solution 50ml, adjusts pH to 7.0, and is fixed molten to 1000ml, 4 ℃ of preservations behind the autoclaving.

The YEPD nutrient solution: yeast extract 10g, peptone 20g, glucose 20g adds tri-distilled water 900ml dissolving, adds 2mg/ml chloramphenicol solution 50ml, and is fixed molten to 1000ml, 4 ℃ of preservations behind the autoclaving.

3, experimental technique

The preparation of bacterium liquid, soup, drug sensitive plate: operate by the standardized method that standard committee of American National clinical labororatory (NCCLS) proposes.

Two, the MIC value is judged

Candidiasis, cryptococcus neoformans and thread fungus are cultivated 24h, 72h and after the week, survey each hole OD value with enzyme micro-plate reader in 630nm respectively at 35 ℃.With the positive control boring ratio, be MIC80 (concentration when fungal growth 80% is suppressed) with the drug level in the minimum concentration hole of OD value decline more than 80%.

MIC when medicine ₈₀Value surpasses when measuring concentration range, adds up by the following method: MIC ₈₀When value is higher than maximum concentration 64mg/L, be designated as "＞64mg/L "; MIC ₈₀Value is not distinguished for minimum concentration or when minimum concentration is following, all is designated as "≤0.125mg/L ".

The equal parallel running of above-mentioned experiment 2 to 3 times is worked as MIC ₈₀Value just is accepted in the time of accurately repeating or only differ from a concentration, and with higher concentration as MIC ₈₀Value; Work as MIC ₈₀Value differs two concentration when above, then needs experiment again, till meeting the requirements.

Three, result's (seeing Table 1)

The extracorporeal antifungal activity of table 1 part target compound

MIC ₈₀(μg/ml)

Embodiment (compound) numbering	Ca.	Cp.	Cn.	Ct.	Tr.	Af.	Ml.	Fc.
Embodiment (compound) numbering	Ca.	Cp.	Cn.	Ct.	Tr.	Af.	Ml.	Fc.	3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 29 30	1 1 ≤0.125 ≤0.125 ≤0.125 ≤0.125 0.25 1 0.5 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 1 4 1 4 16 1 4 16	16 16 16 16 16 16 16 16 32 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 1 0.5 0.25 8 16 4 1 2	8 8 0.25 1 1 1 2 4 4 ＜0.125 ＜0.125 ＜0.125 ＜0.125 0.25 ＜0.125 ＞64 4 32 32 16 8 0.5 0.5	32 32 32 ＞64 ＞64 ＞64 32 32 32 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 ＜0.125 0.5 32 16 16 16 8 0.5 2	0.5 0.5 ≤0.125 ≤0.125 ≤0.125 ≤0.125 0.5 1 1 0.125 0.125 0.125 0.125 0.25 0.125 0.125 0.25 0.125 0.125 0.5 0.5 1 0.25	32 32 2 4 4 4 8 32 16 1 16 8 4 2 1 8 16 8 16 32 16 8 8	≤0.125 ≤0.125 ≤0.125 ≤0.125 ≤0.125 ≤0.125 0.5 0.5 0.5 ＜0.125 ＜0.125 0.5 ＜0.125 0.25 ＜0.125 0.125 0.125 0.125 0.125 0.25 0.125 1 1	2 2 2 8 8 8 1 2 2 0.125 0.125 0.125 0.125 1 0.125 0.5 1 0.25 1 0.5 0.25 0.5 0.25
32	4	0.25	1	0.5	0.125	8	0.25	0.125							32 32 2 4 4 4 8 32 16 1 16 8 4 2 1 8 16 8 16 32 16 8 8
32	4	0.25	1	0.5	0.125	8	0.25	0.125	34	0.125	0.25	＜0.125	0.25	0.5	32	0.125	0.125
37	＜0.125	0.125	＜0.125	0.125	0.125	16	＜0.125	0.125	34	0.125	0.25	＜0.125	0.25	0.5	32	0.125	0.125
37	＜0.125	0.125	＜0.125	0.125	0.125	16	＜0.125	0.125	38	8	32	8	16	0.125	32	4	8
40	＜0.125	＜0.125	＜0.125	＜0.125	0.125	16	0.5	0.125	38	8	32	8	16	0.125	32	4	8
40	＜0.125	＜0.125	＜0.125	＜0.125	0.125	16	0.5	0.125	42	＜0.125	＜0.125	＜0.125	＜0.125	0.125	1	＜0.125	0.125
44	＜0.125	＜0.125	＜0.125	＜0.125	0.125	2	＜0.125	0.5	42	＜0.125	＜0.125	＜0.125	＜0.125	0.125	1	＜0.125	0.125
44	＜0.125	＜0.125	＜0.125	＜0.125	0.125	2	＜0.125	0.5	45	＜0.125	＜0.125	＜0.125	＜0.125	0.125	1	＜0.125	0.125
FLU	1	0.5	2	1	1	64	16	8	45	＜0.125	＜0.125	＜0.125	＜0.125	0.125	1	＜0.125	0.125
FLU	1	0.5	2	1	1	64	16	8	ITR	＜0.125	＜0.125	＜0.125	＜0.125	0.125	1	＜0.125	0.125

Annotate: Ca.=Candida albicans (Candida albicans) ATCC76615, Cp=Candida parapsilosis (Candidaparapsilosis), Cn.=cryptococcus neoformans (Cryptococcus neoformans) ATCC32609, Ct.=Oidium tropicale (Candida tropicalis), Tr.=trichophyton (Trichophyton rubrum), Af.=smokes aspergillus fumigatus (Aspergillusfumigatus), M1.=wool sample sporidiole bacteria (Microsporum lauosum), Fc.=fonsecaea compacta (Fonsecaea compacta).

FLU=fluconazole (fluconazole), ITR=itraconazole (itraconazole).

Above-mentioned experimental result shows that 2-alkyl substituted triazole compounds of the present invention has anti-mycotic activity preferably, most compounds all is better than fluconazole to the vitro inhibition activity of selected fungi, with itraconazole quite or more excellent, illustrate that The compounds of this invention and its esters can be used for preparing the medicine for the treatment of fungi infestation.

Claims

1. A novel alkyl-substituted triazole antifungal compound whose general chemical structure is 1-(1H-1,2,4-triazol-1-yl)-2-alkyl-3-substituted -2-propanol (I),

where R stands for:

Here a, b, and c are respectively groups containing 1-6 carbon atoms including methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which can be Same or different.

2. Various enantiomers, diastereoisomers, nitrogen oxides and prodrugs of a novel alkyl-substituted triazole antifungal compound according to claim 1, and salts thereof Medicinal salts including salts, phosphates, and methanesulfonates.

3. In a novel alkyl-substituted triazole antifungal compound I according to claim 1: M represents hydrogen or 1 to 4 carbon atoms including methyl, ethyl, and trifluoromethyl group, preferably methyl.

4. In a novel alkyl-substituted triazole antifungal compound I according to claim 1, 2 or 3: Z represents a heterocycle or a substituted heterocycle:

The heterocyclic ring here refers to a five-membered or six-membered heterocyclic ring selected from furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, isoxazole, pyridine, pyrimidine, pyrazolone, Hydrogenated pyrazolone, 2-imidazolinone, 4,5-dihydroimidazolinone, 1,2,4-triazol-3-one, piperazine, morpholine and piperidine, the substituent on the heterocycle can be located Each position of the heterocyclic ring can be mono-substituted or multi-substituted; the substituent refers to:

1) groups containing 1-6 carbon atoms, including methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, isopropyl and tert-butyl;

2) Halogen, including F, Cl, Br, I;

3) Electron-withdrawing groups or electron-donating groups, including methylsulfone, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N,N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

4) Para-substituted styryl, the substituents on the benzene ring are F, Cl, Br, I; methylsulfonyl, methylsulfoxide, methyl, ethyl, trifluoromethyl, trifluoromethoxy, Tetrafluoroethoxy, tetrafluoropropoxy, methoxymethyl, isopropyl and t-butyl.

5. In a novel alkyl-substituted triazole antifungal compound I according to claim 1, 2 or 3: Z represents a substituted fused heterocyclic ring:

The fused heterocycle here refers to a benzene ring fused with a five-membered or six-membered heterocycle, and the five-membered or six-membered heterocycle is selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxa Azole, pyran, pyridine and pyrimidine, the substituent can be located on the benzene ring and the heterocyclic ring, and can be mono-substituted or multi-substituted; the substituent refers to:

2) Halogen, including F, Cl, Br, I;

6. In a novel alkyl-substituted triazole antifungal compound I according to claim 1, 2 or 3: Z represents

X-B

X is O, S, NH, SO, _SO2 ; B is:

1) groups containing 1-6 carbon atoms, including methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, isopropyl, cyclopentyl and cyclohexyl;

2) Substituted phenyl, where the substituents are 1-3, which can be the same or different, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl; Methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- Diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

3) Substituted heterocycle, here heterocycle refers to five-membered or six-membered heterocycle, selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine , pyrazolone, hydrogenated pyrazolone, 2-imidazolinone, 4,5-dihydroimidazolinone, 1,2,4-triazol-3-one, piperazine, morpholine and piperidine, heterocyclic The upper substituent can be located at each position of the heterocycle, and can be mono-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl; Methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- Diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

4) Substituted aromatic ring methyl, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole , thiazole, isoxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, Ethyl, trifluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl , N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy.

7. In a novel alkyl-substituted triazole antifungal compound I according to claim 1, 2 or 3: Z represents

X ₁ -C

_X1 is various heterocycles, including furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, piperazine, morpholine, piperidine , pyrazolone, hydrogenated pyrazolone, 2-imidazolinone, 4,5-dihydroimidazolinone, 1,2,4-triazol-3-one;

1) When C is C ₁ , C ₁ is

a. Substituted phenyl, where the substituents on the benzene ring can be 1-3, which can be the same or different, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl, etc.; methylsulfone, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl , N, N-diethylcarbamoyl, methoxyacyl, ethoxyacyl, amino, acetamido, hydroxyl, methoxy, ethoxy; substituents can be located at various positions of the benzene ring;

b. Substituted heterocycle, here heterocycle refers to five-membered or six-membered heterocycle, selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine , morpholine and piperidine, the substituents on the heterocycle can be located at various positions of the heterocycle, and can be single-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl , isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethyl Carbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

c. Substituted aromatic ring methyl, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole , thiazole, isoxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, Ethyl, trifluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl , N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

d. Substituted acetyl group, where the substituents refer to substituted benzene rings and heterocyclic rings, where the heterocyclic rings refer to five-membered or six-membered heterocyclic rings, selected from furan, thiophene, pyrazole, imidazole, triazole, oxazole , thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, the substituents on the benzene ring and the heterocycle are 1-3, which can be mono-substituted or multi-substituted, such as F, Cl, Br, I; methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl, etc.; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl , N, N-dimethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy, etc.;

e. Substituted formylmethyl, where the substituent refers to substituted aniline and heterocyclic amine, where the heterocycle refers to a five-membered or six-membered heterocyclic ring, selected from furan, thiophene, pyrazole, imidazole, triazole , oxazole, thiazole, isoxazole, pyran, pyridine, pyrimidine, morpholine and piperidine, 1-3 substituents on the benzene ring and heterocycle, which can be mono-substituted or multi-substituted, including F , Cl, Br, I; methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N, N-di Methylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxy, methoxy, ethoxy;

2) When C is C ₂ , C ₂ is

_X2 is S, O, NH;

E is: a substituted aromatic ring methyl group, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, Isoxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be mono-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, Trifluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N,N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

When _X2 is NH, E can also be a substituted aromatic ring formyl group, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, Oxazole, thiazole, isoxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; Base, ethyl, trifluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylamino Formyl, N, N-dimethylcarbamoyl, methoxyl, ethoxyl, acetamido, hydroxyl, methoxy, ethoxy;

3) When C is C ₃ , C ₃ is

Q is CH or N; G is:

a. Groups containing 1-6 carbon atoms, including methyl, ethyl, trifluoromethyl, isopropyl, isobutyl, cyclopentyl and cyclohexyl;

b. Substituted aromatic ring, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole , pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl group, isopropyl and tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di Methylcarbamoyl, N,N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

c. Substituted aromatic ring methyl, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, iso Oxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be mono-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, tri Fluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylammonia Formyl, methoxyl, ethoxyl, amino, acetamido, hydroxy, methoxy, ethoxy;

4) When C is C ₄ , C ₄ is

and

R ₂ is: 1-3 F, Cl, Br, can be the same or different, A and A ₁ can be O, S, N or NH, R ₃ is:

1) groups containing 1-6 carbon atoms, including methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

2) A substituted aromatic ring, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole , pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl Base, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl , methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

3) A substituted aromatic ring methyl group, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, iso Oxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be mono-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, tri Fluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylammonia Formyl, methoxyl, ethoxyl, amino, acetamido, hydroxy, methoxy, ethoxy.

8. In a novel alkyl-substituted triazole antifungal compound I according to claim 1, 2 or 3:

Z stands for:

_R1 is:

1) groups containing 1-6 carbon atoms, including methyl, ethyl, acetyl, isopropyl, propionyl and butyryl;

2) A substituted aromatic ring, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, isoxazole , pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, ethyl, trifluoromethyl Base, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-two Methylcarbamoyl, N,N-diethylcarbamoyl, methoxyl, ethoxyl, amino, acetamido, hydroxyl, methoxy, ethoxy;

3) A substituted aromatic ring methyl group, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, iso Oxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be mono-substituted or multi-substituted, including F, Cl, Br, I; methyl, ethyl, tri Fluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N -Dimethylcarbamoyl, N,N-diethylcarbamoyl, methoxyacyl, ethoxyacyl, amino, formamido, acetamido, hydroxyl, methoxy, ethoxy;

4) Substituted aromatic ring formyl, where the aromatic ring refers to a common five-membered or six-membered aromatic (hetero) ring, selected from benzene ring, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole, iso Oxazole, pyran, pyridine and pyrimidine, the substituents on the aromatic (hetero) ring can be located at various positions, and can be single or multiple substitutions, including F, Cl, Br, I; methyl, ethyl, tri Fluoromethyl, isopropyl, tert-butyl; methylsulfonyl, methylsulfoxide, nitro, cyano, acetamido, hydroxyl, methoxy, ethoxy;

5)

Q is CH or N; Y is a group of 1-6 carbon atoms including methyl, ethyl, trifluoromethyl, isopropyl, isobutyl and isopentyl.