CN101723933B

CN101723933B - Piperidine-4-ketone-O-substituted oxime triadimenol-type antifungal compound and preparation method thereof

Info

Publication number: CN101723933B
Application number: CN 200910200074
Authority: CN
Inventors: 张万年; 盛春泉; 徐玉兰; 缪震元; 姚建忠; 董国强; 王文雅; 车晓颖; 张晶
Original assignee: Second Military Medical University SMMU
Current assignee: Second Military Medical University SMMU
Priority date: 2009-12-08
Filing date: 2009-12-08
Publication date: 2013-08-21
Anticipated expiration: 2029-12-08
Also published as: CN101723933A

Abstract

The invention provides a piperidine-4-ketone-O-substituted oxime triadimenol-type compound, namely a 1-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1-group)propyl)piperidine-4-ketone-O-substituted oxime-type compound, hydrochloride, nitrate, hydrobromide and methane sulfonate of the same and a preparation method thereof. The compound has strong antifungal effect on various superficial and deep fungi, has the advantages of high efficiency, low toxicity and wide antifungal spectrum compared with antifungal medicaments in the prior clinical application, and can be used to prepare novel antifungal medicaments.

Description

Piperidin-4-one--O-replaces oxime triazole alcoholic antifungal compound and preparation method thereof

Technical field

The present invention relates to medical technical field, is that a kind of novel trinitrogenazole alcohol antifungal compound 1-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--O-replaces oxime compound and preparation method thereof.

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 very fast increase 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 antifungal drug particularly anti-deep fungal medicine extremely lack, far can not satisfy the treatment needs.Existing antifungal drug is mainly propylene amine, the nitrogen azole that acts on lanosterol 14 α-demethylase that acts on the squalene cyclooxygenase and the lipopeptid class that acts on cell walls β-(1,3)-glucan synthase etc.But yet there are no the report of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(piperidin-4-one--O-replaces oxime)-2-propanol compound and anti-mycotic activity thereof so far.

Summary of the invention

The invention provides the novel nitrogen azoles alcoholic antifungal compound of a kind of efficient, low toxicity, wide spectrum, piperidin-4-one--O-replaces oxime triazole alcoholic antifungal compound and preparation method thereof, be 1-(1H-1,2, the 4-triazol-1-yl)-hydrochloride, nitrate, hydrobromate and methane sulfonates of 2-(2,4 difluorobenzene base)-3-(piperidin-4-one--O-replaces oxime)-2-propanol compound and this compounds and preparation method thereof.

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

Wherein:

X group representation hydroxy or ester group;

The ester group here refers to the straight or branched ester group of 1～4 carbon atom and has the ester group of easy leavings group, as formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, tertiary butyl formic acid ester group, phenylformic acid ester group, toluylic acid ester group, N, N-diethylamide ethylamino benzonitrile perester radical.Special preferred tertiary butyl formic acid ester group and N, N-diethylamide ethylamino benzonitrile perester radical.

Y group represents the substituting group 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;

Z represents hydrogen or group Z1 (benzyl), Z2 (substituted benzyl), Z3 (1 '-methanonaphthalene) and Z4 (2 '-methanonaphthalene);

The Z1 structure is as follows:

The Z2 structure is as follows:

The R group represents the substituting group 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) nitro, trifluoromethyl, cyano group, methoxyl group, vinyl, amino, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, trifluoromethoxy, benzyloxy, kharophen, benzamido;

The straight or branched alkyl of (3) 1～5 carbon atoms is as methyl, ethyl, propyl group, sec.-propyl, isobutyl-, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, tert-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl etc.

Z3 (1 '-methanonaphthalene) and Z4 (2 '-methanonaphthalene) structure are as follows:

The The compounds of this invention salt comprises: hydrochloride, nitrate, hydrobromate and methane sulfonates.

Above-mentioned, piperidin-4-one--O-replaces oxime triadimenol compounds can be its raceme, also can be its R type or S type isomer.

Through the test anti-mycotic efficiency preferably compound be X, Y, Z, R group following compound respectively:

(1) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z1;

(2) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 2-chlorine;

(3) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-fluorine;

(4) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 2-fluorine;

(5) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-bromine;

(6) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 2,4-dichloro;

(7) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 2-bromine;

(8) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-bromine;

(9) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z3;

(10) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z4;

(11) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-nitro;

(12) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 3-chlorine;

(13) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-fluorine;

(14) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 3,4-dichloro;

(15) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 4-chlorine;

(16) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-nitro;

(17) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is 4-cyano group;

(18) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-methoxyl group;

(19) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-ethyl;

(20) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-sec.-propyl;

(21) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-methoxyl group;

(22) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 2-methyl;

(23) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-methyl;

(24) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-trifluoromethyl;

(25) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-trifluoromethyl;

(26) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 4-vinyl;

(27) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is Z2, and the R group is the 3-methyl;

(28) the X group is hydroxyl, and Y group is that 2,4-two is fluorine-based, and Z is hydrogen.

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

Z is:

The R group is with shown in the preamble.

The synthetic of The compounds of this invention salt is on the basis of above-mentioned reaction, further does following reaction:

Wherein HX represents hydrochloride, nitrate, hydrobromate or methane sulfonates.

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 room temperature reaction 24 hours, generate 2-(1H-1,2,4-triazol-1-yl)-2 ', 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 tert-butyl 4-oxo-piperidine-1-carboxide (VI)

Piperidin-4-one-hydrochloride and di-t-butyl carbonate are at 1,4-dioxane: water (4: 1, v/v) in reaction generate tert-butyl 4-oxo-piperidine-1-carboxide (VI);

(5) preparation tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII)

Tert-butyl 4-oxo-piperidine-1-carboxide (VI) reacts in sodium hydroxide, second alcohol and water with oxammonium hydrochloride and generates tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII);

(6) preparation tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VIII)

Compound Z and tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII) is at N, and reaction generates tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VIII) in dinethylformamide and the sodium hydride;

(7) preparation piperidin-4-one--O-replaces oxime trifluoroacetate (IX)

Tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VIII) reacts generation piperidin-4-one--O-with trifluoracetic acid and replaces oxime trifluoroacetate (IX) in methylene dichloride;

(8) preparation target product 1-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--O-replaces oxime (X)

1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV), piperidin-4-one--O-replacement oxime trifluoroacetate (IX) react generation target product 1-with triethylamine in dehydrated alcohol (2-(2, the 4-difluorophenyl)-and 2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--O-replaces oxime (X);

(9) preparation target compound (XI)

Target compound (X) at room temperature reacted 2～3 hours with excessive acid, generated target compound (XI);

The present invention's chemical structure, productive rate, fusing point and molecular formula of synthetic part preferred compound sees Table 1, and spectroscopic data sees Table 2.

Chemical structure, productive rate, fusing point and the molecular formula of table 1 part preferred compound

Compound number	The X group	The Z group	Productive rate (%)	Fusing point (℃)	Molecular formula
						1	OH	C ₆H ₅CH ₂	14.3	oil	C ₂₃H ₂₅F ₂N ₅O ₂
2	OH	2-ClC ₆H ₅CH ₂	14.7	89～90	C ₂₃H ₂₄ClF ₂N ₅O ₂
						3	OH	4-FC ₆H ₅CH ₂	48.3	oil	C ₂₃H ₂₄F ₃N ₅O ₂
4	OH	2-FC ₆H ₅CH ₂	34.5	123～124	C ₂₃H ₂₄F ₃N ₅O ₂
						5	OH	4-Br C ₆H ₅CH ₂	69.1	oil	C ₂₃H ₂₄BrF ₂N ₅O ₂
6	OH	2，4-ClC ₆H ₅CH ₂	16.4	oil	C ₂₃H ₂₃Cl ₂F ₂N ₅O ₂
						7	OH	2-Br C ₆H ₅CH ₂	67.0	oil	C ₂₃H ₂₄BrF ₂N ₅O ₂
8	OH	3-Br C ₆H ₅CH ₂	22.3	oil	C ₂₃H ₂₄BrF ₂N ₅O ₂
						9	OH	H	94.3	oil	C ₁₆H ₁₉F ₂N ₅O ₂
10	OH	1-C ₁₀H ₇CH ₂	21.2	oil	C ₂₇H ₂₇F ₂N ₅O ₂
						11	OH	2-C ₁₀H ₇CH ₂	38.9	102～103	C ₂₇H ₂₇F ₂N ₅O ₂
12	OH	4-NO ₂C ₆H ₅CH ₂	27.3	oil	C ₂₃H ₂₄F ₂N ₆O ₄
						13	OH	3-Cl C ₆H ₅CH ₂	39.1	oil	C ₂₃H ₂₄ClF ₂N ₅O ₂
14	OH	4-ClC ₆H ₅CH ₂	52.3	oil	C ₂₃H ₂₄ClF ₂N ₅O ₂
						15	OH	3-FC ₆H ₅CH ₂	30.3	87～88	C ₂₃H ₂₄F ₃N ₅O ₂

16	OH	3，4-Cl C ₆H ₅CH ₂	22.3	97～98	C ₂₃H ₂₃Cl ₂F ₂N ₅O ₂
						17	OH	3-NO ₂C ₆H ₅CH ₂	33.3	oil	C ₂₃H ₂₄F ₂N ₆O ₄
18	OH	4-CN C ₆H ₅CH ₂	37.1	84～85	C ₂₄H ₂₄F ₂N ₆O ₂
						19	OH	4-CH ₃O C ₆H ₅CH ₂	14.8	oil	C ₂₄H ₂₇F ₂N ₅O ₃
20	OH	4-C ₂H ₅C ₆H ₅CH ₂	34.4	oil	C ₂₅H ₂₉F ₂N ₅O ₂
						21	OH	4-C ₃H ₇C ₆H ₅CH ₂	12.3	oil	C ₂₆H ₃₁F ₂N ₅O ₂
22	OH	3-CH ₃OC ₆H ₅CH ₂	21.7	oil	C ₂₄H ₂₇F ₂N ₅O ₃
						23	OH	2-CH ₃C ₆H ₅CH ₂	32.8	oil	C ₂₄H ₂₇F ₂N ₅O ₂
24	OH	4-CH ₃C ₆H ₅CH ₂	63.5	106～107	C ₂₄H ₂₇F ₂N ₅O ₂
						25	OH	4-CF ₃C ₆H ₅CH ₂	52.9	oil	C ₂₄H ₂₄F ₅N ₅O ₂
26	OH	3-CF ₃C ₆H ₅CH ₂	18.6	oil	C ₂₄H ₂₄F ₅N ₅O ₂
						27	OH	4-C ₂H ₃C ₆H ₅CH ₂	15.3	oil	C ₂₅H ₂₇F ₂N ₅O ₂
28	OH	3-CH ₃C ₆H ₅CH ₂	35.5	oil	C ₂₄H ₂₇F ₂N ₅O ₂

Annotate: C, H, measured value and the calculated value of three kinds of ultimate analyses of N differ less than 0.3%.

The spectroscopic data of table 2 part preferred compound

Compd.	¹H-NMR(CDCl ₃)/δ
		1	2.21(2H，m)，2.42(2H，m)，2.50(2H，m)2.75(1H，d)，3.08(1H，d)，3.45～3.65 (3H，m)，4.46(1H，d)，4.59(1H，d)，5.04(2H，s)，6.7～6.89(2H，m)，7.25～7.33(5H，m)， 7.58(1H，m)，7.79(1H，s)，8.15(1H，s)
2	2.23～2.79(6H，m)，2.94～3.82(4H，m)，4.45～4.9(2H，q)，4.56(1H，d)，4.75(1H，d)， 5.13(2H，s)，6.87～6.90(2H，m)，7.15～7.45(5H，m)，7.80(1H，s)，8.16(1H，s)
		3	1.56(4H，m)，2.20～2.59(6H，m)，2.72(1H，d)，3.08(1H，d)，3.65(1H，s)，4.5(1H，d)，4.53(1H， d)，4.97(2H，s)，6.79～6.82(2H，m)，6.99～7.05(2H，m)，7.26～7.29(4H，m)，7.56(1H， m)，7.79(1H，s)，8.13(1H，s)
4	2.13(2H，m)，2.38～2.49(6H，m)，2.71(1H，d)，3.10(1H，d)，4.51(1H，d)，4.56(1H，d)，5.08(2 H，s)，6.80～6.83(2H，m)，7.02～7..56(6H，m)，7.79(1H，s)，8.13(1H，s)
		5	2.13(2H，m)，2.39～2.50(6H，m)，2.71(1H，d)，3.09(1H，d)，4.54(2H，dd)，4.95(2H，s)，6，78～6 .83(2H，m)，7.16(2H，dd)，7.44(2H，dd)，7.55(1H，m)，7.79(1H，s)，8.12(1H，s)
6	2.13(2H，m)，2.41～2.52(6H，m)，2.71(1H，d)，3.12(1H，d)，4.49(1H，d)，4.54(1H，d)，5.07(2 H，s)，6.80～6.83(2H，m)，7.19～7.56(4H，m)，7.80(1H，s)，8.13(1H，s)
		7	2.50(2H，m)，2.95～3.69(6H，m)，4.56(1H，d)，4.75(1H，d)，5.13(2H，s)，6.83～6.97(2H，m)，7.

	04～7.8(5H，m)，7.87(1H，s)，8.20(1H，s)
		8	2.20(2H，m)，2.42～2.49(6H，m)，2.72(1H，d)，3.10(1H，d)，3.51(1H，s)，4.52(1H，d)，4.56(1H ，d)，4.98(2H，s)，6.78～6.82(2H，m)，7.17～7.57(5H，m)，7.79(1H，s)，8.13(1H，s)
9	2.21(2H，m)，2.33～2.51(6H，m)，2.73(1H，d)，3.11(1H，d)，4.51～4.60(2H，dd)，5.29(2H，s)， 6.78～6.85(2H，m)，7.55(1H，m)，7.81(1H，s)，8.16(1H，s)
		10	2.23(2H，m)，2.34(2H，m)，2.45～2.50(4H，m)，2.69(1H，d)，3.08(1H，d)，3.49(1H，s)，4.50(1 H，d)，4.55(1H，d)，5.47(2H，s)，6.77～6.81(2H，m)，7.42～7.50(5H，m)，7.78～7.81(3H，m)，8. 03(1H，s)，8.12(1H，s)
11	2.21(2H，m)，2.39～2.53(6H，m)，2.71(1H，d)，3.09(1H，d)，4.51(1H，d)，4.56(1H，d)，5.17(2 H，s)，6.79～6.82(2H，m)，7.43～7.47(4H，m)，7.75(1H，s)，7.79～7.81(4H，m)，8.12(1H，s)
		12	2.21(2H，m)，2.42～2.52(6H，m)，2.72(1H，d)，3.10(1H，d)，3.65(1H，s)， 4.52(1H，d)，4.57(1H，d)，5.10(2H，s)，6.79～6.84(2H，m)，7.43～7.46(2H，m)，7.56(1H，m)，7. 80(1H，s)，8.12(1H，s)，8.17～8.19(2H，m)
13	2.20(2H，m)，2.39～2.51(6H，m)，2.72(1H，d)，3.10(1H，d)，4.52(1H，d)，4.56(1H，d)，4.99(2 H，s)，6.79～6.83(2H，m)，7.17(1H，m)，7.24～7.28(3H，m)，7.56(1H，m)，7.80(1H，s)，8.13(1 H，s)
		14	2.20(2H，m)，2.39～2.48(6H，m)，2.71(1H，d)，3.09(1H，d)，4.51(1H，d)，4.56(1H，m)，4.97(2 H，s)，6.78～6.82(2H，m)，7.22～7.30(4H，m)，7.56(1H，m)，7.80(1H，s)，8.13(1H，s)
15	2.28(2H，m)，2.50～2.57(6H，m)，2.87(1H，d)，3.20(1H，d)，4.53(1H，d)，4.57(1H，d)，5.01(2 H，s)，6.80～6.83(2H，m)，6.97～7.06(3H，m)，7.28(1H，m)，7.56(1H，m)，7.79(1H，s)，8.13(1 H，s)
		16	2.20(2H，m)，2.42～2.49(6H，m)，2.72(1H，d)，3.10(1H，d)，4.52(1H，d)，4.56(1H，d)，4.95(2 H，s)，6.80～6.83(2H，m)，7.12(1H，m)，7.38～7.40(2H，m)，7.56(1H，m)，7.80(1H，s)，8.13(1 H，s)
17	2.20(2H，m)，2.48～2.52(6H，m)，2.69(1H，d)，3.10(1H，d)，3.60(1H，s)，4.54(1H，d)，4.56(1H ，d)，5.10(2H，s)，6.81～6.83(2H，m)，7.50～7.60(3H，m)，7.80(1H，s)，8.13～8.15(3H，m)
		18	2.20(2H，m)，2.45～2.55(5H，m)，2.70(1H，d)，3.20(1H，d)，3.50(2H，m)，4.50(1H，d)，4.55(1 H，d)，5.06(2H，s)，6.75～6.80(2H，m)，7.37～7.39(2H，m)，7.60～7.62(3H，m)，7.81(1H，s)，8. 14(1H，s)
19	2.21(2H，m)，2.47～2.50(6H，m)，2.70(1H，d)，3.10(1H，d)，3.79(3H，s)，4.52～4.53(2H，dd)，4 .99(2H，s)，6.80～6.89(5H，m)，7.23(1H，m)，7.60(1H，m)，7.79(1H，s)，8.13(1H，s)
		20	2.21(2H，m)，2.40～2.48(6H，m)，2.72(1H，d)，3.08(1H，d)，4.53(1H，d)，4.54(1H，d)，4.98(2 H，s)，6.80～6.82(2H，m)，7.15～7.26(4H，m)，7.55(1H，m)，7.79(1H，s)，8.13(1H，s)
21	2.21(2H，m)，2.40～2.49(6H，m)，2.70(1H，d)，2.92(1H，m)，3.09(1H，d)，4.49～4.52(2H，dd)， 4.98(2H，s)，6.79～6.82(2H，m)，7.17～7.26(4H，m)，7.79(1H，s)，8.13(1H，s)
		22	2.21(2H，m)，2.47～2.59(6H，m)，2.70(1H，d)，3.10(1H，d)，3.79(3H，s)，4.52(1H，d)，4.54(1H ，d)，4.99(2H，s)，6.80～6.89(5H，m)，7.24(1H，m)，7.56(1H，m)，7.79(1H，s)，8.13(1H，s)
23	2.21(2H，m)，2.31(3H，s)，2.38～2.50(6H，m)，2.70(1H，d)，3.09(1H，d)，4.49～4.54(2H，dd)，5 .03(2H，s)，6.80～6.82(3H，m)，7.14～7.20(3H，m)，7.56(1H，m)，7.79(1H，s)，8.13(1H，s)
		24	2.21(2H，m)，2.33(3H，s)，2.38～2.48(6H，m)，2.70(1H，d)，3.09(1H，d)，4.49～4.57(2H，dd)，4 .97(2H，s)，6.79～6.82(2H，m)，7.12(2H，dd)，7.19(2H，dd)，7.55(1H，m)，7.79(1H，s)，8.13(1 H，s)
25	2.21(2H，m)，2.46～2.51(6H，m)，2.72(1H，d)，3.10(1H，d)，4.50～4.58(2H，dd)，5.06(2H，s)，6 .78～6.83(2H，m)，7.39(2H，dd)，7.55～7.58(3H，m)，7.79(1H，s)，8.12(1H，s)
		26	2.21(2H，m)，2.40～2.51(6H，m)，2.72(1H，d)，3.10(1H，d)，4.50～4.58(2H，dd)，5.06(2H，s)，6 .78～6.83(2H，m)，7.43～7.46(2H，m)，7.52～7.57(3H，m)，7.79(1H，s)，8.12(1H，s)

27	2.21(2H，m)，2.47～2.49(6H，m)，2.70(1H，d)，3.07(1H，d)，4.52～4.54(2H，dd)，5.00(2H，s)，5 .22(1H，dd)，5.73(1H，dd)，6.68(1H，dd)，6.82(2H，m)，7.26(1H，m)，7.36(2H，dd)，7.57(2H， m)，7.79(1H，s)，8.13(1H，s)
		28	2.21(2H，m)，2.33(3H，s)，2.39～2.50(6H，m)，2.70(1H，d)，3.09(1H，d)，4.52～4.54(2H，dd)，4 .98(2H，s)，6.79～6.82(2H，m)，7.09～7.11(3H，m)，7.21(1H，m)，7.56(1H，m)，7.79(1H，s)，8. 12(1H，s)

Embodiment:

Embodiment 1:2-chloro-2 ', 4 '-preparation of difluoro acetophenone (II)

Aluminum trichloride (anhydrous) 100g (0.747mol) and m-difluorobenzene 75.33g (0.667mol) place the 500ml 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 PH7, 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 is filtered, and 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, the preparation of 2,4-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: the preparation of tert-butyl 4-oxo-piperidine-1-carboxide (VI)

In the 250ml three-necked bottle, add 4-piperidone hydrochloride (V) 13.65g (0.1mol), add 180ml1,4-dioxane: water (4: 1, v/v) solution and N, N-diisopropylethylamine 32.31g (0.25mol), stirring at room is even, slowly drip di-t-butyl carbonic ether 32.74g (0.15mol) again, stirring at room reaction 24h.After reaction finished, decompression steamed solvent, among the resistates impouring 5% citric acid solution 80ml, and CH ₂Cl ₂Extraction (100ml * 3) merges organic layer, washing, and anhydrous magnesium sulfate drying filters, and evaporate to dryness gets white solid, and the hexanaphthene recrystallization gets white needle-like crystals 15g, yield: 75.4%, fusing point: 73～75 ℃.

Embodiment 5: the preparation of tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII)

(2.64g, 0.038mol), (3.0g, aqueous solution 100ml 0.075mol) stir 10min to add 100ml ethanol and sodium hydroxide to add oxammonium hydrochloride in the 250ml three-necked bottle.Add again tert-butyl 4-oxo-piperidine-1-carboxide (VI) (5g, 0.025mol), back flow reaction 1h.After reaction finished, steaming desolventized, and resistates adds water 100ml dilution, ethyl acetate extraction (80ml * 3), and the organic phase washing, anhydrous magnesium sulfate drying filters, and evaporate to dryness gets white solid 5.1g, yield 95%, fusing point: 95～96 ℃.

Embodiment 6: the preparation of tert-butyl 4-(benzyloxy amido) piperidines-1-carboxide (VIII)

Under condition of ice bath, with sodium hydride (0.13g 5.3mmol) is dissolved among the 20mlDMF, add tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII) (1.0g, 5mmol), stirring at room 1h.(0.91g, 5.3mmol), stirring at room is reacted 20h to add the benzyl bromine.After reaction is finished, steam except part DMF, add water 30ml dilution, ethyl acetate extraction (50ml * 3) merges organic phase, washing, anhydrous magnesium sulfate drying, filter evaporate to dryness, resistates column chromatography purification, developping agent is sherwood oil: ethyl acetate (120: 1, v/v), get colorless oil 1.2g, yield 78.9%.

Other (VIII) compounds are with different Z1 or Z2, and Z3 and compound (VII) reaction repeats embodiment 6 and obtains.

Embodiment 7: the preparation of piperidin-4-one--O-benzyl oxime trifluoroacetate (IX) (the R group is hydrogen)

(0.5g 1.6mmol) is dissolved in the 15ml methylene dichloride, and ice bath adds the 3ml trifluoracetic acid, stirring at room reaction 15h with tert-butyl 4-(benzyloxy amido) piperidines-1-carboxide (VIII).After reaction was finished, steaming desolventized, and gets brown oil 0.51g, yield 100%.

The preparation (preparation of compound 1 in the table 1) of embodiment 8:1-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--O-benzyl oxime (X)

In the 50ml round-bottomed flask, add piperidin-4-one--O-benzyl oxime trifluoroacetate (IX) (0.3g, 0.95mmol), 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV) (0.26g, 0.79mmol) and the 10ml dehydrated alcohol, stir, add triethylamine 1.5ml.Be warming up to 75 ℃ of back flow reaction 5h.After reaction was finished, steaming desolventized, and resistates column chromatography purification, developping agent are sherwood oil: and ethyl acetate (1.5: 1, v/v), get yellow oil 0.05g, yield 14.3%.

1H-NMR(CDCl ₃，TMS)：2.21(2H，m)，2.42(2H，m)，2.50(2H，m)2.75(1H，d)，3.08(1H，d)，3.45～3.65(3H，m)，4.46(1H，d)，4.59(1H，d)，5.04(2H，s)，6.7～6.89(2H，m)，7.25～7.33(5H，m)，7.58(1H，m)，7.79(1H，s)，8.15(1H，s)

All the other target compounds are so that different tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VIII) is synthesis material, listed as table 1, repeat the step among the embodiment 7 and 8, just can synthesize required piperidin-4-one--O-and replace oxime trinitrogenazole alcohol antifungal compound or its esters.Agents useful for same is commercially available analytical pure among the embodiment.

(2-(2 for the 1-that the present invention synthesizes, the 4-difluorophenyl)-2-hydroxyl-3-(1H-1,2, the 4-triazol-1-yl) propyl group) piperidin-4-one--O-replacement oxime compounds 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 Chemother 1995,39 (5): 1169)

1. materials and methods

(1) experimental strain

This experiment has selected for use following 5 kinds of common human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Long March hospital Mycology Lab.

1) Candida albicans (Candida albicans, type strain SC5314);

2) Candida parapsilosis (Candida parapsilosis, type strain 0306392);

3) Oidium tropicale (Candida tropicalis type strain ATCC12034);

4) Cryptococcus neoformans (Cryptococcus neoformans type strain 34880);

5) the gentle fungi (Candida Krusei clinical strain 0710463) of gram;

(2) experimental technique

The bacteria suspension preparation: above-mentioned fungi was cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted bacteria concentration to 1 * 10 with the RPM1640 liquid nutrient medium ⁴～1 * 10 ⁵Individual/ml.

Soup preparation: get testing compound of the present invention 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 the RPM1640 bacteria suspension before the experiment.

Inoculation: No. 1 hole of 96 orifice plates adds RPM1640100 μ l and makes blank, the 3-12 hole respectively adds bacteria suspension 120 μ l, No. 2 the hole adds bacteria suspension 160 μ l and soup 16 μ l, the drug level in 2-11 hole is made 10 grade of 4 doubling dilution, and each hole drug level is respectively 64,16,4,1,0.25,0.0625,0.0156,0.0039,0.00097,0.00024 μ g/mL.No. 12 the hole does not add soup, makes positive control.The medicine contrast is fluconazole, KETOKONAZOL, itraconazole, Te Binafen, amphotericin B, L17, voriconazole.

Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest drug concentration with optical density value than positive control hole is minimal inhibitory concentration value (MIC).

(2) experimental result

External bacteriostatic experiment the results are shown in Table 3

The external antimycotic minimal inhibitory concentration value of table 3 part selected objective target compound (MIC, μ g/ml)

Compound number	Bai Nian	The torrid zone	Near flat	Gram is gentle	New latent
						1	0.0039	0.00097	0.0039	0.0625	0.0156
2	0.0156	0.0156	0.0039	0.25	0.0156
						3	0.0156	0.0097	0.0039	0.25	0.0156
4	0.0156	0.00097	0.0625	0.25	0.0039
						5	0.0156	0.0039	0.0156	0.25	0.0156
6	0.0156	0.0156	0.0156	0.25	0.0156
						7	0.0156	0.0039	0.0625	0.25	0.0039
8	0.0156	0.0039	0.0156	0.25	0.0156
						11	0.0156	0.0156	0.0156	0.25	0.0156
12	0.0156	0.0039	0.0039	0.25	0.0156
						13	0.0156	0.0625	0.0625	0.25	0.00097
18	0.0625	0.0625	0.0625	0.25	0.0156
						Itraconazole	0.0039	0.0625	0.0625	0.25	0.0039
Fluconazole	0.25	0.25	0.25	1	0.0625

Above-mentioned experimental result shows that compound of the present invention and its esters have anti-mycotic activity preferably, various superficial parts and deep fungal had very strong anti-mycotic efficiency, compare with the antifungal drug of existing clinical application, most vitro inhibition activity to selected fungi all are better than fluconazole, with KETOKONAZOL quite or more excellent, have efficient, toxicity is low, the advantage of antimycotic spectrum width, described compound and its esters can be used for preparing the medicine of new treatment anti-fungal infection.

Claims

1. a trinitrogenazole alcohol compounds or its pharmaceutical salts is characterized in that such structural general formula is:

Wherein: X group representation hydroxy;

Y group represents 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)F、Cl、Br、I；

(2) methyl, ethyl, trifluoromethyl, the tertiary butyl;

The Z1 structure is as follows:

The Z2 structure is as follows:

(1)F、Cl、Br、I；

(3) methyl, ethyl, propyl group, sec.-propyl, isobutyl-, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, tert-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl;

2. by the described trinitrogenazole alcohol compounds of claim 1, it is characterized in that compound is the following compound that X, Y, R group and Z, Z1, Z2, Z3, Z4 are combined into:

3. the salt of claim 1 or 2 described trinitrogenazole alcohol compounds is characterized in that it is hydrochloride, nitrate, hydrobromate or methane sulfonates.

4. claim 1 or 2 or 3 described trinitrogenazole alcohol compounds and salt thereof the application in the preparation antifungal drug.

5. the preparation method of the described trinitrogenazole alcohol compounds of claim 1, synthetic route is as follows, and wherein the Z group is consistent with Z group definition in the claim 1:

Concrete steps are:

(1) preparation 2-chloro-2 ', 4 '-difluoro acetophenone (II)

(2) preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (III)

(4) preparation tert-butyl 4-oxo-piperidine-1-carboxide (VI)

Piperidin-4-one-hydrochloride and di-t-butyl carbonate are at 1,4-dioxane: its v/v of water is that reaction generates tert-butyl 4-oxo-piperidine-1-carboxide (VI) in 4: 1;

(5) preparation tert-butyl 4-(hydroxyl imines) piperidines-1-carboxide (VII)

(6) preparation tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VIII)

(7) preparation piperidin-4-one--0-replaces oxime trifluoroacetate (IX)

Tert-butyl 4-(replacement oxime) piperidines-1-carboxide (VI) reacts generation piperidin-4-one--0-with trifluoracetic acid and replaces oxime trifluoroacetate (IX) in methylene dichloride;

(8) preparation target product 1-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--0-replaces oxime (X)

1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole mesylate (IV), piperidin-4-one--0-replacement oxime trifluoroacetate (IX) react generation target product 1-with triethylamine in dehydrated alcohol (2-(2, the 4-difluorophenyl)-and 2-hydroxyl-3-(1H-1,2,4-triazol-1-yl) propyl group) piperidin-4-one--0-replaces oxime (X).