CN1557808A - 3-substituted piperazine triadimenol antifungal compounds and their salts - Google Patents

3-substituted piperazine triadimenol antifungal compounds and their salts Download PDF

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CN1557808A
CN1557808A CNA2004100161866A CN200410016186A CN1557808A CN 1557808 A CN1557808 A CN 1557808A CN A2004100161866 A CNA2004100161866 A CN A2004100161866A CN 200410016186 A CN200410016186 A CN 200410016186A CN 1557808 A CN1557808 A CN 1557808A
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methyl
heterocycle
carbamyl
hydroxyl
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CN1283630C (en
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刘超美
何秋琴
姜远英
曹永兵
梁爽
门秀峰
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Second Military Medical University SMMU
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Abstract

The present invention relates to medicine technology, and is 3-substituted piperazine triazonyl alcohol as new antifungal compound and its salt. The substituting radical may be in any position of heterocycle, and the compound may be single or multiple substituted. The said compound may form salt with several kinds of organic and inorganic acid. The present invention exhibits very powerful antifungal activity and may be used in preparing antifungal medicine.

Description

3-substituted-piperazinyl trinitrogenazole alcohol antifungal compound and its esters
Technical field
The present invention relates to medical technical field, is a kind of novel 3-substituted-piperazinyl trinitrogenazole alcohol antifungal compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-substituted piperazinyl-2-propanol compound and its esters.
Background technology
In the last thirty years, because a large amount of uses of Broad spectrum antibiotics clinically, the increase of cancer radiation, chemotherapy and organ transplantation patient number, being extensive use of of cortin and immunosuppressor, and acquired immune deficiency syndrome (AIDS) is popular, the deep fungal infection rate has risen 40 times.Updated statistics shows that 60% the direct cause of death is a deep fungal infection among the AIDS patient.Deep fungal infection becomes a kind of common disease, frequently-occurring disease just day by day, has become the one of the main reasons of cancer and immunodeficiency diseases death.Therefore, press for efficient, low toxicity, novel deep antifungal drug that selectivity is high clinically.But at present clinical antifungal drug commonly used such as amphotericin B (Amphotericin B), KETOKONAZOL (Ketoconazole), fluconazole (Fluconazole) and itraconazole (Itraconazole) etc. all exist toxic side effect greatly, narrow antimicrobial spectrum, Resistant strain problem such as increase day by day.
Summary of the invention
The invention provides the novel triadimenol compounds of a kind of efficient, low toxicity, wide spectrum, and common medicinal salts example hydrochloric acid salt, hydrobromate, methane sulfonates, acetate, oxalate, maleate, fumarate, grape hydrochlorate, tartrate, lactic acid salt or succinate.
The general structure of The compounds of this invention is as follows:
Figure A20041001618600051
Wherein: X represents hydrogen or methyl, preferable methyl.
M is for hydroxyl or ester group;
The ester group here refers to have the straight or branched ester group of 1～4 carbon atom, as formic acid ester group, acetate groups, propionic acid ester group, isopropyl acid ester group, preferably has the ester group of 1～3 carbon atom, preferred especially acetate groups;
Y 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:
A. halogen, preferred 2 as F, Cl, Br, I, 4-difluoro or 2, the 4-dichloro replaces;
B. the aliphatic chain that has 1～4 carbon atom, as methyl, ethyl, trifluoromethyl, the tertiary butyl etc., preferred trifluoromethyl replaces;
Preferred especially 2,4-two is fluorine-based;
The R representative:
(1) heterocycle formyl or ethanoyl, substituted heterocycle formyl radical or ethanoyl:
Heterocycle refers to common five Yuans or six element heterocycles, as furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines etc., preferred six element heterocycles, preferred especially pyridine or pyrimidine, substituting group can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of carbon atom is as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl etc.;
B. halogen is as F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, as 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;
(2) heterocyclic methyl or substituted heterocycle methyl:
Heterocycle refers to common five Yuans or six element heterocycles, as furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines etc., preferred six element heterocycles, preferred especially pyridine or pyrimidine, substituting group can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of carbon atom is as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl etc.;
B. halogen is as F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, as 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;
(3) heterocycle p-methoxy-phenyl or substituted heterocycle p-methoxy-phenyl:
Heterocycle refers to common five Yuans or six element heterocycles, as furans, thiophene, pyrazoles, imidazoles, triazole, oxazole, thiazole, isoxazole, pyrans, pyridine, pyrimidine, morpholine and piperidines etc., preferred six element heterocycles, preferred especially pyridine or pyrimidine, substituting group can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of carbon atom is as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl etc.;
B. halogen is as F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, as 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;
(4) 3 ', 4 '-heterocycles thick and phenyl:
At phenyl 3, the heterocycle of 4-position can be a five-membered ring, also can be six membered ring; Can be aliphatic heterocycle, can be aromatic heterocycle also, as 1, and 3-dioxolane, lactonic ring, lactam nucleus, pyrroles, imidazoles, triazole ， oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidines etc.Preferred five-membered ring, preferred especially 1,3-dioxolane and imidazoles.Heterocyclic substituent can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted.Substituting group refers to:
A.1-4 the aliphatic chain of carbon atom is as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl etc.;
B. halogen is as F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, as 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.;
(5) 3 ', 4 '-heterocycles thick and benzyl oxy phenyl:
At benzyl 3, the heterocycle of 4-position can be a five-membered ring, also can be six membered ring; Can be aliphatic heterocycle, can be aromatic heterocycle also, as 1, and the 3-dioxolane, lactonic ring, lactam nucleus, pyrroles, imidazoles, triazole ， oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidines etc., preferred five-membered ring, preferred especially 1,3-dioxolane and imidazoles, heterocyclic substituent can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of carbon atom is as methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl etc.;
B. halogen is as F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group; as 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group etc.
The salt of The compounds of this invention comprises common medicinal salts such as hydrochloride, hydrobromate, methane sulfonates, acetate, oxalate, maleate, fumarate, grape hydrochlorate, tartrate, lactic acid salt and succinate.
The preparation method of The compounds of this invention is as follows:
1. the preparation of intermediate
Difference according to tape base group of target compound institute makes 1-(2-substituted-phenyl-2,3-epoxypropyl)-1H-1 by Y for not isoplastic substituted benzene, 2,4-triazole methane sulfonates or 1-(2-substituted-phenyl-2,3-epoxy butyl)-1H-1,2,4-triazole methane sulfonates ring intermediate.
2. the preparation of target compound
Intermediate 1-(2-substituted-phenyl-2,3-epoxypropyl)-1H-1,2, ring-opening reaction takes place just to generate X is that H, M are the The compounds of this invention of hydroxyl in 4-triazole methane sulfonates and single substituted piperazine like compound of different R groups under alkaline condition; Intermediate 1-(2-substituted-phenyl-2,3-epoxy butyl)-1H-1,2, ring-opening reaction takes place just to generate X is that methyl, M are the The compounds of this invention of hydroxyl in 4-triazole methane sulfonates and single substituted piperazine like compound of different R groups under alkaline condition; M is that the The compounds of this invention of hydroxyl just obtains corresponding ester class with acyl chlorides or anhydride reaction again.
With Y is 2, and 4-is two fluorine-based, X is that H is an example, and the preparation method is as follows:
1. intermediate 1-[2-(2,4 difluorobenzene base)-2,3-epoxypropyl]-1H-1,2, the preparation of 4-triazole methane sulfonates (III) is (referring to Gong Sun Qing and Liu Chaomei etc.: The 2nd Army Medical College journal, 2001; 22 (9): 871)
With the m-difluorobenzene is starting raw material, under the katalysis of aluminum chloride, with chloroacetyl chloride in methylene dichloride in 50～55 ℃ Fu-Ke (Friedel Crafts) take place with mol ratio react at 1: 1, stirring reaction formation in 8 hours 2-chloro-2 ', 4 '-difluoro acetophenone (IV); (IV) in toluene, formed 2 in 24 hours with triazole reaction ', 4 '-two fluoro-2-(1H-1,2,4-triazol-1-yl) methyl phenyl ketone (V); (V) with sulphur Yi Lide (ylid) reagent trimethylammonium oxygen sulphur iodide at 60 ℃ of nucleophilic additions that carbonyls take place, form epoxide, it can with the methanesulfonic salify, get intermediate 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III).
2. the preparation of target compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-substituted-piperazinyl-2-propyl alcohol
Figure A20041001618600082
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.
3. the preparation of salt
The preparation method of 3-substituted-piperazinyl triadimenol compounds salt of the present invention is with the 3-substituted-piperazinyl triazole alcoholic antifungal compound (I) of above-mentioned preparation and equimolar acid-respons 1～2 hour, after reaction finishes, concentration of reaction solution must precipitate, and filters just to obtain corresponding salt.
What table 1 was listed is structure, productive rate, fusing point and the molecular formula of part selected objective target compound among the present invention.
Preparation method of the present invention will be described in further detail in conjunction with the embodiments.
Chemical structure, productive rate, the fusing point of table 1 part preferred compound (a, b)And molecular formula
Figure A20041001618600091
Compound R group productive rate fusing point molecular formula
Numbering (%) (℃)
1 2-furancarbonyl, 84.4 123-5 C 20H 21F 2N 5O 3
2 2-Thenoyls, 79.9 105-7 C 20H 21F 2N 5O 2S
3 2-pyridine formyl radicals, 76.6 144-6 C 21H 22F 2N 6O 2
4 3-pyridine formyl radicals, 83.2 132-3 C 21H 22F 2N 6O 2
5 4-pyridine formyl radicals, 81.8 156-8 C 21H 22F 2N 6O 2
6 6-quinoline formyl bases, 64.2 134-6 C 25H 24F 2N 6O 2
7 5-NO 2-2-furancarbonyl 90.1 118-9 C 20H 20F 2N 6O 5
8 5-Cl-2-Thenoyls, 59.9 107-9 C 20H 20ClF 2N 5O 2S
9 2-thiophene acetyls, 49.2 107-8 C 21H 23F 2N 5O 28
10 2-pyridine ethanoyl, 90.5 154-6 C 22H 24F 2N 6O 2
11 4-pyridine ethanoyl, 76.9 138-40 C 22H 24F 2N 6O 2
12 1-(1,2, the 4-triazol-1-yl) ethanoyl 79.6 121-2 C 19H 22F 2N 8O 2
13 1-imidazoles ethanoyl, 88.2 123-4 C 20H 23F 2N 7O 2
14 4-(2-furans methoxyl group) phenyl, 48.5 96-8 C 26H 27F 2N 5O 3
15 4-(5-NO 2-2-furans methoxyl group) phenyl 55.6 115-7 C 26H 26F 2N 6O 5
16 4-(2-pyridine methoxyl group) phenyl, 52.2 142-4 C 27H 28F 2N 6O 2
17 4-(3-pyridine methoxyl group) phenyl, 62.5 90-2 C 27H 28F 2N 6O 2
18 4-(4-pyridine methoxyl group) phenyl, 56.5 122-4 C 27H 28F 2N 6O 2
19 4-(2-pyrimidine methoxyl group) phenyl, 63.1 114-7 C 26H 27F 2N 7O 2
20 4-(4-pyrimidine methoxyl group) phenyl, 67.1 123-4 C 26H 27F 2N 7O 2
21 4-(4-CF 3-2-pyridine methoxyl group) phenyl 80.1 117-8 C 28H 27F 5N 6O 2
22 4-(5-CF 3-2-pyridine methoxyl group) phenyl 59.2 125-8 C 28H 27F 5N 6O 2
23 4-(6-CF 3-3-pyridine methoxyl group) phenyl 69.7 121-3 C 28H 27F 5N 6O 2
24 4-(2-CF 3-4-pyridine methoxyl group) phenyl 80.1 166-8 C 28H 27F 5N 6O 2
25 4-(4-F-2-pyridine methoxyl group) phenyl, 57.3 115-6 C 27H 27F 3N 6O 2
26 4-(5-Cl-2-pyridine methoxyl group) phenyl, 60.3 109-10 C 27H 27ClF 2N 6O 2
27 4-(3-CN-2-pyridine methoxyl group) phenyl, 64.1 111-3 C 28H 27F 2N 7O 2
28 4-(5-Cl-3-pyridine methoxyl group) phenyl, 76.2 107-9 C 27H 27ClF 2N 6O 2
29 4-(4-OCH 3-2-pyridine methoxyl group) phenyl 67.2 93-5 C 28H 30F 2N 6O 3
30 4-(4-quinoline methoxy) phenyl, 82.1 136-8 C 31H 30F 2N 6O 2
31 4-(6-quinoline methoxy) phenyl, 79.9 141-3 C 31H 30F 2N 6O 2
32 4-(5-isoxazole methoxyl group) phenyl, 84.8 132-4 C 25H 30F 2N 6O 3
33 4-(benzo [d] 1,3-dioxolane-5-methoxyl group) benzene 67.8 145-7 C 29H 29F 2N 5O 4
Base
34 4-(benzo [d] thiazole-5-methoxyl group) phenyl 74.7 152-4 C 29H 28F 2N 6O 2S
35 4-(benzo [d] oxazole-5-methoxyl group) phenyl 71.8 163-5 C 29H 28F 2N 6O 3
36 4-(1-sec.-propyl benzo [d] imidazoles-5-methoxyl group)
Phenyl 58.3 138-9 C 32H 35F 2N 7O 2
37 4-(1-ethyl benzo [d] triazole-5-methoxyl group)
Phenyl 60.6 126-8 C 30H 32F 2N 8O 2
(a) .C, H, the measured value and the calculated value of three kinds of ultimate analyses of N differ less than 0.3%.
(b). thermometer is not proofreaied and correct.
Pharmacological evaluation shows that The compounds of this invention has stronger anti-mycotic activity, has a broad antifungal spectrum, and effective to the clinical bacterial strain of anti-the fluconazole, therefore can be used for preparing antifungal drug.
Embodiment
Embodiment 1
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(2-furancarbonyl) piperazine]-preparation of 2-propyl alcohol (compound 1 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 2-mercaptopyridine 1.08g (6mmol), Anhydrous potassium carbonate 2.07g (15mmol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 30ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, and ethyl acetate extraction (3 * 70ml), washing (30ml * 3), anhydrous Na 2SO 4Drying reclaims solvent, gets white solid 1.76g with the dehydrated alcohol recrystallization, 123～5 ℃ of fusing points, productive rate 84.4%.
1H-NMR (DMSO-d 6) δ, ppm:8.24 (1H, s, triazole C 3-H), 7.82 (1H, s, triazoleC 5-H), 6.77～8.30 (6H, m, Ar-H), 5.10 (1H, s, OH), 4.49-4.58 (2H, AB system, triazole-CH 2), 3.33-3.35 (4H, m, N (CH 2) 4N), 3.04-3.08 (1H, d, J=13.6Hz ,-N (CH 2) 4N-CHa), 2.66-2.72 (1H, d, J=13.6Hz ,-N (CH 2) 4N-CHb), 2.32-2.34 (4H, m, N (CH 2) 4N)
IR(cm -1，KBr)：3341，3057，2970，2806，1615，1588，1559，1272，1102，1060
Embodiment 2
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(2-(1,2, the 4-triazol-1-yl) ethanoyl) piperazine]-preparation of 2-propyl alcohol (compound 12 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 2-(1,2, the 4-triazol-1-yl) acetylpiperazine 1.17g (6mmol), Anhydrous potassium carbonate 2.07g (0.015mol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 25ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, with ethyl acetate extraction (60ml * 3), united extraction liquid, and washing (25ml * 3), anhydrous Na 2SO 4Drying is filtered, and gets crude product behind the recovery solvent, and crude product is carried out column chromatography, uses CHCl 3: C 2H 5OH=9: 1 wash-out gets faint yellow solid 1.72g, 121～2 ℃ of fusing points, productive rate 79.6%.
1H-NMR (DMSO-d 6) δ, ppm:8.12-8.15 (2H, m, triazole C 3-H), 7.75-7.78 (2H, m, triazole C 5-H), 6.75～7.58 (3H, m, Ar-H), 5.20 (1H, s, OH), 4.56-4.64 (2H, AB system, triazole-CH 2), 3.60-3.68 (4H, m, N (CH 2) 4N), 3.17-3.20 (1H, d, J=13.2Hz ,-N (CH 2) 4N-CHa), 2.80-2.84 (1H, d, J=13.2Hz ,-N (CH 2) 4N-CHb), 2.60-2.66 (4H, m, N (CH 2) 4N)
IR(cm -1，KBr)：3234，3077，2975，2891，2806，1612，1564，1273，1249，1060
Embodiment 3
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-(2-pyridine methoxyl group) phenyl) piperazine]-preparation of 2-propyl alcohol (compound 16 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 4-(4-(2-pyridine methoxyl group) phenyl) piperazine 1.62g (6mmol), Anhydrous potassium carbonate 2.07g (0.15mol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 25ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, with ethyl acetate extraction (60ml * 3), united extraction liquid, and washing (25ml * 3), anhydrous Na 2SO 4Drying is filtered, and gets crude product behind the recovery solvent, and crude product is carried out column chromatography, uses CHCl 3: C 2H 5OH=9: 1 wash-out gets yellow solid 1.32g, 142～4 ℃ of fusing points, productive rate 52.2%.
1H-NMR(DMSO-d 6)δ，ppm：8.29(1H，s，triazole?C 3-H)，7.75(1H，s，triazoleC 5-H)，6.80～8.56(11H，m，Ar-H)，5.62(1H，s，OH)，5.08(2H，s，-OCH 2-)，4.59(2H，s，triazole-CH 2)，2.90-2.94(1H，d，J＝13.6Hz，-N(CH 2)4N-CHa)，2.87-2.90(4H，m，N(CH 2) 4N)，2.71-2.75(1H，d，J＝13.6Hz，-N(CH 2) 4N-CHb)，2.50-2.56(4H，m，N(CH 2) 4N)
IR(cm -1，KBr)：3421，3137，2806，2230，2180，1621，1580，1561，1174，1024
Embodiment 4
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-(3-pyridine methoxyl group) phenyl) piperazine]-preparation of 2-propyl alcohol (compound 17 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 4-(4-(3-pyridine methoxyl group) phenyl) piperazine 1.62g (6mmol), Anhydrous potassium carbonate 2.07g (0.15mol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 25ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, with ethyl acetate extraction (60ml * 3), united extraction liquid, and washing (25ml * 3), anhydrous Na 2SO 4Drying is filtered, and gets crude product behind the recovery solvent, and crude product carries out column chromatography, uses CHCl 3: C 2H 5OH=9: 1 wash-out gets yellow solid 1.58g, 90～2 ℃ of fusing points, productive rate 62.5%.
1H-NMR(DMSO-d 6)δ，ppm：8.28(1H，s，triazole?C 3-H)，7.74(1H，s，triazoleC 5-H)，6.80～8.63(11H，m，Ar-H)，5.57(1H，s，OH)，5.08(2H，s，-OCH 2-)，4.60(2H，s，triazole-CH 2)，2.91-2.95(1H，d，J＝13.6Hz，-N(CH 2) 4N-CHa)，2.87-2.90(4H，m，N(CH 2) 4N)，2.72-2.76(1H，d，J＝13.6Hz，-N(CH 2) 4N-CHb)，2.51-2.56(4H，m，N(CH 2) 4N)
IR(cm -1，KBr)：3432，3154，3118，2941，1617，1610，1551，1301，1271，1015
Embodiment 5
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-(4-pyridine methoxyl group) phenyl) piperazine]-preparation of 2-propyl alcohol (compound 18 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 4-(4-(4-pyridine methoxyl group) phenyl) piperazine 1.62g (6mmol), Anhydrous potassium carbonate 2.07g (0.15mol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 25ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, with ethyl acetate extraction (60ml * 3), united extraction liquid, and washing (25ml * 3), anhydrous Na 2SO 4Drying is filtered, and gets crude product behind the recovery solvent, and crude product carries out column chromatography, uses CHCl 3: C 2H 5OH=9: 1 wash-out gets yellow solid 1.43g, 122～4 ℃ of fusing points, productive rate 56.5%.
1H-NMR(DMSO-d 6)δ，ppm：8.28(1H，s，triazole?C 3-H)，7.75(1H，s，triazoleC 5-H)，6.80～8.56(11H，m，Ar-H)，5.62(1H，s，OH)，5.08(2H，s，-OCH 2-)，4.59(2H，s，triazole-CH 2)，2.89-2.93(1H，d，J＝13.6Hz，-N(CH 2) 4N-CHa)，2.87-2.89(4H，m，N(CH 2) 4N)，2.71-2.75(1H，d，J＝13.6Hz，-N(CH 2) 4N-CHb)，2.50-2.57(4H，m，N(CH 2) 4N)
IR(cm -1，KBr)：3431，3154，3020，2838，1621，1598，1574，1428，1138，1063
Embodiment 6
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-(benzo [d] 1,3-dioxolane-5-methoxyl group) phenylpiperazine)]-preparation of 2-propyl alcohol (compound 33 in the table 1)
Get 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole methane sulfonates (III) 1.65g (5mmol), 4-(4-(benzo [d] 1,3-dioxolane-5-methoxyl group) phenylpiperazine 1.87g (6mmol), Anhydrous potassium carbonate 2.07g (0.15mol) and phase-transfer catalyst cetyl trimethylammonium bromide 0.1g, dimethyl formamide 25ml, the heated and stirred reaction is 8 hours in 90-95 ℃ of oil bath.Cooling under agitation adds in the 50ml water, with ethyl acetate extraction (60ml * 3), united extraction liquid, and washing (25ml * 3), anhydrous Na 2SO 4Drying is filtered, and gets crude product behind the recovery solvent, and crude product carries out column chromatography, uses CHCl 3: C 2H 5OH=9: 1 wash-out gets white solid 1.86g, 145～7 ℃ of fusing points, productive rate 67.8%.
1H-NMR (DMSO-d 6) δ, ppm:8.13 (1H, s, triazole C 3-H), 7.79 (1H, s, triazoleC 5-H), 6.77～7.61 (10H, m, Ar-H), 5.94 (1H, s ,-OCH 2O-), 5.19 (1H, s, OH), 4.89 (2H, s ,-OCH 2-), 4.50-4.59 (2H, AB system, triazole-CH 2), 3.10-3.14 (1H, d, J=13.2Hz ,-N (CH 2) 4N-CHa), 2.94-2.97 (4H, m, N (CH 2) 4N), 2.72-2.76 (1H, d, J=13.2Hz ,-N (CH 2) 4N-CHb), 2.51-2.53 (4H, m, N (CH 2) 4N)
IR(cm -1，KBr)：3442，3346，3178，2930，1618，1592，1564，1440，1235，1088
Embodiment 7
1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[4-(4-(3-pyridine methoxyl group) phenyl) piperazine]-preparation of 2-propyl alcohol (compound 18 in the table 1) fumarate
Get 1-(1H-1,2,4-triazol-1-yl)-2-(2, the 4-difluorophenyl)-3-[4-(4-(3-pyridine methoxyl group) phenyl) piperazine]-propyl alcohol-2 (compound 18 in the table 1) 2.53g (5mmol), fumaric acid 0.58g (5mmol) adds 25ml methyl alcohol, stirring and refluxing 1 hour, put cold, add the 25ml methylene dichloride, place, filter out solid, get white solid 2.73g with the dehydrated alcohol recrystallization, productive rate 87.8%.
All the other target compounds can repeat the operation steps of the foregoing description, react with key intermediate epoxide (III) under alkaline condition with different single substituted-piperazinyls, just can obtain various 3-substituted-piperazinyl triadimenol compounds and its esters.Agents useful for same is commercially available analytical pure among the embodiment.
Synthetic 1-of the present invention (1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-substituted-piperazinyl-2-propanol compound and its esters have antifungic action, and 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, and the concentration that suppresses selected fungi 80% growth with target compound is as judging terminal point (MIC 80, reference: Antimicrob Agents Chemother 45 (9): 2420,2001).
(1), materials and methods
1, experiment fungal bacterial strain
The present invention selects two kinds of ATCC type strains and six kinds of clinical strains for use, and the ATCC type strain is provided by bacterial classification preservation center, Shanghai Long March Hospital, and clinical strain is provided by the Shanghai Changhai Hospital Mycology Lab, and through morphology and biochemical evaluation.
8 kinds of fungies selecting for use comprise: 4 kinds of deep fungals, a kind of superficial fungi, 2 kinds of subcutaneous fungies and smoke aspergillus fumigatus.
Deep fungal: Candida albicans (Candida albicans) ATCC76615 (being called for short Ca.)
Cryptococcus neoformans (Cryptococcus neoformans) ATCC32609 (being called for short Cn.)
Oidium tropicale (Candida tropicalis) (being called for short Ct.)
Candida parapsilosis (Candida parapsilosis) (being called for short Cp.)
Superficial fungi: trichophyton (Trichophyton rubrum) (being called for short Tr.)
Subcutaneous fungi: sporotrichum schenckii (Sporothrix schenckii) (being called for short Ss.)
Fonsecaea pedrosoi (Fonsecaea pedrosoi) (being called for short Fp.)
Smoke aspergillus fumigatus (Aspergillus fumigatus) (being called for short Af.)
2, nutrient solution
RPMI1640 nutrient solution: RMPI1640 (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
Bacterium liquid: get yeast and be seeded to the 1mlYEPD nutrient solution, cultivate 16h for 35 ℃, adjust bacterial concentration to 1 * 10 with the RPMI1640 nutrient solution 3～5 * 10 3Individual/ml; Get mould and be seeded to the SDA inclined-plane, cultivate a week for 35 ℃, adjust spore concentration to 1 * 10 with the RPMI1640 nutrient solution 3～5 * 10 3Individual/ml.
Soup: be subjected to reagent thing and contrast medicine fluconazole and KETOKONAZOL to be made into 6.4g/L solution with dimethyl sulfoxide (DMSO) respectively, be diluted to 640mg/L with the RPMI1640 nutrient solution before the experiment.
Drug sensitive plate: get aseptic 96 orifice plates, add RPMI1640 nutrient solution 100 μ l in No. 1 hole of every row and make blank; 3～No. 12 the hole respectively adds freshly prepared bacterium liquid 100 μ l; No. 2 the hole adds bacterium liquid 190 μ l and test-compound solution 10 μ l respectively; The 10 grades of doubling dilutions in 2～No. 11 holes; No. 12 the hole does not contain medicine, makes positive control.
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.The results are shown in Table 2.
The extracorporeal antifungal activity of table 2 target compound
MIC 80(μg/ml)
In the table 1
Compound C a. Cn. Ct. Cp. Ss. Fp. Tr. Af.
Numbering
1 ≤0.125 1 2 16 ＞64 ≤0.125 64 8
3 ≤0.125 2 ≤0.125 ≤0.125 ＞64 ≤0.125 2 4
5 0.125 1 2 16 ＞64 ≤0.125 64 8
12 ≤0.125 ≤0.125 ≤0.125 ≤0.125 16 ≤0.125 32 16
13 ≤0.125 0.25 0.5 16 16 ≤0.125 ＞64 32
16 ≤0.125 ≤0.125 ≤0.125 ≤0.125 ＞64 ≤0.125 4 64
17 ≤0.125 ≤0.125 ≤0.125 ≤0.125 ＞64 ≤0.125 16 64
18 ≤0.125 ≤0.125 ≤0.125 0.25 64 0.25 8 8
33 ≤0.125 1 ≤0.125 ≤0.125 ＞64 ≤0.125 4 8
KETOKONAZOL≤0.125 0.5≤0.125≤0.125 4≤0.125≤0.125 8
Fluconazole 0.5 16 0.5 0.5＞64 28＞64
Above-mentioned experimental result shows that heterocycle triadimenol compounds of the present invention and its esters have anti-mycotic activity preferably, most compounds all is better than fluconazole to the vitro inhibition activity of selected fungi, with KETOKONAZOL 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 (4)

1, a kind of 3-substituted-piperazinyl trinitrogenazole alcohol antifungal compound, its chemical structure of general formula is:
Figure A2004100161860002C1
Wherein: X represents hydrogen or methyl;
M representation hydroxy or ester group;
The ester group here refers to have the straight or branched ester group of 1～4 carbon atom, be selected from the formic acid ester group,
Acetate groups, propionic acid ester group, isopropyl acid ester group;
Y represents the various substituting groups on the aromatic ring, the position of substitution can be positioned at the neighbour,, contraposition, can be
The single replacement also can be polysubstituted, and substituting group refers to:
(1) halogen is selected from F, Cl, Br, I;
(2) have the aliphatic chain of 1～4 carbon atom, be selected from methyl, ethyl, trifluoromethyl, uncle's fourth
Base;
The R representative:
(1) heterocycle formyl or ethanoyl, substituted heterocycle formyl radical or ethanoyl:
Heterocycle refers to that five Yuans or six element heterocycles are 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, and substituting group refers to:
A.1-4 the aliphatic chain of a carbon atom is selected from methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;
B. halogen is selected from F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, be selected from 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group;
(2) heterocyclic methyl or substituted heterocycle methyl:
Heterocycle refers to five Yuans or six element heterocycles, be 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, substituting group refers to:
A.1-4 the aliphatic chain of a carbon atom is selected from methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;
B. halogen is selected from F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, be selected from 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group;
(3) heterocycle p-methoxy-phenyl or substituted heterocycle p-methoxy-phenyl:
Heterocycle refers to five Yuans or six element heterocycles, be 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, substituting group refers to:
A.1-4 the aliphatic chain of a carbon atom is selected from methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;
B. halogen is selected from F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, be selected from 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group;
(4) 3 ', 4 '-heterocycles thick and phenyl:
At phenyl 3, the heterocycle of 4-position can be a five-membered ring, also can be six membered ring; Can be aliphatic heterocycle, can be aromatic heterocycle also, is selected from 1, the 3-dioxolane, lactonic ring, lactam nucleus, the pyrroles, imidazoles, triazole oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidines, heterocyclic substituent can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of a carbon atom is selected from methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;
B. halogen is selected from F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group, be selected from 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group;
(5) 3 ', 4 '-heterocycles thick and benzyl oxy phenyl:
At benzyl 3, the heterocycle of 4-position can be a five-membered ring, also can be six membered ring; Can be aliphatic heterocycle, can be aromatic heterocycle also, is selected from 1, the 3-dioxolane, lactonic ring, lactam nucleus, the pyrroles, imidazoles, triazole oxazole, thiazole, pyridine, pyrimidine, morpholine and piperidines, heterocyclic substituent can be positioned at each position of heterocyclic, can be single replacement, also can be polysubstituted, and substituting group refers to:
A.1-4 the aliphatic chain of a carbon atom is selected from methyl, ethyl, trifluoromethyl, methylol, methoxyl methyl, ethoxymethyl, sec.-propyl and the tertiary butyl;
B. halogen is selected from F, Cl, Br, I;
C. electron-withdrawing group or electron-donating group; be selected from 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, formamido group, kharophen, hydroxyl, methoxyl group, oxyethyl group.
2, by the described 3-substituted-piperazinyl of claim 1 triazole alcoholic antifungal compound, it is characterized in that M, X, Y and R group are respectively:
(1) M is a hydroxyl, and X is H, and Y is 2, and 4-two is fluorine-based, and R is a furancarbonyl;
(2) M is a hydroxyl, and X is a methyl, and Y is 2, and 4-two is fluorine-based, and R is a 4-pyridine formyl radical;
(3) M is a hydroxyl, and X is a methyl, and Y is 2, and 4-two is fluorine-based, and R is 2-(1,2, a 4-triazol-1-yl) ethanoyl;
(4) M is a hydroxyl, and X is H, and Y is 2, and 4-two is fluorine-based, and R is benzo [d] thiazole-5-base;
(5) M is a hydroxyl, and X is H, and Y is 2, and 4-two is fluorine-based, and R is 4-(2-pyridine methoxyl group) phenyl;
(6) M is a hydroxyl, and X is H, and Y is 2, and 4-two is fluorine-based, and R is 4-(3-pyridine methoxyl group) phenyl;
(7) M is a hydroxyl, and X is H, and Y is 2, and 4-two is fluorine-based, and R is 4-(4-pyridine methoxyl group) phenyl;
(8) M is a hydroxyl, and X is a methyl, and Y is 2, and 4-two is fluorine-based, and R is 4-(2-pyridine methoxyl group) phenyl;
(9) M is a hydroxyl, and X is a methyl, and Y is 2, and 4-two is fluorine-based, and R is 4-(benzo [d] 1, a 3-dioxolane-5-methoxyl group) phenyl.
3, the salt of claim 1 or 2 described 3-substituted-piperazinyl triadimenol compounds is selected from hydrochloride, hydrobromate, methane sulfonates, acetate, oxalate, maleate, fumarate, grape hydrochlorate, tartrate, lactic acid salt or the succinate of this compounds.
4, claim 1 or 2 or 3 described 3-substituted-piperazinyl triazole alcoholic antifungal compounds or the salt application in the preparation antifungal drug.
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