CN101445488A - Triazoles compounds with antimicrobial activity and preparation method and pharmaceutical use thereof - Google Patents
Triazoles compounds with antimicrobial activity and preparation method and pharmaceutical use thereof Download PDFInfo
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Abstract
The invention discloses novel triazoles compounds, whose chemical names are 3-(substituted phenyl)-1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)-2-propen-1-one, 1-[3-(substituted phenyl)-1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)allyl]piperidinium, 3-(substituted phenyl)-1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)-2-propen-1-ol, and 1-[3-(substituted phenyl)-1-(2,4-difluoropheny)-2-(1,2,4-triazol-1-yl)proyl]piperidinium, with antimicrobial activity; further discloses the preparation method and pharmaceutical use thereof.
Description
Technical field
The present invention relates to have the novel triazole antifungal agents of anti-microbial effect, particularly relate to triazole ketenes, triazole enol, triazole piperidines and preparation method and medicinal use.
Background technology
In recent years, widespread use along with Broad spectrum antibiotics, hormone, immunosuppressor, AIDS's spreads, applying of organ transplantation and interventional technique, make the sickness rate of infected by microbes such as fungi, bacterium present ascendant trend, variation has also taken place in infection bacteria species, and the report of relevant Resistant strain increases gradually, and the treatment of fungi and infectation of bacteria is faced with formidable challenges.For solving fungi, drug-resistance of bacteria problem, countries in the world are strengthened the research and development of new drug just energetically.In new drug research, triazole class compounds receives much attention because of it has numerous biologic activity.Have now found that triazole class compounds has various active such as antimicrobial, antitumor, anxiety, anticonvulsion, hypertension, anti-inflammatory.Wherein, triazole class compounds has become a hot fields of antifungal drug research in recent years as the research of anti-mycotic agent.
At present, the research of antifungal drug mainly contains three directions: (1), act on sterol synthetic anti-mycotic agent in the fungal cell membrane, as azole drug (P such as KETOKONAZOL
450-14 α demethylation enzyme inhibitorss), polyene antibiotics amphotericin etc., and propylamine medicine Terbinafine (cyclooxygenase inhibitors of squalene) etc.(2), act on fungal cell wall synthetic anti-mycotic agent, as echinocandin class medicine Caspofungin (it suppresses fungal cell wall main component 1,3-beta-glucan synthetic), and suppress chitin synthetic nikemycin and Polyoxin etc.(3), act on nucleic acid synthetic anti-mycotic agent, as 5-flurocytosine (5-FC) etc.
Wherein the nitrogen azole is the most active compounds of present research with fastest developing speed, comprises imidazoles and triazole two big classes.This compounds can be divided into the three generations, the first-generation with the end of the sixties imidazoles such as synthetic clotrimazole and miconazole be sign, be mainly used in the treatment mycotic infection of superficial part; The s-generation is with the sign that appears as of KETOKONAZOL, and once with its wide spectrum, characteristics of high efficiency is widely used in the deep fungal infection treatment, and the back now is mainly used in mycotic infection of superficial part because of its serious liver toxicity.The third generation is 1,2, and the 4-triazole type medicine is as: Triaconazole (Terconazole), itraconazole (Itraconazole), dimension fourth azoles (Vibunazole), fluconazole (Fluconazole) etc.The third generation is compared with preceding two generations and is had more broad-spectrum high efficacy, and the characteristics of low toxicity can be used for the treatment of deep and superficial fungal infection.In recent years to having obtained impressive progress in the research of fluconazole analogue again.Compared antimicrobial spectrum at the voriconazole (Voriconazole) of U.S.'s listing with the triazole type medicine of continuing to use in 2002 and widen, anti-microbial activity strengthens.Phosphorus fluconazole (Fosfluconazole) in Japan's listing was the phosphoric acid ester prodrug of fluconazole in 2003, compared water-soluble big raising with fluconazole, and onset is rapid, and security is good, and side effect is little.
In addition, also found some anti-mycotic activities compound preferably, as T-8581, genaconazole (Genaconazole), KP-103, D-0870, TAK-187, ravuconazole (Ravuconazole), Albaconazole, posaconazole (Posaconazole), Saperconazole (Saperconazole) etc.Wherein genaconazole had than higher bacteriostatic activity of fluconazole and longer transformation period, also can be oral, and effective especially to aids patient.In the body of D-0870 and in vitro tests effective to the Candida albicans of fluconazole tolerance, and this compound is to the synthetic not influence of testosterone, entered the clinical II phase now to test.It is suitable that TAK-187 infects the meningitis curative effect and the fluconazole that cause to cryptococcus.The activity of its anti-candida albicans of ravuconazole, Candida glabrata, Cryptococcus neoformans and fumigation look aspergillus tubigensis is better than itraconazole, and pulmonary candidiasis due to the bacterial strain of anti-the fluconazole is demonstrated good efficacy.Having entered the clinical II phase now tests.Posaconazole is better than itraconazole, fluconazole and amphotericin B to candidiasis, Cryptococcus neoformans and aspergillus tubigensis activity.Entered the III clinical trial phase at present.Its anti-microbial activity of Saperconazole is better than fluconazole, and its curative effect to aspergillus tubigensis is better than amphotericin B and itraconazole.Finished the II clinical trial phase.Triazole class compounds is because the superiority that shows in clinical deep fungal infection treatment has become one of focus in the synthetic antifungal drug research.
Compare with the imidazoles antifungal drug, triazole type medicine is to mammiferous P
450A little less than suppressing, so toxicity is less.The antimicrobial spectrum of triazole type medicine is wideer in addition, and indication is wider, can be used for the treatment of superficial part and deep fungal infection.But existing triazole type medicine still has some shortcomings, narrow as antimicrobial spectrum, and the fungi resistance problem that constantly produces.Fluconazole a large amount of uses clinically in recent years, Resistant strain constantly increases.In addition, the interaction between medicine makes the deep fungal infection treatment become complicated more.This just needs the new antifungal drug with efficient, low toxicity, wide spectrum of development.
Summary of the invention
The purpose of this invention is to provide a triazole class compounds class new texture, that have efficient antibacterium, antifungic action or their pharmacy acceptable salts and preparation method, medicinal use.
The objective of the invention is to realize by following method:
Structure following (I) with triazole class compounds of antimicrobial acivity of the present invention, (II), (III), (IV), (V) or (VI):
R is hydrogen atom, halogen atom, dimethylamino, nitro, alkoxyl group, replacement aralkoxy or aldehyde radical in the formula, and X is hydroxide ion, chlorion or bromide anion.
Its Chinese style (I), (II) and (III) shown in be that triazole is enols used, formula (IV), (V) and (VI) shown in be triazole allyl group piperidines.
Triazole derivative or its preparation method that the present invention further proposes at pharmacy acceptable salt, with 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone is a raw material, obtain condensation product (I) and (IV) with substituted benzaldehyde condensation in toluene, condensation product obtains product (II), (III), (V) and (VI) with sodium borohydride reduction respectively again.
Concrete preparation comprises the steps:
1), (I) and (IV) synthetic
With 1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) ethyl ketone, substituted benzaldehyde, 0.5mL hexahydropyridine and 40mL toluene are loaded onto water trap, reflux condensing tube, reflux 6h under nitrogen protection.After cold slightly, use the saturated common salt water washing, chloroform (20mL * 3) extraction also merges organic layer, and anhydrous sodium sulfate drying concentrates after silica gel column chromatography separates purifies, faint yellow solid (I) and (IV);
2), (II), (III), (V) and (VI) synthetic
Be dissolved in the methyl alcohol with (I) with (IV) respectively, the methanol solution with sodium borohydride under stirring slowly is added drop-wise in the reaction system, and temperature of reaction is 25 ℃, and system is become colorless by yellow.React after 30 minutes, add dilute hydrochloric acid system is transferred to neutrality, pressure reducing and steaming methyl alcohol.Chloroform (20mL * 3) extraction merges organic phase, and anhydrous sodium sulfate drying concentrates after silica gel column chromatography separates purifies, white solid (II), (III), (V) and (VI);
3), (I), (II) and (III) hydrochloride synthetic
Be dissolved in the ether with (I), (II) with (III) respectively, slow dripping hydrochloric acid is not till having white solid and generating.Filter after drying and get white solid (I), (II) and hydrochloride (III).
Reaction formula is:
R is hydrogen atom, halogen atom, dimethylamino, nitro, alkoxyl group, replacement aralkoxy or aldehyde radical in the formula; X is hydroxide ion, chlorion or bromide anion.
The present invention adopts said synthesis route and method, obtains the simple synthetic method of target compound of the present invention, and raw material is easy to get, and cost is lower.
Adopt above-mentioned triazole derivative or its pharmacy acceptable salt can prepare the antimicrobial acivity pharmaceutical composition, this pharmaceutical composition contains triazole derivative or its pharmacy acceptable salt of physiology significant quantity, and their consumption weight ratios in composition are 0.1%～90%.
The compounds of this invention or its pharmacy acceptable salt form of administration can be pharmaceutically acceptable preparations such as tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment or liniment.
Above-mentioned triazole derivative or its pharmacy acceptable salt can be used on the preparation antimicrobial acivity, especially in antibacterium and the antifungal medicament.
Embodiment
Below by some embodiments are described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1:(E)-3-(4-chloro-phenyl-)-1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl)-2-propylene-1-ketone (be called for short compound 1a) and (Z)-3-(4-chloro-phenyl-)-1-(2, the 4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-preparation of 2-propylene-1-ketone (being called for short compound 1b)
In the 100mL three-necked bottle, add 2.23g (0.01mol) 1-(2,4 difluorobenzene base)-2-(1H-1,2; the 4-triazol-1-yl) ethyl ketone, 4-chlorobenzaldehyde 1.41g (0.01mol), 0.5mL hexahydropyridine and 40mL toluene; load onto water trap, reflux condensing tube, reflux 6h under nitrogen protection.After cold slightly, use the saturated common salt water washing, tell organic phase.Water extracts with chloroform (20mL * 3), merges organic phase, uses anhydrous magnesium sulfate drying, concentrates after the silica gel column chromatography separation is purified, and gets faint yellow solid 2.61g, is compound 1a, productive rate: 75.4%; Fusing point: 102～104 ℃; Also obtain another faint yellow solid 0.45g simultaneously, be compound 1b, productive rate: 13.0%; Fusing point:〉270 ℃.(E)-and the spectral data of 1a: UV-vis (CH
3OH) λ
Max: 204,309nm; IR (KBr): 3033.2 (Ar-H ,=C-H), 1662.5 (C=O), 1636.3,1611.6,1499.6 (aromatic ring frame, C=C), 820.3 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.11 (s, 2H, triazole-H), 6.80～7.76 (m, 8H, Ar-H, C=CH) ppm;
13C NMR (300MHz, CDCl
3) δ: 186.8 (C=O), 163.6,162.2,158.8,152.9,145.2,140.9,138.0,133.4,132.3,131.5,131.1,129.5,129.3,121.8,112.6,105.2 (Ar-C, triazole-C, C=CH) ppm; MS (m/z): 346[M]
+. (Z)-and the spectral data of 1b: UV-vis (CH3OH) λ
Max: 204,255nm; IR (KBr): 3118.5 (Ar-H ,=C-H), 1675.3 (C=O), 1642.1,1609.6,1493.3 (aromatic ring frame, C=C), 838.1 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.06 (s, 1H, triazole 3H), 7.95 (s, 1H, triazole5-H), 6.55～7.59 (m, 8H, Ar-H, C=CH) ppm;
13C NMR (300MHz, CDCl
3) δ: 185.2 (C=O), 162.6,161.1,157.6,151.9,144.3,140.0,137.5,132.8,131.8,130.7,130.4,129.0,128.3,120.8,111.8,105.3 (Ar-C, triazole-C, C=CH) ppm; MS (m/z): 346[M]
+.
Embodiment 2: hydroxide (E)-1-[3-(3, the 4-dichlorophenyl)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) allyl group] preparation of piperidines (be called for short compound 2)
The synthetic preparation method of compound 2 according to compound 1, starting raw material is 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone 2.23g (0.01mol), 3,4-dichlorobenzaldehyde 1.75g (0.01mol), getting product is faint yellow solid 2.52g, is compound 2, productive rate: 65.8%; M.p.141～143 ℃; UV-vis (CH
3OH) λ
Max: 205,296nm; IR (KBr): 3121.3 (Ar-H ,=C-H), 1603.8,1498.6,1427.3 (aromatic ring frame, C=C), 842.8 (=C-H) cm
-1 1HNMR (300MHz, CDCl
3) δ: 8.06 (d, 1H, triazole3-H), 8.04 (d, 1H, triazole5-H), 6.60～7.40 (m, 7H, Ar-H, C=CH), 2.88～2.90 (piperidine 2 for t, 4H, and 6-H) 1.50～1.72 (piperidine 3,4,5-H) ppm for m, 6H;
13C NMR (300MHz, CDCl
3) δ: 192.1 (C=N
+-), 167.1,163.7,154.4,152.5,145.2,136.9,135.4,133.9,132.5,132.3., 131.9,131.1,128.5,127.1,109.4,105.8 (C=CH), 54.0 (piperidine 2 for Ar-C, triazole-C, 6-C), 25.9 (piperidine 3,5-C), and 23.8 (piperidine 4-C) ppm; MS (m/z): 445[M-OH]
+.
Embodiment 3:(E)-preparation of 3-(4-p-methoxy-phenyl)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl)-2-propylene-1-ketone (be called for short compound 3)
The synthetic preparation method of compound 3 according to compound 1, starting raw material is 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone 2.23g (0.01mol), aubepine 1.36g (0.01mol), getting product is faint yellow solid 2.60g, be compound 3, productive rate: 76.8%; M.p.144～145 ℃; UV-vis (CH
3OH) λ
Max: 343nm; IR (KBr): 3055.8 (Ar-H ,=C-H), 2966.1,2839.5 (CH
3), 1660.5 (C=O), 1606.1,1507.3,1460.2 (aromatic ring frame, C=C), 833.4 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.10 (d, 2H, triazole-H), 6.74～7.57 (m, 8H, Ar-H, C=CH), 3.73 (s, 3H, OCH
3) ppm;
13C NMR (300MHz, CDCl
3) δ: 187.1 (C=O), 163.3,162.8,158.7,153.0,145.3,142.8,133.3,132.9,131.9,131.0,123.3,122.4,114.8,114.1,112.4,104.8 (Ar-C, triazole-C, C=CH), 55.5 (OCH
3) ppm; MS (m/z): 342[M]
+, 366[M+Na]
+
Embodiment 4:4-(2,4-dichlorobenzene p-methoxy-phenyl)-preparation of 3-methoxybenzaldehyde (be called for short compound 4) adds 1.52g (10mmol) Vanillin in the 100mL three-necked bottle, 2.4-dichlorobenzyl chloride 1.95g (10mmol), 0.67g (12mmol) potassium hydroxide, and 40mL dehydrated alcohol, 50 ℃ of reaction 4h, the adularescent solid generates.Behind the most of ethanol of pressure reducing and steaming, the chloroform dissolving washes (30mL * 3) with water, and water extracts with chloroform (20mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, concentrate after silica gel column chromatography separates purification, get white solid 2.40g, be compound 4, productive rate: 76.4%; M.p.112～114 ℃; UV-vis (CH
3OH) λ
Max: 226,272nm; IR (KBr): 2907.7,2833.6 (CH
3), 2720.5 (CHO), 1689.4 (C=O), 1591.3,1512.3,1472.1,1453.3,1428.3 (aromatic ring frame, C=C) cm
-1 1H NMR (300MHz, CDCl
3) δ: 10.07 (s, 1H ,-CHO), 6.87～7.77 (m, 6H, Ar-H), 5.22 (s, 2H, CH2), 3.90 (s, 3H, OCH
3) ppm;
13C NMR (300MHz, CDCl
3) δ: 190.8 (C=O), 153.1,150.3,134.5,133.1,132.6,130.9,129.5,127.6,126.5,112.6,112.5,109.8 (Ar-C), 67.5 (OCH
2-), 56.2 (OCH
3) ppm; MS (m/z): 311[M]
+, 275[M-Cl]
+.
Embodiment 5:(E)-3-[4-(2,4-dichlorobenzene p-methoxy-phenyl)-the 3-p-methoxy-phenyl]-1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl)-2-propylene-1-ketone (being called for short compound 5a) and hydroxide (E)-1-3-[4-(2,4 dichloro benzene p-methoxy-phenyl)-3-p-methoxy-phenyl]-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) preparation of allyl group piperidines (being called for short compound 5b)
The synthetic preparation method of compound 5a and 5b according to compound 1, starting raw material is 1-(2,4 difluorobenzene base)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone 1.15g (5mmol), compound 41.55g (5mmol), product be a faint yellow solid, i.e. compound 5a0.80g, productive rate: 31.0%; M.p.173～174 ℃; Also obtain another yellow solid simultaneously, i.e. compound 5b1.21g, productive rate: 40.2%; M.p.77～79 ℃. the spectral data of compound 5a: UV-vis (CH
3OH) λ
Max: 204,358nm; IR (KBr): 3104.9 (Ar-H ,=C-H), 3065.4 (Ar-H ,=C-H), 2930.3 (OCH
2-H, OCH-H), 2850.3 (OCH
2-H, OCH-H), 1668.7 (C=O), 1590.1,1510.8,1472.1,1454.9 (aromatic ring frame, C=C), 812.5 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.13 (d, 2H, triazole-H), 6.60～7.58 (m, 9H, Ar-H), 6.06 (s, 1H, C=CH), 5.13 (s, 2H, CH
2), 3.57 (s, 3H, OCH
3) ppm;
13C NMR (300MHz, CDCl
3) δ: 187.1 (C=O), 163.5,158.7,153.0,151.2,149.8,145.6,142.7,134.5,133.0,132.5,132.2,132.1,129.5,129.3,127.5,126.5,124.4,122.3,113.2,112.6,112.0,104.9 (Ar-C, triazole-C, C=CH), 67.4 (OCH
2-), 55.8 (OCH
3) ppm; MS (m/z): 516[M]
+, 538[M+Na]
+. the spectral data of compound 5b: UV-vis (CH
3OH) λ
Max: 204,353nm; IR (KBr) v:2936.5 (CH
2-H, CH-H), 2852.5 (CH
2-H, CH-H), 1653.4 (C=NH), 1628.2,1596.8,1513.2,1464.4,1422.8 (aromatic ring frame, C=C);
1H NMR (300MHz, CDCl
3) δ: 8.06 (triazole 3 for d, 2H, 5-H), 6.56～7.44 (m, 9H, Ar-H), 6.03 (d, 1H, C=CH), 5.11 (s, 2H, OCH
2), 3.55 (s, 3H, OCH
3), 2.85 (piperidine 2 for m, 4H, 6-H), 1.42 (piperidine 3 for m, 4H, 5-H), and 1.21 (m, 2H, piperidine 4-H); MS (m/z): 581[M-OH]
+, 603[M+Na]
+.
Embodiment 6: hydroxide (E)-1-[3-(4-aldehyde radical phenyl)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) allyl group] preparation of piperidines (be called for short compound 6)
The synthetic preparation method of compound 6 according to compound 1, starting raw material is 1-(2,4 difluorobenzene base)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone 2.23g (0.01mol), to two phenyl aldehyde 1.34g (0.01mol), get yellow solid 1.60g, promptly compound 6, productive rate: 40%; M.p.178～179 ℃;
1H NMR (300MHz, CDCl
3) δ: 9.91 (s, 1H, CHO), 8.06 (d, 2H, triazole-H), 7.35 (m, 7H, Ar-H), 6.81 (m, 1H, C=CH), 1.71 (m, 10H, piperidine-H) ppm; MS (m/z): 405[M]
+.
Embodiment 7:(E)-preparation of 3-(4-chloro-phenyl-)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl)-2-propylene-1-alcohol (be called for short compound 7)
Add 0.69g (2mmol) compound 1 in the 50mL three-necked bottle, add the 20mL dissolve with methanol, under the room temperature sodium borohydride 0.08g (2mmol) is added drop-wise in the reaction system after with the 5mL dissolve with methanol, system is become colorless by yellow.React after 30 minutes, add a small amount of dilute hydrochloric acid system is transferred to neutrality, pressure reducing and steaming methyl alcohol.Add 30mL water, fully stir, the adularescent solid generates.Add chloroform (20mL * 3) and extract, merge organic phase, use anhydrous magnesium sulfate drying, concentrate after silica gel column chromatography separates purification, get white solid 0.49g, promptly compound 7, productive rate: 70.1%; M.p.102～104 ℃; UV-vis (CH
3OH) λ
Max: 258nm; IR (KBr): 3203.5 (O-H), 3102.7 (Ar-H ,=C-H), 2890.5 (CH), 1618.7,1505.3,1432.2 (aromatic ring frame, C=C), 843.5 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.00 (s, 1H, triazole 3-H), 7.57 (s, 1H, triazole 5-H), 6.47～7.31 (m, 7H, Ar-H), 5.82 (d, 1H, C=CH), 3.80 (d, 1H, CH-OH) ppm;
13C NMR (300MHz, CDCl
3) δ: 164.5,158.2,152.5,144.4,135.9,135.1,130.8,129.7,129.2,128.9,128.8,126.5,122.6,111.9,104.0 (Ar-C, triazole-C, C=CH), 69.5 (CH-OH) ppm; MS (m/z): 348[M]
+.
Embodiment 8: the preparation of chlorination 1-3-(3, the 4-dichlorophenyl)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl) propyl group piperidines (being called for short compound 8)
The synthetic preparation method of compound 8 according to compound 7, starting raw material is compound 20.38g (1mmol), sodium borohydride 0.04g (1mmol), getting product is white solid 0.31g, promptly compound 8, productive rate: 80.0%; M.p.158～159 ℃; UV-vis (CH
3OH) λ
Max: 209nm; IR (KBr): 3202.5 (O-H), 3112.7 (Ar-H ,=C-H), 1607.9,1502.3,1470.5,1442.1 (aromatic ring frame, C=C) cm
-1 1H NMR (300MHz, CDCl
3) δ: 7.97 (s, 1H, triazole 3-H), 7.50 (s, 1H, triazole 5-H), 6.52～7.23 (m, 6H, Ar-H), 5.17 (s, 1H, 2,4-F
2PhCH), 4.57 (m, 1H, 2,4-F
2PhCHCH), 3.21～3.36 (m, 2H, 3,4-Cl
2PhCH
2), 2.80～2.90 (m, 4, piperidine2,6-H), 1.64～1.71 (piperidine 3,4,5-H) ppm for m, 6H;
13C NMR (300MHz, CDCl
3) δ: 164.6,161.3,153.3,152.2,143.4,138.2,132.7,131.0,130.6., 130.4,129.5,129.3,128.0,112.8,110.1 (Ar-C, triazole-C), 74.9 (2,4-F
2PhCH), 67.9 (2,4-F
2PhCHCH), 55.2 (piperidine 2,6-C), 34.77 (3,4-Cl
2PhCH
2), 26.7 (piperidine 3,5-C), and 23.8 (piperidine 4-C) ppm MS (m/z): 449[M-Cl]
+.
Embodiment 9:(E)-3-(4-p-methoxy-phenyl)-1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl)-2-propylene-1-alcohol (being called for short compound 9a) and 1-(2, the 4-difluorophenyl)-3-(4-p-methoxy-phenyl)-2-(1H-1,2,4-triazol-1-yl)-preparation of 1-propyl alcohol (being called for short compound 9b)
The synthetic preparation method of compound 9a-b according to compound 7, starting raw material is compound 3 1.71g (5mmol), sodium borohydride 0.19g (5mmol), product be white solid 1.24g, be compound 9a, m.p.82～84 ℃; Productive rate: 72.1%, simultaneously must white solid 0.45g, be compound 9b, m.p.158～159 ℃; Productive rate: 26.1%.The spectral data of product 9a: UV-vis (CH
3OH) λ
Max: 272nm; IR (KBr): 3200.3 (O-H), 3102.2 (Ar-H ,=C-H), 2935.7 (CH
3, CH), 1620.2,1506.7,1432.8,1420.3 (aromatic ring frame, C=C), 843.7 (=C-H) cm
-1 1H-NMR (CDCl
3, 300MHz) δ: 8.01 (s, 1H, triazole 3-H), 7.59 (s, 1H, triazole 5-H), 6.48～7.44 (m, 7H, Ar-H), 5.80 (s, 1H, C=CH), 3.96 (m, 1H, CH-OH), 3.68 (s, 4H, OCH
3, OH) (ppm);
13C
NMR (300MHz, CDCl
3) δ: 161.6,160.2,158.3,152.3,144.5,133.3,130.1,128.8,127.9,124.7,123.3,114.4,111.8,103.9 (Ar-C, triazole-C, C=CH), 69.6 (CH-OH), 55.3 (OCH
3) ppm; MS (m/z): 344[M]
+. the spectral data of product 9b: UV-vis (CH
3OH) λ
Max: 204,226nm; IR (KBr) v:3200.3 (O-H), 3108.8 (Ar-H ,=C-H), 2925.7 (CH, CH
2), 1620.2,1506.7,1445.0,1435.0 (aromatic ring frame) cm
-1 1H NMR (300MHz, CDCl
3) δ: 7.88 (s, 1H, triazole 3-H), 7.39 (s, 1H, triazole 5-H), 6.64～7.02 (m, 7H, Ar-H), 5.30 (m, 1H, CH-OH), 4.51 (m, 1H, CH-CHOH), 4.22 (d, 1H, OH), 3.68 (s, 3H, OCH
3), 3.10～3.35 (m, 2H, CH2) ppm; MS (m/z): 346[M]
+.
Embodiment 10:(E)-preparation of 3-(4-(2,4 dichloro benzene p-methoxy-phenyl)-3-p-methoxy-phenyl)-1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazol-1-yl)-2-propylene-1-alcohol hydrochloride (be called for short compound 10)
The synthetic preparation method of compound 10 according to compound 7, starting raw material is compound 5a 0.52g (1mmol), sodium borohydride 0.04g (1mmol), the solvent tetrahydrofuran (THF), getting product is white solid 0.42g.White solid is dissolved in the ether, and slow dripping hydrochloric acid solution till not having white precipitate and generating, filters after drying then and gets white solid, is compound 10, productive rate: 81.0%; M.p.133～135 ℃; UV-vis (CH
3OH) λ
Max: 206,271nm; IR (KBr): 3323.8 (O-H), 3116.4 (Ar-H ,=C-H), 2906.9,2840.5 (CH, CH
2, CH
3), 1606.8,1514.2,1450.4,1425.5 (aromatic ring frame, C=C), 814.6 (=C-H) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.03 (s, 1H, triazole 3-H), 7.63 (s, 1H, triazole 5-H), 6.40～7.37 (m, 9H, Ar-H), 6.07 (d, 1H, C=CH), 5.80 (d, 1H, CH-OH), 5.07 (s, 2H, CH
2), 3.74 (d, 1H, CH-OH), 3.55 (s, 3H, OCH
3) ppm;
13C NMR (300MHz, CDCl
3) δ: 161.6,158.3,152.5,149.7,148.5,144.8,134.2,133.6,133.1,133.0,129.5,129.2,128.8,128.1,127.5,125.9,122.9,122.5,113.8,111.6,111.2,104.0 (Ar-C, triazole-C, C=CH), 69.9 (CHOH), 67.5 (CH
2), 55.7 (OCH
3) ppm; MS (m/z): 520[M]
+.
Embodiment 11:(E)-chlorination 1-{3-[4-(2,4-dichlorobenzene p-methoxy-phenyl)-the 3-p-methoxy-phenyl]-1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) allyl group } piperidines (being called for short compound 11a) and chlorination 1-{3-[4-(2,4 dichloro benzene p-methoxy-phenyl)-3-p-methoxy-phenyl]-1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) propyl group } piperidines (abbreviation compound 11b-1, preparation 11b-2)
The synthetic preparation method of compound 11a-b according to compound 7, starting raw material is compound 5b0.90g (1.5mmol), sodium borohydride 0.06g (1.5mmol), getting product is that three kinds of white solids are respectively: compound 11a, 0.08g, productive rate: 8.7%; M.p.78～80 ℃; Compound 11b-1,0.28g, productive rate: 30.7%; M.p.71～73 ℃; Compound 11b-2,0.37g, productive rate: 40.0%; M.p.70～72 ℃. the spectral data of product 11a: UV-vis (CH
3OH) λ
Max: 205,269nm; IR (KBr): 3257.4 (N-H), 2936.9,2853.4 (CH
3, CH
2), 1590.6,1514.6,1454.8,1420.2 (aromatic ring frame, C=C) cm
-1 1H NMR (300MHz, CDCl
3) δ: 8.01 (s, 1H, triazole 3-H), 7.66 (s, 1H, triazole 5-H), 6.43～7.37 (m, 9H, Ar-H), 6.00 (d, 1H, C=CH), 5.72 (d, 1H, 2,4-F
2PhCH), 5.07 (s, 2H, OCH
2), 3.55 (s, 3H, OCH
3), 2.72 (piperidine 2 for m, 4H, 6-H), 1.68 (m, 4H, piperidine3,5-H), 1.53 (m, 2H, piperidine 4-H) ppm; MS (m/z): 583[M-Cl]
+, 607[M+Na]
+. the spectral data of product 11b-1: UV-vis (CH
3OH) λ
Max: 205nm; IR (KBr) v:3237.4 (N-H), 2936.5,2851.5 (CH
3, CH
2), 1591.2,1512.6,1469.8,1420.3 (aromatic ring frame, C=C) cm
-1 1H NMR (300MHz, CDCl
3) δ: 7.91 (s, 1H, triazole 3-H), 7.40 (s, 1H, triazole 5-H), 6.24～7.38 (m, 9H, Ar-H), 5.13 (t, 1H, 2,4-F
2PhCH), 5.02 (s, 2H, OCH
2), 5.02 (m, 1H, 2,4-F
2PhCHCH), 3.61 (s, 3H, OCH
3), 3.18 (q, 2H, 2,4-F
2PhCHCHCH
2), 2.50～2.83 (piperidine 2 for m, 4H, 6-H), 1.63 (piperidine 3 for m, 4H, 5-H), and 1.58 (m, 2H, piperidine 4-H) ppm; MS (m/z): 585[M-Cl]
+, 607[M+Na]
+. the spectral data of product 11b-2: UV-vis (CH
3OH) λ
Max: 208nm; IR (KBr): 3408.4 (N-H), 2935.7,2851.5 (CH
3, CH
2), 1591.9,1510.8,1454.0,1420.3 (aromatic ring frame, C=C) cm
-1 1H NMR (300MHz, CDCl
3) δ: 7.81 (s, 1H, triazole 3-H), 7.57 (s, 1H, triazole 5-H), 6.12～7.42 (m, 9H, Ar-H), 5.21 (t, 1H, 2,4-F
2PhCH), 5.06 (s, 2H, OCH
2), 4.67 (m, 1H, 2,4-F
2PhCHCH), 3.71 (s, 3H, OCH
3), 3.23 (m, 2H, 2,4-F
2PhCHCH CH
2), 2.58 (m, 4, piperidine 2, and 6-H), 1.53～1.65 (piperidine 3,4,5-H) ppm for m, 6H; MS (m/z): 585[M-Cl]
+, 607[M+Na]
+.
Embodiment 12: external antibacterium, anti-mycotic activity experiment
Test method:
The drug sensitive experiment method that the antimicrobial acivity test is adopted is the 96 hole micro-dilution methods that the American National laboratory standard council (NCCLS) is recommended.With methyl-sulphoxide (DMSO) sample dissolution, water (DMSO/H
2O 60%) to be assigned to concentration be 1mg/mL in dilution, is diluted to 256 μ g/mL with the RPMI1640 nutrient solution again, makes nutrient solution with RPMI1640, in 35 ℃ of cultivations 24～72 hours.Survey each hole OD value with enzyme micro-plate reader respectively at 492 (bacteriums) and 620nm (fungi).With the positive control boring ratio, be MIC with the drug level in the minimum concentration hole of OD value decline more than 80%
80(concentration when fungi or bacterial growth 80% is suppressed).MIC when medicine
80Value surpasses when measuring concentration range, adds up by the following method: MIC
80When value is higher than maximum concentration 64 μ g/mL, be designated as "〉64 μ g/mL "; MIC
80Value is designated as "＜0.125 μ g/mL " for minimum concentration or when minimum concentration is following.
Test-results:
Preliminary antibacterium, antimycotic activity of compound 1～11 the results are shown in Table 1.
The antimicrobial acivity data of table 1 compound 1～11
Table?1?The?data?of?antimicrobial?activities?of?compounds?1～11
Annotate: S.aureus is a streptococcus aureus; E.coli is intestinal bacteria; C.albicans is a Candida albicans
1～11 pair of fungi of compound has good active, and compound 2,3,5a, 7,8,9a, 9b and 10 pairs of Candida albicans anti-microbial effects are remarkable, and wherein the activity of compound 3 and 5a and fluconazole are suitable, and triazole enol 9a and 10 activity are better than fluconazole.Part of compounds shows significant antibacterial activity, and wherein compound 1a, 2 and 7 pairs of streptococcus aureuses have better restraining effect, and compound 2,5a and 7 pairs of intestinal bacteria have good inhibitory effect.
Embodiment 13: the preparation method of institute's invention compound 7 tablets
Prescription:
Method for making: preparation 4% is through propyl methocel (E-30) solution, and is standby.Taking by weighing 10g starch, to put 105 ℃ of dryings 5 hours standby.Take by weighing institute's invention compound 7, the Microcrystalline Cellulose of 20g starch and recipe quantity, mixing was pulverized 80 mesh sieves.With 4% through propyl methocel (E-30) solution with material system softwood, granulate with 20 mesh sieves, in 50 ℃～60 ℃ moisture content about 3% that are dried in the particle.Cross the whole grain of 20 mesh sieves, add dry starch (105 ℃ drying 5 hours), the Magnesium Stearate of recipe quantity, mix eventually, survey intermediate content, stator is heavy; Compressing tablet.
Embodiment 14: the preparation method of institute's invention compound 7 injection liquids
Prescription:
Method for making: take by weighing the institute's invention compound 7 and the propylene glycol of recipe quantity, add injection water 500ml, stirring and dissolving; Add 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, filter through the millipore filtration essence of 0.45 micron of filter cartridge and 0.22 micron again; Embedding is in the 10ml ampoule, and 100 ℃ of flowing steams were sterilized 45 minutes, promptly got institute's invention compound 7 injection liquids.
Claims (8)
1, a kind of as shown in the formula (I), (II) or triazole class compounds or their pharmacy acceptable salts (III), the structure that it is characterized in that compound as shown in the formula:
R is hydrogen atom, halogen atom, dimethylamino, nitro, alkoxyl group, replacement aralkoxy or aldehyde radical in the formula.
2, a kind of as shown in the formula (IV), (V) or the piperidine derivative of the triazole (VI), the structure that it is characterized in that compound as shown in the formula:
R is hydrogen atom, halogen atom, dimethylamino, nitro, alkoxyl group, replacement aralkoxy or aldehyde radical in the formula; X is hydroxide ion, chlorion or bromide anion.
3, the described triazole class compounds of claim 1 or its are at pharmacy acceptable salt, and it is characterized in that: these salt are inorganic acid salt.
4, the described triazole class compounds of claim 1 or its are at pharmacy acceptable salt, and it is characterized in that: these mineral acids are hydrochloric acid or nitric acid.
5, the preparation method of claim 1 or 2 described compounds, adopt 1-(2, the 4-difluorophenyl)-2-(1H-1,2, the 4-triazol-1-yl) ethyl ketone is a raw material, with replace aromatic aldehyde, hexahydropyridine heating reflux reaction 6h in toluene, under the nitrogen protection, the product chloroform extraction obtains product (I) and (IV) through column chromatography; Condensation product (I) and (IV) in methyl alcohol, react 3h with sodium borohydride at ambient temperature respectively, the adjusting pH value is 6-7, uses chloroform extraction after boiling off solvent, drying obtains product (II), (III), (V) and (VI) after concentrating.
6, claim 1 or 2 described preparation methods, described aromatic aldehyde is the aromatic aldehyde that halogen atom, dimethylamino, nitro, alkoxyl group, replacement aralkoxy or aldehyde radical replace.
7, the pharmaceutical composition of the described triazole class compounds of claim 1 or their pharmacy acceptable salts, this pharmaceutical composition contains triazole class compounds or their pharmaceutically acceptable carriers of physiology significant quantity, and triazole class compounds and the consumption weight ratio of their pharmaceutically acceptable carriers in composition are 0.1%-90%; Composition exists with following pharmaceutically acceptable dosage form: tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment or liniment.
8, claim 1 or 2 described triazole class compounds or their pharmacy acceptable salts are used to prepare the purposes of antibacterium, antifungal drug.
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