CN108329304A - A kind of preparation method of Itraconazole derivative - Google Patents
A kind of preparation method of Itraconazole derivative Download PDFInfo
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- CN108329304A CN108329304A CN201810305224.1A CN201810305224A CN108329304A CN 108329304 A CN108329304 A CN 108329304A CN 201810305224 A CN201810305224 A CN 201810305224A CN 108329304 A CN108329304 A CN 108329304A
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- 0 *c(cc1)ccc1NCCNc(cc1)ccc1OC[C@@]1O[C@@](C[n]2ncnc2)(C(CC(Cl)=C2)=CC=C2Cl)OC1 Chemical compound *c(cc1)ccc1NCCNc(cc1)ccc1OC[C@@]1O[C@@](C[n]2ncnc2)(C(CC(Cl)=C2)=CC=C2Cl)OC1 0.000 description 1
- DOTMNIKVSPPEKQ-GEVKEYJPSA-N CC1(/C=[O]/c(cc2)ccc2N(CC2)CCN2C(C)=O)O[C@@](C[n]2ncnc2)(c(c(C)c2)ccc2Cl)OC1 Chemical compound CC1(/C=[O]/c(cc2)ccc2N(CC2)CCN2C(C)=O)O[C@@](C[n]2ncnc2)(c(c(C)c2)ccc2Cl)OC1 DOTMNIKVSPPEKQ-GEVKEYJPSA-N 0.000 description 1
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Abstract
The invention discloses a kind of preparation method of Itraconazole derivative, the present invention, by six-step process, realizes the synthesis of Itraconazole derivative using 1 acetyl 4 (4 hydroxy phenyl) piperazine as raw material.Preparation method provided by the invention, technological design is reasonable, and operability is strong, and reaction condition is milder, and yield height is, it can be achieved that industrialized production.The Itraconazole derivative that the present invention is prepared, important evidence can be provided for Itraconazole quality, safety and efficiency scientific evaluation, and Itraconazole derivative pharmacological activity is good, the drug of fungal infection caused by can developing for treating a variety of causes, has important application value.
Description
Technical field
The present invention relates to a kind of preparation methods of compound, specifically design a kind of preparation method of Itraconazole derivative.
Technical background
Itraconazole is a kind of broad-spectrum antifungal medicine of synthesis, is triazole derivatives, was invented in 1984, this medicine can
To take orally, can also be injected intravenously.It is [new to dermatophyte (trichophyton, Microsporon, acrothesium floccosum), saccharomycete
Raw cryptococcus, Pityrosporum, Mycotoruloides (including Candida albicans, Candida glabrata and candida krusei), Aspergillus
Category, Histoplasma, Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea, Cladosporium, Blastomyces dermatitidis with
And various other saccharomycete and fungal infection is effective.In vitro study has proven to the main ingredient that the product can inhibit fungal cell membrane
One of ergosterol synthesis, to play antifungal effect.
It is the essential drugs inventory of the World Health Organization, is most important drug in basic health department.With Fluconazole
It compares, the field of activity of Itraconazole is wider.It can be additionally used in capsule bacterium disease, spore mildew, histoplasmosis and first ringworm
Using.Itraconazole is more than 99% protein, almost without penetrating into cerebrospinal fluid.Therefore, it should not be used to treat brain
Film inflammation or other central nervous system infections.It is also used for systemic infection, such as aspergillosis, candidiasis and cryptococcus
Disease.Have been reported that Itraconazole can also be used to treat basal-cell carcinoma, non-small cell lung cancer and prostate cancer.
With the progress in epoch, the raising of scientific and technological level, people to drug before marketing drugs to that must carry out quality, safety
Property and the importance etc. of efficiency scientific evaluation, which have, more fully to be recognized, wherein with drug quality it is closely related be drug institute
Control containing derivative.Derivative is often related with drug safety, and also related with efficiency in a few cases.Therefore, it controls
The level of derivative processed is increasingly paid attention to by medical personal during drug development.
The synthetic method of Itraconazole derivative provided by the invention, there is not been reported, is carried out to Itraconazole derivative
Relevant pharmacology, pharmacokinetic study, Itraconazole derivative may also have better prospect in medicine.
Invention content
Goal of the invention：It is an object of the present invention to solve the deficiency of the existing technology and provide a kind of technological design is reasonable, production
Rate is high, and operating process facilitates the synthetic method of controllable newtype drug molecule Itraconazole derivative.
Technical solution：In order to achieve the goal above, the technical solution that the present invention takes is：
A kind of preparation method of Itraconazole derivative, includes the following steps：
(1) it takes 1- acetyl -4- (4- hydroxy phenyls) piperazine I to be dissolved in polar non-solute, alkali is added, then additionization
Object X is closed, compound ii is obtained by the reaction in heating stirring；
(2) it takes compound ii to be dissolved in organic solvent, alkali, heating stirring reaction is added, then obtain through recrystallizing purification ＆ isolation
To compound III；
(3) it takes compound III to be dissolved in polar non-solute, under ice bath, is added to nitro halogeno-benzene and inorganic base,
Compounds Ⅳ is obtained by the reaction；
(4) it takes compounds Ⅳ to be dissolved in organic solvent, reducing agent is added and restores to obtain compound V；
(5) it takes compound V to be suspended in pyridine and triethylamine, under condition of ice bath, diformylhydrazine is added, reaction is overnight
Afterwards, cooling treatment, isolated compound VI；
(6) compound VI is suspended in organic solvent, sec-butyliodide back flow reaction is added, obtains compound VII, i.e.,
Itraconazole derivative.
Preferably, the preparation method of above-described Itraconazole derivative, includes the following steps：
(1) 1- acetyl -4- (4- hydroxy phenyls) piperazine I is taken to be dissolved in polar non-solute, after alkali is added, 0~20
Compound X is added under the conditions of degree, heating stirring 2 to 4 hours obtains compound ii；
(2) it takes compound ii to be dissolved in organic solvent, alkali is added, carried in 50-120 degree heating stirring 20h, then through recrystallization
Pure isolated compound III；
(3) it takes compound III to be dissolved in polar non-solute, under ice bath, is added to nitro halogeno-benzene and inorganic base,
110 degree are reacted 18 hours, and compounds Ⅳ is obtained；
(4) it takes compounds Ⅳ to be dissolved in organic solvent, compound V is obtained after reducing agent reduction is added；
(5) it takes compound V to be suspended in pyridine and triethylamine, under condition of ice bath, diformylhydrazine, 100 degree of reactions is added
After overnight, cooling treatment obtains compound VI through pillar layer separation；
(6) compound VI is suspended in organic solvent, sec-butyliodide back flow reaction is added after 20 hours, obtains chemical combination
Object VII, i.e. Itraconazole derivative.
The Itraconazole derivative that the present invention is prepared, chemical name are 4- (4- (4- (4- (((2R, 4S) -2- ((1H-
1,2,4- triazole -1- bases) methyl) -2- (2,4 dichloro benzene base) -1,3- dioxa -4- bases) methoxyl group) phenyl) piperazine -1-
Base) phenyl) -1- (sec-butyl) -1H-1,2,4- triazole -4- iodine molecule amounts are 817.55, molecular formula C35H39Cl2IN8O3,
Structural formula is as follows：
Preferably, the preparation method of above-described Itraconazole derivative, the non-matter of polarity described in step (1)
Sub- solvent is dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide or acetonitrile.
Preferably, the preparation method of above-described Itraconazole derivative, the alkali described in step (1) are hydrogenation
Sodium, sodium hydroxide or potassium hydroxide；Reaction time is 2 to 4 hours.
Preferably, the preparation method of above-described Itraconazole derivative, the organic solvent described in step (2)
For methanol, ethyl alcohol, isopropanol, tetrahydrofuran or acetone.
Preferably, the preparation method of above-described Itraconazole derivative, the alkali described in step (2) are hydrogen-oxygen
Change sodium or potassium hydroxide.
Preferably, the preparation method of above-described Itraconazole derivative, the non-matter of polarity described in step (3)
Sub- solvent is dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide or acetonitrile.
Preferably, the preparation method of above-described Itraconazole derivative, the inorganic base described in step (3) are
Potassium carbonate or cesium carbonate.
Preferably, the preparation method of above-described Itraconazole derivative, the organic solvent described in step (4)
For ethyl alcohol, methanol, isopropanol, tetrahydrofuran or ethyl acetate.
Preferably, the preparation method of above-described Itraconazole derivative, the reducing agent described in step (4) are
Iron powder, zinc powder, palladium carbon or stannous chloride.
Preferably, the preparation method of above-described Itraconazole derivative, the organic solvent described in step (6)
For acetonitrile, acetone or 2- butanone.
Preferably, the preparation method of above-described Itraconazole derivative, the compound X described in step (1)
For cis- methanesulfonic acids-[2- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yls methyl) -1,3- dioxolanes -4- bases]
Methyl esters.
Advantageous effect：The preparation method of Itraconazole derivative provided by the invention has the following advantages：
1. the synthetic method of newtype drug molecule Itraconazole derivative provided by the invention, technological design is reasonable, operation
Method is simple, raw material is easy to get, combined coefficient is high, and technique can amplify that production, purity is high, reaction process is controllable and environmental protection effect
It is good.
2. and the Itraconazole derivative that the present invention is prepared, can be quality, safety and the efficiency of Itraconazole
Scientific evaluation provides important evidence, and the drug of fungal infection caused by can also developing for treating a variety of causes has important
Application value.
Description of the drawings
Fig. 1 is the preparation technology flow chart of Itraconazole derivative provided by the invention.
Specific implementation mode
Embodiment below is that the present invention will be described in detail, but is not the limitation present invention.
Embodiment 1
As shown in Figure 1：The preparation method of Itraconazole derivative, specifically includes following steps：
(1) preparation of compound ii:
1- acetyl -4- (4- hydroxy phenyls) piperazine (chemical compounds I) (22.00g, 96mmol) is taken to be dissolved in dimethyl sulfoxide (DMSO)
In (500mL), the dimethyl sulphoxide solution of sodium hydroxide (2.5g) is added dropwise thereto under ice bath, finishes and continues to stir under ice bath
Compound X (30g) is added after mixing one hour thereto, finishes, rise to 90 degrees Celsius be stirred to react two hours after, cooling plus water is dilute
Be extracted with ethyl acetate after releasing, extract liquor concentrate after drying through silica gel column chromatography purification (eluent is methylene chloride-methanol,
Volume ratio 50:1) compound object II (35g), yield 89.0% are obtained.
Compound II's1H NMR(400MHz,CDCl3):δ 8.23 (s, 1H), δ 7.92 (s, 1H), δ 7.60~7.59 (d,
1H), δ 7.50 (d, 1H), δ 6.98~6.96 (d, 2H), δ 6.83~6.80 (d, 2H), δ 4.86~4.75 (dd, 2H), δ 4.52
(br, 2H), δ 4.38~4.35 (m, 1H), δ 3.94~3.92 (t, 1H), δ 3.90~3.80 (m, 2H), δ 3.52~3.50 (m,
1H), δ 3.50~3.40 (m, 4H), δ 3.30~3.25 (m, 4H), δ 2.10 (s, 3H) .MS:532.2[M-H]+。
(2) preparation of compound III:It takes compound ii (23g, 43mmol) to be suspended in methanol (350mL), is added
The NaOH solution of 230mL3N, 68 degree of reactions are extracted after water is added when being concentrated into 50mL after 20 hours with dichloromethane (500mLx 2)
It takes, organic phase merges, and after drying, concentration obtains 19g compound as white solid III, yield is after being beaten with n-hexane
89.7%.
Compound III1H NMR(400MHz,CDCl3):δ 8.21 (s, 1H), δ 7.90 (s, 1H), δ 7.59~7.57 (d,
1H), δ 7.48 (d, 1H), δ 6.96~6.94 (d, 2H), δ 6.82~6.80 (d, 2H), δ 4.86~4.75 (dd, 2H), δ 4.52
(br, 2H), δ 4.38~4.35 (m, 1H), δ 3.94~3.92 (t, 1H), δ 3.90~3.80 (m, 2H), δ 3.52~3.50 (m,
1H), δ 3.50~3.40 (m, 4H), δ 3.30~3.25 (m, 4H) .MS:490.2[M-H]+。
(3) preparation of compounds Ⅳ:Compound III (19g, 39mmol) is taken to be dissolved in dimethyl sulfoxide (DMSO) (190mL), in ice
Under the conditions of bath, parachloronitrobenzene (6.3g, 39mmol) is added, 110 degree of potassium carbonate (11g, 77mmol) is reacted 18 hours, is cooled to
It after room temperature, is poured into ice water and obtains light yellow suspension, 22g yellow solid chemical combination is obtained after vacuum drying is washed with water after suction filtration
Object IV, yield 92.8%.
Compounds Ⅳ1H NMR(400MHz,CDCl3):δ 8.25 (s, 1H), δ 7.90 (s, 1H), δ 7.59~7.57 (d,
1H), δ 7.48 (d, 1H), δ 7.29~7.25 (m, 2H), δ 7.08~7.05 (d, 2H), δ 6.96~6.94 (d, 2H), δ 6.82~
6.80 (d, 2H), δ 4.86~4.75 (dd, 2H), δ 4.38~4.35 (m, 1H), δ 3.94~3.92 (t, 1H), δ 3.90~
3.80 (m, 2H), δ 3.52~3.50 (m, 1H), δ 3.50~3.40 (m, 4H), δ 3.30~3.25 (m, 4H) .MS:611.2[M-
H]+。
(4) preparation of compound V:Compounds Ⅳ (11g, 18mmol) is taken to be suspended in ethyl alcohol (180mL) and water (40mL)
In, iron powder (11g) and ammonium chloride (4g) is added and is filtered while hot, it is light brown that filtrate obtains 11g after being spin-dried for after 110 degree are reacted 3 hours
Color solid chemical compound V, yield 100%.
Compound V1H NMR(400MHz,CDCl3):δ 8.24 (s, 1H), δ 7.90 (s, 1H), δ 7.59~7.57 (d,
1H), δ 7.48 (d, 1H), δ 7.29~7.25 (m, 2H), δ 7.08~7.05 (d, 2H), δ 6.96~6.94 (d, 2H), δ 6.82~
6.80 (d, 2H), δ 4.86~4.75 (dd, 2H), δ 4.52 (br, 2H), δ 4.38~4.35 (m, 1H), δ 3.94~3.92 (t,
1H), δ 3.90~3.80 (m, 2H), δ 3.52~3.50 (m, 1H), δ 3.50~3.40 (m, 4H), δ 3.30~3.25 (m, 4H)
.MS:581.2[M-H]+。
(5) preparation of compound VI:Compound V (7.5g, 13mmol) is taken to be suspended in pyridine (180mL) and triethylamine
In (45mL), under condition of ice bath, diformylhydrazine (3.43g, 39mmol) is added, 100 degree are reacted 22 hours, under ice bath cooling,
It after saturated salt solution is added, is extracted with ethyl acetate (300mLx 3), organic phase merges, and is 10 with volume ratio after drying:1
Dichloromethane：Methanol makees eluant, eluent, and pillar layer separation obtains 8.01g faint yellow solids compound VI, yield 97.9%.
Compound VI1H NMR(400MHz,CDCl3):δ8.40(s,2H),δ8.21(s,1H),δ7.90(s,1H),δ
7.59~7.57 (d, 1H), δ 7.48 (d, 1H), δ 7.29~7.25 (m, 2H), δ 7.08~7.05 (d, 2H), δ 6.96~6.94
(d, 2H), δ 6.82~6.80 (d, 2H), δ 4.86~4.75 (dd, 2H), δ 4.38~4.35 (m, 1H), δ 3.94~3.92 (t,
1H), δ 3.90~3.80 (m, 2H), δ 3.52~3.50 (m, 1H), δ 3.50~3.40 (m, 4H), δ 3.30~3.25 (m, 4H)
.MS:633.2[M-H]+。
(6) preparation of compound VII:Compound VI (3.6g, 6mmol) is taken to be suspended in acetonitrile (100mL), at room temperature,
Sec-butyliodide (2.5g, 12mmol) is added, 90 degree are reacted 24 hours, and light yellow suspension is formed.Reaction solution is cooled to room
Temperature filters, and methanol is washed, and off-white powder compound VII (99.77%HPLC), yield 91.0% are obtained after vacuum drying.
Compound VII1H NMR(400MHz,CDCl3):δ12.2(s,1H),δ8.54(s,1H),δ8.21(s,1H),δ
7.90(s,1H),δ7.75(d,2H),δ7.60(d,2H),δ7.48(s,1H),δ7.27(d,1H),δ7.10(d,2H),δ6.90
(d, 2H), δ 6.80 (d, 2H), δ 5.15~5.30 (m, 1H), δ 4.70~4.90 (dd, 2H), δ 4.30~4.40 (m, 1H), δ
3.80~4.0 (m, 3H), δ 3.4~3.60 (m, 6H), δ 3.21 (m, 4H), δ 2.0~2.2 (m, 2H), δ 1.74 (d, 3H), δ
0.98(t,3H).MS:689.2[M-H]+。
2 antimycotic experiment of embodiment
1, experimental method：
It is prepared by bacterium solution
Before experiment, after experimental bacteria is activated, on the weak agar medium in husky fort (SDA), 30 DEG C are cultivated 48 hours saccharomycete；
On potato dextrose agar (PDA) culture medium, 26 DEG C are cultivated 7-10 days filamentous fungi；It is made into sterile saline outstanding
Liquid is counted through blood counting chamber, with again amount containing 2% glucose RMPI-1640 fluid nutrient mediums be diluted to candida albicans 1.0 ×
103cfu/mL；Other filamentous fungis are made into 2.5 × 104cfu/mL.Bacterium solution 0.1mL, addition is taken to be prepared into containing embodiment 1 respectively
To compound VII culture medium to each hole in, 11 holes be Vehicle controls, 12 holes be culture medium control.Vehicle controls are added in hole
The distilled water of 0.1mL is added in control wells for solvent after the dilution of 0.1mL.It after sample-adding, is placed on rocker machine, rotating speed is
100r/min × 10min makes drug and bacterium solution come into full contact with.To contain 2% glucose RMPI-1640 liquid without any antibiotic
Body culture medium is as basic culture medium.
2, experimental result determination method
80% minimum inhibitory concentration (80%MIC)：It is grown to reference, medicine datum hole with blank control and Vehicle controls pore fungi
Middle bacterium only grows 80% and indicates bacteriostasis, and bacterium, which has grown, indicates no bacteriostasis.The results are shown in Table 1 for specific experiment：
1 Itraconazole derivative of table is to fungi 80%MIC measurement results
The experimental results showed that, the Itraconazole derivative that the method provided by the present invention is prepared has certain anti-by above
Antifungal effect.
Claims (12)
1. a kind of preparation method of Itraconazole derivative, which is characterized in that include the following steps：
(1) it takes 1- acetyl -4- (4- hydroxy phenyls) piperazine to be dissolved in polar non-solute, alkali is added, compound is then added
Compound ii is obtained by the reaction in X, heating stirring；
(2) it takes compound ii to be dissolved in organic solvent, alkali is added, heating stirring is reacted, then through recrystallizing purification ＆ isolation
Close object III；
(3) it takes compound III to be dissolved in polar non-solute, under ice bath, is added to nitro halogeno-benzene and inorganic base, reaction
Obtain compounds Ⅳ；
(4) it takes compounds Ⅳ to be dissolved in organic solvent, reducing agent is added and restores to obtain compound V；
(5) it takes compound V to be suspended in pyridine and triethylamine, under condition of ice bath, diformylhydrazine is added, it is after reaction overnight, cold
But it handles, isolated compound VI；
(6) compound VI is suspended in organic solvent, sec-butyliodide back flow reaction is added, obtains compound VII, i.e. Yi Qu
Health Zole derivatives.
2. the preparation method of Itraconazole derivative according to claim 1, which is characterized in that include the following steps：
(1) 1- acetyl -4- (4- hydroxy phenyls) piperazine is taken to be dissolved in polar non-solute, after alkali is added, in 0~20 degree of condition
Lower addition compound X, heating stirring 2 to 4 hours obtain compound ii；
(2) it takes compound ii to be dissolved in organic solvent, alkali is added, in 50-120 degree heating stirring 20h, then through recrystallization purification point
From obtaining compound III；
(3) it takes compound III to be dissolved in polar non-solute, under ice bath, is added to nitro halogeno-benzene and inorganic base, 110 degree
Reaction 18 hours, obtains compounds Ⅳ；
(4) it takes compounds Ⅳ to be dissolved in organic solvent, compound V is obtained after reducing agent reduction is added；
(5) it takes compound V to be suspended in pyridine and triethylamine, under condition of ice bath, diformylhydrazine is added, 100 degree of reactions are overnight
Afterwards, cooling treatment obtains compound VI through pillar layer separation；
(6) compound VI is suspended in organic solvent, sec-butyliodide back flow reaction is added after 20 hours, obtains compound
VII, i.e. Itraconazole derivative.
3. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that described in step (1)
Polar non-solute is dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide or acetonitrile；Alkali described in step (1) is
Sodium hydride, sodium hydroxide or potassium hydroxide.
4. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that 1- acetyl -4- (4-
Hydroxy phenyl) the mole dosage ratio of piperazine and compound X is 1:1~1:1.5, preferably 1:1.3.
5. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that described in step (2)
Organic solvent is methanol, ethyl alcohol, isopropanol, tetrahydrofuran or acetone.
6. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that described in step (2)
Alkali is sodium hydroxide or potassium hydroxide.
7. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that described in step (3)
Polar non-solute is dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide or acetonitrile；The inorganic base is carbonic acid
Potassium or cesium carbonate.
8. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that step (3) compound
III, it is 1 to the mole dosage ratio of nitro halogeno-benzene and inorganic base:1~1:3, preferably 1:2.
9. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that described in step (4)
Organic solvent is ethyl alcohol, methanol, isopropanol, tetrahydrofuran or ethyl acetate；The reducing agent be iron powder, zinc powder, palladium carbon or
Stannous chloride.
10. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that step (5) chemical combination
The mole dosage ratio of object V and diformylhydrazine is 1:1~1:5, preferably 1:3.
11. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that step (6) is described
Organic solvent be acetonitrile, acetone or 2- butanone；The mole dosage ratio of compound VI and sec-butyliodide is 1:1~1:3, preferably
It is 1:2.
12. the preparation method of Itraconazole derivative according to claim 1 or 2, which is characterized in that step (1) is described
Compound X be cis- methanesulfonic acids-[2- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yls methyl) -1,3- dioxies penta
Ring -4- bases] methyl esters.
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| CN111138421A (en) * | 2019-12-26 | 2020-05-12 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble compound and preparation method and application thereof |
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| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
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2018
- 2018-04-08 CN CN201810305224.1A patent/CN108329304B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
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| Title |
|---|
| ILA SIRCAR ET AL.: "Cardiotonic Agents. 2. Synthesis and Structure-Activity Relationships of 4,5-Dihydro-6-[4-( 1H-imidazol-l-yl)phenyl]-3(2H)-pyridazinones: A New Class of Positive Inotropic Agents"", 《J. MED. CHEM.》 * |
| J. HEERES ET AL.: "Antimycotic Azoles. 7. Synthesis and Antifungal Properties of a Series of Novel Triazol-3-ones", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111138421A (en) * | 2019-12-26 | 2020-05-12 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble compound and preparation method and application thereof |
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