CN102329326B - Pyrrole derivatives and preparation method and application thereof - Google Patents
Pyrrole derivatives and preparation method and application thereof Download PDFInfo
- Publication number
- CN102329326B CN102329326B CN201110319866.5A CN201110319866A CN102329326B CN 102329326 B CN102329326 B CN 102329326B CN 201110319866 A CN201110319866 A CN 201110319866A CN 102329326 B CN102329326 B CN 102329326B
- Authority
- CN
- China
- Prior art keywords
- compound
- acceptable salt
- pharmacy acceptable
- salt
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *N1C=CC[C@@]1C(N(CC1)Cc2c1[s]cc2)=N* Chemical compound *N1C=CC[C@@]1C(N(CC1)Cc2c1[s]cc2)=N* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines and provides pyrrole derivatives with a structure shown as a general formula I and medicinal salts of the pyrrole derivatives. R1-R4 is defined in the claim. The invention also relates to a method for preparing the compounds, and discloses a medical composition in which the compounds or pharmaceutically acceptable salts of the compounds are taken as active ingredients, and use of the compounds and the pharmaceutically acceptable salts of the compounds as antifungal medicines.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to compound, its preparation method, composition and application that a class has anti-mycotic activity.
Background technology
Fungi infestation is invaded position difference according to it can be divided into superficial part and deep two classes.Mycotic infection of superficial part is a kind of common disease, frequently-occurring disease, is more common in skin and first portion; What deep fungal was more common is Candida albicans and Cryptococcus neoformans, though the low harm of sickness rate is larger, infecting can threat to life when serious.Particularly in recent decades, along with being widely used of broad-spectrum antibiotics, cortin, antitumor drug and immunosuppressor, extensively carrying out of radiotherapy and organ transplantation, generally carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immune deficiency patient, destroyed the symbiotic relationship of normal flora, human body is reduced the resistibility of fungi, thereby cause fungi infestation particularly deep fungal infection significantly rise, and become one of major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.
In existing antifungal drug, nitrogen azole drug is a class with better prospect, is widely used clinically.Nitrogen azole drug is especially comparatively desirable to the curative effect of deep fungal infection, so be the focus of studying in antifungal drug always.They can rely on C14-α-demethylase (ERGl1) by Antifungi Cytochrome P450 3A, and this enzyme is lanosterol to be changed into the key enzyme of ergosterol.Its mechanism of action is blocking-up substrate hydroxylation reaction, and the methylated sterol of lanosterol 14-in fungus body is accumulated in a large number, and ergosterol is synthetic to be lacked, and causes many enzyme activity changes on membrane permeability and film, thus the growth of Antifungi.
Treat clinically at present the choice drug of deep fungal infection, mainly contain and take the glyoxaline compound that KETOKONAZOL (Ketoconazole), miconazole (Miconazole), tioconazole (Tioconazole) be representative, and take the Research of Triazole Antifungal Agents that fluconazole (Fluconazole), itraconazole (Itraconazole) and voriconazole (Voriconazole) be representative.But along with long-term widespread use, engender the Resistant strain to existing nitrogen azole drug, and have the trend of showed increased.Have been reported and claim Candida albicans B41628 to existing multi-medicament resistance, resistance problem makes mycosis control face more stern challenge.Simultaneously in clinical large-scale experiment for many years, find existing medicine, mostly there is toxic side effect to a certain degree as hepatic disorder, gi tract infringement, fash etc., cause its clinical application to be restricted.
The limitation existing for existing medicine, as narrow antimicrobial spectrum, resistance is serious, bioavailability is low, have the stronger problems such as toxic side effect.Except optimizing the preparation of the existing medicine of improvement, make novel antifungal drugs research become one of hot fields of global new drug development.In addition, the interaction between medicine makes Therapy of Invasive Fungal Infections become more complicated, therefore, and the clinical novel deep antifungal drug in the urgent need to high-efficiency low-toxicity, has a broad antifungal spectrum, highly selective.
Summary of the invention
One object of the present invention is openly have pyrrole derivative and the pharmaceutical salts thereof of general formula I structure.
Another object of the present invention is openly have the pyrrole derivative of general formula I structure and the preparation method of pharmaceutical salts thereof.
A further object of the present invention is, openly take and has the pyrrole derivative of general formula I structure and the pharmaceutical composition that pharmaceutical salts is main active ingredient thereof.
A further object of the invention is, openly has the pyrrole derivative of general formula I structure and pharmaceutical salts thereof as the purposes of antifungal drug aspect.
Now, in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of general formula I structure:
Wherein:
R
1for: hydrogen, C
1-C
4straight or branched alkyl, phenyl, by C
1-C
4the phenyl that straight or branched alkyl, halogen, nitro, cyano group replace, by C
1-C
4the pyridyl that straight or branched alkyl, cyano group, alkoxyl group replace.
R
2, R
3, R
4for: hydrogen, C
1-C
4straight or branched alkyl.
Wherein preferably following compound and pharmacy acceptable salt thereof:
I-1 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (1H-pyrroles-2-yl) ketoxime
I-2 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (3,5-dimethyl-1H-pyrroles-2-yl) ketoxime
I-3 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (1-methyl isophthalic acid H-pyrroles-2-yl) ketone-O-methyloxime
I-4 (1-(3,5-dichlorophenyl)-1H-pyrroles-2-yl) (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) ketone-O-methyloxime
I-5 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (1-(2-fluorophenyl)-1H-pyrroles-2-yl) ketoxime
I-6 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (1-p-methylphenyl-1H-pyrroles-2-yl) ketone-O-ethyl oxime
I-7 2-(2-((6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (propyl group oxime) methyl)-1H-pyrroles-1-yl)-4-methoxyl group nicotinic acid nitrile
Compound or its pharmacy acceptable salt with formula I structure of the present invention means: the compounds of this invention and mineral acid, organic acid salify.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate etc.
The syntheti c route of formula I compound is as follows:
Substituted azole benzaldehyde compound (II), in methyl alcohol, ethanol or acetone equal solvent, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide ,-30～85 ℃ of reactions make key intermediate III with N-substituted hydroxylamine hydrochloride compounds.Intermediate III again with the halogenating agent such as bromine, NBS or NCS in methylene dichloride, trichloromethane or toluene-10～110 ℃ react, generate intermediate compound IV.Intermediate compound IV and 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine is under the acid binding agent such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exists, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, and 0～120 ℃ of reaction makes Compound I.
Reaction is made to various intermediates or products therefrom and be dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip mineral acid or organic acid solution, make pharmacy acceptable salt.
Specifically various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip hydrochloric acid diethyl ether solution to pH=2, make hydrochloride; Or various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, and mole taurine such as adding, heated and stirred obtains its taurate; Or various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip concentrated sulfuric acid solution to pH=3, make vitriol, etc.
This compounds is effective for treatment mankind fungal infectious disease.Although compound of the present invention can be without the direct administration of any preparation, described various compounds are preferably used with the form of pharmaceutical preparation, and route of administration can be parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition preparation method of the compounds of this invention is as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient containing in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, and the amount of compound used or concentration regulate in a wider scope.Conventionally, the 0.05%-90% that the scope of active compound amount is composition (weight), another preferred scope is 0.05%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, has obvious restraining effect to fungi.Adopt standard micro-dilution method (NCCLSM-27A) to measure its minimum inhibitory concentration below, further illustrate the In Vitro Bacteriostatic of the compounds of this invention to clinical several frequently seen fungi.Concentration (the MIC that suppresses selected fungi 90% growth with target compound
90) as judgement terminal.
Test strain: 5 kinds of deep fungals: Candida albicans (Candida albicans, C.alb.) ATCC 76615, Cryptococcus neoformans (Cryptococcus neoformans, C.neo.) ATCC 32609, Oidium tropicale (Candida tropicalis, C.tro.) ATCC 12034, Candida parapsilosis (Candida paropsilosis, C.par.) ATCC22019, smoke aspergillus fumigatus (Aspergillus fumigatus, A.fum.).3 kinds of superficial fungis: trichophyton (Trichophyton rubrum, T.rub.), sporotrichum schenckii (Sporothrix schenckii, S.sch.) and fonsecaea pedrosoi (Fonsecaea pedrosoi, F.ped.).Above bacterial strain provides by our unit's pharmacological experiment chamber.
Test drug: the compounds of this invention (I-1～I-7), select amphotericin B (AmB) (Hua Yao group) and KETOKONAZOL (KCZ) (mesophytization Manufacturing Co., Ltd is closed in Wuhan) as positive control drug, dimethyl sulfoxide (DMSO) (DMSO), AR level (Tianjin Kai Xin chemical industry company limited).Microplate reader, BIO-RAD680.
Test method: the RPMI-1640 (Sigma) of take is nutrient solution, it is 1 * 10 that experimental strain is made into concentration
4～1 * 10
5the suspension of/ml.Compound is dissolved with sterile purified water and DMSO, make medicine storage liquid (6400 μ g/ml) ,-20 ℃ of preservations are stand-by.During use, with RPMI-1640, be diluted to 640 μ g/ml, establish solvent control and blank simultaneously.Get the aseptic 96 flat microtest plates in hole, No. 1 hole adds RPMI-1640100 μ L and makes blank, and No. 2 hole adds bacteria suspension 180 μ L and liquid 20 μ L, and 3-12 hole respectively adds bacteria suspension 100 μ L, 10 grades, 2-11 hole doubling dilution, finally from No. 11 holes, 100 μ L of sucking-off abandon.Each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ gmL
-1.No. 12 hole does not add liquid, makes medicine negative control.Candida, in 35 ℃ of constant temperature culture 24h, is observed the growing state of 3d.Measurement result after Cryptococcus neoformans cultivation 72h, 26 ℃ of constant temperature culture of superficial mycosis, observe the growing state of 1 week.By microplate reader, analyze, compare with medicine negative control hole, take the corresponding lowest drug concentration of 90% inhibition as its minimal inhibitory concentration value (MIC
90).
Table 1 In vitro antifungal activities of compounds (MIC
90, μ gmL
-1)
Visible by In Vitro Bacteriostasis test experiments result, all target compounds all have inhibition to a certain degree active to 8 kinds of pathomycetes, and what have surpasses amphotericin B.
Further by minimal inhibitory concentration (MIC) determination test, the restraining effect of the compounds of this invention to bacterium is described below.
Substratum: microorganism identification medium pH 7.9 ± 0.1 Beijing San Yao scientific and technological development company products; Bacterial classification: standard gold staphylococcus aureus CMCC26003, color standard white staphylococcus CMCC26101, standard faecalis CMCC32220, standard staphylococcus epidermidis CMCC26069, above bacterial classification is all purchased from Chinese pharmaceutical biological product and identifies institute.
Test method: with the positive contrast medicine of Linezolid, adopt doubling dilution.In first 1 hole at 96 orifice plates of having sterilized, 12 holes, add respectively bacterium liquid and broth culture contrast, then, in 2-11 hole, with micro-adjustable pipette, from lower concentration to high density, add successively above-mentioned sample solution 0.25～128 μ gmL with substratum doubling dilution
-1, every hole 100 μ L, make sample concentration in each hole be respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ gmL
-1.Be placed in and on vibrator, shake 1min, make in hole after solution fully mixes, microwell plate is added a cover and is sealed to reduce the evaporation in the process of hatching with gummed paper, in 37 ℃ of incubators, hatches 18h, and naked-eye observation is minimal inhibitory concentration without the contained lowest drug concentration in bacterial growth hole.
Table 2 In vitro antibacterial activities of compounds (MIC, μ gmL
-1)
Embodiment
Below in conjunction with embodiment, the present invention is described further, embodiment is only indicative, never means that it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1h NMR,
13c NMR), mass spectrum (MS) etc. is further confirmed its structure.
reference example 1:
Synthesizing of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 9.5g 1H-pyrrole-2-aldehyde, with 30mL dehydrated alcohol, dissolved, under stirring, add sodium hydroxide 8.0g.6.9g oxammonium hydrochloride is added to reaction system in batches.Add, under room temperature, continue reaction 5h (flaggy demonstration reacts completely).By dehydrated alcohol evaporate to dryness, with 3 * 15mL water washing reaction solution, with dichloromethane extraction, anhydrous sodium sulphate is fully dry, filters, and methylene dichloride is to the greatest extent steamed in decompression, obtains white solid (HPLC:97.2%).Rf=0.58[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=8: 1].
With reference to the method for reference example 1, can synthetic intermediate III-2～III-7.
Table 3 intermediate III-2～III-7 list
reference example 2:
Synthesizing of intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 11.0g intermediate III-1, with 50mL methylene dichloride, dissolved, under stirring, add NBS 17.8g.Room temperature reaction 6h under illumination (flaggy demonstration reacts completely).With 3 * 30mL 35%Na
2s
2o
3solution washing reaction solution, dichloromethane layer anhydrous sodium sulphate is fully dry, filters, and methylene dichloride is to the greatest extent steamed in decompression, obtains light yellow oily product (HPLC:97.7%).Rf=0.50[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=8: 1].
With reference to the method for reference example 2, can synthetic intermediate IV-2～IV-7.
Table 4 intermediate compound IV-2～IV-7 list
embodiment 1:
Synthesizing of (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (1H-pyrroles-2-yl) ketoxime (Compound I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 18.9g intermediate compound IV-1, with 50mL anhydrous methanol, dissolved, under stirring, add Anhydrous potassium carbonate 12.0g.By 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine 13.9g add reaction system in batches.Add, in the lower reaction 3.5h (flaggy demonstration reacts completely) that continues that refluxes.Filtering solid matter, by anhydrous methanol evaporate to dryness, with 3 * 30mL water washing reaction solution, with dichloromethane extraction, anhydrous sodium sulphate is fully dry, filter, methylene dichloride is to the greatest extent steamed in decompression, obtains dark oil thing, post separated [moving phase: v (methylene dichloride): v (methyl alcohol)=8: 1], Rf=0.62, obtains white solid (HPLC:99.5%).
With reference to the method for embodiment 1, can obtain target compound I-2～I-7.
Table 5 Compound I-2～I-7 list
embodiment 2:
Compound I-1 one-tenth hydrochloride: get Compound I-1 white solid product 2.5g, be dissolved in 10mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains white solid powder.
embodiment 3:
Compound I-2 one-tenth taurate: get Compound I-2 white solid product 2.0g, be dissolved in 10mL anhydrous methanol.After being heated to reflux, add and wait mole taurine, continue at time about 1.5h of stirring reaction that refluxes.React complete, standing 24h under room temperature.Separate out transparent crystallization, filter vacuum-drying.
embodiment 4:
Compound I-3 one-tenth vitriol: get Compound I-3 light yellow solid product 2.0g, be dissolved in 12mL acetone.Ice-water bath is cooled to 0 ℃, drip concentrated sulfuric acid solution to pH be 3, continue at stir about 1h under ice-water bath.Filter, obtain white solid.
For the pharmaceutical composition of the oxime compounds containing pyrroles of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment is only for explanation, rather than for limiting the scope of the invention.Described preparation can be used any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-4.
embodiment 5:
By following compositions, prepare hard gelatin capsule:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
embodiment 6:
By following compositions, prepare tablet:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.First the auxiliary material of recipe quantity is fully mixed.Bulk drug is added in auxiliary material to increase progressively dilution method, and each added-time fully mixes 2-3 time, guarantees that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dry particle is crossed the whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
embodiment 7:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic to regulate pH value to 4～8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
embodiment 8:
The preparation of injection lyophilized powder:
The taurate 100mg of Compound I-2
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.Add N.F,USP MANNITOL again, by the requirement of injection, carry out autoclaving, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, and sealing, obtains.
Claims (8)
1. compound and the pharmacy acceptable salt thereof with formula I structure:
Wherein:
R
1for: hydrogen, C
1-C
4straight or branched alkyl, phenyl, by C
1-C
4the phenyl that straight or branched alkyl, halogen, nitro, cyano group replace, by C
1-C
4the pyridyl that straight or branched alkyl, cyano group replace;
R
2, R
3, R
4for: hydrogen, C
1-C
4straight or branched alkyl.
2. compound and the pharmacy acceptable salt thereof with following structure:
3. compound as claimed in claim 1 or 2 and pharmacy acceptable salt thereof, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. compound as claimed in claim 3 and pharmacy acceptable salt thereof, pharmacy acceptable salt refers to: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate.
5. the preparation method of claim 1 Chinese style I compound, it is characterized in that: intermediate IV and 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine under triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent, 25～120 ℃ of reactions make chemical compounds I;
Wherein X is Cl, Br; R
1, R
2, R
3, R
4as claimed in claim 1.
6. an antimycotic pharmaceutical composition, the compound that it comprises claim 1～2 any one for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical carriers.
7. the compound of claim 1～2 any one and pharmacy acceptable salt thereof are in the application aspect antifungal drug.
8. application as claimed in claim 7, the purposes aspect the medicine for the preparation for the treatment of fungi infestation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110319866.5A CN102329326B (en) | 2011-10-20 | 2011-10-20 | Pyrrole derivatives and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110319866.5A CN102329326B (en) | 2011-10-20 | 2011-10-20 | Pyrrole derivatives and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102329326A CN102329326A (en) | 2012-01-25 |
| CN102329326B true CN102329326B (en) | 2014-04-09 |
Family
ID=45481312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110319866.5A Active CN102329326B (en) | 2011-10-20 | 2011-10-20 | Pyrrole derivatives and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102329326B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325268A (en) * | 1998-11-06 | 2001-12-05 | 辛根塔参与股份公司 | Fungicidal combinations comprising thieno [2,3-d] pyrimidin-4-one |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
| WO2010027236A2 (en) * | 2008-09-08 | 2010-03-11 | Lg Life Sciences Ltd. | Fused heterocyclic compound |
-
2011
- 2011-10-20 CN CN201110319866.5A patent/CN102329326B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325268A (en) * | 1998-11-06 | 2001-12-05 | 辛根塔参与股份公司 | Fungicidal combinations comprising thieno [2,3-d] pyrimidin-4-one |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
| WO2010027236A2 (en) * | 2008-09-08 | 2010-03-11 | Lg Life Sciences Ltd. | Fused heterocyclic compound |
Non-Patent Citations (4)
| Title |
|---|
| Synthesis, spectral investigation and biological evaluation of novel noncytotoxic tetrahydrothieno[3, 2-c]pyridine hydrazide derivatives;Visha P.Modi,等;《Der Pharmacia Lettre》;20110831;第3卷(第4期);第120-133页 * |
| Visha P.Modi,等.Synthesis, spectral investigation and biological evaluation of novel noncytotoxic tetrahydrothieno[3, 2-c]pyridine hydrazide derivatives.《Der Pharmacia Lettre》.2011,第3卷(第4期),第120-133页. |
| 噻吩并吡啶类衍生物的设计、合成、活性评价及其药效团模型;成碟;《天津大学博士学位论文》;20101215;第48-49页 * |
| 成碟.噻吩并吡啶类衍生物的设计、合成、活性评价及其药效团模型.《天津大学博士学位论文》.2010,第48-49页. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102329326A (en) | 2012-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP4011871A2 (en) | Processes for preparing oxathiazin-like compounds | |
| CN102180890B (en) | Cefathiamidine hydrate and preparation method and application thereof | |
| CN101817834B (en) | Pyrazole derivatives and preparation method and application thereof | |
| CN105820130B (en) | Triazole n Propanoic acid class URAT1 inhibitor, preparation method and its purposes in hyperuricemia and gout treatment | |
| CN101781294B (en) | Imidazole derivative, and preparation method and application thereof | |
| AU2016269359B2 (en) | Sodium salt of uric acid transporter inhibitor and crystalline form thereof | |
| CN102329326B (en) | Pyrrole derivatives and preparation method and application thereof | |
| CN107365272A (en) | A kind of novel imidazole class compound and preparation method thereof and application medically | |
| CN101798303B (en) | Azole derivatives, preparation method and application thereof | |
| CN104447938A (en) | O-(piperazinyl) ethyl derivative of cleistanone, preparation method of O-(piperazinyl) ethyl derivative of cleistanone and use of O-(piperazinyl) ethyl derivative of cleistanone | |
| CN102002054B (en) | Pyrazole type compound and preparation method and application thereof | |
| CN110981888B (en) | N-aryl dithiopyrryl ketonuria and amino ester derivatives, preparation and application thereof | |
| CN101792437B (en) | Tolyltriazole derivatives, preparation method thereof and use thereof | |
| CN102503954B (en) | Imidazole derivative and preparation method and application thereof | |
| CN102351881B (en) | Stable levofloxacin hydrochloride compound | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN104926804A (en) | Compounds with anti-tumor effect, and preparation method and application of compounds | |
| CN110041368B (en) | Organic phosphine clinafloxacin derivative and preparation method and application thereof | |
| CN102276626B (en) | Isoxazole-containing compound | |
| CN103145732B (en) | Antimycotic derivative, the Preparation Method And The Use of one class piperazine | |
| CN113636976A (en) | Isoniazid-flavone pharmaceutical co-crystal and preparation method thereof | |
| CN104610191B (en) | Crystal formation of rhodanine chirality hexamethylene spiro-compound and preparation method thereof and purposes | |
| CN104873509A (en) | Application of O-(diethylamino) ethyl derivative of Daphmalenine A in preparation of antibacterial drug | |
| CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
| CN102329327B (en) | Furan derivatives and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee after: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH CO., LTD. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research |