CN102875566A - Thiophene derivatives with anti-gastric ulcer effect - Google Patents
Thiophene derivatives with anti-gastric ulcer effect Download PDFInfo
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- CN102875566A CN102875566A CN2011101987074A CN201110198707A CN102875566A CN 102875566 A CN102875566 A CN 102875566A CN 2011101987074 A CN2011101987074 A CN 2011101987074A CN 201110198707 A CN201110198707 A CN 201110198707A CN 102875566 A CN102875566 A CN 102875566A
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- 0 C*(C1=O)=C(CN(CC2)Cc3c2[s]cc3)Nc2c1[s]c(-c1cc(*)ccc1)c2 Chemical compound C*(C1=O)=C(CN(CC2)Cc3c2[s]cc3)Nc2c1[s]c(-c1cc(*)ccc1)c2 0.000 description 3
- ZFXOKYFFMJOKGI-UHFFFAOYSA-N CC(C)(C)c(cc1)ccc1-c1cc(NC(CN(CC2)Cc3c2[s]cc3)=O)c(C(OC)=O)[s]1 Chemical compound CC(C)(C)c(cc1)ccc1-c1cc(NC(CN(CC2)Cc3c2[s]cc3)=O)c(C(OC)=O)[s]1 ZFXOKYFFMJOKGI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of anti-gastric ulcer medicines, and provides thiophene derivatives and pharmaceutically acceptable salts thereof, which have a structural formula I, relates to a preparation method for the thiophene derivatives and the pharmaceutically acceptable salts thereof, and discloses medical compositions comprising the compounds and the pharmaceutically acceptable salts thereof, which serve as active ingredients, and use of the compounds and the pharmaceutically acceptable salts thereof as anti-gastric ulcer medicines.
Description
Technical field
The invention belongs to medical technical field, more precisely, relate to a class and have compound of anti-ulcer effect and preparation method thereof, contain their pharmaceutical composition and as the purposes of medicament for anti-gastric ulcer.
Background technology
Peptide ulceration is common clinical and frequently-occurring disease, has the features such as the chronic course of disease, periodical attack, rhythmicity epigastric pain.Think that at present its origin cause of formation is because due to the Stomach duodenum local mucous membrane protection factor and mucosal injury factor balance be damaged.Its protection factor mainly comprises mucus-mucosal barrier, mucosal blood flow and epithelial cell turnover, prostaglandin(PG) and Urogastron etc.; Its infringement factor comprises hydrochloric acid in gastric juice-pepsic digestion, helicobacter pylori, gastrin and the delay of stomach hole section, eating and drinking without temperance and insomnia, drinks, emotional stress, adverse drug effect etc.
Peptide ulceration mainly refers to stomach ulcer and duodenal ulcer.Stomach ulcer is a kind of common digestive tract diseases, and sickness rate is up to 10%.Though the pathogenesis of stomach ulcer imperfectly understands, most experts think that the invasion and attack of main and the gastric mucosa injury factor and mucous membrane self-defence ability reduce, and helicobacter pylori infection is relevant.The clinical treatment aspect of stomach ulcer mainly contains three kinds: antiacid therapy, receptor blocking method, the sour pump method of inhibition.
Antiacid therapy is to adopt in weakly alkaline medicine such as sodium bicarbonate, Magnesium Trisilicate, aluminium hydroxide and the bismuth subnitrate etc. and hydrochloric acid in gastric juice to the treatment of stomach ulcer in early days, make pH value rising in the gastral cavity, weakened on the contrary the effect of the negative feedback inhibition gastric acid secretion of hydrochloric acid in gastric juice, make parietal cell generate more hydrochloric acid in gastric juice, cause " knock-on ".Therefore, this method is eliminated basically.
H
2Receptor antagonist (H
2RA) can selectivity and histamine H
2-R combination, the competitive antagonism histamine H
2-R effect, thereby gastric acid secretion inhibiting are the most widely acid inhibitors of present clinical application.Such as cimitidine, Ranitidine HCL, famotidine etc.
Proton pump inhibitor is a strongest present class acid inhibitor, but the strongly inhibited gastric acid secretion, almost completely gastric acid inhibitory and effect are lasting, and Healing is better than H
2RA.Such as omeprazole, lansoprazole, pantoprazole.Wherein.Omeprazole is by Sweden ASTRA company research and development, and the gastric acid secretion that various stimuluss are caused increases all strong and lasting restraining effect, than the H that only can block the gastric acid secretion that tissue excitement causes
2The good effect of receptor blocking agent such as Cimitidine Type A/AB and Ranitidine HCL etc. has rapid alleviating pain, short treating period, advantage that the pathology healing rate is high.And this medicine is without severe side effect, and tolerance is good, is one of powerhouse of curative effect in the acid inhibitor of having found at present.
At present, in view of the gastric acid inhibitory effect of proton pump inhibitor than H
2Receptor blocking agent is strong, and the hydrochloric acid in gastric juice barrier of nature is reduced, and causes the growth of pathogen enterobacteria.
Although the medicine for the treatment of peptide ulceration is a lot, treatment plan also is variation, and short term effect is all more satisfied, still unavoidably recurrence after the drug withdrawal, and Long-term taking medicine has again many untoward reactions, needs such new medicine.
Summary of the invention
One object of the present invention is, discloses a kind of thiophene derivant and pharmaceutical salts thereof of novel texture.
Another object of the present invention is, discloses the preparation method of thiophene derivant and pharmaceutical salts thereof.
A further object of the present invention is, discloses the pharmaceutical composition take thiophene derivant and pharmaceutical salts thereof as main active ingredient.
A further object of the invention is, discloses thiophene derivant and pharmaceutical salts thereof, as the application of medicament for anti-gastric ulcer 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
4The straight or branched alkyl;
R
2For: hydrogen, C
1-C
4The straight or branched alkyl;
R
3For: C
1-C
4The straight or branched alkyl, C
3-C
6Cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, thienyl, itrile group, nitro, phenyl;
R
4, R
5For: hydrogen; C
1-C
4The straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4The straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1For: hydrogen, methyl, ethyl;
R
2For: hydrogen, methyl, ethyl;
R
3For: methyl, ethyl;
R
4, R
5For: hydrogen; The tertiary butyl; Trifluoromethyl; Phenyl; Chlorophenyl; Nitrophenyl; Cyano group; Methylthio group; Methylsulfonyl.
More preferably its pharmacy acceptable salt of following compound:
I-1:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-2-methoxycarbonyl thiophene;
The I-2:5-tertiary butyl-3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-2-methoxycarbonyl thiophene;
I-3:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-4-phenyl-5-(trifluoromethyl)-2-methoxycarbonyl thiophene;
I-4:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-5-(4-fluorophenyl)-2-methoxycarbonyl thiophene;
I-5:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-5-(3-nitrophenyl)-2-methoxycarbonyl thiophene;
I-6:5-(4-tert-butyl-phenyl)-3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-2-methoxycarbonyl thiophene;
I-7:4-cyano group-3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) acetamido also)-5-(methylthio group)-2-ethoxycarbonyl thiophene;
I-8:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) amide-based small also)-4-(methylsulfonyl)-5-(methylthio group)-2-methoxycarbonyl thiophene.
Formula I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein preferred: 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.
X is Cl, Br; R
1～R
5Such as aforementioned definitions
Thiophenes (II), in DMF, with 2-halogen acyl halide compounds under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide ,-30～10 ℃ of reactions make key intermediate III.Intermediate III is again with 4,5,6, the 7-tetrahydrothieno pyridines is in the presence of the acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide, take methylene dichloride, trichloromethane or acetonitrile as solvent, 10～80 ℃ of reactions make Compound I.
Reaction make various compounds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol, Virahol, ether or the DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol, Virahol, ether or the DMSO, drips the salt acid ether to pH2, make hydrochloride.Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, the molar lactic acid such as adding get its lactic acid salt.
This compounds is effective for treatment human digestive road ulcer.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (such as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: Application 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 a 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 that contains in pharmaceutical composition and the unit dosage form (the compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in a wider scope.Usually, the scope of active compound amount is 0.5～90% (weight) of composition, and another preferred scope is 0.5～70%.
Compound and pharmacy acceptable salt thereof with formula I structure of the present invention having obvious effect aspect the treatment anti-gastric-ulcer.
Further specify the anti-ulcer effect of the compounds of this invention below by pharmacodynamic experiment.
Experiment on Function to rat gastric ulcer
Gastric ulcer model-acetic acid calcination gastric ulcer model:
1. Experimental agents and reagent:
Compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8.
2. laboratory animal:
Wistar rat: 150-200g, male and female half and half, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, credit number SCXK (capital) 2005-0013.
3. experimental technique and result:
Get 90 of 150-200g Wistar rats, male and female half and half, fasting 48h freely drinks water.Use the etherization rat, the abdominal cavity is opened in sterilization, expose stomach, inject 10% acetic acid 0.05mL at body of stomach and pyloric antrum intersection with microsyringe 04～0.5mm place under the rat serous coat, the blank group is injected the physiological saline of isodose, the reduction stomach is sewed up stomach wall.The postoperative rat freely drinks water, and begins normal raising next day.
Animal grouping and administration: divide at random 5 groups with rat by sex and body weight, 6 every group, be respectively (1) model group: modeling began to use the distilled water gavage on the 3rd day; (2) compound group: modeling, the 3rd day begins with compound (0.2g/kg) gavage.
The 15th day sacrificed by decapitation rat opens abdomen, ligation stomach pylorus and orifice of the stomach, and full stomach takes out.Inject 1% formalin 10ml in the stomach, again stomach is soaked in 1% formalin solution 10min with fixing stomach ectonexine.Cut off stomach along greater gastric curvature, stomach is turned up, outwell content and wash gently with distilled water and remove gastric content, stomach is flattened on glass plate, corresponding mucosal surface is observed the ulceration situation at injection acetic acid solution position, the results are shown in Table 1.
Table 1 burns the impact of type gastric ulcer model on rats acetic acid
Test-results shows that behind the rat stomach serous coat hemostasis acetic acid, can make gastric tissue impaired, ulcer is rounded or oval, central concave, all around little protuberance.Each administration group all has antiulcer action in various degree, even ulcer occurs, the impaired degree of gastric tissue is obviously slight.The result shows that compound of the present invention has significant protective effect to rats acetic acid calcination type gastric ulcer model.
Embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never 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 proved conclusively its structure.
Embodiment 1
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 15.7g 3-amino-2-methoxycarbonyl thiophene, with 100mlDMF it is dissolved the rear 20.2g of adding triethylamine,-10 ℃～5 ℃ lower stirrings, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30ml), behind low-temp reaction 3h (the flaggy demonstration reacts completely) the stirring at room 1h, reaction solution is poured in the 200ml cold water, fully stirred, filter, namely get brown solid (HPLC:90.5%).The Rf=0.66[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
Method with reference to embodiment 1 can conveniently prepare compound: intermediate III-2～III-7.Replace chloroacetyl chloride to get intermediate III-8 with 2-bromo butyryl bromide.
Table 2 intermediate III-2～III-8 tabulation
Embodiment 2
3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) kharophen also)-2-methoxycarbonyl thiophene (Compound I-1)
Stirring is being housed, condenser, add successively 23.3g intermediate III-1 in the reaction flask of thermometer, the 100mL acetonitrile, 20.2g triethylamine, with 17.5g 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine, under room temperature, stir 6h, in reaction solution, add the 100mL saturated aqueous common salt, extract with ethyl acetate (50mL * 3), anhydrous sodium sulphate is fully dry, filters, and removes solvent under reduced pressure, namely get sorrel oily matter, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=3: 1], and Rf=0.55 gets white solid I-1 (HPLC:99.5%).
1H-NMR(DMSO-d
6，400MHz)δ：2.832-2.859(t，2H，-CH
2CH
2-)，2.908-2.934(t，2H，-CH
2N(CH
2)-)，3.370(s，2H，-CH
2CONH-)，3.672(s，3H，-OCH
3)，3.683(s，2H，-CH
2N(CH
2-)
2)，6.803-6.816(d，1H，-CH＝CHS-)，7.286-7.299(d，1H，＝CHS-)，7.866-7.900(d，1H，＝CHSC(COOCH
3)＝)，8.077-8.091(d，1H，-CH＝CHS-)，11.182(s，1H，-NH-)。HRMS(m/z)[M+H]
+：337.0675。Method with reference to embodiment 2 prepares Compound I-2～I-8.
Table 3 Compound I-2～I-8 tabulation
Embodiment 3
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.0g, be dissolved in the 10mL anhydrous methanol.Ice-water bath is cooled to 10 ℃, drip 10.5% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get white solid, vacuum-drying, m.p.227 ℃-230 ℃.
Embodiment 4
Compound I-3 one-tenth vitriol: get I-3 white solid product 4.1g, be dissolved in 25mL acetone.Ice-water bath is cooled to 6 ℃, drip 9.3% sulfuric acid acetone soln to pH be 3, continue at stir about 1h under the ice-water bath.Filter, get pink solid, vacuum-drying, m.p.219 ℃-221 ℃.
Embodiment 5
Compound I-6 one-tenth lactic acid salt: get I-6 white solid product 3.5g, be dissolved in the 20mL dehydrated alcohol.Be heated to the molar lactic acid such as the rear adding that refluxes, continue at the lower about 1h of stirring reaction that refluxes.React complete, under room temperature, leave standstill 24h.Separate out yellow crystal, filter vacuum-drying, m.p.208 ℃-210 ℃.
Embodiment 6
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, and it is for subsequent use to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 7
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is for subsequent use to cross 100 mesh sieves.First with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 8
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves sorb ester and propylene glycol, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 9
The preparation of injection lyophilized powder:
The lactic acid salt 100mg of Compound I-6
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate the pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, sealing, and get final product.
Claims (8)
1. the compound and the pharmacy acceptable salt thereof that have formula I structure:
Wherein:
R
1For: hydrogen, C
1-C
4The straight or branched alkyl;
R
2For: hydrogen, C
1-C
4The straight or branched alkyl;
R
3For: C
1-C
4The straight or branched alkyl, C
3-C
6Cycloalkyl, this alkyl or cycloalkyl is replaced by following one or more group: halogen, hydroxyl, carboxyl, amino, thienyl, itrile group, nitro, phenyl;
R
4, R
5For: hydrogen; C
1-C
4The straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4The straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
2. the compound of formula I structure as claimed in claim 1 and pharmacy acceptable salt thereof, the compound of formula I structure is preferred: wherein:
R
1For: hydrogen, methyl, ethyl;
R
2For: hydrogen, methyl, ethyl;
R
3For: methyl, ethyl;
R
4, R
5For: hydrogen; The tertiary butyl; Trifluoromethyl; Phenyl; Chlorophenyl; Nitrophenyl; Cyano group; Methylthio group; Methylsulfonyl.
3. the compound of formula I structure as claimed in claim 1 and pharmacy acceptable salt thereof, the compound of described formula I structure is:
4. formula I compound as claimed in claim 1 and pharmacy acceptable salt thereof, its pharmacy acceptable salt is: formula I compound and mineral acid, organic acid salify.
5. formula I compound as claimed in claim 4 and pharmacy acceptable salt thereof, its pharmacy acceptable 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.
6. the preparation method of claim 1 Chinese style I compound; it is characterized in that: thiophenes (II); in DMF; with 2-halogen acyl halide compounds at triethylamine; pyridine; salt of wormwood; yellow soda ash; sodium bicarbonate; under the catalysis of sodium hydroxide or potassium hydroxide;-30～10 ℃ of reactions make key intermediate III; intermediate III and 5; 6; 7; 7a-tetramethylene sulfide [3; 2-c] pyridine-2 (4H)-ketone; at triethylamine; pyridine; salt of wormwood; yellow soda ash; sodium bicarbonate; sodium hydroxide or potassium hydroxide exist lower, with methyl alcohol; ethanol; ethyl acetate; methylene dichloride; trichloromethane; acetonitrile or toluene are solvent, 10-100 ℃ of reaction; after the acid anhydrides acidylate, make Compound I
Wherein X is Cl, Br, R
1～R
5Such as claim 1 definition.
7. the pharmaceutical composition of an anti-gastric-ulcer, it comprises formula I compound as claimed in claim 1 or its pharmacy acceptable salt and one or more pharmaceutical carriers of effective therapeutic dose.
Claim 1-3 each formula I compound and pharmacy acceptable salt in the application aspect medicament for anti-gastric ulcer.
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| CN201110198707.4A CN102875566B (en) | 2011-07-15 | 2011-07-15 | Thiophene derivatives with anti-gastric ulcer effect |
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|---|---|---|---|
| CN201110198707.4A CN102875566B (en) | 2011-07-15 | 2011-07-15 | Thiophene derivatives with anti-gastric ulcer effect |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389352A (en) * | 2006-02-24 | 2009-03-18 | 安斯泰来制药株式会社 | Agent for treating or preventing digestive ulcer |
| CN101863902A (en) * | 2010-06-29 | 2010-10-20 | 天津药物研究院 | Preparation method and application of 2-substituted phenyl-2-(4,5,6,7-thiophane [3,2-c] pyridine-5(4H)-group) acetic acid (substituted alkyl alcohol) ester |
| US20110021494A1 (en) * | 2007-09-19 | 2011-01-27 | 4Sc Ag | Novel tetrahydro-fused pyridines as histone deacetylase inhibitors |
| CN101962388A (en) * | 2010-10-14 | 2011-02-02 | 天津药物研究院 | Acetamide derivatives, preparation method and application thereof |
-
2011
- 2011-07-15 CN CN201110198707.4A patent/CN102875566B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389352A (en) * | 2006-02-24 | 2009-03-18 | 安斯泰来制药株式会社 | Agent for treating or preventing digestive ulcer |
| US20110021494A1 (en) * | 2007-09-19 | 2011-01-27 | 4Sc Ag | Novel tetrahydro-fused pyridines as histone deacetylase inhibitors |
| CN101863902A (en) * | 2010-06-29 | 2010-10-20 | 天津药物研究院 | Preparation method and application of 2-substituted phenyl-2-(4,5,6,7-thiophane [3,2-c] pyridine-5(4H)-group) acetic acid (substituted alkyl alcohol) ester |
| CN101962388A (en) * | 2010-10-14 | 2011-02-02 | 天津药物研究院 | Acetamide derivatives, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 瞿建国，等: "H+ / K+-ATP 酶抑制剂的研究进展", 《中国药物化学杂志》, vol. 10, no. 2, 30 June 2000 (2000-06-30) * |
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