CN101863902A - 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 - Google Patents
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 Download PDFInfo
- Publication number
- CN101863902A CN101863902A CN 201010212486 CN201010212486A CN101863902A CN 101863902 A CN101863902 A CN 101863902A CN 201010212486 CN201010212486 CN 201010212486 CN 201010212486 A CN201010212486 A CN 201010212486A CN 101863902 A CN101863902 A CN 101863902A
- Authority
- CN
- China
- Prior art keywords
- compound
- ester
- acetate
- pyridines
- tetramethylene sulfide
- 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.)
- Granted
Links
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of gastric ulcer resistant medicaments and provides 2-substituted phenyl-2-(4,5,6,7-thiophane [3,2-c] pyridine-5(4H)-group) acetic acid (substituted alkyl alcohol) ester with a structure of a formula I and a salt thereof, wherein R1 and R2 are simultaneously or respectively hydrogen, halogen or a nitro group; and R3 is a halogen substituted C1-C4 alkyl group or a hydroxyl group substituted C1-C4 alkyl group. The invention also relates to a preparation method of the compound, and also discloses a medical composition using the compound or the pharmaceutically acceptable salt thereof as an active and effective component and application thereof as gastric ulcer resistant medicaments.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of anti-gastric-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 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 stomach, the 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 renewal, 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 portion, 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 early stage treatment to stomach ulcer, adopts in weakly alkaline medicine such as sodium bicarbonate, Magnesium Trisilicate, aluminium hydroxide and the bismuth subnitrate etc. and hydrochloric acid in gastric juice, makes pH value rising in the gastral cavity.This therapy has weakened the effect of negative feedback inhibition gastric acid secretion on the contrary, makes parietal cell generate more hydrochloric acid in gastric juice, causes " knock-on ".Therefore, this method is eliminated basically.
H
2Receptor antagonist (H
2RA) can selectivity and histamine H
2Antihistamine H is picked up in-R combination, competitiveness
2-R effect, thus the gastric acid inhibitory secretion is a present clinical application acid inhibitor the most widely.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 the healing effect is better than H
2RA.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 persistent 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 does not have 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.
Though the medicine of treatment peptide ulceration is a lot, treatment plan also is variation, and short term effect is all more satisfied, and still recurrence unavoidably after the drug withdrawal is taken medicine for a long time and many untoward reactions are arranged, and needs such new medicine.
Summary of the invention
One object of the present invention is that (4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (substituted alkyl alcohol) ester and pharmaceutical salts thereof also to disclose a class 2-substituted-phenyl-2-.
Another object of the present invention is, discloses that (4,5,6,7-tetramethylene sulfide also [3,2-c] pyridines-5 (4H)-yl) acetate (substituted alkyl alcohol) ester and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient with a class 2-substituted-phenyl-2-.
A further object of the present invention is, (4,5,6, the 7-tetramethylene sulfide is the preparation method of [3,2-c] pyridines-5 (4H)-yl) acetate (substituted alkyl alcohol) ester and pharmaceutical salts thereof also to disclose a class 2-substituted-phenyl-2-.
A further object of the invention is, disclose a class 2-substituted-phenyl-2-(4,5,6, the 7-tetramethylene sulfide also [3,2-c] pyridines-5 (4H)-yl) acetate (substituted alkyl alcohol) ester and pharmaceutical salts thereof as the application of medicament for anti-gastric ulcer aspect.
Now, content of the present invention is described in detail in conjunction with the object of the invention.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of general formula I structure:
Wherein:
R
1, R
2Be at the same time or separately: hydrogen, halogen, nitro;
R
3C for the halogen replacement
1-C
4Alkyl, the C that hydroxyl replaces
1-C
4Alkyl.
The compound that the present invention relates to formula I structure, representation compound is as follows:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-fluoroethanol) ester also for I-12-(2-chloro-phenyl-)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (ethylene chlorhydrin) ester also for I-22-(2-chloro-phenyl-)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2,2)-trifluoroethanol) ester also for I-32-(4-fluorophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2)-dichlroroethanol) ester also for I-42-(4-fluorophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl ethanol) ester also for I-52-(3-nitrophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl propyl alcohol) ester also for I-62-(3-nitrophenyl)-2-.
The compound that has the I structure among the present invention, its salt means: The compounds of this invention and mineral acid, organic acid salify.Particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts, or the like.
The preparation route of formula I compound is as follows:
Can prepare Compound I by two kinds of methods:
1. alpha-brominated substituted-phenyl toluylic acid (1) is solvent, band aqua with toluene with substituted alkyl alcohol (2), is catalyzer with the tosic acid, and reflux makes ester class intermediate (3).(3) again with 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (4) is in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, with methylene dichloride, trichloromethane, acetonitrile or toluene etc. is solvent, and 25～100 ℃ of reactions make Compound I;
2. (5) and (2) are solvent with methylene dichloride or trichloromethane in the presence of DCC and DMAP or Vinyl chloroformate, and-5～25 ℃ of reactions make Compound I.
Reaction is made various intermediates or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, dropping inorganic acid or organic acid solution are made pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, the dripping hydrochloric acid diethyl ether solution is made hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, and adding and wait a mole citric acid, heated and stirred gets its Citrate trianion; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, drips the vitriol oil down to pH=3, make vitriol in ice-water bath, or the like.
This compounds is effective for the human disease that causes because of stomach ulcer of treatment.Although compound of the present invention can be without the direct administration of any configuration, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions method of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.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 for example 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 or the like.
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 the scope of a broad.Usually, the weight range of active compound is 0.5%～90% (weight) of composition, and another preferred range is 0.5%～70%.
Compound and pharmacy acceptable salt thereof with formula I structure of the present invention has obvious effects aspect anti-gastric-ulcer.
Further specify the anti-gastric-ulcer effect of The compounds of this invention below by pharmacodynamic experiment.
Effect test to rat gastric ulcer:
Acetate calcination gastric ulcer model:
1. test medicine and reagent:
The vitriol of the hydrochloride of Compound I-1, I-2, I-3, I-4, I-5, I-6, I-1, the Citrate trianion of I-3, I-5 (synthetic) by the contriver.
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 0.4～0.5mm 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 5 groups with rat at random by sex and body weight, 10 every group, be respectively (1) model group: modeling, the 3rd day begins to irritate stomach with physiological saline; (2) compound group: modeling, the 3rd day begins to irritate stomach with compound (0.2g/kg).
The 15th day sacrificed by decapitation rat opens abdomen, ligation stomach pylorus and orifice of the stomach, and full stomach takes out.In stomach, inject to inject 1% formalin 10mL, 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 tap 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.
Rats acetic acid is burnt the influence of type gastric ulcer model
Test-results shows that the rat stomach serous coat can make coat of the stomach tissue damaged after injecting acetate down, and ulcer is rounded or oval, central concave, little all around protuberance.Each administration group all has antiulcer action in various degree.The ulcer index of each administration group and model group compare P all＜0.05.This result shows that compound of the present invention has significant protective effect to rats acetic acid calcination type gastric ulcer model.
Embodiment
Below in conjunction with example the present invention is described further.Example 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), further its structure of conclusive evidence such as mass spectrum (MS).
Reference example 1:
Referenced patent US 5,036, and the method for 156A1 (Bouisset et al.) prepares compound (1-1):
Can make white crystalline powder, m.p.106～110 ℃, HPLC:99.6%.
Reference example 2:
The same, referenced patent US 5,036, the method of 156A1 (Bouisset et al.) prepares compound: alpha-brominated para-fluorophenylacetic acid, alpha-brominated m nitrophenylacetic acid, then with 4,5,6, the 7-tetramethylene sulfide is the further reacting generating compound of [3,2-c] pyridine (5a), (5b) also.
Can make white crystalline powder, Rf:0.36[developping agent: v (ethyl acetate): v (methyl alcohol)=7: 3].
Can make yellow crystalline powder, Rf:0.32[developping agent: v (ethyl acetate): v (methyl alcohol)=7: 3].
Embodiment 1:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-fluoroethanol) ester (Compound I-1) also for 2-(2-chloro-phenyl-)-2-
In the reaction flask that agitator, condenser, water trap are housed, add alpha-brominated o-chlorobenzene acetic acid 5.0g (0.020mol), 2-fluoroethanol 7.06g (0.110mo) l), tosic acid 1.0g, toluene 30mL, reflux.When in the reaction process moisture in the water trap being gone out, add a small amount of alcohol if still anhydrous telling can be thought and react completely to obvious anhydrous generation.Be cooled to room temperature, with saturated sodium bicarbonate solution washing 2 times, distilled water wash 2 times is got the organic layer anhydrous sodium sulfate drying, filters, and evaporate to dryness gets light yellow oily liquid.To go up the step reaction product and pack in the dry single port bottle, and with the toluene dissolving, add Anhydrous potassium carbonate 5.0g (0.036mol), and drip 4,5,6 under the stirring at room, the 7-tetramethylene sulfide is [3,2-c] pyridine 3.07g (0.022mol) also, some plate control reaction process.The after-filtration evaporate to dryness that reacts completely, with quick preparative chromatography separate colourless transparent oil liquid.Yield 94.8%.Rf:0.41[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
1H-NMR(CDCl
3，400MHz)δ：2.871～2.934(m，4H)，3.670(d，J＝14Hz，1H)，3.734(d，J＝14Hz，1H)，4.274～4.502(m，3H)，4.610～4.628(t，1H)，4.958(s，1H)，6.662(d，J＝4.8Hz，1H)，7.048(d，J＝4.8Hz，1H)，7.233～7.295(m，2H)，7.385～7.406(m，1H)，7.669～7.693(q，1H)。IR?v：3412，3066，2959，1751，1209，1182，1035cm
-1。
Embodiment 2:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (ethylene chlorhydrin) ester (Compound I-2) also for 2-(2-chloro-phenyl-)-2-
Replace the 2-fluoroethanol with ethylene chlorhydrin, with reference to the method synthetic compound I-2 of embodiment 1.Colourless transparent crystal, yield 93.7%, m.p.91.8～92.8 ℃.Rf:0.43[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
1H-NMR(CDCl
3，400MHz)δ：2.877～2.940(m，4H)，3.617～3.668(q，3H)，3.744(d，J＝14Hz，1H)，4.337～4.412(m，2H)，4.947(s，1H)，6.664(d，J＝4.8Hz，1H)，7.052(d，J＝5.2Hz，1H)，7.235～7.298(m，2H)，7.384～7.407(m，1H)，7.679～7.703(m，1H)。IR?v：3099，3085，2962，2931，2902，2844，1744，1204，1183，1047，1035，761cm
-1。
Embodiment 3:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2,2)-trifluoroethanol) ester (Compound I-3) also for 2-(4-fluorophenyl)-2-
In being housed, the reaction flask of drying tube adds (5a) 3.44g, methylene dichloride 50mL, and (2,2,2)-trifluoroethanol 5.07g (0.07mol), DCC 2.54g (0.012mol), DMAP 1.37g (0.011mol) stirs under the room temperature.Behind the 3h, filter, it is a small amount of to add 36% hydrochloric acid, washes 2 times, and saturated sodium bicarbonate solution is washed 2 times, and saturated nacl aqueous solution is washed 1 time, divides and gets organic layer dry filter, evaporate to dryness.Fast preparative chromatography separate colourless transparent oil liquid.Rf:0.44[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
Embodiment 4:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2)-dichlroroethanol) ester (Compound I-4) also for 2-(4-fluorophenyl)-2-
In the exsiccant reaction flask, add (5a) 5.0g, triethylamine 1.80g (0.018mol), chloroform 50mL, be stirred to dissolving under-5 ℃, drip the mixed solution of Vinyl chloroformate 1.94g (0.018mol) and 20mL chloroform then, be warming up to 10 ℃ after dropwising, stir 30min.Drip 2 again, the mixed solution of 2-dichlroroethanol 2.05g (0.018mol) and chloroform 20mL.Dropwise the back and continue to stir 0.5h.Stopped reaction with reaction solution washing 3 times, is got the organic layer drying with distilled water, filters evaporate to dryness.Fast preparative chromatography separate faint yellow transparent oily liquid.Rf:0.42[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
Embodiment 5:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl ethanol) ester (Compound I-5) also for 2-(3-nitrophenyl)-2-
Replace (5a) with (5b), ethylene glycol replaces (2,2,2)-trifluoroethanol, with reference to the method synthetic compound I-5 of embodiment 3, yield 88.7%.Rf:0.39[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
Embodiment 6:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl propyl alcohol) ester (Compound I-6) also for 2-(3-nitrophenyl)-2-
Replace (5a) with (5b), 1, the 2-propylene glycol replaces 2, and the 2-dichlroroethanol is with reference to the method synthetic compound I-6 of embodiment 4, yield 85.3%.Rf:0.37[developping agent: v (sherwood oil): v (ethyl acetate)=4: 1].
Embodiment 7:
Compound I-1 one-tenth hydrochloride: get I-1 oily product 2.0g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 25% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get white solid.
Embodiment 8:
Compound I-3 one-tenth Citrate trianion: get I-3 oily product 2.0g, be dissolved in the 15mL dehydrated alcohol.Be heated to the back adding that refluxes and wait a mole citric acid, continue at the about 2h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Filter, get light yellow solid.
Embodiment 9:
Compound I-5 one-tenth vitriol: get I-5 oily product 2.0g, be dissolved in the 20mL anhydrous methanol.Ice-water bath is cooled to 5 ℃, drip concentrated sulfuric acid solution to pH be 3, continue at stir about 0.5h under the ice-water bath.Filter, get yellow solid.
For 2-substituted-phenyl-2-(4 of the present invention is described more fully, 5,6,7-tetramethylene sulfide also [3,2-c] pharmaceutical composition of pyridine-5 (4H)-yl) acetate (substituted alkyl alcohol) ester, following example of formulations is provided below, and described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention.
Embodiment 10:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-2 72mg
Pregelatinized Starch 100mg
Sodium starch glycolate 10mg
Magnesium Stearate 20mg
10% polyvidone ethanolic soln is an amount of
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.
Embodiment 11:
Prepare tablet with following compositions:
Consumption/sheet
The Citrate trianion 65mg of Compound I-3
Starch 45mg
Microcrystalline Cellulose 40mg
Talcum powder 1mg
Poloxamer 3mg
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier 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 whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 12:
The preparation of injection liquid:
The hydrochloride 40mg of Compound I-1
Propylene glycol 90mg
Polysorbate 80 is an amount of
Distilled water 300mL
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol 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 13:
The preparation of injection lyophilized powder:
The vitriol 44mg of Compound I-5
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparation method: get activeconstituents and add water for injection, regulate pH value to 4～8 with medicinal basic and make its dissolving.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, seals, promptly.
Claims (7)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1, R
2Be at the same time or separately: hydrogen, halogen, nitro;
R
3C for the halogen replacement
1-C
4Alkyl, the C that hydroxyl replaces
1-C
4Alkyl.
2. the preferred following compound of formula I compound as claimed in claim 1:
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-fluoroethanol) ester also for I-12-(2-chloro-phenyl-)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (ethylene chlorhydrin) ester also for I-22-(2-chloro-phenyl-)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2,2)-trifluoroethanol) ester also for I-32-(4-fluorophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate ((2,2)-dichlroroethanol) ester also for I-42-(4-fluorophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl ethanol) ester also for I-52-(3-nitrophenyl)-2-;
(4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines-5 (4H)-yl) acetate (2-hydroxyl propyl alcohol) ester also for I-62-(3-nitrophenyl)-2-.
3. compound according to claim 1, its pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. the formula I compound pharmacy acceptable salt described in claim 3 is preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
5. the preparation method of claim 1 Chinese style I compound is characterized in that:
Prepare by two kinds of methods:
1. alpha-brominated substituted-phenyl toluylic acid (1) is solvent, band aqua with toluene with substituted alkyl alcohol (2), is catalyzer with the tosic acid, and reflux makes ester class intermediate (3).(3) again with 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (4) is in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, with methylene dichloride, trichloromethane, acetonitrile or toluene is solvent, and 25～100 ℃ of reactions make Compound I;
2. (5) and (2) are solvent with methylene dichloride or trichloromethane in the presence of DCC and DMAP or Vinyl chloroformate, and-5～25 ℃ of reactions make Compound I.
6. the pharmaceutical composition of an anti-gastric-ulcer, it comprises formula I compound or its salt and one or more pharmaceutical carriers, vehicle or the thinner for the treatment of significant quantity.
7. claim 1～4 Chinese style I compound and salt thereof the application aspect the preparation medicament for anti-gastric ulcer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102124867A CN101863902B (en) | 2010-06-29 | 2010-06-29 | 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102124867A CN101863902B (en) | 2010-06-29 | 2010-06-29 | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101863902A true CN101863902A (en) | 2010-10-20 |
| CN101863902B CN101863902B (en) | 2012-06-27 |
Family
ID=42955859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102124867A Expired - Fee Related CN101863902B (en) | 2010-06-29 | 2010-06-29 | 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 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101863902B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250114A (en) * | 2011-04-27 | 2011-11-23 | 青岛黄海制药有限责任公司 | Preparation method of clopidogel and sulfate thereof |
| CN102875566A (en) * | 2011-07-15 | 2013-01-16 | 天津药物研究院 | Thiophene derivatives with anti-gastric ulcer effect |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4847265A (en) * | 1987-02-17 | 1989-07-11 | Sanofi | Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it |
| US5190938A (en) * | 1989-10-02 | 1993-03-02 | Sanofi | Derivatives of 2-hydroxythiophene and -furan fused with a nitrogen-containing ring and their application in therapy |
| JP2001158789A (en) * | 1999-12-03 | 2001-06-12 | Nikken Chem Co Ltd | 4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative |
| CN101693718A (en) * | 2009-10-28 | 2010-04-14 | 天津药物研究院 | Ester derivative containing thienopyridine and preparation method and application thereof |
-
2010
- 2010-06-29 CN CN2010102124867A patent/CN101863902B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4847265A (en) * | 1987-02-17 | 1989-07-11 | Sanofi | Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it |
| US5190938A (en) * | 1989-10-02 | 1993-03-02 | Sanofi | Derivatives of 2-hydroxythiophene and -furan fused with a nitrogen-containing ring and their application in therapy |
| JP2001158789A (en) * | 1999-12-03 | 2001-06-12 | Nikken Chem Co Ltd | 4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative |
| CN101693718A (en) * | 2009-10-28 | 2010-04-14 | 天津药物研究院 | Ester derivative containing thienopyridine and preparation method and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250114A (en) * | 2011-04-27 | 2011-11-23 | 青岛黄海制药有限责任公司 | Preparation method of clopidogel and sulfate thereof |
| CN102875566A (en) * | 2011-07-15 | 2013-01-16 | 天津药物研究院 | Thiophene derivatives with anti-gastric ulcer effect |
| CN102875566B (en) * | 2011-07-15 | 2014-08-13 | 天津药物研究院 | Thiophene derivatives with anti-gastric ulcer effect |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101863902B (en) | 2012-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110054624B (en) | Berberine hydrochloride and caffeic acid eutectic compound, preparation method, composition and application thereof | |
| KR101380140B1 (en) | Triacetyl-3-hydroxyphenyladenosine and its use for regulating blood fat | |
| CN101633662A (en) | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof | |
| CN101412690A (en) | Medicinal acid addition salt of silodosin, and preparation and medicament use thereof | |
| CN101712692A (en) | Medicinal acid addition salt of tenofovir disoproxil fumarate and preparation method and medicinal application thereof | |
| CN101098867B (en) | Substituted sulfoxide compound and its preparing method and application | |
| CN110041326B (en) | Eutectic compound of berberine hydrochloride and fumaric acid, preparation method, composition and application thereof | |
| CN101747305A (en) | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof | |
| CN101974015B (en) | Ester compound and preparation method and application thereof | |
| CN101863902B (en) | 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 | |
| CN101962388B (en) | Acetamide derivatives, preparation method and application thereof | |
| CN102838651B (en) | Oleanolic acid derivatives, and preparation method and application thereof | |
| CN113214209B (en) | Hesperetin and carbamazepine eutectic, preparation method, composition and application thereof | |
| CN101863901A (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
| CN113214207B (en) | Hesperetin and betaine eutectic A, preparation method, composition and application thereof | |
| CN103626722B (en) | Nitric oxide donator type Hypoglycemics, Preparation Method And The Use | |
| CN102875566B (en) | Thiophene derivatives with anti-gastric ulcer effect | |
| CN113214208A (en) | Hesperetin and isonicotinamide eutectic crystal, preparation method, composition and application thereof | |
| CN103923033B (en) | There is the piperazine derivative of anti-ulcer effect | |
| CN101863900B (en) | Novel nitric oxide donating thienopyridine derivative and preparation method and application thereof | |
| CN115124419B (en) | Rhein and cytisine eutectic crystal, preparation method, composition and application thereof | |
| CN110452156B (en) | Donepezil and irbesartan eutectic crystal, preparation method, composition and application thereof | |
| CN101492452B (en) | Sulfhydryl benzimidazole derivative containing dioxepane-pyridine | |
| CN101492459B (en) | Compound containing alcoxyl acetyl dihydrogen isoxazole-pyridine | |
| CN101497623B (en) | Compound containing imidazopyridine |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120627 Termination date: 20210629 |