CN102875566B - Thiophene derivatives with anti-gastric ulcer effect - Google Patents
Thiophene derivatives with anti-gastric ulcer effect Download PDFInfo
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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, the pharmaceutical composition that relates to a class and there is compound of anti-ulcer effect and preparation method thereof, contain them and the purposes as 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 the Stomach duodenum local mucous membrane protection factor and mucosal injury are because of due to quantum balancing is 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 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, suppress sour pump method.
Antiacid therapy is in early days to adopt weakly alkaline medicine as in sodium bicarbonate, Magnesium Trisilicate, aluminium hydroxide and bismuth subnitrate etc. and hydrochloric acid in gastric juice to the treatment of stomach ulcer, pH value in gastral cavity is raise, weaken 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 substantially.
H
2receptor antagonist (H
2rA) can selectivity and histamine H
2-R combination, competitive antagonism histamine H
2-R effect, thereby gastric acid secretion inhibiting are current clinical application acid inhibitors the most widely.As cimitidine, Ranitidine HCL, famotidine etc.
Proton pump inhibitor is a current the strongest class acid inhibitor, can strongly inhibited gastric acid secretion, and almost gastric acid inhibitory and effect are lasting completely, and Healing is better than H
2rA.As omeprazole, lansoprazole, pantoprazole.Wherein.Omeprazole is by the research and development of ASTRA company of Sweden, 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 excited gastric acid secretion causing of tissue
2receptor blocking agent is as the good effect of Cimitidine Type A/AB and Ranitidine HCL etc., has advantages of that rapid alleviating pain, short treating period, pathology healing rate are high.And this medicine is without severe side effect, and tolerance is good, be 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 is compared with H
2receptor blocking agent is strong, therefore can make natural hydrochloric acid in gastric juice barrier reduce, and causes the growth of pathogen enterobacteria.
Although the medicine for the treatment of peptide ulceration is a lot, treatment plan is also variation, and short term effect is all more satisfied, still recurrence unavoidably after 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 taking 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
4straight or branched alkyl;
R
2for: hydrogen, C
1-C
4straight or branched alkyl;
R
3for: C
1-C
4straight 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
4straight or branched alkyl, this alkane can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
Preferably 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 also) acetamido)-2-methoxycarbonyl thiophene;
The I-2:5-tertiary butyl-3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-2-methoxycarbonyl thiophene;
I-3:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-4-phenyl-5-(trifluoromethyl)-2-methoxycarbonyl thiophene;
I-4:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-(4-fluorophenyl)-2-methoxycarbonyl thiophene;
I-5:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-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 also) acetamido)-2-methoxycarbonyl thiophene;
I-7:4-cyano group-3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) acetamido)-5-(methylthio group)-2-ethoxycarbonyl thiophene;
I-8:3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) amide-based small)-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
5as aforementioned definitions
Thiophenes (II), in DMF, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide ,-30～10 DEG C of reactions make key intermediate III with 2-halogen acyl halide compounds.Intermediate III is again with 4,5,6,7-tetrahydrothieno pyridines is under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide exist, taking methylene dichloride, trichloromethane or acetonitrile as solvent, 10～80 DEG C of reactions, make Compound I.
Reaction make various compounds or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, Virahol, ether or DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, Virahol, ether or DMSO, drips salt acid ether to pH2, make hydrochloride.Or products therefrom is dissolved in to DMF, acetone, methyl alcohol or ethanol, and the molar lactic acid such as add, obtain 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 parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared 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 (the compounds of this invention) containing in pharmaceutical composition and unit dosage form 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, 0.5～90% (weight) that the scope of active compound amount is composition, another preferred scope is 0.5～70%.
Compound and the pharmacy acceptable salt thereof with formula I structure of the present invention, is having obvious effect aspect treatment anti-gastric-ulcer.
Further illustrate the anti-ulcer effect of the compounds of this invention below by pharmacodynamic experiment.
To the Experiment on Function of 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 etherization rat, sterilization, opens abdominal cavity, expose stomach, inject 10% acetic acid 0.05mL at body of stomach and pyloric antrum intersection with microsyringe 04～0.5mm place under rat serous coat, blank group is injected the physiological saline of isodose, reduction stomach, sews up stomach wall.Postoperative rat freely drinks water, and starts normal raising next day.
Animal grouping and administration: divide 5 groups by rat at random by sex and body weight, 6 every group, be respectively (1) model group: modeling, starts to use distilled water gavage on the 3rd day; (2) compound group: modeling, starts by compound (0.2g/kg) gavage on the 3rd day.
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 1% formalin 10ml, then stomach is soaked in 1% formalin solution to 10min to fix stomach ectonexine.Cut off stomach along greater gastric curvature, stomach is turned up, outwell content distilled water and rinse gently and remove gastric content, stomach is flattened on glass plate, at injection acetic acid solution position, corresponding mucosal surface is observed ulceration situation, the results are shown in Table 1.
Table 1 burns the impact of type gastric ulcer model on rats acetic acid
Test-results demonstration, after rat stomach serous coat hemostasis acetic acid, can make gastric tissue impaired, and ulcer is rounded or oval, central concave, the micro-protuberance of surrounding.Each administration group all has antiulcer action in various degree, even if there is ulcer, the impaired degree of gastric tissue is obviously slight.Result shows, compound of the present invention has significant protective effect to rats acetic acid calcination type gastric ulcer model.
Embodiment
Below in conjunction with embodiment, the present invention is described further, and 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.
Embodiment 1
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 15.7g 3-amino-2-methoxycarbonyl thiophene, after being dissolved with 100mlDMF, add 20.2g triethylamine, at-10 DEG C～5 DEG C, stir, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30ml), after low-temp reaction 3h (flaggy demonstration reacts completely) stirring at room temperature 1h, reaction solution is poured in 200ml cold water, fully stir, filter, obtain brown solid (HPLC:90.5%).Rf=0.66[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
Method with reference to embodiment 1 can conveniently be prepared compound: intermediate III-2～III-7.With 2-bromo butyryl bromide replace chloroacetyl chloride obtain intermediate III-8.
Table 2 intermediate III-2～III-8 list
Embodiment 2
3-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) kharophen)-2-methoxycarbonyl thiophene (Compound I-1)
Stirring is being housed, condenser, in the reaction flask of thermometer, add successively 23.3g intermediate III-1, 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 100mL saturated aqueous common salt, extract by ethyl acetate (50mL × 3), anhydrous sodium sulphate is fully dry, filter, remove solvent under reduced pressure, obtain sorrel oily matter, post separates [moving phase: v (sherwood oil): v (ethyl acetate)=3: 1], Rf=0.55, obtain 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 list
Embodiment 3
Compound I-1 one-tenth hydrochloride: get I-1 white solid product 3.0g, be dissolved in 10mL anhydrous methanol.Ice-water bath is cooled to 10 DEG C, drip 10.5% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under ice-water bath.Filter, obtain white solid, vacuum-drying, m.p.227 DEG C-230 DEG C.
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 DEG C, drip 9.3% sulfuric acid acetone soln to pH be 3, continue at stir about 1h under ice-water bath.Filter, obtain pink solid, vacuum-drying, m.p.219 DEG C-221 DEG C.
Embodiment 5
Compound I-6 one-tenth lactic acid salt: get I-6 white solid product 3.5g, be dissolved in 20mL dehydrated alcohol.After being heated to reflux, the molar lactic acid such as add, 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 DEG C-210 DEG C.
Embodiment 6
Prepare hard gelatin capsule by following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
Embodiment 7
Prepare tablet by following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.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, ensures that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle is crossed 16 mesh sieves and is arranged, 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 to regulate pH value to 4～8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
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 pH value to make its dissolving to 4-8 with medicinal basic.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, and sealing, to obtain final product.
Claims (8)
1. there is compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R
1for: hydrogen, C
1-C
4straight or branched alkyl;
R
2for: hydrogen, C
1-C
4straight or branched alkyl;
R
3for: C
1-C
4straight 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
4straight or branched alkyl, this alkyl can be replaced by halogen; Phenyl, this phenyl can be by halogen, nitro, C
1-C
4straight or branched alkyl replaces; Cyano group; Methylthio group; Methylsulfonyl.
2. compound and the pharmacy acceptable salt thereof of formula I structure as claimed in claim 1, 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. compound and the pharmacy acceptable salt thereof of formula I structure as claimed in claim 1, 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, sodium carbonate, sodium bicarbonate, under the catalysis of sodium hydroxide or potassium hydroxide,-30～10 DEG C of reactions make key intermediate III, intermediate III and 4, 5, 6, 7-tetrahydrothieno pyridines is at triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, under sodium hydroxide or potassium hydroxide exist, with methylene dichloride, trichloromethane or acetonitrile are solvent, 10～80 DEG C of reactions, make chemical compounds I,
Wherein X is Cl, Br; R
1～R
5as claim 1 defines.
7. a pharmaceutical composition for anti-gastric-ulcer, the formula I compound as claimed in claim 1 that it comprises effective therapeutic dose or its pharmacy acceptable salt and one or more pharmaceutical carriers.
8. the formula I compound of claim 1-3 any one and pharmacy acceptable salt thereof are in the application aspect medicament for anti-gastric ulcer.
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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 |
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| Title |
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| 瞿建国，等.H+ / K+-ATP 酶抑制剂的研究进展.《中国药物化学杂志》.2000,第10卷(第2期),全文. * |
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