CN101497605B - Benzimidazole derivative containing alkoxy substituted pyridine - Google Patents

Benzimidazole derivative containing alkoxy substituted pyridine Download PDF

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CN101497605B
CN101497605B CN200810014119A CN200810014119A CN101497605B CN 101497605 B CN101497605 B CN 101497605B CN 200810014119 A CN200810014119 A CN 200810014119A CN 200810014119 A CN200810014119 A CN 200810014119A CN 101497605 B CN101497605 B CN 101497605B
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acceptable salt
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salt
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methyl
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CN101497605A (en
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a benzimidazole derivative containing pyridine substituted by alkoxy as well as pharmaceutically acceptable salts or isomers thereof shown in a general formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5> and n are defined as the specification. The invention also relates to a method for preparing the compounds and a pharmaceutical composition containing the compounds, and application of the compounds to preparing the medicines for treating and/or preventing peptic ulcer.

Description

The benzimidizole derivatives that contains the substituted pyridine of alkoxy
1, technical field
The invention belongs to medical technical field; Be specifically related to contain benzimidizole derivatives, its pharmacy acceptable salt and the isomer thereof of the substituted pyridine of alkoxy; The preparation method of these compounds; The pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent the application in the medicine of peptide ulceration in preparation.
2, background technology
Digestive system is one of common frdquently encountered disease, and wherein the Peptic Ulcers sickness rate accounts for 10%～12% of total population.Initial treat-ment mainly is to use in the antacid (like sodium hydrogencarbonate, white lake etc.) purpose that reaches mitigation symptoms with hydrochloric acid in gastric juice.After the seventies in 20th century, along with H 2The discovery of gastric acid secretion inhibitor such as receptor blocking agent, proton pump inhibitor, the New Times of having started treatment of peptic ulcer, these medicines have instant effect, characteristics that ulcer healing rate is high, reduce the surgical operation rate greatly.
Omeprazole is the proton pump inhibitor of first listing, relies on its unique curative effect, at anti-ulcer medicament market and H 2In the competition of receptor blocking agent, progressively obtain windward, 1996, become the first in the world best-selling drugs, and occupy the first place for successive years.Behind omeprazole, new proton pump inhibitor constantly comes out, lansoprazole, pantoprazole, rabeprazole and the esomeprazole in addition of listing successively.Yet; This type drug effect time is slow, and drug effect is strong inadequately, and need take medicine several times (after being several days) just can be obtained the maximum sour effect that presses down; And differ to stablize in 24 hours surely and press down acid; Take medicine and eating time all possibly influence drug effect and pharmacokinetic parameter, the pharmacokinetics difference between individuals is big, interacts obviously with other drug.
Therefore develop one type rapid-action, it is effective to press down acid, can continue in 24 hours to press down acid, difference between individuals is little, becomes market demand with other medicines few proton pump inhibitor that interacts.
3, summary of the invention
The inventor provides one type of proton pump inhibitor through a large amount of experimental studies, has good gastric acid inhibitory excretory effect.
Technical scheme of the present invention is following:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt and isomer thereof:
Figure S2008100141199D00011
Wherein: R 1Represent Wasserstoffatoms or carboxyl-protecting group;
R 2, R 3Independently represent Wasserstoffatoms, C respectively 1-6Alkyl or C 1-6Alkoxyl group;
R 4, R 5Independently represent Wasserstoffatoms respectively, halogen atom or be not substituted or by the substituted C of halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
N represents 1～6 integer.
Preferred compound is:
Wherein: R 1Represent Wasserstoffatoms or carboxyl-protecting group, described carboxyl-protecting group is selected from: methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl-, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R 2, R 3Independently represent Wasserstoffatoms respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy or butoxy;
R 4, R 5Independently represent Wasserstoffatoms respectively, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, propyl group; Sec.-propyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, methyl fluoride; Difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy or 1,1-two fluoro-oxyethyl groups;
N represents 1,2,3 or 5.
Further preferred compound is:
Wherein: R 1Represent Wasserstoffatoms or carboxyl-protecting group, described carboxyl-protecting group is selected from: methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R 2, R 3Independently represent Wasserstoffatoms respectively, methyl, ethyl, propyl group, methoxyl group, oxyethyl group or propoxy-;
R 4, R 5Independently represent Wasserstoffatoms respectively, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, methoxyl group, oxyethyl group, difluoromethyl, trifluoromethyl, difluoro-methoxy or trifluoromethoxy;
N represents 1,2,3 or 4.
Further preferred compound is:
Wherein: R 1Represent Wasserstoffatoms or carboxyl-protecting group, described carboxyl-protecting group is selected from: methyl, the tertiary butyl, to nitrobenzyl, allyl group or benzyl;
R 2, R 3Independently represent Wasserstoffatoms, methyl, ethyl, methoxy or ethoxy respectively;
R 4, R 5Independently represent Wasserstoffatoms, methyl, ethyl, methoxy or ethoxy respectively;
N represents 1,2,3 or 4.
" halogen atom " according to the invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.
" C according to the invention 1-6Alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, neo-pentyl, hexyl etc.
" C according to the invention 1-6Alkoxyl group " be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.
" carboxyl-protecting group " mentioned above refers to that routine is used for the blocking group of substituted carboxylic acid character.This examples of groups comprises: methoxymethyl, first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxyethyl methyl, benzyloxymethyl, phenacyl-, to bromobenzene formyl methyl, Alpha-Methyl phenacyl-, to methoxybenzoyl methyl, diacyl methyl, N-phthalimidomethyl, ethyl, 2; 2; 2-three chloroethyls, 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9; The 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, 2; 4; The 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, sec.-propyl dimetylsilyl, phenyl dimetylsilyl, the S-tertiary butyl, S-phenyl, S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2; 4-dinitrobenzene sulfenyl, 2-alkyl-1; 3-oxazoline, 4-alkyl-5-oxo-1; 3-oxazolidine, 5-alkyl-4-oxo-1,3-diox, triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides.
Further preferred compound is following:
Chemical name: 4-carboxyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methylsulfinyl]-benzoglyoxaline, be called for short compound 1.Structural formula:
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method,
Reactions step:
The preparation of step 1 midbody 1
Raw material 1 is dropped in the reaction flask, add ETHYLE ACETATE, add oxyethyl group sulphur ortho acid potassium then, reflux, reaction is finished; Be chilled to room temperature, reaction solution is poured in the frozen water, after stirring, regulate pH, separate out solid with hydrochloric acid; Filtration, washing is to neutral, and filter cake in vacuum is dry, gets midbody 1.
The preparation of step 2 midbody 2
Adding raw material 2 in the exsiccant reaction flask, raw material 3, potassium carbonate powder, heated and stirred refluxes, and stopped reaction is chilled to room temperature, filters, and filtrate decompression concentrates and reclaims excessive raw material 3, gets midbody 2.
The preparation of step 3 midbody 3
In the exsiccant reaction flask, add midbody 2, diacetyl oxide, the intensification stirring reaction removes diacetyl oxide under reduced pressure, hydro-oxidation sodium solution in residue, stirring reaction use chloroform extraction, dry concentrated midbody 3.
The preparation of step 4 midbody 4
In midbody 3, add methylene dichloride, cooling is added dropwise to sulfur oxychloride, stirs after dripping off, and removes methylene dichloride and sulfur oxychloride under reduced pressure, and in debris, add yellow soda ash then and dissolve, chloroform extraction, combining extraction liquid, drying concentrates, and gets midbody 4.
The preparation of step 5 midbody 5
In midbody 4, add ethanol, midbody 1, sodium hydroxide, the intensification stirring reaction removes ethanol under reduced pressure, and chloroform extraction is dry, concentrates, and ethyl alcohol recrystallization gets midbody 5.
The preparation of step 6 The compounds of this invention
Add midbody 5 in the reaction flask, methylene dichloride stirs cooling down, adds raw material 4 in batches, adds the back stirring reaction; Add triethylamine, stir the back and heat up, add sodium carbonate solution, stir layering; The water dichloromethane extraction, extraction liquid merges, and drying concentrates, and crosses to filter bullion.Bullion is added absolute ethyl alcohol, and heating for dissolving is filtered, and filtrating adds diethyl ether, and deposition occurs, filters, and gets The compounds of this invention.
Reaction equation:
Figure S2008100141199D00041
R in the above reaction equation 1, R 2, R 3, R 4, R 5Said with n such as preamble.
The The compounds of this invention pharmacy acceptable salt does not have special restriction, and instance comprises inorganic acid addition salt, example hydrochloric acid salt, vitriol, nitrate salt, phosphoric acid salt, hydrobromate and hydriodate; Organic acid addition salt is like formate, acetate, propionic salt, oxalate, malonate, SUMATRIPTAN SUCCINATE, PHENRAMINE MALEATE, fumarate, lactic acid salt, malate, Citrate trianion, tartrate, mesylate, esilate, benzene sulfonate, tosylate and a tetrafluoro borate; Amino acid salts is like arginic acid salt, aspartate and glutaminate; Metal-salt is like lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and bismuth salt.Be preferably: hydrochloride, hydrobromate, hydriodate; Acetate, PHENRAMINE MALEATE, fumarate, lactic acid salt, malate, Citrate trianion, tartrate, mesylate, benzene sulfonate; Arginic acid salt, glutaminate, sodium salt, sylvite, calcium salt, magnesium salts.
The compounds of this invention can also exist with enantiomeric forms, and when a key was represented with a wedge, this was illustrated in three-dimensional this key of going up and will comes out from paper, and when a key was shade, this was illustrated in three-dimensional this key of going up and will returns in the paper.Formula (I) compound has three-dimensional center, and these isomer are also included within the scope of the present invention.
The compounds of this invention also can with hydrate or form exist, these hydrates should be also included within the scope of the present invention.
Proton pump inhibitor (PPIs) can gastric acid inhibitory secretion treatment peptide ulceration, its mechanism be through with near the stomach H that is positioned at the parietal cell secretory tubyle acid space +/ K +Serine molecule on the-ATP enzyme combines to play a role, and in the sour environment of secretory tubyle, is converted into the active amide based compound earlier, presents the dose-dependent inhibition basis then and stimulates the back gastric acid secretion.
A large amount of researchs prove that anti-Hp (Hp) infects and the generation and the recurrence of peptide ulceration have close getting in touch, and it is particularly important therefore in treatment ulcer, to eradicate Hp.Proton pump inhibitor has the effect that suppresses or kill Hp; Show two aspects: (1) directly suppresses Hp; Its mechanism is PPIs increased activity in sour environment, and penetrable rete malpighii combines with the urease on Hp top layer, suppresses urease activity and reaches the Hp effect that suppresses; (2) PPIs can act synergistically with antimicrobial drug; Many antimicrobial drugs have very strong anti-Hp effect external, but not acidproof, in gastric juice, are prone to degraded; Can not play one's part to the full; Raise with stomach pH behind the PPIs, bring into play anti-Hp effect for antimicrobial drug environment preferably is provided, make acid nonfast antimicrobial drug can bring into play maximum bactericidal effect.
The compounds of this invention is a proton pump inhibitor; The invention still further relates to The compounds of this invention or its pharmacy acceptable salt inhibition Mammals and people's gastric acid secretion; Prevention and treatment Mammals and people's gastroenteritis disease and with the hydrochloric acid in gastric juice diseases associated, for example: gastritis, stomach ulcer, duodenal ulcer and backflow esophagitis.In addition; The compounds of this invention also can be used for other gastrointestinal illness that need utilize the gastric acid inhibitory secretion to treat; For example, be used for carrying out the patient of NSAIDs (NSAID) treatment, be used to treat stomach gangrene (Gastrinomas) and acute upper stomach enterorrhagia.It also can be used for the patient that need give someone extra help, and is used for before the art absorbing and stress ulcer formation with the acid that prevents of postoperative.The compounds of this invention also can be used to treat or prevent to comprise people's mammiferous inflammation, particularly relevant with N,O-Diacetylmuramidase disease.
The present invention further requires to protect the pharmaceutical composition that comprises The compounds of this invention, its pharmacy acceptable salt or its isomer and other activeconstituents; Be used to treat or prevent the relevant disease of peptide ulceration; Described other active ingredient can be an antiseptic-germicide, particularly:
1) β-Nei Xiananleikangshengsu is like amoxycilline Trihydrate bp, Ampicillin Trihydrate, cefoxitin, cefaclor or Cefixime Micronized etc.;
2) Macrolide is like Oxacyclotetradecane,erythromycin deriv or clarithromycin etc.;
3) tetracyclines is like tsiklomitsin or Vibravenos etc.;
4) aminoglycoside is like qingfengmeisu qiong, kantlex or amikacin etc.;
5) quinolones is like norfloxicin, CIPROFLOXACIN USP 24 or enoxacin etc.;
6) other, like metronidazole, Norwich) or paraxin etc.; Or
7) comprise the preparation of bismuth salt, like preparation of acid bismuth citrate, bismuth subsalicylate, Bismuth Subcarbonate, Vikaline or Bismuth Subgallate etc.
Can also be antacid, like white lake, Marinco H, magnesiumcarbonate and magnesium aluminate etc.;
Sedative drugs prescriptions like tranquilizer, comprises diamino heterocycle heptantriene etc.;
Spasmolytic is like bietamiverine and acamylophenine etc.;
Anticholinergic is like oxygen phenyl ring imines and phenol urea etc.;
Part narcotic is like tetracaine and PROCAINE HCL, PHARMA GRADE etc.;
Non-steroidal anti-inflammatory drug is like INDOMETHACIN BP99, Frosst) and NAPROXEN USP /BP2000 etc.;
Steroid or nitrite remover are like xitix and thionamic acid etc.;
Other stomach ulcer medicines for treatment are like pirenzipine etc.;
The prostaglandin(PG) medicine, as 16,16-dimethyl-PGE2 etc.;
Histamine H 2-antagonist, for example CIMETIDINE etc.
The present invention further requires to protect the pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner; For clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral prepns or injection.Wherein contain the compound 0.01～500mg shown in the general formula (I) of physiology significant quantity; Be preferably 0.05～200mg; More preferably 0.1～120mg specifically comprises 0.1mg, 0.5mg, 1mg, 2mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 80mg, 100mg, 120mg; Can be by 1～4 time arrangement every day, give said compound 1～2 time preferred every day.
Arbitrary compound of the present invention and pharmacy acceptable salt thereof can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means that confession that medicine is processed injects intravital solution, emulsion or suspension and confession and face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution, and injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is processed is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and big volume (generally the being not less than 100ml) injection liquid that wherein supplies intravenous drip to use is also claimed intravenous infusion.Injectable sterile powder means that confession that medicine is processed is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension; Available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is processed faces the aseptic strong solution that supplies intravenous drip to use with preceding dilution.
When processing injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection VT 18, and other also have the aqueous solution of ethanol, Ucar 35, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, like osmotic pressure regulator, pH value regulator, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value regulator commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium hydrogencarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, Ucar 35, Yelkin TTS, Witconol 5909 etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, Expex etc.; Oxidation inhibitor commonly used has S-WAT, sodium sulfite anhy 96, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, like tablet, capsule, pill, granule etc.; Also can be made into oral liquid, like oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and suitable auxiliary materials and mixing compacting form; With oral ordinary tablet is main, and other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in the solid preparation in the soft capsule material; According to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is processed comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material process the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution is processed and supplies oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, processes to supply oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When processing oral prepns, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, TKK 021, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, PVPP, Sodium Croscarmellose, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The benzimidizole derivatives that contains the substituted pyridine of alkoxy of the present invention is compared with immediate prior art, has the following advantages:
1) The compounds of this invention can suppress Mammals and people's gastric acid secretion significantly, does not have potential toxic side effect, oral no GI irritation property;
2) be lower than when being generally used for gastric acid inhibitory excretory effective dose when taking; Then has provide protection to organs such as stomach, intestines; Be meant prevention and treatment, refer in particular to the disease and the damage (for example stomach ulcer, duodenal ulcer and because the gastric irritation that hyperchlorhydria or medicament cause) of stomach inflammation gastroenteropathy;
3) The compounds of this invention has higher chemicalstability, less by people CYP 2C 19Metabolism, and have low CYP 1A 2Inducibility;
4) the weak curative effect heteropole of The compounds of this invention between individuality is little, guarantees that the patient who accepts the same dose medicine can obtain suitable curative effect comparably;
5) The compounds of this invention has low passing through and induces CYP 1The danger of A family member enzyme and the drug interaction that causes and low cancer development are dangerous, safe;
6) The compounds of this invention is rapid-action, strong drug action, and long half time presses down sour effect stability;
7) The compounds of this invention preparation technology is simple, and medicine purity is high, high, the steady quality of yield, is easy to carry out large-scale commercial prodn.
Below further set forth the beneficial effect of compound of the present invention, but should this be interpreted as that The compounds of this invention only has following beneficial effect through experimental example.
1 couple of H of experimental example The compounds of this invention +-K +The inhibition of atpase activity
(1) H +-K +The preparation of ATPase
Improve one's methods (seeing Biochem.and Biophys.Acta, 464,313 (1977)) according to people such as Saccomani prepares H with the substrate body of gland of fresh pig stomach mucous membrane +-K +ATPase.
(2) H +-K +The mensuration of atpase activity
In pH is 7.40 40mM Tri(Hydroxymethyl) Amino Methane Hydrochloride buffered soln, with the The compounds of this invention methanol solution and the H of different concns +-K +The protein of ATPase and 10 μ g/ml at 37 ℃ of following constant temperature culture 30min, adds 15mM Repone K after mixing then.Behind the 10min, add 3mM magnesium chloride and Triphosaden again and make the atp enzyme reaction begin to carry out.After 10min, measure the amount of the inorganic phosphate that discharges according to the method (seeing Biochem.Biophys.Res.Com., 40,880 (1970)) of Yoda and Hokin.
(3) mensuration of inhibition effect: in above-mentioned experiment; To deduct the amount of the inorganic phosphate of behind the solution that adds a certain experimental compound, being emitted in the amount of the inorganic phosphate that only adds in the controlled trial to be emitted; The gained difference is represented with percentage ratio divided by the amount of the inorganic phosphate of controlled trial again, suppressed effect and use IC 50Expression.
Experimental result:
Table 1 couple H +-K +The restraining effect of atpase activity
Compound IC 50(M)
Rabeprazole compound 1 2.7×10 -5 4.6×10 -7
Experimental result shows, 1 couple of H of The compounds of this invention +-K +The activity of ATPase has higher inhibition effect, and the security of height is arranged.So, can suppress the secretion of acid effectively, thereby can effectively treat and prevention of digestive tract ulcers.Compare more remarkable effect with rabeprazole.
4, embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 2-sulfydryl-4-methoxycarbonyl-benzoglyoxaline
With 2,3-diamino--oil of Niobe 10g (60mmol) drops in the reaction flask, adds ETHYLE ACETATE 200ml, adds oxyethyl group sulphur ortho acid potassium 12.8g (80mmol) then, at 80 ℃ of following reflux 4h.Reaction is finished, and is chilled to room temperature, and reaction solution is poured in the 200ml frozen water, after stirring, regulates pH3～4 with the hydrochloric acid of 4N, separates out solid, filtration, and washing is to neutral, and filter cake in vacuum is dry, gets product 9.1g, yield: 73.2%.
Embodiment 2 4-(3-methoxy propoxy)-2, the preparation of 3-dimethyl--N-pyridine oxide
The 4-(3-methoxy propoxy)-2 that in the exsiccant reaction flask, adds 16.8g (100mmol), 3-dimethyl--N-pyridine oxide, 1, ammediol monomethyl ether 100ml; Potassium carbonate powder 20g, heated and stirred backflow 12h, stopped reaction is chilled to room temperature; Filter, filtrate decompression concentrate reclaim excessive 1, the ammediol monomethyl ether, oily matter 4-(3-methoxy propoxy)-2; 3-dimethyl--N-pyridine oxide 11.2g, yield: 53.2%, directly drop into to go on foot down and react.
The preparation of embodiment 3 4-(3-methoxy propoxy)-2-methylol-3-methyl-pyridine
The 4-(3-methoxy propoxy)-2 that in the exsiccant reaction flask, adds 21.1g (100mol), 3-dimethyl--N-pyridine oxide, 200ml diacetyl oxide; Be warmed up to 60 ℃ of stirring reactions 1 hour, remove diacetyl oxide under reduced pressure, in residue, add 2N sodium hydroxide solution 150ml; 40 ℃ of stirring reactions 4 hours; With chloroform (100ml * 3) extraction, dry concentrate oily matter 14.8g, yield 70.2%.
The preparation of embodiment 4 4-(3-methoxy propoxy)-2-chloromethyl-3-methyl-pyridine
In 4-(3-methoxy propoxy)-2-methylol-3-methyl-pyridine 16.9g (80mmol), add methylene dichloride 400ml, be as cold as 0 ℃, be added dropwise to sulfur oxychloride 15ml; Drip off back stirring at room 1 hour, remove methylene dichloride and sulfur oxychloride under reduced pressure, in debris, add 10% sodium carbonate solution 90ml then; Chloroform extraction (100ml * 3), combining extraction liquid, drying; Concentrate, get product 16.7g, yield 91.1%.
The system of embodiment 5 4-methoxycarbonyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methyl sulphur]-benzoglyoxaline Be equipped with
In 4-(3-methoxy propoxy)-2-chloromethyl-3-methyl-pyridine 16.1g (70mmol), add ethanol 200ml, 2-sulfydryl-4-methoxycarbonyl-benzoglyoxaline 15.6g (75mmol), 2N sodium hydroxide 50ml; Be warmed up to 70 ℃ of stirring reactions 1 hour, remove ethanol under reduced pressure, chloroform extraction (150ml * 3) drying; Concentrate; Ethyl alcohol recrystallization gets solid 14.6g, yield 52.1%.
Embodiment 6 4-methoxycarbonyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methylsulfinyl]-benzo miaow The preparation of azoles
Add 4-methoxycarbonyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methyl sulphur]-benzoglyoxaline 12.0g (30mmol) in the reaction flask, methylene dichloride 160ml is as cold as-30 ℃ under stirring, under this temperature; Add 5g (29mmol) metachloroperbenzoic acid in batches, added the back stirring reaction 2 hours, add the 2ml triethylamine; Stir and be warmed up to 0 ℃ after 30 minutes, add 5% sodium carbonate solution 200ml, stirring at room 1 hour; Layering, water dichloromethane extraction (150ml * 2), extraction liquid merges; Drying concentrates, and crosses and filters bullion.Bullion is added the 100ml absolute ethyl alcohol, heating for dissolving, filtration, filtrating adds the 200ml ether, deposition occurs, filters, and gets off-white color solids 11.3g, yield 90.6%.
Embodiment 7 4-carboxyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methylsulfinyl]-benzoglyoxaline Preparation
In reaction flask, add 4-methoxycarbonyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methylsulfinyl] benzoglyoxaline 4.2g (10mmol), absolute ethyl alcohol 20ml, the 1N HCl of 10ml, heated and stirred backflow 2h.Reaction is finished, and removes solvent under reduced pressure, and residuum adds 20ml ethanol again, and heating for dissolving postcooling crystallization gets product 3.2g, yield: 78.5%.
Molecular formula: C 19H 21N 3O 5S
Molecular weight: 403.45
Ultimate analysis: measured value: C, 56.34%; H, 5.46%; N, 10.21%; S, 8.18%
Calculated value: C, 56.56%; H, 5.25%; N, 10.42%; S, 7.95%
The preparation of embodiment 8 The compounds of this invention freeze-dried powders
1, prescription:
Prescription 1:
Any one 20g in compound 1 or derivatives thereof
N.F,USP MANNITOL 80g
EDTA-Na 2 5g
Water for injection adds to 1000ml
Prescription 2:
Any one 40g in compound 1 or derivatives thereof
N.F,USP MANNITOL 160g
EDTA-Na 2 10g
Water for injection adds to 1000ml
2, preparation technology: take by weighing supplementary material by prescription; There is the water for injection of dosing amount 80% to dissolve in N.F,USP MANNITOL, adds EDTA-Na 2Dissolving; Any one stirring and dissolving in compound 1 or derivatives thereof is complete, measures the pH value, regulates pH to proper range with hydrochloric acid and the sodium hydroxide of 1mol/L, adds water for injection to full dose; The gac that adds dosing amount 0.05%, 30 ℃ of insulated and stirred 20min, filtering decarbonization is with 0.45 μ m filtering with microporous membrane; The inspection of semifinished product, soup are checked clarity with 0.22 μ m filtering with microporous membrane; Can, false add plug, freeze-drying, freeze-dry process is: 40mg;
Specification freeze-dry process :-40 ℃ of pre-freeze 3h ,-40～-5 ℃ of low-temperature distillation 15h ,-5～30 ℃ of dry 4h that heat up, 30 ℃ of high temperature drying 2.5h; Freeze-drying finishes, and lid is rolled in tamponade, packing, full inspection.
The preparation of embodiment 9 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 15g in compound 1 or derivatives thereof
Microcrystalline Cellulose 15g
Pregelatinized Starch 20g
Low-substituted hydroxypropyl methylcellulose 10g
Magnesium Stearate 0.6g
Micropowder silica gel 1g
Prepare 1000 altogether
Prescription 2:
Any one 30g in compound 1 or derivatives thereof
Microcrystalline Cellulose 30g
Pregelatinized Starch 40g
Low-substituted hydroxypropyl methylcellulose 20g
Magnesium Stearate 1.2g
Micropowder silica gel 2g
Prepare 1000 altogether
2, preparation technology: raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are subsequent use; Take by weighing raw material and auxiliary material according to recipe quantity; With in compound 1 or derivatives thereof any one, Microcrystalline Cellulose, pregelatinized Starch, low-substituted hydroxypropyl methylcellulose mix granulation, adds Magnesium Stearate then, micropowder silica gel is lubricated, sampling, work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
The capsular preparation of embodiment 10 The compounds of this invention
1, prescription:
Prescription 1:
Any one 15g in compound 1 or derivatives thereof
Microcrystalline Cellulose 15g
Pregelatinized Starch 15g
Starch 10g
Magnesium Stearate 0.5g
Micropowder silica gel 1g
Prepare 1000 altogether
Prescription 2:
Any one 30g in compound 1 or derivatives thereof
Microcrystalline Cellulose 30g
Pregelatinized Starch 30g
Starch 20g
Magnesium Stearate 1g
Micropowder silica gel 2g
Prepare 1000 altogether
2, preparation technology: raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are subsequent use; Take by weighing raw material and auxiliary material according to recipe quantity; With in compound 1 or derivatives thereof any one, Microcrystalline Cellulose, pregelatinized Starch, starch mix granulation, adds Magnesium Stearate then, micropowder silica gel is lubricated, sampling, work in-process chemical examination; The loading amount of confirming according to chemical examination incapsulates; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 11 The compounds of this invention enteric coated tablet
1, prescription:
Prescription 1:
Any one 10g in compound 1 or derivatives thereof
Microcrystalline Cellulose 15g
Pregelatinized Starch 20g
Low-substituted hydroxypropyl methylcellulose 10g
Magnesium Stearate 0.6g
Micropowder silica gel 1g
Prepare 1000 altogether
Prescription 2:
Any one 20g in compound 1 or derivatives thereof
Microcrystalline Cellulose 30g
Pregelatinized Starch 40g
Low-substituted hydroxypropyl methylcellulose 20g
Magnesium Stearate 1.2g
Micropowder silica gel 2g
Prepare 1000 altogether
2, preparation technology:
Plain sheet preparation: main ingredient was pulverized 100 mesh sieves, took by weighing supplementary material by recipe quantity, with Microcrystalline Cellulose, and pregelatinized Starch; Low-substituted hydroxypropyl methylcellulose and main ingredient mix, and add water and make softwood in right amount, and softwood is crossed 18 mesh sieves and granulated, and particle is at 60 ℃ of baking oven inner dryings; Drying finishes, and crosses the whole grain of 18 mesh sieves, adds Magnesium Stearate and micropowder silica gel; Mix, the inspection of semifinished product, trim plate is heavy, compressing tablet.Dressing: it is subsequent use that Virahol and the water stirring and evenly mixing that Opadry enteric coating powder adds recipe quantity is prepared into coating liquid, gets plain sheet and put in the coating pan, and label is preheating to 40 ℃, begins to spray coating liquid.Coating pan rotating speed 25r/min, spray pressure 0.3Mpa-0.4Mpa, the label temperature is controlled at 30～40 ℃, dressing increase weight sheet heavy 7%, stop spraying, continue heating, be put in the pallet after treating to take out after the tablet drying and cool.

Claims (9)

1. the compound shown in the general formula (I), its pharmacy acceptable salt:
Figure FSB00000764749400011
Wherein: R 1Represent Wasserstoffatoms;
R 2, R 3Independently represent Wasserstoffatoms, C respectively 1-6Alkyl or C 1-6Alkoxyl group;
R 4, R 5Independently represent Wasserstoffatoms, C respectively 1-6Alkyl or C 1-6Alkoxyl group;
N represents 1～6 integer.
2. compound as claimed in claim 1, its pharmacy acceptable salt:
Wherein: R 1Represent Wasserstoffatoms;
R 2, R 3Independently represent Wasserstoffatoms respectively, methyl, ethyl, propyl group, methoxyl group, oxyethyl group or propoxy-;
R 4, R 5Independently represent Wasserstoffatoms, methyl, ethyl, methoxy or ethoxy respectively;
N represents 1,2,3 or 4.
3. compound as claimed in claim 2, its pharmacy acceptable salt:
Wherein: R 1Represent Wasserstoffatoms;
R 2, R 3Independently represent Wasserstoffatoms, methyl, ethyl, methoxy or ethoxy respectively;
R 4, R 5Independently represent Wasserstoffatoms, methyl, ethyl, methoxy or ethoxy respectively;
N represents 1,2,3 or 4.
4. compound as claimed in claim 3, its pharmacy acceptable salt, said compound does
4-carboxyl-2-[[4-(3-methoxy propoxy)-3-methyl-pyridine-2-yl] methylsulfinyl]-benzoglyoxaline.
5. like the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt; Its pharmacy acceptable salt is an inorganic acid addition salt; Organic acid addition salt and metal-salt are selected from hydrochloride, hydrobromate, hydriodate, acetate, PHENRAMINE MALEATE, fumarate, lactic acid salt, malate, Citrate trianion, tartrate, mesylate, benzene sulfonate; Arginic acid salt, glutaminate, sodium salt, sylvite, calcium salt, magnesium salts.
6. the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
7. pharmaceutical composition as claimed in claim 6 contains the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt 0.01～500mg as essential activeconstituents.
8. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt and other activeconstituentss.
9. the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt treat and/or prevent the application in the medicine of peptide ulceration in preparation.
CN200810014119A 2008-01-30 2008-01-30 Benzimidazole derivative containing alkoxy substituted pyridine Active CN101497605B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4359465A (en) * 1980-07-28 1982-11-16 The Upjohn Company Methods for treating gastrointestinal inflammation
CN1642941A (en) * 2002-03-29 2005-07-20 泽里新药工业株式会社 1-N-aminobenzimidazole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4359465A (en) * 1980-07-28 1982-11-16 The Upjohn Company Methods for treating gastrointestinal inflammation
CN1642941A (en) * 2002-03-29 2005-07-20 泽里新药工业株式会社 1-N-aminobenzimidazole derivatives

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