CN101492460B - Benzimidazole derivative containing alkoxyl oxygen alkyl substituted pyridine-tetrahydrochysene isoxazole - Google Patents
Benzimidazole derivative containing alkoxyl oxygen alkyl substituted pyridine-tetrahydrochysene isoxazole Download PDFInfo
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- CN101492460B CN101492460B CN2008100138904A CN200810013890A CN101492460B CN 101492460 B CN101492460 B CN 101492460B CN 2008100138904 A CN2008100138904 A CN 2008100138904A CN 200810013890 A CN200810013890 A CN 200810013890A CN 101492460 B CN101492460 B CN 101492460B
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Abstract
The invention belongs to the pharmaceutical technical field and specifically relates to benzoglioxaline derivatives which are shown in general formula (I) and contain naphthyridine tetrahydrochysene isoxazole substituted by alcoxyl alkyl, pharmaceutically acceptable salts and isomers thereof, wherein, R<1>, R<2> and R<3> are defined as in the specification. The invention also relates to preparation methods of the compounds, drug compositions containing the compounds and the application of the compounds in preparing drugs for preventing and/or treating digestive ulcer.
Description
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 pyridine-tetrahydrochysene isoxazole that alkoxyalkyl replaces, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent application in the medicine of peptide ulceration in preparation.
2, background technology
Digestive system is one of common frequently-occurring disease, and wherein the Peptic Ulcers sickness rate accounts for 10%～12% of total population.Initial methods of treatment mainly is to use the purpose that reaches mitigation symptoms in the antacid (as sodium bicarbonate, aluminium hydroxide etc.) 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, have lowered 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 antagonist, 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 class drug effect time is slow, drug effect is strong inadequately, need take medicine several times (and after several days) just can obtain 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 may influence drug effect and pharmacokinetic parameter, the pharmacokinetics individual difference is big, interacts obviously with other drug.
Therefore it is rapid-action to develop a class, but sour effective, and energy continued to press down sour in 24 hours, and individual difference is little, and the proton pump inhibitor few with the other medicines interaction becomes market demand.
3, summary of the invention
In order to address the above problem, the inventor provides a class proton pump inhibitor through great deal of experimental, has good gastric acid inhibitory excretory effect.
Technical scheme of the present invention is as follows:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt and isomer thereof:
Wherein: R
1, R
2Independently represent hydrogen atom respectively, replaced by halogen atom or unsubstituted C
1-6Alkyl or C
1-6Alkoxyl group;
R
3Representative is replaced by halogen atom or unsubstituted C
1-6Alkyl.
Preferred compound is:
Wherein: R
1Represent hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, methoxyl group, oxyethyl group, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 1-fluoro-oxyethyl group, 1,1-two fluoro-oxyethyl groups, 1,1,1-three fluoro-oxyethyl groups, 2,2-two fluoro-oxyethyl groups or 1,1,2,2-tetrafluoro-oxyethyl group;
R
2Represent methylidene, ethyl, propyl group, sec.-propyl, the tertiary butyl, methoxyl group, oxyethyl group, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 1-fluoro-oxyethyl group, 1,1-two fluoro-oxyethyl groups, 1,1,1-three fluoro-oxyethyl groups, 2,2-two fluoro-oxyethyl groups or 1,1,2,2-tetrafluoro-oxyethyl group;
R
3Represent methylidene, ethyl, propyl group, sec.-propyl, difluoromethyl or trifluoromethyl.
Further preferred compound is:
Wherein: R
1Represent hydrogen atom, methyl, methoxyl group, methyl fluoride, difluoromethyl, trifluoromethyl, fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;
R
2Represent methylidene, methyl fluoride, difluoromethyl, trifluoromethyl, ethyl, methoxy or ethoxy;
R
3Represent methylidene, difluoromethyl, trifluoromethyl or ethyl.
Further preferred compound is:
Wherein: R
1Represent hydrogen atom, methoxyl group, fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;
R
2Represent methylidene, ethyl or methoxyl group;
R
3Represent methylidene or ethyl.
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.
" C of the present invention
1-6Alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" C of the present invention
1-6Alkoxyl group " be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.
Further preferred compound is as follows:
Chemical name: 2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline, be called for short compound 1, structural formula is as follows:
Chemical name: 5-methoxyl group-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline, be called for short compound 2, structural formula is as follows:
Chemical name: 5-difluoro-methoxy-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline, be called for short compound 3, structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd, and reaction equation is as follows, but is not limited only to following method:
Reactions steps:
The preparation of step 1 intermediate 1
Raw material 1 is dropped in the reaction flask, add ethanolic soln, 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, filter, be washed to neutrality, filter cake vacuum-drying gets intermediate 1.
The preparation of step 2 intermediate 2
Oxammonium hydrochloride is dissolved in the dehydrated alcohol, and the adding sodium ethylate has a large amount of solids to separate out under stirring, and will react to filter solid after liquid cooling is placed, and the filtrate sealing is preserved standby.
Add dehydrated alcohol and raw material 2 in the reaction flask, stir down and be added dropwise to the above-mentioned azanol ethanolic soln for preparing, finish and continue the stirring and refluxing reaction, cooling, suction filtration, the filter cake washing, standing and drying gets the glassy yellow solid, and promptly intermediate 2.
The preparation of step 3 intermediate 3
Under the nitrogen protection, in the reaction flask of drying, sealing, add intermediate 2, toluene; add NaH (mineral oil) then, slowly be warming up to backflow, the insulated and stirred reaction; be added dropwise to the chloroformic solution of raw material 3 then; and then back flow reaction, reaction is finished, and removes solvent under reduced pressure; in residue, add chloroform; after using HCl solution, saturated nacl aqueous solution, sodium hydroxide solution, deionized water wash respectively, anhydrous sodium sulfate drying, concentrate intermediate 3.
The preparation of step 4 intermediate 4
Add diacetyl oxide in intermediate 3, the intensification stirring reaction removes diacetyl oxide under reduced pressure, hydro-oxidation sodium solution in residue, stirring reaction is used chloroform extraction, drying, concentrate oily matter intermediate 4.
The preparation of step 5 intermediate 5
Add methylene dichloride in intermediate 4, cooling is added dropwise to sulfur oxychloride, drips off the back stirring at room, remove methylene dichloride and sulfur oxychloride under reduced pressure, in debris, add sodium carbonate solution, chloroform extraction, combining extraction liquid then, drying concentrates, and gets oily matter intermediate 5.
The preparation of step 6 intermediate 6
In intermediate 5, add ethanol, intermediate 1, sodium hydroxide, the intensification stirring reaction removes ethanol under reduced pressure, and the chloroform extraction drying concentrates, and ethyl alcohol recrystallization gets intermediate 6.
The preparation of step 7 The compounds of this invention
Add intermediate 6 in the reaction flask, methylene dichloride stirs cooling down, adds metachloroperbenzoic acid in batches, add the back stirring reaction, add triethylamine, stir the back and heat up, add sodium carbonate solution, stirring at room, layering, the water dichloromethane extraction, extraction liquid merges, drying concentrates, filter crude product, crude product is added dehydrated alcohol, heating for dissolving is filtered, and filtrate adds diethyl ether, precipitation occurs, filter, get The compounds of this invention.
R in the above reaction equation
1, R
2And R
3As mentioned before.
The The compounds of this invention pharmacy acceptable salt does not have special restriction, and example comprises inorganic acid addition salt, example hydrochloric acid salt, vitriol, nitrate, phosphoric acid salt, hydrobromate and hydriodate; Organic acid addition salt is as formate, acetate, propionic salt, oxalate, malonate, succinate, maleate, fumarate, lactic acid salt, malate, Citrate trianion, tartrate, mesylate, esilate, benzene sulfonate, tosylate and a tetrafluoro borate; Amino acid salts is as arginic acid salt, aspartate and glutaminate; Metal-salt is as lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and bismuth salt.Be preferably: hydrochloride, hydrobromate, hydriodate, acetate, 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 showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has three-dimensional center, and these isomer are also included within the scope of the present invention.
Compound of the present 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 by with near the stomach H that is positioned at the parietal cell secretory tubyle acid space
+/ K
+Serine molecule on the-ATP enzyme is converted into the active amide based compound earlier in conjunction with playing a role in the sour environment of secretory tubyle, present the dose-dependent inhibition basis then and stimulate the back gastric acid secretion.
A large amount of studies have shown 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 to eradicate Hp in treatment ulcer.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 a very strong anti-Hp effect external, but it is not acidproof, easily degraded in gastric juice, 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 NSAID (non-steroidal anti-inflammatory drug) (NSAID) treatment, be used for the treatment of stomach gangrene (Gastrinomas) and acute upper stomach enterorrhagia.It also can be used for the patient that need give someone extra help, and be used for before the art and postoperative prevent that acid from absorbing and stress ulcer formation.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 is the claimed pharmaceutical composition that comprises The compounds of this invention, its pharmacy acceptable salt or its isomer and other activeconstituents further; the disease that is used for the treatment of or prevents peptide ulceration to be correlated with; described other active ingredient can be an antiseptic-germicide, particularly:
1) β-Nei Xiananleikangshengsu is as amoxycilline Trihydrate bp, Ampicillin Trihydrate, cefoxitin, cefaclor or Cefixime Micronized etc.;
2) Macrolide is as erythromycin or clarithromycin etc.;
3) tetracyclines is as tsiklomitsin or Vibravenos etc.;
4) aminoglycoside is as gentamicin, kantlex or amikacin etc.;
5) quinolones is as norfloxicin, Ciprofloxacin or enoxacin etc.;
6) other, as metronidazole, furadantin or paraxin etc.; Or
7) comprise the preparation of bismuth salt, as preparation of acid bismuth citrate, bismuth subsalicylate, Bismuth Subcarbonate, Vikaline or Bismuth Subgallate etc.
Can also be antacid, as aluminium hydroxide, magnesium hydroxide, magnesiumcarbonate and magnesium aluminate etc.;
Sedative drugs prescriptions as tranquilizer, comprises diamino heterocycle heptantriene etc.;
Spasmolytic is as bietamiverine and acamylophenine etc.;
Anticholinergic is as oxygen phenyl ring imines and phenol urea etc.;
Part narcotic is as tetracaine and PROCAINE HCL, PHARMA GRADE etc.;
Non-steroidal anti-inflammatory drug is as INDOMETHACIN, acetylsalicylic acid and naprosine etc.;
Steroid or nitrite remover are as xitix and thionamic acid etc.;
Other stomach ulcer medicines for treatment are as pirenzipine etc.;
The prostaglandin(PG) medicine, as 16,16-dimethyl PGE2 etc.;
Histamine H
2-antagonist, for example CIMETIDINE etc.
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations 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 described 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 the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made 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 wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made 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 made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making 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 soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, 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 conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, 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, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, 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 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 made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make 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 makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, 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, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention contains the benzimidizole derivatives of the pyridine-tetrahydrochysene isoxazole of alkoxyalkyl replacement and compares with immediate prior art, has the following advantages:
1) The compounds of this invention can suppress mammiferous gastric acid secretion significantly, does not have potential toxic side effect, oral no GI irritation;
2) when taking when being lower than the effective dose that is generally used for peptide ulceration, 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 chemical stability, 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
1A family member enzyme and the danger of the drug interaction that causes and low cancer development danger are 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 height, yield height, steady quality are easy to carry out large-scale commercial production.
Below example is further set forth the beneficial effect of compound of the present invention by experiment, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
Experimental example is to H
+-K
+The inhibition of atpase activity
(1) H
+-K
+The preparation of adenosine triphosphatase
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
+Adenosine triphosphatase.
(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 adenosine triphosphatase 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 adenosine triphosphate 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 IC
50Expression.
Experimental result:
Table 1 couple H
+-K
+The restraining effect of atpase activity
| Compound | IC 50(M) |
| Omeprazole compound 1 compound 2 compounds 3 | 1.1×10 -5 1.2×10 -6 6.8×10 -7 6.3×10 -6 |
Experimental result shows that The compounds of this invention is to H
+-K
+The activity of adenosine triphosphatase 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 with omeprazole, effect is more obvious.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits 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-benzoglyoxaline
O-dihydroxy ammon 6.5g (60mmol) is dropped in the reaction flask, add 95% ethanolic soln 200ml, add 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, reaction solution is poured in the 200ml frozen water, after stirring, regulated pH3～4 with the hydrochloric acid of 4N, separate out solid, filter, be washed to neutrality, filter cake vacuum-drying, get product 7.2g, yield: 79.7%.
The preparation of embodiment 2 2-sulfydryl-5-methoxyl group-benzoglyoxaline
Preparation method's reference example 1 is thrown 4-methoxyl group O-Phenylene Diamine 8.3g (60mmol), and oxyethyl group sulphur ortho acid potassium 12.8g (80mmol) gets product 8.2g, yield: 75.4%.
The preparation of embodiment 3 2-sulfydryl-5-difluoro-methoxy-benzoglyoxaline
Preparation method's reference example 1 is thrown 4-difluoro-methoxy O-Phenylene Diamine 10.4g (60mmol), and oxyethyl group sulphur ortho acid potassium 12.8g (80mmol) gets product 9.5g, yield: 73.5%.
The preparation of embodiment 4 1-(4-chloro-5,6-dimethyl-N-pyridine oxide-3-yl)-N-hydroxyl methylamine
Oxammonium hydrochloride 14g (0.2mol) is dissolved in the 250ml dehydrated alcohol, and adding 13.6g (0.2mmol) sodium ethylate has a large amount of solids to separate out under stirring, and will react to filter solid after 2h is placed in liquid cooling, and the filtrate sealing is preserved standby.
Add 200ml dehydrated alcohol and 38g (0.2mol) 4-chloro-5-chloromethyl-2 in the reaction flask, 3-dimethyl-N-pyridine oxide, stir and be added dropwise to the above-mentioned azanol ethanolic soln for preparing down, finish and continue stirring and refluxing reaction 6h, cooling, suction filtration, filter cake washing, standing and drying gets glassy yellow solid 29.8g, yield 73.5%.
Embodiment 5 2-(2-methoxyethyl)-6,7-dimethyl-2,3-dihydro-isoxazole are the preparation of [4,5-c] pyridine-N-oxide also
Under the nitrogen protection; in drying; 1-(the 4-chloro-5 that adds 20.3g (100mmol) in the reaction flask of sealing; 6-dimethyl-N-pyridine oxide-3-yl)-N-hydroxyl methylamine; 100ml toluene; add 60%NaH (mineral oil) 8g then; slowly be warming up to backflow, insulated and stirred is reacted 2h, is added dropwise to the chloroformic solution of the 2-methoxy ethyl bromine of 13.9g (100mmol) then; and then back flow reaction 4h; reaction is finished, and removes solvent under reduced pressure, adds the 100ml chloroform in residue; use the HCl solution of 1N respectively; saturated nacl aqueous solution; the 1N sodium hydroxide solution; behind the deionized water wash; anhydrous sodium sulfate drying, concentrate product 12.4g, yield 55.2%.
Embodiment 6 2-(2-methoxyethyl)-7-methyl-6-methylol-2,3-dihydro-isoxazole are the preparation of [4,5-c] pyridine also
To 22.4g (100mmol) 2-(2-methoxyethyl)-6,7-dimethyl-2,3-dihydro-isoxazole also add the 200ml diacetyl oxide in [4,5-c] pyridine-N-oxide, be warmed up to 60 ℃ of stirring reaction 1h, remove diacetyl oxide under reduced pressure, in residue, add 2N sodium hydroxide solution 150ml, 40 ℃ of stirring reaction 4h, extract with chloroform (90ml * 3), drying, concentrate oily matter 15.6g, yield 69.5%.
Embodiment 7 2-(2-methoxyethyl)-7-methyl-6-methyl chloride-2,3-dihydro-isoxazole are the preparation of [4,5-c] pyridine also
To 2-(2-methoxyethyl)-7-methyl-6-methylol-2, the 3-dihydro-isoxazole also adds methylene dichloride 450ml among [4,5-c] the pyridine 15.7g (70mmol), be as cold as 0 ℃, be added dropwise to sulfur oxychloride 15ml, drip off back stirring at room 1h, remove methylene dichloride and sulfur oxychloride under reduced pressure, in debris, add 10% sodium carbonate solution 90ml, chloroform extraction (90ml * 3), combining extraction liquid then, dry, concentrate, get 15.1g oily matter, yield 88.9%.
Embodiment 8 2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole are [4,5-c] pyridine-6-yl also] methyl sulphur]-the benzo miaow
The preparation of azoles
To 2-(2-methoxyethyl)-7-methyl-6-methyl chloride-2, the 3-dihydro-isoxazole also adds ethanol 200ml, 2-sulfydryl-benzoglyoxaline 11.3g (75mmol) among [4,5-c] the pyridine 17.0g (70mmol), 2N sodium hydroxide 30ml, be warmed up to 70 ℃ of stirring reaction 1h, remove ethanol under reduced pressure, chloroform extraction (150ml * 3) drying, concentrate, ethyl alcohol recrystallization gets solid 1 5.2g, yield 61.1%.
Embodiment 9 5-methoxyl group-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole are [4,5-c] pyridine-6-yl also] methyl
Sulphur]-preparation of benzoglyoxaline
Preparation method's reference example 8 is thrown 2-(2-methoxyethyl)-7-methyl-6-methyl chloride-2,3-dihydro-isoxazole also [4,5-c] pyridine 17.0g (70mmol), 2-sulfydryl-5-methoxyl group-benzoglyoxaline 13.5g (75mmol) gets product 16.5g, yield: 60.9%.
Embodiment 10 5-difluoro-methoxy-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole [4,5-c] pyridine-6-yl] first
Base sulphur]-preparation of benzoglyoxaline
Preparation method's reference example 8 is thrown 2-(2-methoxyethyl)-7-methyl-6-methyl chloride-2,3-dihydro-isoxazole also [4,5-c] pyridine 17.0g (70mmol), 2-sulfydryl-5-difluoro-methoxy-benzoglyoxaline 16.2g (75mmol) gets product 17.6g, yield: 59.6%.
Embodiment 11 2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole are [4,5-c] pyridine-6-yl also] methylsulfinyl]-
The preparation of benzoglyoxaline
Add 2-[[2-(2-methoxyethyl)-7-methyl-2 in the reaction flask, 3-dihydro-isoxazole also [4,5-c] pyridine-6-yl] methyl sulphur]-benzoglyoxaline 10.7g (30mmol), methylene dichloride 160ml is as cold as-30 ℃ under stirring, under this temperature, add 5g (29mmol) metachloroperbenzoic acid in batches, add back stirring reaction 2h, add the 2ml triethylamine, be warmed up to 0 ℃ behind the stirring 30min, add 5% sodium carbonate solution 200ml, stirring at room 1h, layering, water dichloromethane extraction (150ml * 2), extraction liquid merges, drying concentrates, filter crude product.Crude product is added the 100ml dehydrated alcohol, and heating for dissolving is filtered, and filtrate adds the 200ml ether, precipitation occurs, filters, and gets off-white color solids 9.6g, yield 85.5%.
Molecular formula: C
18H
20N
4O
3S
Molecular weight: 372.44
Ultimate analysis:
Measured value: C, 57.87%; H, 5.66%; N, 14.79%; S, 8.44%
Theoretical value: C, 58.05%; H, 5.41%; N, 15.04%; S, 8.61%
Embodiment 12 5-methoxyl group-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole are [4,5-c] pyridine-6-yl also] methyl
Sulfinyl]-preparation of benzoglyoxaline
Preparation method's reference example 11 is thrown 5-methoxyl group-2-[[2-(2-methoxyethyl)-7-methyl-2, and the 3-dihydro-isoxazole is [4,5-c] pyridine-6-yl also] methyl sulphur]-benzoglyoxaline 11.6g (30mmol), get product 10.2g, yield: 84.3%.
Molecular formula: C
19H
22N
4O
4S
Molecular weight: 402.47
Ultimate analysis:
Measured value: C, 56.48%; H, 5.83%; N, 13.67%; S, 7.82%
Theoretical value: C, 56.70%; H, 5.51%; N, 13.92%; S, 7.97%
Embodiment 13 5-difluoro-methoxy-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole are [4,5-c] pyridine-6-yl also]
Methylsulfinyl]-preparation of benzoglyoxaline
Preparation method's reference example 11 is thrown 5-difluoro-methoxy-2-[[2-(2-methoxyethyl)-7-methyl-2, and the 3-dihydro-isoxazole is [4,5-c] pyridine-6-yl also] methyl sulphur]-benzoglyoxaline 12.7g (30mmol). get product 11.0g, yield: 83.8%.
Molecular formula: C
19H
20F
2N
4O
4S
Molecular weight: 438.45
Ultimate analysis:
Measured value: C, 51.87%; H, 4.91%; F, 8.45%; N, 12.64%; S, 7.09%
Theoretical value: C, 52.05%; H, 4.60%; F, 8.67%; N, 12.78%; S, 7.31%
The preparation of embodiment 14 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 15g in the compound 1-3 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 the compound 1-3 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 standby; Take by weighing raw material and auxiliary material according to recipe quantity; With in the compound 1-3 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 15 The compounds of this invention
1, prescription:
Prescription 1:
Any one 15g in the compound 1-3 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 the compound 1-3 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 standby; Take by weighing raw material and auxiliary material according to recipe quantity; With in the compound 1-3 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 determining according to chemical examination incapsulates; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 16 The compounds of this invention freeze-dried powders
1, prescription:
Prescription 1:
Any one 20g in the compound 1-3 or derivatives thereof
N.F,USP MANNITOL 80g
EDTA-Na
2 5g
Water for injection adds to 1000ml
Prescription 2:
Any one 40g in the compound 1-3 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 the compound 1-3 or derivatives thereof is complete, measures the pH value, regulates pH to proper range with hydrochloric acid and the sodium hydroxide of 1mol/L, add water for injection to full dose, add the gac of dosing amount 0.05%, 30 ℃ of insulated and stirred 20min, filtering decarbonization, with 0.45 μ m filtering with microporous membrane, the inspection of semifinished product, soup is with 0.22 μ m filtering with microporous membrane, check clarity, 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 17 The compounds of this invention enteric coated tablet
1, prescription:
Prescription 1:
Any one 10g in the compound 1-3 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 the compound 1-3 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, pregelatinized Starch, low-substituted hydroxypropyl methylcellulose and main ingredient mix, and add water and make softwood in right amount, softwood is crossed 18 mesh sieves and is granulated, particle is at 60 ℃ of baking oven inner dryings, and drying finishes, and crosses the whole grain of 18 mesh sieves, add Magnesium Stearate and micropowder silica gel, mix, the inspection of semifinished product, trim plate is heavy, compressing tablet.Dressing: Opadry enteric coating powder adds the Virahol of recipe quantity and water stirring and evenly mixing, and to be prepared into coating liquid standby, 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 (7)
1. compound and the pharmacy acceptable salt thereof shown in the logical formula I:
Wherein: R
1Represent hydrogen atom or replaced or unsubstituted C by halogen atom
1-6Alkoxyl group;
R
2Represent C
1-6Alkyl;
R
3Represent C
1-6Alkyl.
2. compound as claimed in claim 1 and pharmacy acceptable salt thereof:
Wherein: R
1Represent hydrogen atom, methoxyl group, oxyethyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 1-fluoro-oxyethyl group, 1,1-two fluoro-oxyethyl groups, 1,1,1-three fluoro-oxyethyl groups, 2,2-two fluoro-oxyethyl groups or 1,1,2,2-tetrafluoro-oxyethyl group;
R
2Represent methylidene, ethyl, propyl group, the sec.-propyl or the tertiary butyl;
R
3Represent methylidene, ethyl, propyl group or sec.-propyl.
3. compound as claimed in claim 2 and pharmacy acceptable salt thereof:
Wherein: R
1Represent hydrogen atom, methoxyl group, fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;
R
2Represent methylidene or ethyl;
R
3Represent methylidene or ethyl.
4. compound as claimed in claim 3 and pharmacy acceptable salt thereof, described compound is
2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline,
5-methoxyl group-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline, or
5-difluoro-methoxy-2-[[2-(2-methoxyethyl)-7-methyl-2,3-dihydro-isoxazole be [4,5-c] pyridine-6-yl also] methylsulfinyl]-benzoglyoxaline.
5. as described compound of the arbitrary claim of claim 1～4 and pharmacy acceptable salt thereof, its pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, acetate, maleate, fumarate, lactic acid salt, malate, Citrate trianion, tartrate, mesylate, benzene sulfonate, arginic acid salt, glutaminate.
6. as the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～4 and pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
As the described compound of the arbitrary claim of claim 1～4 and pharmacy acceptable salt thereof in the application that is used for preparing the medicine for the treatment of peptide ulceration.
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|---|---|---|---|
| CN2008100138904A CN101492460B (en) | 2008-01-25 | 2008-01-25 | Benzimidazole derivative containing alkoxyl oxygen alkyl substituted pyridine-tetrahydrochysene isoxazole |
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2008
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Non-Patent Citations (1)
| Title |
|---|
| 赵冬梅等.抗溃疡药泰妥拉唑的合成.《中国药物化学杂志》.2006,第16卷(第6期),第360-362页. * |
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