CN1803793A - Razole derivatives and application thereof - Google Patents
Razole derivatives and application thereof Download PDFInfo
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- CN1803793A CN1803793A CN 200410037985 CN200410037985A CN1803793A CN 1803793 A CN1803793 A CN 1803793A CN 200410037985 CN200410037985 CN 200410037985 CN 200410037985 A CN200410037985 A CN 200410037985A CN 1803793 A CN1803793 A CN 1803793A
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Abstract
The invention relates to the derivatives and the salts having a general formula (I) and (II), wherein R1 is low level alkyl or halogen atom substituted low level alkyl, R2 is C1-4 straight chain or branched chain alkyl, R3 represents hydrogen, Li, Na or K.
Description
Technical field
The present invention relates to two kinds of Prazole derivatives, products therefrom can be transformed into its pharmaceutically acceptable salt through conventional method, uses as the active substance of making medicine.
Background technology
Disclose 2-(pyridylmethyl sulfo--or-sulfinyl)-benzoglyoxaline in the European patent application EP 150 586, also can have been replaced on the 4-position of pyridine moiety in this compound molecule by alkyl thio-base or aryl thio group.This application has pointed out that this compound that is reached has a kind of long-time gastric acid inhibitory secretion that continues.In the International Patent Application WO 92/12967, put down in writing with ad hoc fashion and replace the 2-should be able to kill helicobacter effectively (pyridyl methylthio group-or-sulfinyl)-benzoglyoxaline, these compounds can be suitable for preventing and treating stomach trouble.In the International Patent Application WO 93/24480, put down in writing other 2-(pyridyl methylthio group-or-the sulfinyl)-benzoglyoxaline that replaces, can kill effectively helicobacter with ad hoc fashion.
Summary of the invention
The object of the present invention is to provide two kinds of new oxazole derivatives or its salt of drawing.
In order to finish purpose of the present invention, the invention provides general formula is (I) or derivative (II) and/or its salt.
The R1 low alkyl group representing low alkyl group or replaced wherein by halogen atom; R2 represents the straight or branched alkyl of 1-4 carbon atom, and R3 represents hydrogen atom or lithium, sodium, potassium.
In general formula (I), R1 represent methylidene or difluoromethyl, preferred difluoromethyl, R3 represents hydrogen atom or sodium.R3 is sodium preferably.
In general formula (II), the preferred represent methylidene of R2, R3 represents hydrogen atom or sodium, preferably sodium.
The invention still further relates to contain medicine effective dose as the pharmaceutical composition of general formula for (I) or derivative (II) and/or the acceptable salt of its pharmacology.
The invention still further relates to The compounds of this invention and/or its salt and kill application in the medicine that Hp belongs to bacterium, and treat and/or prevent application in the medicine of stomach and/or intestinal disease in preparation in preparation.
With The compounds of this invention (I) is example, can be synthetic by following route:
Intermediate (2) is by raw material 2,3-dimethyl-4-chlorine nitrogen oxy picolinate and 3-methoxyl group-1-sodium propylate substitution reaction prepares, wherein the latter is by 3-methoxyl group-1-propyl alcohol and highly basic reaction gained, and used highly basic comprises sodium Metal 99.5, sodium hydrogen (60%-80%), sodium amide etc.; Anhydrous tetrahydro furan, the N of being reflected at of the present invention carries out in dinethylformamide, the methyl-sulphoxide equal solvent, preferred tetrahydrofuran (THF); Temperature of reaction is reacted about preferred 100 degree from the 50-150 degree.
Intermediate (3) is by 2, and 3-dimethyl-4 (3-methoxy propoxy) nitrogen oxo pyridine and acid anhydrides or chloride of acid such as Acetyl Chloride 98Min., trichoroacetic chloride, trifluoroacetyl chloride react gained, preferred anhydrides; Reaction of the present invention can be carried out in acetonitrile, benzene, chloroform, methylene dichloride, dimethyl formamide, methyl-sulphoxide, dioxane, tetrahydrofuran (THF), toluene equal solvent, preferred acetate; Temperature of reaction is spent from room temperature to 150, preferred 80-100 degree, and the reaction times, reaction finished back evaporated under reduced pressure solvent from 2-10 hour, was directly used in down to go on foot to feed intake.
Intermediate (4) is by intermediate hydrolysis of last step gained.Originally be reflected in hydroxyl polar solvent such as water, methyl alcohol, ethanol, Virahol or the butanols and carry out, preferably water and methyl alcohol; The used alkali of reaction of the present invention has sodium hydroxide, potassium hydroxide, salt of wormwood, ammoniacal liquor, sodium methylate etc., preferred sodium hydroxide; The Controllable Temperature of this reaction is built in the 20-80 degree, preferred 30-50 degree; Reaction times was controlled at 1-10 hour, after reaction finishes, and extractions such as reaction solution usefulness organic solvent such as methylene dichloride, chloroform, ether, t-butyl methyl ether, ethyl acetate, toluene, isopropyl ether, preferred chloroform; After the organic layer drying, decompression and solvent recovery is extremely done, and is directly used in down to go on foot to feed intake.
Intermediate (5) is by intermediate of last step and halide reagent such as halogenation sulfoxide or the inferior phosphorus reaction gained of halogenation, preferred sulfur oxychloride; Originally be reflected in inert solvent such as acetonitrile, benzene, chloroform, methylene dichloride, dimethyl formamide, methyl-sulphoxide, the tetrahydrofuran (THF) etc. and carry out, preferred methylene dichloride and chloroform; This temperature of reaction is controlled at-10 and spends the solvent refluxing temperature, preferred 0-25 degree; After reacting end, use neutralizations such as alkali such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, preferred yellow soda ash is transferred pH=7-8, uses extractions such as organic solvent such as methylene dichloride, chloroform, ether, ethyl acetate, preferably chloroform and methylene dichloride; The organic phase drying, concentrating under reduced pressure is done, and is directly used in down to go on foot to feed intake.
Intermediate (6) is formed by intermediate 2-of last step chloromethyl-3-methyl-4-(3-methoxy propoxy) pyridine and 5-difluoro-methoxy-2-mercaptobenzimidazole condensation.This reaction can be carried out under the liquid-liquid phase jump condition, used mineral alkali has sodium hydroxide, potassium hydroxide etc., used phase-transfer catalyst has R4NX, series such as R4PX, crown ether, preferred R4NX series, as TBuA, tetraethyl ammonium, triethyl phenyl ammonium etc., X refers to chlorine, bromine, iodine etc., preferred triethylbenzene ammonium chloride; This temperature of reaction is from the 0-100 degree, preferred 15-30 degree, and the reaction times was from 1-10 hour; This reaction also can be carried out in homogeneous phase, and used polar solvent has water, methyl alcohol, ethanol, Virahol, propyl carbinol etc., under this kind condition, at first generates 5-difluoro-methoxy-2-mercaptobenzimidazole salt, then and intermediate (5) reaction obtain intermediate (6).
The preparation of intermediate (7) is with reaction gained such as intermediate of last step and oxygenant such as metachloroperbenzoic acid, Peracetic Acid, hydrogen peroxide, preferred metachloroperbenzoic acid, and temperature of reaction is from-80 degree-0 degree, and is preferred-the 50-40 degree.
The temperature of using among the present invention is degree centigrade.
The compounds of this invention and Sodium rabeprazole have been done antiulcer agent comparative study, by experiment, have drawn following data and conclusion:
(1) to rat water stress type ulcer model influence
Table 1.The Sodium rabeprazole series compound is to the provide protection of stress in rats type ulcer model
| Group | Dosage (mg/kg) | Number of animals | Ulcer is counted x ± s | P |
| Contrast | 8 | 23.6±11.3 | ||
| Sodium rabeprazole | 10 | 6 | 05±0.8 | 0.001 |
| Compound (I) | 10 | 6 | 2.3±2.2 | 0.01 |
| Compound (II) | 10 | 6 | 10.5±6.3 | 0.05 |
Table 2.The Sodium rabeprazole series compound is to the provide protection of stress in rats type ulcer model
| Group | Dosage (mg/kg) | Number of animals | The ulcer number | P |
| Contrast | 8 | 23.0±8.8 | ||
| Sodium rabeprazole | 10 | 5 | 0.8±1.2 | 0.001 |
| Sodium rabeprazole | 3 | 6 | 11.8±4.7 | 0.05 |
| Compound (I) | 10 | 5 | 4.8±4.6 | 0.01 |
| Compound (I) | 3 | 6 | 12.7±7.1 | |
| Compound (II) | 10 | 5 | 10.8±7.8 | 0.05 |
| Compound (II) | 3 | 6 | 21.2±9.8 |
As seen, after rat gave Sodium rabeprazole, the ulcer number obviously reduced, and stomach is had significant protective effect; The compounds of this invention (I) has good effect equally; And compound (II) is though have certain effect, and effect does not have the above two obvious.
(2) to the influence of rat dehydrated alcohol ulcer model
Table 3.The Sodium rabeprazole series compound is to the provide protection of rat dehydrated alcohol ulcer model
| Group | Dosage (mg/kg) | Number of animals | The ulcer area | P |
| Contrast | 8 | 24.8±12.4 | ||
| Sodium rabeprazole | 10 | 5 | 11.1±2.7 | 0.05 |
| Sodium rabeprazole | 3 | 6 | 26.4±20.6 | |
| Compound (I) | 10 | 5 | 5.5±9.9 | 0.05 |
| Compound (I) | 3 | 6 | 12.1±18.1 | |
| Compound (II) | 10 | 5 | 3.2±4.5 | 0.01 |
| Compound (II) | 3 | 6 | 6.6±5.8 | 0.01 |
As seen, after rat was given Sodium rabeprazole, the ulcer area reduced; Compound (I), (II) have same effect, and effect is better than Sodium rabeprazole.
(3) to the effect of rat chronic acetic acid type ulcer model
Table 4 Sodium rabeprazole series compound is to the provide protection of stress in rats type ulcer model
| Group | Dosage (mg/kg) | Number of animals | Ulcer area mm2x ± s |
| Contrast | 12 | 11.6±6.7 | |
| Sodium rabeprazole | 10 | 11 | 5.6±3.2 |
| Sodium rabeprazole | 3 | 12 | 8.8±3.6 |
| Compound (I) | 10 | 12 | 8.1±6.2 |
| Compound (I) | 3 | 11 | 9.1±4.1 |
| Compound (II) | 10 | 10 | 5.1±4.5 |
| Compound (II) | 3 | 10 | 8.1±3.4 |
Therefore, after rat was given Sodium rabeprazole, ulcer area comparison illumination showed minimizing; The compounds of this invention (II) shows same result, and effect slightly is better than Sodium rabeprazole, and compound (I) has certain effect that alleviates to ulcer area and ulcer volume.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment one: 4-(3-methoxy propoxy)-2, the preparation of 3-dimethyl-N-oxo pyridine
Sodium 7.8 gram is suspended from 90 milliliters of the 3-methoxyl groups-1-propyl alcohol, and oil bath 100 degree make it molten entirely, cooling, add THF120 milliliter, 2,3-dimethyl-4-chloro-N-oxo pyridine 30 grams, back flow reaction 12 hours, cooling adds 200 ml waters, and concentrated hydrochloric acid is transferred PH=7, chloroform extraction, anhydrous magnesium sulfate drying filters reclaim under reduced pressure chloroform and 3-methoxyl group-1-propyl alcohol, must this product, be directly used in down the step to feed intake.
Embodiment two: the preparation of 2-chloromethyl-4-(3-methoxy propoxy)-3-picoline
To go up step intermediate 50 grams, 150 milliliters of diacetyl oxides, 8 of the vitriol oils are put in the reaction flask, oil bath 90 degree reactions 3 hours remove diacetyl oxide under reduced pressure, add 100 ml waters under the room temperature, add (20 gram sodium hydroxide and 100 ml waters), 50 degree water-baths 1 hour, chloroform extraction is used in cooling, dry, filter, concentrate and do, add 200 milliliters of fresh chloroforms in the resistates, add 30 milliliters of sulfur oxychlorides, room temperature reaction 5 hours, concentrating under reduced pressure adds 400 ml waters in the resistates, transfer PH=8 with sodium carbonate solution, chloroform extraction, drying, filtering and concentrating do product (brown semisolid).
Embodiment three: 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl]-methylthio group }-preparation of 1H-5-difluoro-methoxy benzo imidazoles
To go up step intermediate 42 grams, 5-difluoro-methoxy-2-mercaptobenzimidazole 29 grams, Tetrabutyl amonium bromide 0.3 gram, salt of wormwood 35 grams and dehydrated alcohol puts in the reaction flask for 200 milliliters, 70 degree reactions 1 hour, filtering and concentrating, resistates adds 300 milliliters of methylene dichloride, washing, drying, filtering and concentrating is done, add 100 milliliters of re-crystallizing in ethyl acetate, get solid product.
Embodiment four: 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl]-methanesulfinyl }-1H-5-difluoro-methoxy benzo imidazoles
To go up step intermediate 10 grams is dissolved in 100 milliliters of methylene dichloride, cooling, drip the mixed solution of 150 milliliters of metachloroperbenzoic acid 5 grams and methylene dichloride, drip off, continue to react half an hour, add 8 milliliters of triethylamines, reaction solution washs with 10% sodium bisulfite, 10% Sulfothiorine successively, drying, and filtering and concentrating is done, with methylene dichloride/ether=1: 1 mixed solution recrystallization, filtration drying gets solid product.
Embodiment five: 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl]-methanesulfinyl }-preparation of 1H-5-difluoro-methoxy benzo imidazole natrium salt
Product of last step 4.4 gram is joined in the solution of 0.412 gram sodium hydroxide and the configuration of 100 ml waters, molten clear after, adds 200 milliliters of ethanol, be evaporated to driedly, in resistates, add t-butyl methyl ether, filter the dry compound (I) that gets.
Claims (6)
1. a general formula (I) or derivative (II) and/or its salt,
The R1 low alkyl group representing low alkyl group or replaced wherein by halogen atom; R2 represents the straight or branched alkyl of 1-4 carbon atom, and R3 represents hydrogen atom or lithium, sodium, potassium.
2. derivative according to claim 1 and/or its salt, wherein in general formula (I), R1 represent methylidene or difluoromethyl, R3 are represented hydrogen atom or sodium.
3. derivative according to claim 1 and/or its salt, in general formula (II), R2 represent methylidene, R3 are represented hydrogen atom or sodium.
4. the pharmaceutical composition that contains medicine effective dose as any one described compound of claim 1-3 and/or the acceptable salt of its pharmacology.
5. kill application in the medicine that Hp belongs to bacterium according to any one described compound of claim 1-3 and/or its salt in preparation.
6. treat and/or prevent application in the medicine of stomach and/or intestinal disease according to any one described compound of claim 1-3 and/or its salt in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410037985 CN1803793A (en) | 2004-05-14 | 2004-05-14 | Razole derivatives and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410037985 CN1803793A (en) | 2004-05-14 | 2004-05-14 | Razole derivatives and application thereof |
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| CN1803793A true CN1803793A (en) | 2006-07-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364989C (en) * | 2004-09-30 | 2008-01-30 | 江苏豪森药业股份有限公司 | Prazole derivative and its salt and use |
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- 2004-05-14 CN CN 200410037985 patent/CN1803793A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364989C (en) * | 2004-09-30 | 2008-01-30 | 江苏豪森药业股份有限公司 | Prazole derivative and its salt and use |
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