CN1073446A - The benzoglyoxaline and preparation technology and the purposes that replace - Google Patents

The benzoglyoxaline and preparation technology and the purposes that replace Download PDF

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CN1073446A
CN1073446A CN92114364A CN92114364A CN1073446A CN 1073446 A CN1073446 A CN 1073446A CN 92114364 A CN92114364 A CN 92114364A CN 92114364 A CN92114364 A CN 92114364A CN 1073446 A CN1073446 A CN 1073446A
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compound
methyl
formula
benzoglyoxaline
pyridyl
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CN1031827C (en
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K·B·C·崔尔斯坦
G·E·森登
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

The novel cpd of Formula I, R in the formula 1And R 2Difference, respectively be methyl ,-C (O) CH 3Or-C (O) OCH 3, thereby R 1Or R 2In a methyl is always arranged; M is physiologically acceptable to positively charged ion; And the preparation method of described compound, contain described compound as the pharmaceutical composition of active ingredient and these compounds in medically use.

Description

The benzoglyoxaline and preparation technology and the purposes that replace
Thereby the purpose of this invention is to provide the novel cpd that the gastric acid secretion that can suppress exogenesis or endogenous stimulation is used to prevent and treat digestive system and ulcer.
The present invention also relates to compound of the present invention to suppressing the purposes that Mammals comprises the gastric acid secretion of human body.On general significance more, compound of the present invention can be used for prevention and treatment gastroenteritis disease, and Mammals comprises in the human body and hydrochloric acid in gastric juice diseases associated, for example gastritis, stomach ulcer, duodenal ulcer, reflux esophagitis and Zuo Linge-Ai Lisen syndromes.In addition, these compounds also can be used for treating the gastrointestinal disorder that other needs stomach secretion inhibitor effect, as are used for gastrinoma (gastrinomas) patient and the acute gastrointestinal hemorrhage patient of going up.They also can be used for being in the patient under the intensive nursing care situation, and suck and the tonus ulcer function in order to prevent acid at perioperatively.Compound of the present invention also can be used for treating and prevents Mammals to comprise the inflammation of human body, relates in particular to the inflammation of N,O-Diacetylmuramidase.The inflammation that can specifically mention is rheumatoid arthritis and gout.The present invention also relates to contain the pharmaceutical composition of compound of the present invention as activeconstituents.On the other hand, the present invention relates to the preparation technology of this class new compound, and relate to the pharmaceutical composition that uses these active compounds to prepare above-mentioned medical usage.
Compound of the present invention can not hinder the picked-up of Tiroidina to iodine.Having disclosed the present inventor in early time in some documents of our company is studying Tiroidina toxicity and is depending on whether lipophilic of these compounds.The present inventor is surprised to find that now lipotropy is not decisive parameter.The compound of these requests power of patenting comprises hydrophilic a little compound, does not produce any Tiroidina toxic effect, has high acid secretion retarding effect simultaneously.
Compound of the present invention also will show high-dissolvability and high chemical stability in water.
Similar two replace 2-((3,4-dialkoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline-1-based compound sees PCT/SE91/00415 for details, the document is handled Sweden at this patent and is applied for that substantially fashion can not openly obtain, but has just delivered soon after.
In many patent documents, disclose and be intended to gastric acid inhibitory excretory benzimidizole derivatives.Wherein can mention GB1,500,043; GB1,525,958; US4,182,766; US4,255,431; US4,599,347; BE898,880; EP124,495; EP208,452; EP221,041; EP279,149; EP176,308 and Derwent digest 87-294449/42.US4 discloses the benzimidizole derivatives that is proposed to be used in treatment or prevents special gastroenteritis disease in 359,465.
Compound of the present invention can comprise people's gastric acid secretion inhibitor effectively as Mammals, do not hinder the picked-up of Tiroidina to iodine simultaneously.
In addition, compound of the present invention shows high-dissolvability and high chemical stability in water.
Therefore, compound of the present invention is particularly useful for parenteral, and is particularly transvenous and through the administration of muscle.High-dissolvability and chemical stability also make compound of the present invention be suitable for other route of administration, for example per os and per rectum administration.
Compound of the present invention has following chemical formula I:
Figure 921143648_IMG7
R in the formula 1And R 2Difference, respectively be methyl ,-C(O) CH 3Or-C(O)-OCH 3, thereby R 1Or R 2In a methyl is always arranged, and M be one physiologically acceptable to positively charged ion.
The constitutional isomer of compound of formula I can use separately, perhaps to equate or the use of unequal mixture.
The The compounds of this invention of chemical formula I has an asymmetric center on sulphur atom, promptly exist with two kinds of optical isomers (enantiomorph) form.Both pure enantiomorph racemic mixtures (every kind enantiomorph each 50%) and unequal mixture all belong to scope of the present invention.
Can think compound of formula I the performance its effect before just by metabolism.Such metabolism betides the N substituting group on 1 of the benzimidazole nucleus, i.e. phosphorus-containing groups.
Preparation
Compound of the present invention can be prepared as follows:
A) make the compound of chemical formula II and the compound reaction of chemical formula III:
R in the formula 1And R 2Definition with the chemical formula I, Z is a suitable group on halogen such as Cl, Br or I or the function,
Figure 921143648_IMG9
In the formula Q be one to ion such as Na +, K +, Ag +Or trialkyl ammonium.
Resulting salt can be transformed into the salt that is suitable in a kind of medical treatment, for example respectively by adding NaOH and KOH or by ion-exchange, being transformed into sodium salt and sylvite.
B) make the compound oxidation of chemical formula IV obtain compound of formula I
Figure 921143648_IMG10
R in the formula 1, R 2With M have given meaning.
This oxidation can be carried out with a kind of oxygenant, for example use nitric acid, hydrogen peroxide, (randomly in the presence of vanadium compound), peracid, peresters, ozone, nitrogen tetroxide, iodosobenzene, N-halo succinimide, 1-chlorobenzotriazole, t-butyl hypochlorate, diazabicyclo (2,2,2) octane bromine title complex, sodium metaperiodate, tin anhydride, Manganse Dioxide, chromic acid, the high cerium of ammonium nitrate, bromine, chlorine and sulfuryl chloride.Oxidation is carried out in a kind of solvent such as halohydrocarbon, alcohol, ether, ketone usually.
Also can utilize oxydase to carry out the enzyme process oxidation, or utilize suitable microorganism to carry out the microbial method oxidation.
Resulting constitutional isomer can separate with crystallization process or chromatography.
Resulting racemoid can as with optics strong solvent recrystallization, separate in accordance with known methods.
For clinical application, compound of the present invention is mixed with supplies per os, per rectum, non-formula of medicine through intestines or alternate manner administration.Especially good is compound of the present invention to be mixed with can to supply non-formula of medicine through enteral administration.This formula of medicine contains a kind of The compounds of this invention of and pharmaceutically acceptable carrier combinations.Carrier format can be solid, semisolid or liquid diluent, or a kind of capsule.These pharmaceutical preparations are further purposes of the present invention.The content of active compound is generally 0.1～95%(weight of preparation), non-be 0.2～20%(weight in the preparation of intestines purposes), and be 1～50%(weight in peroral administration preparation).
In the preparation of the formula of medicine that contains The compounds of this invention with the oral administration dosage unit form, selected compound can mix a kind of pressed powder carrier, as lactose, sucrose, Sorbitol Powder, mannitol, starch, amylopectin, derivatived cellulose, gelatin, or another kind of suitable carrier, but and hybrid lubricant such as Magnesium Stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax.Then mixture is processed into particle or is pressed into tablet.The particle or the tablet that contain sulfoxide can coat a kind of enteric coating coating, as long as this dosage form keeps under one's belt, this coating just can protect active compound to avoid the acid catalysis degraded.Enteric coating coating is selected from pharmaceutically acceptable enteric coat material, as beeswax, shellac, or anionic film-forming polymer, as Cellacefate, Hydroxypropyl Methylcellulose Phathalate, the methacrylate polymer of part esterification etc., if be ready, also can be also with a kind of suitable softening agent.For tablet or the particle of distinguishing the active compound that different activities compound or different amounts are arranged, can in this coating, add various dyestuffs.
Soft capsule can be with containing one or more active compounds of the present invention, the capsule preparation of the mixture of vegetables oil, fat or other suitable soft capsule vehicle.Soft capsule also can be by coating enteric coating as mentioned above.Hard capsule can contain the particle of active compound or coat the particle of enteric coating.Hard capsule also can contain the active compound with pressed powder carrier such as lactose, sucrose, Sorbitol Powder, mannitol, yam starch, amylopectin, derivatived cellulose or gelatin combination.Hard capsule can be by coating enteric coating as mentioned above.
The dosage device of per rectum administration can be prepared into the suppository form that contains with neutral fat base blended active substance, maybe it can be prepared into the rectal capsule form that contains with the active substance of vegetables oil, paraffin oil or other suitable rectum capsule mixed with excipients, maybe it can be prepared into the little enema forms of finished product, only maybe it can be prepared into needs before administration with the synthetic again dried slight irrigation intestines agent prescription form of appropriate solvent.
Peroral administration liquid preparation can be prepared into syrup or form of suspension, for example contains 0.2% to 2%(weight) solution or the suspension of active ingredient, rest part is the mixture of sugar or sugar alcohol and ethanol, water, glycerine, propylene glycol and polyoxyethylene glycol.If wish that such liquid preparation can also contain tinting material, flavouring agent, asccharin and carboxymethyl cellulose or other thickening material.Peroral administration liquid preparation also can be prepared into can be before use with the synthetic again dry powder doses form of appropriate solvent.
Non-solution through enteral administration can be prepared into the solution of a kind of compound of the present invention in pharmaceutically acceptable solvent, and its concentration is preferably 0.1% to 10%(weight).These solution also can contain stablizer and/or buffer reagent, and can manufacture different dosage unit ampullas or phial agent.Non-solution through enteral administration also can be prepared into can be before use temporarily with the synthetic again dry preparation of appropriate solvent.
The typical per daily dose of this active substance is widely different, and will depend on various factors, for example every patient's individual need, route of administration and disease.In general, per os and non-will be 5～500 milligrams of active substance/skies through the intestines dosage range.
Following example explanation the present invention.
Example 1 phosphoric acid (5-ethanoyl-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-and 1H-benzoglyoxaline-1-yl) the methyl esters disodium salt; or the preparation of phosphoric acid (6-ethanoyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
Under agitation Tributylamine (1.7 milliliters, 7.0 mmoles) is joined in ethanol (2 milliliters) solution of 85% phosphoric acid (0.24 milliliter, 3.6 mmoles).Evaporating solvent, residue is collected with methylene dichloride (2.5 milliliters).Organic phase dried over sodium sulfate, filtration and evaporation.5-ethanoyl-1-chloromethyl-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline or 6-ethanoyl-1-chloromethyl-5-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline (0.12 gram, 0.28 mmole) and the tricresyl phosphate fourth ammonium salt of above preparation be dissolved in the methylene dichloride (6 milliliters).Methylene dichloride is steamed, and residue heated 5 minutes in 60 ℃ water-bath.Residue is dissolved in the methylene dichloride (6 milliliters), once more methylene dichloride is steamed, the oily product mixture heated 5 minutes in 60 ℃ of water-baths.This step repeats 4 times, finishes until reaction.Residue is dissolved in the methylene dichloride (4 milliliters), with 3 parts of (4 milliliters) water washings.Under agitation sodium hydroxide solution (0.2M) is added in the organic phase to the pH of careful simultaneously control water.When the pH of water reaches 9～9.5, with the mixture centrifugation.Water is with 3 parts of (4 milliliters) washed with dichloromethane, and freeze-drying then provides 40 milligram of 27% title compound.
The NMR(nucleus magnetic resonance) data provide following.
Example 2 phosphoric acid (5-methoxycarbonyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-and 1H-benzoglyoxaline-1-yl) the methyl esters disodium salt, or the preparation of phosphoric acid (6-methoxycarbonyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
Under agitation Tributylamine (1.8 milliliters, 7.8 mmoles) is joined in ethanol (2.5 milliliters) solution of 85% phosphoric acid (0.26 milliliter, 3.9 mmoles).Evaporating solvent, residue is collected with methylene dichloride (3 milliliters).Organic phase dried over sodium sulfate, filtration and evaporation.5-methoxycarbonyl-1-chloromethyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline or 6-methoxyl methyl-1-chloromethyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline (0.14 gram, 0.32 mmole) and the tricresyl phosphate fourth ammonium salt of above preparation be dissolved in the methylene dichloride (6.5 milliliters).Methylene dichloride is steamed, and residue heated 5 minutes in 60 ℃ of water-baths.Residue is dissolved in the methylene dichloride (6.5 milliliters), steams methylene dichloride once more, the oily product mixtures heated 5 minutes in 60 ℃ of water-baths.This step repeats 4 times, finishes until reaction.Residue is dissolved in the methylene dichloride (4 milliliters), with 3 parts of (4 milliliters) water washings.Under agitation sodium hydroxide solution (0.2M) is added in the organic phase to the pH of careful simultaneously control water layer.When the pH of water reaches 9～9.5, with the mixture centrifugation.Water layer is with 3 parts of (4 milliliters) washed with dichloromethane, and freeze-drying then provides 11 milligram of 6% title compound.
The NMR data provide following.
Table 1
The proton of water is decided to be 4.80.
Example solvent NMR data δ ppm
1 D 2O 2.67 (s,3H),2.78(s,3H),3.85
(s,3H),
(300?MHz) 3.98(s,3H),4.98(d,1H),5.08(d,
1H),5.98(m,2H),7.15(d,1H),7.78
(s,1H),8.12(d,1H),8.18(s,1H).
2 D 2O 2.75(s,3H),3.83(s,3H),3.97(s,
3H),
(300MHz) 4.05(s,3H),4.98(d,1H),5.08(d,
1H),5,95(m,2H),7.15(d,1H),7.83
(s,1H),8.15(d,1H),8.28(s,1H).
Intermediate preparation
Example I 1
5-ethanoyl-1-methylol-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-preparation of 1H-benzoglyoxaline or 6-ethanoyl-1-methylol-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline
To 5-ethanoyl-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline (2.00 grams; 5.4 add 5M formalin (5.0 milliliters, 25 mmoles) mmole) and in the mixture of methylene dichloride (100 milliliters).Mixture swayed 3 minutes.After the separation, organic solution Na 2SO 4Dry, reduction vaporization provide a kind of red soup compound (1.7 grams, 78%).Product mainly contains constitutional isomer and a small amount of starting raw material of title compound.
The NMR data provide following.
Example I 2
5-ethanoyl-1-chloromethyl-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-preparation of 1H-benzoglyoxaline or 6-ethanoyl-1-chloromethyl-5-methyl-2-(((3,4 dimethoxys-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline
5-ethanoyl-1-methylol-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline and 6-ethanoyl-1-methylol-5-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-suspension of 1H-benzoglyoxaline (1.7 gram, 4.2 mmoles) in acetonitrile (40 milliliters) is cooled to-15 ℃.Drip thionyl chloride (0.50 gram, 4.2 mmoles) and triethylamine (0.50 gram, 4.2 mmoles) by given order.Mixture is at stirring at room 5 minutes, reduction vaporization then.Residue uses the mixture of ethyl acetate and methylene dichloride as eluent, separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (70 gram).The quantity of ethyl acetate increases during chromatographic separation.Product 0.14 gram (8%) mainly is made up of one of constitutional isomer.
The NMR data provide following.
Example I 3
5-methoxycarbonyl-1-methylol-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-preparation of 1H-benzoglyoxaline or 6-methoxycarbonyl-1-methylol-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline
To 5-methoxycarbonyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl)-sulfinyl)-1H-benzoglyoxaline (0.34 gram, 0.87 in methylene dichloride mmole) (25 milliliters) solution, add 5M formalin (1.7 milliliters, 8.5 mmoles).Mixture swayed 3 minutes.After the separation, organic solution Na 2SO 4Dry, reduction vaporization provide a kind of red soup compound (0.36 gram, 100%).The product composition mainly is one of constitutional isomer of title compound and a small amount of parent material.
The NMR data provide following.
Example I 4
5-methoxycarbonyl-1-chloromethyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-preparation of 1H-benzoglyoxaline or 6-methoxycarbonyl-1-chloromethyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline
With 5-methoxycarbonyl-1-methylol-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline and 6-methoxycarbonyl-1-methylol-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-acetonitrile (20 milliliters) solution of 1H-benzoglyoxaline (0.36 gram, 0.87 mmole) is cooled to-20 ℃.Drip thionyl chloride (0.066 milliliter, 0.9 mmole) and triethylamine (0.10 gram, 1.0 mmoles) by given order.Mixture at room temperature stirred 5 minutes, then reduction vaporization.Residue separates in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (20 gram) as eluent with the mixture of ethyl acetate and methylene dichloride.The quantity of ethyl acetate increases during chromatographic separation.The composition of product 0.16 gram (43%) mainly is one of constitutional isomer.
The NMR data provide following.
Table 2
Example solvent NMR data δ ppm
Ⅰ1 CDCl 32.60(s,3H),2.70(s,3H),3.90(s,3H),
3.95(s,3H),4.8-5.1(m,2H),5.70(d,
1H),6.10(d,1H)6.75(d,1H),7.40(s,
1H),
7.90(d,1H),8.10(s,1H).
Ⅰ2 CDCl 32.66(s,3H),2.72(s,3H),3.90(s,3H),
3.91(s,3H),4.91(d,1H),5.02(d,1H),
6.23(d,1H),6.55(d,1H),6.80(d,1H),
7.39(s,1H),8.15(d,1H),8.20(s,1H).
Ⅰ3 CDCl 32.75(s,3H),3.8-4.0(m,9H),4.7-5.1(m,
2H),5.75(d,1H),6.10(d,1H),
6.75(d,1H),7.40(s,1H),7.90(d,1H),
8.30(s,1H).
Ⅰ4 CDCl 32.79(s,3H),3.89(s,3H),3.91(s,3H),
3.93(s,3H),4.90(d,1H),5.02(d,1H),
6.23(d,1H),6.57(d,1H),6.80(d,1H),
7.39(s,1H),8.15(d,1H),8.40(s,1H).
Table 3
Examples for compounds included in the chemical formula I is listed in the table below.
Productive rate is identified
Example R 1R 2M % data remarks
1 CH 3C(O)CH 3
Or Na +27 NMR are isolating
Isomer
C(O)CH 3CH 3
2 CH 3C(O)OCH 3
Or Na +6 NMR are isolating
Isomer
C(O)OCH 3CH 3
3 C(O)CH 3CH 3
Or Na +--isolating
Isomer
CH 3C(O)CH 3
4 C(O)OCH 3CH 3
Or Na +--isolating
Isomer
C(O)OCH 3CH 3
5 CH 3C (O) CH 3Na +--isomer
Mixture
C(O)CH 3CH 3
6 CH 3C (O) OCH 3Na +--isomer
C (O) OCH 3CH 3Mixture
Present known enforcement best mode of the present invention is to use a kind of compound according to example 2.Contain the pharmaceutical preparation of compound of the present invention, be illustrated with following prescription as active ingredient.
Syrup
Prepare a kind of 1%(of containing weight/volume from following component) syrup of active substance:
Compound 1.0 grams according to example 1
Sugar, powder 30.0 grams
Asccharin 0.6 gram
Glycerine 5.0 grams
Flavouring agent 0.05 gram
Ethanol, 96% 5.0 grams
Distilled water, supplying final volume is 100 milliliters
Sugar and asccharin are dissolved in the 60 gram warm water.After the cooling, active compound is added in the sugar soln, and add the flavouring agent solution that is dissolved in the ethanol.It is 100 milliliters that mixture is diluted with water to final volume.
The tablet that enteric coating coats
Prepare a kind of 20 milligrams of active compounds of containing from following component, coated the tablet of enteric coating:
I is according to compound 200 grams of example 2
Lactose 700 grams
Methylcellulose gum 6 grams
Crosslinked Polyvinylpyrolidone (PVP) 50 grams
Magnesium Stearate 15 grams
Yellow soda ash 6 grams
Distilled water is an amount of
II Cellacefate 200 grams
Hexadecanol 15 grams
Virahol 2000 grams
Methylene dichloride 2000 grams
I is mixed with lactose according to the compound powder of example 2, and with the aqueous solution granulation of methylcellulose gum and yellow soda ash.Wet stock is forced through a sieve, and particle is dry in stove.After the drying, particle mixes with Polyvinylpyrolidone (PVP) and Magnesium Stearate.On tabletting machine,, dry mixture is pressed into every label (10000) that contains 20 milligrams of active substances with 6 mm dia punching machines.
Virahol/the dichloromethane solution of II Cellacefate and hexadecanol is with an Accela Cota R, the Manesty coating apparatus is sprayed onto on these sheets.Getting to the end, sheet heavily is 110 milligrams.
Solution through intravenously administrable
Prepare a kind of every milliliter from following component and contain 4 milligrams of active compounds, through vein use non-through the intestines prescription:
Compound 4 grams according to example 2
Sterilized water, supplying final volume is 1000 milliliters
Active compound is soluble in water, and supplying final volume is 1000 milliliters.Solution filters by one 0.22 micron filter, is assigned to immediately in 10 milliliters of aseptic ampoules.Ampoule is sealed.
Before facing use, the active compound that is dissolved in 10 ml sterile waters is transferred in 100 milliliters of standard infusion of saline solution, making cumulative volume is about 110 milliliters.This solution with about 30 minutes time with through the venoclysis form administration.
Tablet
The tablet that contains 30 milligrams of active compounds from following component preparation:
Compound 300 grams according to example in the table 33
Lactose 700 grams
Methylcellulose gum 6 grams
Crosslinked Polyvinylpyrolidone (PVP) (PVP-XL) 62 grams
Sodium phosphate dibasic 2 grams
Magnesium Stearate 30 grams
Pure water is an amount of
Active compound mixes with lactose and part PVP-XL, with the solution granulation of methylcellulose gum and Sodium phosphate dibasic.Wet stock is forced through a sieve, and is dry in the fluidised form bed dryer.Adding Magnesium Stearate and all the other PVP-XL and mixture, it is 110 milligrams tablet that pharmaceutical mixture is pressed into weight in average, and every contains 30 milligrams of active compounds.
The tablet that enteric coating coats
The above-mentioned tablet of 500 grams is carried out enteric coating to coat.A kind of solution of following composition is sprayed onto on the tablet in the fluidised form bed apparatus with the Wurster coating technique.
Coating solution:
Cellacefate 40 grams
Hexadecanol 2 grams
Virahol 400 grams
Methylene dichloride 400 grams
Last coated tablets weighs 117 milligrams.
Suppository
Prepare suppository with the welding step from following component.Each suppository contains 40 milligrams of active compounds.
Compound 4 grams according to example in the table 34
Witepsol H-15 180 grams
Active compound combinations is at 41 ℃ temperature and Witepsol H-15 uniform mixing.Molten materials integral body is filled in the ready-formed suppository bag, and reaching net weight is 1.84 grams.After the cooling, with these bag heat-sealings.Each suppository contains 40 milligrams of active compounds.
Syrup
Prepare a kind of syrup that contains 1% active substance from following component:
Compound 1.0 grams according to example in the table 33
Sugar, powder 30.0 grams
Asccharin 0.6 gram
Flavouring agent 0.05 gram
Ethanol, 96% 5.0 grams
Purified water is supplied 100 milliliters
Sugar and asccharin are dissolved in the 60 gram warm water.After the cooling, active compound is added in the sugar soln, and add the flavouring agent solution that is dissolved in the ethanol.It is 100 milliliters that mixture is diluted with water to final volume.
Through vein or through the solution of intramuscular injection
Compound 60 grams according to example 1
Water for injection is made into 1000 milliliters
Soluble in water active compound, reaching last volume is 1000 milliliters.Solution filters by aseptic 0.22 micron filter, is assigned in 1 milliliter of aseptic ampoule with asepsis.Ampoule is sealed.
Prescription through venoclysis
According to 60 milligrams of the asepticize compounds of example 2
Aseptic injection phial and stopper
60 milligrams of sterile active compounds are put in 10 milliliters of aseptic injection phials.Phial clogs with aseptic soft rubber ball.Under the aseptic condition in sterile production district, carry out the vokale fill operations in the vertical laminar flow mode.
Biological effect
Influence to Tiroidina picked-up iodine
Compound of formula I is right with the active compound that is produced in the compound metabolism in the scope of the invention to the influence of Tiroidina picked-up iodine within the scope of the present invention 125The effect of accumulation of I in Tiroidina weighed.
Right 125The effect of accumulation of I in Tiroidina
125The accumulation of I in Tiroidina is to study with 24 hours male Sprague-Dawley rat of fasting before the test.Adopt Searle, people's such as CE experimental program (Biochem J, 1950; 47: 77-81).
Be suspended in the substances in 0.5% buffering (pH9) methylcellulose gum, with the volume administration of oral gavage with 5 ml/kg body weight.After 1 hour, 125I (300 kilobecquerel(kBq)/kilograms, 3 ml/kg) is through the peritoneal injection administration. 125After the I administration 4 hours, use CO 2Chamber breath method is killed these animals, and bloodletting.Tiroidina scales off together with one section tracheae, is placed in the small test tube and measures radioactivity with gamma counter (LKB-Wallac model 1282 Compugamma).Suppress percentage according to formula 100(1-T/P) to calculate, T and P are respectively the thyroid average radioactivities with the animal of test agent and placebo (buffered methylcellulose gum) processing in the formula.The statistical significance of difference is estimated with Mann-Whitney U test (two tail) between the animal that test agent and placebo are handled.P＜0.05 is considered to meaningful.
The biological test result
Table 4 is listed the testing data that compound of the present invention can get.
Table 4 biological test data
Test compound 400 micromole/kilograms absorb Tiroidina
(n=animal number) 125The inhibition percentage of I
Example 1,3 and 5 activity-7
Metabolite (n=5)
Example 2,4 and 6 activity 0
Metabolite (n=5)

Claims (19)

1, compound of formula I
Figure 921143648_IMG2
R in the formula 1And R 2Difference, respectively be methyl ,-C (O)-CH 3Or
-C (O)-OCH 3, thereby R 1Or R 2In a methyl is always arranged, M is physiologically acceptable to positively charged ion.
2, according to the compound of claim 1, wherein M is Na, K, Ag or trialkyl ammonium.
3, according to the compound of the Chemical formula 1 of claim 1; it is phosphoric acid (5-ethanoyl-6-methyl-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-and 1H-benzoglyoxaline-1-yl) mixture of methyl esters disodium salt and phosphoric acid (6-ethanoyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
4, according to the compound of formula I of claim 1, it is phosphoric acid (5-methoxycarbonyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) sulfinyl methyl))-and 1H-benzoglyoxaline-1-yl) mixture of methyl esters disodium salt and phosphoric acid (6-methoxycarbonyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
5, according to the compound of claim 1, i.e. phosphoric acid (5-ethanoyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
6, according to the compound of claim 1, i.e. phosphoric acid (6-ethanoyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
7, according to the compound of claim 1, i.e. phosphoric acid (5-methoxycarbonyl-6-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
8, according to the compound of claim 1, i.e. phosphoric acid (6-methoxycarbonyl-5-methyl-2-(((3,4-dimethoxy-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline-1-yl) methyl esters disodium salt.
9, contain according to the compound of claim 1 pharmaceutical composition as active ingredient.
10, the compound that is used for the treatment of of definition in the claim 1.
11, in the claim 1 definition be used to suppress the compound that Mammals comprises people's gastric acid secretion.
12, in the claim 1 definition be used for the treatment of the compound that Mammals comprises people's gastroenteritis disease.
13, by the compound of definition in the claim 1 is comprised people's administration gastric acid inhibitory excretory method to Mammals.
14, by the compound administration treatment Mammals of definition in the claim 1 being comprised the method for people's gastroenteritis disease.
15, utilize compound manufacturing to be used to suppress the medicament that Mammals comprises people's gastric acid secretion according to claim 1.
16, utilize compound manufacturing to be used for the treatment of the medicament that Mammals comprises people's gastroenteritis disease according to claim 1.
17, according to the preparation method of the compound of formula I of claim 1, comprise
A) make the compound of chemical formula II and the compound reaction of chemical formula III:
Figure 921143648_IMG3
R in the formula 1And R 2Definition with the chemical formula I, Z is a suitable group on halogen such as Cl, Br or I or the function,
Figure 921143648_IMG4
In the formula Q be one to ion such as Na +, K +, Ag +Or trialkyl ammonium, or
B) make the compound oxidation of chemical formula IV obtain compound of formula I
Figure 921143648_IMG5
R in the formula 1, R 2Has given implication with M.
18, the compound of chemical formula II
Figure 921143648_IMG6
R in the formula 1And R 2Definition with the chemical formula I, Z is a suitable group on halogen such as Cl, Br or I or the function.
19, according to the compound of claim 18, R wherein 1And R 2Definition the same, Z is Cl or OH.
CN92114364A 1991-12-19 1992-12-18 Substituted benzimidazoles, process for their preparation as well as their use Expired - Fee Related CN1031827C (en)

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US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US8188119B2 (en) 2008-10-24 2012-05-29 Eisai R&D Management Co., Ltd Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same
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