CN1096295A - New benzo five-membered ring derivatives, contain their pharmaceutical composition and preparation method thereof - Google Patents
New benzo five-membered ring derivatives, contain their pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN1096295A CN1096295A CN93112986A CN93112986A CN1096295A CN 1096295 A CN1096295 A CN 1096295A CN 93112986 A CN93112986 A CN 93112986A CN 93112986 A CN93112986 A CN 93112986A CN 1096295 A CN1096295 A CN 1096295A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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Abstract
The invention relates to the new formula with therapeutic activity (I) benzo five-membered naphthenic acid, salt, ester and amide derivatives and when X in the formula be oxygen and R they and H when being hydroxyl
2Receptor antagonist institute salify, and contain the pharmaceutical composition of above-claimed cpd.
The invention still further relates to preparation above-claimed cpd and method for compositions.
Tangible gastric cells provide protection of formula (I) compound exhibits and gastric acid inhibitory secretion activity.They also have anti-microbial effect to pathogenic agent bacterial strain pylorus convolution bacillus in addition.So they can be used for preventing and/or treating the ulcer disease of various Digestive tract (ESD).
Description
The invention relates to benzo five-membered naphthenic acid, salt, ester and the amide derivatives of new formula I with therapeutic activity,
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R when being hydroxyl, they and H
2Receptor antagonist (preferred famotidine) institute's salify; And contain the pharmaceutical composition of above-claimed cpd.
The invention still further relates to preparation above-claimed cpd and method for compositions.
The invention still further relates to the ulcer disease of the various ESDs that prevent and/or treat dried meat breast animal (comprising the people), comprising taking the formula I compound of dose therapeutically effective for described dried meat breast animal.
Alkyl has the straight or branched carbochain of the saturated carbonatoms that contains above-mentioned definition, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl separately or as the part of other group.
Halogenic substituent can be chlorine, bromine, fluorine or iodine, preferred bromine.
The crowd who suffers from digestive tract ulcer increases sharply.Ulcer causes and has an intense pain, and also can cause bleeding in its active phase.According to traditional medicine, ease the pain earlier, promote the damaged tissue healing again.Conventional medicament is (as pyrene and azepine
, the west is for fourth, Omepragole etc.) attempt respectively to secrete and reach above-mentioned effect by reducing hydrochloric acid in gastric juice level and gastric acid inhibitory.Under suitable medical treatment and nutritional condition, general 4-6 week of ulcer cures.But ulcer often recurs, and needs to cure again.
Nearest research concentrates on more and more and is called on the gastric cells protection compound.These compounds increase the protective capability to stomach, thereby take the possibility that this compound can obviously reduce ulcer recurrence, and can stop the generation of acute ulcer, and the latter is that easily sending out of ulcer is inclined to.Recently think that on the nosetiology of gastritis and gastric duodenal ulcer, pathogenic agent bacterial strain pylorus convolution bacillus (Helicobacter pylori) plays an important role.
Certainly except that cell protection activity, it is meaningful especially also gastric acid secretion to be played inhibiting compound.
Make us finding uncannily that the compound exhibits valuable pharmacological activity of formula I is as gastric acid inhibitory secretion, protection gastric cells and antibacterial activity.Therefore, they can be used for preventing and/or treating the inflammation and the ulcer disease of various ESDs.The compound of formula I to the cause of disease be pathogenic agent bacterial strain pylorus convolution bacillus cause infection the time case effective especially.
Biological activity according to compound of the present invention illustrates with following experiment.
1) the gastric acid inhibitory secretion activity in the pylorus ligation experiment
The method of [Gastroenterology5, p43-61(1945)] such as use Shay.
Hungry 24 hours of the female Hannover-Wistar mouse of every heavy 120-150g, ligation animal pylorus then.Preceding 30 minutes of ligation pylorus is to the promoting agent of animal oral (P.O) formula I.Performed the operation back 4 hours, and put to death animal, measure hydrochloric acid in gastric juice content.
The gastric acid secretion inhibiting activity of experimental compound is decided by the relation with the hydrochloric acid in gastric juice content of the control animal of not taking medicine.
In above-mentioned experiment, find the ED of the compound of embodiment 1 behind the oral administration
50Value is the 31mg/kg body weight.
Experimentize under above-mentioned similarity condition, the ED of fourth is not replaced in the known drug west
50Be 50mg/kg.
2) by containing the gastric damage effect that acid alcohol causes
Use the method [Gasttroenterology77, P.761-767(1979)] of A.Robert.
Use the female mice of every heavy 120-150g of hungry 24 hours.The mixture that contains 1ml concentrated hydrochloric acid and 50ml absolute ethanol is as downright bad agent, and dosage is the 0.5ml/100g body weight.
Giving before the acid alcohol 30 minutes, in the stomach to the compound of formula I.Give behind the acid alcohol 1 hour, put to death animal.Measure the gland part of stomach and handle the vertical hemorrhage length that causes, calculate the average total length in every stomach by acid alcohol.
The gastric cells provide protection is represented with the per-cent of the average total length that vertical hemorrhage average total length records with respect to control group.
In the above-mentioned experiment, find the ED of the compound of embodiment 1 behind the oral administration
50Value is the 0.8mg/kg body weight.
Be used for measuring in the experiment of gastric cells provide protection the ED of known drug ulcerlmin above-mentioned
50Value is the 150mg/kg body weight.
The compound of formula I has further increased their therapeutic importance to the germicidal action of pylorus convolution bacillus according to the present invention, and the existence of above-mentioned bacterium has adverse influence to the ulcer of treatment Digestive tract; Or their existence is the Hazard Factor [Internist29, P745-754(1988)] of acute ulcer.
3) activity experiment of anti-pylorus convolution bacillus
Activity with agar diffusion method and agar dilution test formula I compound of the present invention.Experimentize with the pylorus convolution bacillus culture that is separated to from five different Peptic Ulcers philtrums.
To five kinds of experimental strains, the MIC(minimum inhibitory concentration of the compound of embodiment 1) value is 62.5 μ g/ml, and the MIC value of Metronidazole plain BP.98 99 (chemistry 2-methyl-5-nitro by name-1H-imidazoles-1-ethanol) is 320-400 μ g/ml[J.R.Lambert:Drug Investigation2(suppl.1), P.52-55(1990)].
Therefore, the compound of formula I according to the present invention in the experiment of the secretion of performance gastric acid inhibitory and gastric cells provide protection and anti-pylorus convolution bacilli-cell, all substantially is better than reference compound.Adult patient's therapeutic dose can change between the 100mg at 10mg every day.
The promoting agent of formula I can with generally be used for non-enteron aisle or enterally administering formula of medicine, nontoxic, inertia, solid or liquid vehicle and/or other additive mix, and change pharmaceutical composition into.Useful carrier is as water, gelatin, lactose, starch, pectin, Magnesium Stearate, stearic acid, talcum, vegetables oil such as peanut oil, olive wet goods.Promoting agent can be made into general pharmaceutical composition, particularly solids composition, as sphere or edge of a knife tablet, dragee or capsule such as gelatine capsule, granula, suppository etc.The quantitative change wide ranges of solid activator, preferred every dose unit (as tablet, capsule, a unit solution etc.) contains 25mg-1g.These compositions also can contain other conventional medicament additive, as stablizer, sanitas, wetting agent, emulsifying agent etc.These compositions can prepare with currently known methods, as the situation to solids composition, can assign to prepare by sieve, mixing, granulating, the various one-tenth of compacting.These compositions also can carry out other pharmaceutical technology operation, as sterilization.
The dosage level that uses can be in the range of broad according to severity and the frequency and the concrete route of administration of animal of being treated or patient's body weight, individual reaction and infection state.
Suitable dosage can be determined at an easy rate by the skilled doctor in this area.
The invention still further relates to the method for the ulcer disease that prevents and/or treats various ESDs.This method comprises the promoting agent of the formula I of the therapeutic action amount that doses a patient with.
When the X substituting group was oxygen, the compound of formula I was new 2, the 3-dihydro-benzofuran derivative; And when the X substituting group is methylene radical, or the compound of (I) is new 1, the 2-indane derivatives.
When X was oxygen, the compound of formula I was (Z) configuration; When X was methylene radical, compound was (E) configuration.
The compound of formula I can be divided into two big classes, i.e. ester and acid amides are except the special case when X is hydroxyl for oxygen R.Under one situation of back, the invention still further relates to and H
2Receptor antagonist institute salify is preferably with famotidine institute salify.(chemistry of famotidine is called 3-{ [[2-[(amino imino methyl) amino] thiazolyl] methyl] sulphur }-N-(sulfamide groups) propionyl imines).
Famotidine salt can react in alcohol (preferred alcohol) by stoichiometric two kinds of compositions and form.
According to new benzo five-membered naphthenic acid, ester and the amide derivatives of formula I of the present invention, can prepare by following step:
A) benzofuran derivative of formula III
Wherein X is an oxygen
React in the presence of acid catalyst with Glyoxylic acid hydrate, obtain the compound of formula I, wherein R is a hydroxyl, and X is an oxygen; With
B) salt of the carboxylic acid of formula II
Wherein X is oxygen or methylene radical
With the reaction of halogenated acetic acids ester, obtain the ester derivative of formula I; Or
C) primary amine or the secondary amine of carboxylic acid of formula II (wherein X is oxygen or methylene radical) and formula IV react in the presence of activating reagent, obtain the amide derivatives of formula I,
R wherein
1Represent hydrogen, R
2Be selected from C
1-4Alkyl, cyclohexyl; By any phenyl that replaces of halogen; (C
1-4) alkoxycarbonyl methyl;
And 1-(C
1-4) carbalkoxy-2-phenylethyl; Or R
1And R
2Form pyrrolidyl or N-(C with their institute's azine atoms
1-4) the carbalkoxy piperazinyl; Be the formula I compound of oxygen and R representation hydroxy with the wherein X that obtains in a) going on foot in case of necessity, use H
2Receptor antagonist is converted into its salt.
The reaction that generates the formula I compound is preferably carried out in inert solvent, is advisable with methylene dichloride, ethyl acetate or benzene.
Preferably the carboxylate salt (being advisable with triethylamine salt) by formula II and halogenated acetic acids ester (volt selects the bromoacetic acid alkyl ester) are in inert organic solvents (ethyl acetate) for the ester of formula I, and heating a few hours prepare.
The acid amides of formula I is preferably used the carboxyl of the carboxylic acid of formula II, and is earlier activated, connects with primary amine or secondary amine to prepare again.
The carboxylic acid halides (preferred acyl chlorides) that forms from carboxylic acid is preferably used as derivatives reactivity.Acyl chlorides can react in inert organic solvents such as benzene by carboxylic acid and thionyl chloride and prepare.
For the activating carboxy acid, also can use the general method that uses in the chemistry of peptides [to see that the title as M.Bodanszky is the monograph of " Principres of Peptide Syntresis ", Springer-Verlag, Berlin, Heidelberg, New-York, Tokyo, (1984)].The activating carboxy acid preferably uses the mixed acid anhydride method.According to this method, in the presence of stoichiometric alkali (preferred triethylamine), cooling (preferred-15 ℃) down forms mixed acid anhydride with stoichiometric chloro-formic ester.Inert organic solvents (being advisable with methylene dichloride) is as solvent.
Then, activatory derivative and stoichiometric uncle or secondary amine cooling reaction down, reaction mixture is cooled to room temperature gradually then.
Wherein X is that the compound of the formula II of oxygen can pass through 3-oxo-2, and 3-Dihydrobenzofuranes and the condensation in Glacial acetic acid of single water Glyoxylic acid hydrate prepare.Obtain (Z)-2-carboxyl methylene radical-3-oxo-2,3-Dihydrobenzofuranes with this method.
Wherein X is the formula II compound of methylene radical, as (E)-2-carboxyl methylene radical-2, the 3-bihydrogen-1-indenone, available disclosed international patent application No, the method of describing in 91/17,983 is from 2, and the 3-bihydrogen-1-indenone prepares. in this method, 2, the 3-bihydrogen-1-indenone under alkaline condition with the on-the-spot condensation of Glyoxylic acid hydrate.
In the initiator of formula III, 3-oxo-2, the 3-Dihydrobenzofuranes can use that currently known methods prepares in the document [Chem, Ber, 43P212(1910)].2, the 3-bihydrogen-1-indenone is that market can get product.
The present invention is elaborated with following indefiniteness embodiment.
Embodiment 1
Preparation (Z)-2-carboxyl methylene radical-3-oxo-2, the 3-Dihydrobenzofuranes
To contain 13.4g(0.1mol in the 150ml Glacial acetic acid) 3-oxo-2,3-Dihydrobenzofuranes and 13.8g(0.15mol) the outstanding of single water Glyoxylic acid hydrate be subjected to the liquid reflux 5 hours.Half solvent of vacuum-evaporation and cooling, the title product precipitates with crystallized form, obtains 7.6g(40%), M.P.:180-181 ℃, R
f=0.5(development system: ethyl acetate/acetic acid 19: 1).
Embodiment 2
Preparation (Z)-2-carboxyl methylene radical-3-oxo-2,3-Dihydrobenzofuranes famotidine salt
Stir in the 50ml ethanol and contain 0.95g(5mmol) compound and the 1.68g(5mmol of preparation in the example 1) the outstanding of famotidine alkali be subjected to liquid 6 hours.The title salt precipitation is leached, and uses the 10mml washing with alcohol, obtain 2.5g(95%), m.p.:175 ℃ (decomposition).
Embodiment 3
Preparation (E)-2-(ethoxy carbonyl-methoxycarbonyl methylene radical)-and 3-oxo-2, the 3-bihydrogen-1-indenone
Contain 2.8g(15mmol) 2-carboxyl methylene radical-3-oxo-2,3-bihydrogen-1-indenone, 1.5g(15mmol) triethylamine and 2.75g(16mmol) the mixture of bromoethyl acetate, in the 70ml ethyl acetate, react.80 ℃ are heated after 5 hours, in reaction mixture impouring water down.Ethyl acetate is carried out continuous extraction with 1N hydrochloric acid, water, saturated sodium carbonate solution, water mutually.Dry also evaporating solvent, resistates is crystallization in ether, produces 1.8g(44%) title compound, m.p:114-116 ℃, R
f=0.75(benzene/methyl alcohol 14: 3).
Embodiment 4
Preparation (Z)-2-(phenyl amino-carbonyl methylene radical)-and 3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, contain 1.9g(0.01mol) the outstanding of compound of preparation in the example 1 be subjected in the liquid, adds 1.4ml(0.01mol) triethylamine, cooling solution is to-15 ℃ then.Under uniform temp, in this solution, add 0.96ml(0.01mol) Vinyl chloroformate, stirred reaction mixture is 30 minutes then.Adding 0.91ml(0.01mol) behind the aniline, reaction mixture stirs 1 hour, 0 ℃ at-15 ℃ and stirred 1 hour, stirs 2 hours at 20 ℃ at last.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates obtains 2.1g(79% with the crystallization of 50ml ether) title compound, m.p.=212-214 ℃, R
f=0.66(ethyl acetate).
Embodiment 5
Preparation (Z)-2-[(4-bromophenyl)-amino-carbonyl methylene radical]-3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, contain 1.9g(0.01mol) example 1 in the outstanding of compound of preparation be subjected in the liquid, add 1.4ml(0.01mol) triethylamine, cooling solution is to-15 ℃ then.Under uniform temp, in this solution, add 0.96ml(0.01mol) Vinyl chloroformate, stirred reaction mixture is 30 minutes then.Add 1.72g(0.01mol) behind the 4-bromaniline, reaction mixture keep-15 ℃ 1 hour, 0 ℃ 1 hour, then stirring at room 2 hours.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates obtains 2.3g(67% with the crystallization of 50ml ether) title compound, m.p.=252-254 ℃, R
f=0.7(ethyl acetate).
Embodiment 6
Preparation (Z)-2-(1-pyrrolidyl-carbonyl methylene radical)-and 3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, containing 1.9g(0.01mol) the outstanding of compound of preparation in the example 1 be subjected in the liquid,-15 ℃ add 1.4ml(0.01mol down) triethylamine, add 0.96ml(0.01mol again) Vinyl chloroformate, stirred reaction mixture is 30 minutes then, under uniform temp, add 0.85ml(0.01mol then) tetramethyleneimine, reaction mixture stirred 1 hour at-15 ℃, and 0 ℃ was stirred 1 hour, stirred 2 hours at 20 ℃ at last.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase with anhydrous magnesium sulfate drying and evaporation after, resistates obtains 2.1g(86% with the crystallization of 50ml ether) title compound .m.p:116-118 ℃, R
f=0.34(ethyl acetate).
Embodiment 7
Preparation (Z)-2-[(4-ethoxy carbonyl-1-piperazinyl) carbonyl methylene radical]-3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, containing 1.9g(0.01mol) the outstanding of compound of preparation in the example 1 be subjected in the liquid ,-15 ℃ add 1.4ml(0.01mol) triethylamine, and add 0.96ml(0.01mol again) Vinyl chloroformate, stirred reaction mixture is 30 minutes then.Add 1.5ml(0.01mol then) the 4-(ethoxy carbonyl) piperazine, reaction mixture stirs 1 hour, 0 ℃ at-15 ℃ and stirred 1 hour, stirs 2 hours at 20 ℃ at last.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates obtains 2.2g(66% with the crystallization of 50ml ether) title compound, m, p=106-108 ℃, R
f=0.6(ethyl acetate/acetic acid 19: 1).
Embodiment 8
Preparation (Z)-2-[1-methoxycarbonyl-2(S)-phenylethyl-amino-carbonyl methylene radical]-3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, contain 1.9g(0.01mol) example 1 in the preparation the outstanding of compound be subjected in the liquid, add 1.4ml(0.01mol) triethylamine, cooling solution adds 0.96ml(0.01mol to-15 ℃ then) Vinyl chloroformate, stirred reaction mixture is 30 minutes then.Under uniform temp, add 2.15g(0.01mol then) L-phenyl methyl lactamine hydrochloride and 1.4ml(0.01mol) triethylamine, reaction mixture stirs 1 hour, 0 ℃ at-15 ℃ and stirred 1 hour, stirs 2 hours at 20 ℃ at last.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates obtains 2.1g(60% with the crystallization of 50ml ether) title compound, m.p.:107-109 ℃, R
f=0.66(ethyl acetate),
[α]=+ 27.43 ° (c=0.5, chloroform).
Embodiment 9
Preparation (Z)-2-[1-methoxycarbonyl-2(S)-styroyl)-amino-carbonyl methylene radical]-3-oxo-2, the 3-Dihydrobenzofuranes
In the 150ml methylene dichloride, contain 1.9g(0.01mol) example 1 in the preparation the outstanding of compound be subjected in the liquid, add 1.4ml(0.01mol) triethylamine, cooling solution is to-15 ℃ then, adding 0.96ml(0.01mol) behind the Vinyl chloroformate, stirred reaction mixture is 30 minutes under uniform temp.Add 1.25g(0.01mol then) hydrochloric acid Glyoxylic acid hydrate methyl esters and 1.4ml(0.01mol) behind the triethylamine, reaction mixture stirs under cooling, 0 ℃ 1 hour, room temperature 2 hours.Then, reaction mixture water, 10% sodium hydrogen carbonate solution, 5% hydrochloric acid, water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates obtains 1.5g(57% with the crystallization of 50ml ether) title compound, m.p.:168-170 ℃, R
f=0.5(ethyl acetate).
Embodiment 10
Preparation (E)-2-(normal-butyl amino-carbonyl methylene radical)-2, the 3-bihydrogen-1-indenone
In 20ml benzene, contain 2.8g(15mmol) (E)-2-carboxyl methylene radical-2, in the solution of 3-bihydrogen-1-indenone, add the 10ml thionyl chloride, 60 ℃ were stirred this solution 90 minutes, then evaporating solvent.Resistates is dissolved in the 40ml methylene dichloride, and join under 0 ℃ be dissolved with 2.2g(0.03mol) in the 20ml methylene dichloride of n-Butyl Amine 99.Then, reaction mixture stirring at room 90 minutes, again in the impouring water, organic phase is with saturated sodium carbonate solution, water, 1N hydrochloric acid, water continuous extraction.After the dry also evaporation of organic phase, resistates ether crystallization obtains 1.8g(50%) title compound, m.p.:152-154 ℃, R
f=0.65(benzene/methyl alcohol 14: 3).
Embodiment 11
Preparation (E)-2-(cyclohexyl amino-carbonyl methylene radical)-2, the 3-bihydrogen-1-indenone
In the 20ml dry-out benzene, contain 2.8g(15mmol) 2-carboxyl methylene radical-2, in the solution of 3-bihydrogen-1-indenone, add the 10ml thionyl chloride, 60 ℃ were stirred this solution 90 minutes, then evaporating solvent.Resistates is dissolved in the 40ml methylene dichloride, and join under 0 ℃ be dissolved with 3.0g(0.03mol) in the 20ml methylene dichloride of hexahydroaniline.The reaction mixture stirring at room is 12 hours then, again in the impouring water.Organic phase extracts with saturated sodium carbonate solution.Organic phase is with anhydrous magnesium sulfate drying and evaporating solvent.Resistates ether crystallization obtains 2.6g(68%) title compound, m.p.:202-205 ℃, R
f=0.73(benzene/methyl alcohol 14: 3).
Embodiment 12
Preparation (E)-2-(1-pyrrolidyl-carbonyl methylene radical)-2, the 3-bihydrogen-1-indenone
In 100ml benzene, contain 2.88g(15mmol) 2-carboxyl methylene radical-2, in the solution of 3-bihydrogen-1-indenone, add 5ml(0.07mol) thionyl chloride, 60 ℃ were heated this solution 1 hour, then evaporating solvent.Resistates is dissolved in the 100ml ethyl acetate, and this drips of solution is added to be dissolved with 3.0g(35mmol) in the 100ml methylene dichloride of tetramethyleneimine.React after 1 hour, evaporate this solution, resistates is dissolved in the ethyl acetate, and the water extraction.After the drying, the evaporation organic phase.Resistates ether crystallization obtains 1.8g(50%) title compound, m.p.:164-166 ℃, R
f=0.36(ethyl acetate).
Embodiment 13
Preparation (E)-2-(phenyl amino-carbonyl methylene radical)-2,3-dihydro 1-indone
In 100ml benzene, contain 2.88g(15mmol) 2-carboxyl methylene radical-2, in the solution of 3-bihydrogen-1-indenone, add 5ml(0.07mol) thionyl chloride, 60 ℃ were heated this solution 1 hour.Behind the evaporating solvent, resistates is dissolved in the 100ml anhydrous ethyl acetate, and this solution is added to be dissolved with 3.1ml(35mmol) in the 100ml methylene dichloride of aniline.Stir after 1 hour, reaction mixture leaches precipitation with the extraction of 0.01M hydrochloric acid soln, obtains 3.1g(78%) title compound, m.p.=241-243 ℃, R
f=0.7(ethyl acetate).
Embodiment 14
Preparation (E)-2-[(1-ethoxycarbonyl-4-piperazinyl) carbonyl methylene radical]-2, the 3-bihydrogen-1-indenone
Make in the 60ml ethyl acetate and contain 1.88g(0.01mol) after 2-carboxyl-methylene radical-2.3-bihydrogen-1-indenone outstanding be subjected to liquid, cooling off this outstanding is subjected to liquid to arrive-10 ℃, add 1.01g(0.01mol in batches) triethylamine and 2.6g(11mmol) hexichol time phosphonyl chloride, reaction mixture stirred 1 hour under uniform temp.Then, add 1.01g(0.01mol in batches) triethylamine and 1.6g(0.01mol) the N-(ethoxycarbonyl)-piperazine.Reaction mixture stirred 1 hour at-10 ℃, at room temperature stirred then 1 hour.The elimination precipitation, filtrate water, 1N hydrochloric acid, water, saturated sodium carbonate solution and water continuous extraction.Organic phase is with anhydrous magnesium sulfate drying and after evaporating, and resistates ether crystallization obtains 1.06g(31%) title compound, m.p.=172-174 ℃, R
f=0.63(ethyl acetate/pyridine/Glacial acetic acid/water 90: 5: 2: 3).
Embodiment 15
The preparation tablet
A) every weighs 150mg, contains the tablet of 5mg active ingredient
Composition g
Activeconstituents 5
Gelatin 3
Magnesium Stearate 2
Talcum 5
Yam starch 40
Lactose 95
B) every weighs 300mg, contains the tablet of 50mg activeconstituents
Composition g
Activeconstituents 50
polyvidone 6
Magnesium Stearate 3
Talcum 9
Yam starch 84
Lactose 148
Contain above-mentioned a) or b) in the powdered mixture of composition of definition, with wet granulation of ordinary method and compacting, obtain 150 or the tablet of 300mg respectively.Every contains activeconstituents 5mg or 50mg respectively.
Claims (12)
1, new acid, salt, ester, the amide derivatives of the five-membered ring fused benzene of formula I:
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R they and H when being hydroxyl
2Receptor antagonist institute salify.
2, (Z)-2-carboxyl methylene radical-3-oxo-2, the 3-Dihydrobenzofuranes.
3, pharmaceutical composition, wherein contain new acid, salt, ester or amide derivatives as one or more formula I five-membered ring fused benzenes of activeconstituents:
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R they and H when being hydroxyl
2Receptor antagonist institute salify,
With the medicine that generally is used for enteron aisle or parenterai administration, the mixture of nontoxic, inertia, solid or liquid vehicle and/or additive.
4, new acid, salt, ester and the amide derivatives of formula I five-membered ring fused benzene
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R they and H when being hydroxyl
2Receptor antagonist institute salify,
The preparation method, comprising
A) benzofuran derivative of formula III
Wherein X is an oxygen
React in the presence of acid catalyst with Glyoxylic acid hydrate, obtain the compound of formula I, wherein R is a hydroxyl, and X is an oxygen; Or
B) salt of the carboxylic acid of formula II
Wherein X is oxygen or methylene radical
With the reaction of halogenated acetic acids ester, obtain the ester derivative of formula I; Or
C) primary amine or the secondary amine of carboxylic acid of formula II (wherein X is oxygen or methylene radical) and formula IV react in the presence of activating reagent, obtain the amide derivatives of formula I,
R wherein
1Represent hydrogen, R
2Be selected from (C
1-4) alkyl, cyclohexyl; By any phenyl that replaces of halogen; (C
1-4) alkoxycarbonyl methyl; And 1-(C
1-4) carbalkoxy-2-phenylethyl; Or R
1And R
2Form 1-pyrroles wash base or 4-(C with their institute's azine atoms
1-4) carbalkoxy-1-piperazinyl; With
Be the formula I compound of oxygen and R representation hydroxy with the wherein X that obtains in a) going on foot in case of necessity, use H
2Receptor antagonist is converted into its salt.
5, according to the method for step a) in the claim 4, comprising the famotidine salt of preparation gained compound.
6,, it is characterized in that being reflected in the Glacial acetic acid and carry out according to the method for step a) in the claim 4.
7, according to the method for step b) in the claim 4, the triethylamine salt that it is characterized in that the formula II carboxylic acid is as starting raw material, and X is oxygen or methylene radical in the formula II.
8, according to the method for step c) in the claim 4, it is characterized in that using the carboxylic acid of acyl chlorides (preferred thionyl chloride) or carbonochloridic acid ester activation formula II, X is oxygen or methylene radical in the formula II.
9, method according to Claim 8 is characterized in that being reflected under inertia organic bases (preferred triethylamine) existence and carries out.
10,, it is characterized in that being reflected under this reaction conditions and carry out in the inert solvent according to each method among the claim 4-8.
11, preparation of drug combination method is characterized in that acid, salt, ester or amide derivatives with one or more formula I five-membered ring fused benzenes
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R when being hydroxyl, they and H
2Receptor antagonist
Institute's salify, with the medicine that generally is used for enteron aisle or parenterai administration, nontoxic, inertia, solid or liquid vehicle and/or additive mix, and change this mixture into medicine agent shape.
12, prevent and/or treat the method for various oesophaguses, stomach or the ulcer and duodenal ulcer of dried meat breast animal (comprising the people), it is characterized in that taking new acid, salt, ester or the amide derivatives of one or more formula I five-membered ring fused benzenes of effective therapeutic dose to described dried meat breast animal
Wherein:
R is selected from hydroxyl, (C
1-4) carbalkoxy methoxyl group, (C
1-4) alkylamino, cyclohexyl amino; By any phenyl amino that replaces of halogen; (C
1-4) alkoxycarbonyl methyl amino, 1-(C
1-4) carbalkoxy-2-phenylethyl amino, 1-pyrrolidyl and 4-(C
1-4) carbalkoxy-1-piperazinyl; With
X represents oxygen or methylene radical,
Condition is: when the R representation hydroxy, X is an oxygen;
With as X be oxygen and R they and H when being hydroxyl
2Receptor antagonist institute salify, above compound can be taken separately or take with the form of pharmaceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9204112 | 1992-12-23 | ||
| HU9204112A HU211212B (en) | 1992-12-23 | 1992-12-23 | Process to prepare novel benzofurane and indane derivs. and pharmaceutical compns. contg. the said compds. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1096295A true CN1096295A (en) | 1994-12-14 |
Family
ID=10982764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93112986A Pending CN1096295A (en) | 1992-12-23 | 1993-12-22 | New benzo five-membered ring derivatives, contain their pharmaceutical composition and preparation method thereof |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1096295A (en) |
| AU (1) | AU5821694A (en) |
| HU (1) | HU211212B (en) |
| WO (1) | WO1994014788A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117160A (en) * | 2016-08-26 | 2016-11-16 | 浙江野风药业股份有限公司 | A kind of preparation method of 3 [(2 guanidine radicals 4 thiazole) methylsulfany] third methyl ester imidate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0530264B1 (en) * | 1990-05-15 | 1996-10-23 | E.I. Du Pont De Nemours And Company | Arthropodicidal tetrahydropyridazines |
-
1992
- 1992-12-23 HU HU9204112A patent/HU211212B/en not_active IP Right Cessation
-
1993
- 1993-12-17 WO PCT/HU1993/000078 patent/WO1994014788A1/en active Application Filing
- 1993-12-17 AU AU58216/94A patent/AU5821694A/en not_active Abandoned
- 1993-12-22 CN CN93112986A patent/CN1096295A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117160A (en) * | 2016-08-26 | 2016-11-16 | 浙江野风药业股份有限公司 | A kind of preparation method of 3 [(2 guanidine radicals 4 thiazole) methylsulfany] third methyl ester imidate |
| CN106117160B (en) * | 2016-08-26 | 2019-02-05 | 浙江野风药业股份有限公司 | A kind of preparation method of the third methyl ester imidate of 3- [(2- guanidine radicals -4- thiazole) methylsulfany] |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5821694A (en) | 1994-07-19 |
| WO1994014788A1 (en) | 1994-07-07 |
| HU9204112D0 (en) | 1993-04-28 |
| HU211212B (en) | 1996-02-28 |
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