CN1094027A - The benzoyl-acrylic acid di-esters contains their pharmaceutical composition and prepares their method - Google Patents
The benzoyl-acrylic acid di-esters contains their pharmaceutical composition and prepares their method Download PDFInfo
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- CN1094027A CN1094027A CN 93112995 CN93112995A CN1094027A CN 1094027 A CN1094027 A CN 1094027A CN 93112995 CN93112995 CN 93112995 CN 93112995 A CN93112995 A CN 93112995A CN 1094027 A CN1094027 A CN 1094027A
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- phenyl
- oxo
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to new general formula (I) benzoyl-acrylic acid di-esters, contain their pharmaceutical composition and their preparation method.In general formula (I), R represents C
1-4Alkyl; Or by one or more C
1-4The phenyl that alkoxyl group replaces arbitrarily; Or 3-phenyl-3-oxo-1 (E-propenyl; And n is 2,3 or 4.General formula (I) compound has good antiulcer agent performance and has significant anti-helicobacter pylori activity.Therefore, these compounds can be used for the various ulcers of therapeutic and/or prophylactic treatment ESD.
Description
The present invention relates to new logical formula I benzoyl-acrylic acid di-esters and the pharmaceutical composition that contains these compounds:
Wherein:
R represents C
1-4Alkyl; By one or more C
1-4The phenyl that alkoxyl group replaces arbitrarily; Or 3-phenyl-3-oxo-1(E)-propenyl; And
N is 2,3 or 4.
Another aspect of the present invention provides the method for preparing new logical formula I compound.
In this manual, C
1-4Alkyl and C
1-4The C of alkoxyl group
1-4Moieties be saturated, straight or branched alkyl such as methyl, ethyl, just or sec.-propyl, just, the second month in a season or the tertiary butyl.
The biological study of mutual-through type (I) compound shows these compound biologically actives, and promptly they have significant antiulcer action, cytoprotection for example, and in addition, they also have significant anti-microbial effect.
Therefore, the invention still further relates to methods of treatment, this method comprise to Mammals (comprising the people) organism with separately or with the logical formula I compound (wherein R and n are as defined above) of pharmaceutical compositions drug treatment effective dose to prevent and/or treat the various ulcers of ESD.
Therapeutic activity with the logical formula I compound of following method research.
The research of the gastric damage that brings out by acidiferous alcohol.
Method [Gastroenterology 77,761-767(1979)] according to A.Robert is tested.Every heavy female rats of 120 to 150g is used for these experiments in fasting after 24 hours.To treat that substances adds in the stomach of animal by stomach tube as 80% tween suspension.After half an hour, the acidiferous alcohol of every 100g body weight 0.5ml is applied in the stomach of animal by stomach tube.Put to death animal after 1 hour, take out its stomach, and cut along greater gastric curvature.Measure reddish-brown striped (going out blood injury) and calculate the average total length of a stomach.The activity and the control group of test compound are compared.Behind oral administration, the ED that the The compounds of this invention described in the embodiment 1 shows
50Value is 0.3mg/kg.
The test of Shay ' s ulcer
According to Gastroenterology 5b, 5-13(1945) described method is tested.With the fasting 24 hours in the grid cage of every heavy 120 to 150g male H-Wister mouse.Drink water the pylorus of ligation animal under the slight anesthesia of ether arbitrarily to animal.After 4 hours, put to death animal, take out its stomach, and measure the volume and the pH value of stomach, use the output of titration measuring HCl in some cases with excessive ether.
Found that the ED of The compounds of this invention behind oral administration
50Value is 26mg/kg.
The activity of anti-helicobacter pylori
With agar diffusion and agar dilution, in activity from the isolated helicobacter pylori culture research of patient's various ulcer logical formula I compound of the present invention.
Minimum inhibition concentration (MIC) value of having found embodiment 1 compound is 0.9/ μ g/ml.
The result can be clear that by these pharmacology, and logical formula I compound of the present invention has good antiulcer agent performance, and the effect of significant anti-helicobacter pylori.
New logical formula I compound (wherein R and n are as defined above) of the present invention prepares by following method:
Use logical formula III alcohol:
The activity derivatives reaction of (wherein n is as defined above) and logical formula II carboxylic acid,
(wherein R is as defined above), or
Make the derivative of logical formula IV alcohol:
(wherein R and n are as defined above) is with the activity derivatives reaction of formula (V) carboxylic acid.
According to the preferred embodiment of the inventive method, with the logical formula III alcohol of the reactive derivative acidylate of logical formula II carboxylic acid.The preferred acyl chloride derivative of acyl halide can be used as the reactive derivative of logical formula II carboxylic acid.The preparation method of acyl halide is known.Esterification is preferably to use the acyl halide derivative of the preferably few excessive logical formula II carboxylic acid of stoichiometry at least in inert organic solvents under about 0 ℃ temperature, at the preferred triethylamine of stoichiometric at least alkali as carrying out in the presence of the acid binding agent.With the average yield is that 50-60% obtains product.The anhydride ester derivs of logical formula II carboxylic acid also is fit to carry out esterification; This reaction also is at room temperature to use the preferably few excessive acid anhydrides of stoichiometry to carry out in the presence of the preferred 4-dimethylaminopyridine of pyridine derivate of catalytic amount in the preferred anhydrous methylene chloride of inert organic solvents.The additive method that in chemistry of amino acids, generally uses [referring to: M.Bod á nyszky: " Principles of Peptide Synthesis ", P9-52, Springer Verlag, Berlin, Heidelberg, New York, Tokyo(1984)] also can be used for activating logical formula II carboxylic acid.Logical formula II carboxylic acid great majority are the products that can buy from the market.Press the described methods of people such as O.Grummit [Org.Synth.Coll.Vol.3,109(1955)], make benzene and maleic anhydride carry out Friedel-Crafts reaction and can make 4-phenyl-4-oxo-2(E)-butenoic acid.
The other method of the logical formula I dibasic acid esters of preparation comprises the hydroxy alkyl ester (wherein R and n are as defined above) with the logical formula IV of reactive derivative acidylate of formula (V) carboxylic acid.The reactive derivative of formula (V) compound can lead to the same quadrat method preparation of the reactive derivative of formula II carboxylic acid by preparation.In various possibilities, preferably use the logical formula IV compound of anhydride ester derivs acidylate of formula (V) compound.
Make formula (V) 4-phenyl-4-oxo-2(E)-butenoic acid and stoichiometric at least logical formula VI alcohol;
(wherein X represents halogen) preferably can make logical formula III compound with ethylene bromohyrin or the reaction of 3-bromopropyl alcohol.This esterification is to carry out in the presence of the suitable triethylamine of stoichiometric at least alkali in the preferred dimethyl formamide of dipolar nature aprotonic solvent.Temperature of reaction is suitable to remain on about 90 ℃.The halohydrin of logical formula VI is the product that can buy from the market.
By with The compounds of this invention with parenteral or in enteral administration treatment nontoxic inert solid commonly used or liquid vehicle and/or additive mix, The compounds of this invention can be converted into pharmaceutical composition.Suitable carrier is as water, gelatin, lactose, starch, pectin, Magnesium Stearate, stearic acid, talcum, vegetables oil such as peanut oil or olive wet goods.Promoting agent can be formulated into conventional medicine composition, particularly solids composition, as tablet, drageeing, capsule such as the gelatine capsule of circle or deburring and pill, suppository etc.
Composition can also at random contain medicated premix commonly used, as sanitas, stablizer, wetting agent and emulsifying agent etc.These compositions are to prepare with method commonly used, for example when the preparation solids composition, with each composition screening, mixing, granulation and compacting.Can make the ordinary method of composition in addition, for example sterilization through other pharmaceutical technologies.
The invention still further relates to the methods of treatment of the various ulcers that are used to prevent and/or treat ESD.This method comprises the formula I promoting agent to the Mammals of this treatment of needs (comprising the people) administering therapeutic significant quantity.
Describe the present invention in detail by following indefiniteness embodiment.
Embodiment 1
The preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (2-acetoxyl group ethyl) ester
A) preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (2-hydroxyethyl) ester
With 15ml(0.121mol) triethylamine is added to 17.6g(0.1mol) in the 100ml anhydrous dimethyl formamide solution of 4-phenyl-4-oxo-2(E)-butenoic acid.After stirring in the short period of time, add 15g(0.11mol) ethylene bromohyrin, and with reaction mixture 90 ℃ of heating 8 hours down.After in its impouring 100ml water, use the dichloromethane extraction reaction mixture, organic phase is used 5% sodium carbonate solution, saturated nacl aqueous solution and 1N hcl as extraction agent successively.Gained solution also evaporates with anhydrous magnesium sulfate drying.1: 1 crystalline mixture oily residue with tetracol phenixin and sherwood oil.With 3: 1 mixtures of ethyl acetate/normal hexane as eluent by the column chromatography purified product, obtain the 7.58g(35% productive rate) target product of step a), m.p:55-57 ℃.
B) preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (2-acetoxyl group ethyl) ester
With 4.4g(0.02mol) hydroxyethyl ester [a) being prepared by above-mentioned steps] is dissolved in the 50ml anhydrous methylene chloride, adds 0.1g4-dimethyl aminopyridine and 5g(0.05mol) acetic anhydride.Reaction mixture was at room temperature stirred 5 hours, successively with 5% aqueous sodium carbonate, water, saturated brine solution extraction, use the 1N hcl as extraction agent at last, gained solution anhydrous magnesium sulfate drying, evaporation then then.Add normal hexane and make the oily residue become crystal, obtain 4.03g(77%) target product of embodiment 1, M.P.:52-54 ℃.
Embodiment 2
The preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (2-benzoyloxy ethyl) ester
With 3.1ml(0.022mol) triethylamine is added to and contains 4.4g(0.02mol) in the 50ml anhydrous methylene chloride solution of hydroxyethyl ester [by the foregoing description 1a) preparation], mixture was at room temperature stirred 30 minutes, be cooled to-10 ℃ then.Adding 3.1g(0.022mol) behind the Benzoyl chloride, reaction mixture was at room temperature stirred 12 hours.Then, reaction mixture with 5% aqueous sodium carbonate, water, saturated nacl aqueous solution washing, is used IN salt acid elution successively at last.Gained organic solution is also evaporated with anhydrous magnesium sulfate drying.After in residue, adding sherwood oil,, thereby obtain 3.4g(53% through the resulting yellow crystals shape of recrystallizing methanol product) target compound, M.P.:62-64 ℃.
Embodiment 3
1, the preparation of 2-two [4-phenyl-4-oxo-2(E)-butylene acyloxy] ethane
With 5.4g(0.016mol) 4-phenyl-4-oxo-2(E)-crotonic anhydride and 0.01g4-dimethyl aminopyridine be added to 2.34g(0.01mol) in the 50ml anhydrous methylene chloride solution of hydroxyethyl ester [by the foregoing description 1a) preparation].After reaction mixture at room temperature stirred 12 hours, with the gained mixture successively with 5% aqueous sodium carbonate, saturated nacl aqueous solution, use 1N salt acid elution at last.Gained organic solution is also evaporated with anhydrous magnesium sulfate drying.Then sherwood oil is added in the buttery evaporation residue, behind ethyl alcohol recrystallization, obtains the 2.9g(77% of orange lenticular) target product, M.P.:107-109 ℃.
Embodiment 4
4-phenyl-4-oxo-2(E)-butenoic acid (2-(2,3,4-trimethoxy benzoyloxy) ethyl] preparation of ester
To containing 2.88g(0.013mol) 2,3, in the 20ml diox suspension of 4-trimethoxybenzoic acid, add the 30ml thionyl chloride, after 3 hours, mixture is cooled to room temperature and evaporation at 80 ℃ of following reacting by heating mixtures, the yellow evaporation residue of gained oily is 2,3, the 4-trimethoxy-benzoyl chloride is used it for following step.
With 2.3g(0.011mol) and hydroxyethyl ester [by the foregoing description 1a) preparation] be dissolved in the 50ml anhydrous methylene chloride, in gained solution, add 1.9ml(0.013mol then) triethylamine, then it is cooled to 0 ℃, then to wherein slowly being added dropwise to the 3.0g(0.013mol that is dissolved in the above-mentioned preparation in the methylene dichloride) 2,3, the 4-trimethoxy-benzoyl chloride.Mixture was stirred 1 hour down at 0 ℃, at room temperature stirred then 12 hours, reaction mixture is successively with 5% aqueous sodium carbonate, saturated nacl aqueous solution, use 1N salt acid elution at last.Gained organic solution is also evaporated with anhydrous magnesium sulfate drying.Add normal hexane, the yellow evaporation residue of oily becomes crystal.Product obtains 2.5g(55% through recrystallizing methanol) target product, M.P.:59-61 ℃.
Embodiment 5
The preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (3-benzoyloxy propyl group) ester
A) preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (3-hydroxypropyl) ester
With 3.08ml(0.022mol) triethylamine is added to 3.52g(0.02mol) in the 50ml anhydrous dimethyl formamide solution of 4-phenyl-4-oxo-2(E)-butenoic acid after, at room temperature the short period of time stirs the mixture, add 2.08ml(0.024mol afterwards) 3-bromo-1-propyl alcohol, mixture was stirred 6 hours down at 90 ℃, then with in the reaction mixture impouring water, use dichloromethane extraction, organic phase is successively with 5% aqueous sodium carbonate, saturated nacl aqueous solution, use 1N salt acid elution at last.After anhydrous magnesium sulfate drying organic solution and evaporation, 3: 1 mixtures using ethyl acetate/normal hexane are as eluent, by the yellow residue of column chromatography purifying oily.Add sherwood oil and make sublimed product become crystal, obtain 2.91g(63%) target product of step a), M.P.:46-48 ℃.
B) preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (3-benzoyloxy propyl group) ester
With 1.6ml(0.011mol) triethylamine is added to and contains 2.34g(0.01mol) in the 50ml anhydrous methylene chloride solution of hydroxypropyl ester [a) preparing] by above-mentioned steps after, short period of time stirs the mixture, splash into 1ml(0.011mol then) Benzoyl chloride, stirred 2 hours down at 0 ℃, at room temperature stirred then 12 hours, reaction mixture is successively with 5% aqueous sodium carbonate, saturated nacl aqueous solution, use the 1N hcl as extraction agent at last.Gained organic solution is also evaporated with anhydrous magnesium sulfate drying.Add normal hexane and make the crystallization of oily evaporation residue.Products therefrom obtains 2.25g(66% through recrystallizing methanol) target product, M.P.:51-53 ℃.
Embodiment 6
The preparation of 4-phenyl-4-oxo-2(E)-butenoic acid (2-benzoyloxy ethyl) ester
With 3.3g(0.02mol) phenylformic acid 2-hydroxyethyl ester [presses L.H.Cretcher and W.H.Pittinger, J.Am.Chem.Soc.47,2561(1925) described preparation] be dissolved in the 50ml anhydrous methylene chloride, in gained solution, add 8.35g(0.025mol then) 4-phenyl-4-oxo-2(E)-crotonic anhydride (by the 198th, No. 292 preparation of Hungarian patent specification) and 0.1g4-dimethyl aminopyridine.After at room temperature stirring 12 hours, reaction mixture is used 5% aqueous sodium carbonate, water, 1N salt acid elution successively, washes with water again.The organic solution of gained is also evaporated with anhydrous magnesium sulfate drying.Add sherwood oil, make the yellow residue of oily become crystal.This product obtains 2.2g(68% after recrystallizing methanol) target product, M.P.:62-64 ℃.
Claims (7)
1, logical formula I benzoyl-acrylic acid di-esters:
Wherein:
R represents C
1-4Alkyl; By one or more C
1-4The phenyl that alkoxyl group replaces arbitrarily; Or 3-phenyl-3-oxo-1 (E)-propenyl; And
N is 2,3 or 4.
2, be selected from following compound:
4-phenyl-4-oxo-2(E)-butenoic acid (2-acetoxyl group ethyl) ester,
4-phenyl-4-oxo-2(E)-butenoic acid (2-benzoyloxy ethyl) ester,
1,2-pair [4-phenyl-4-oxo-2(E)-the butylene acyloxy] ethane,
4-phenyl-4-oxo-2(E)-butenoic acid [2-(2,3,4-trimethoxy benzoyloxy) ethyl] ester, and
4-phenyl-4-oxo-2(E)-butenoic acid (3-benzoyloxy propyl group) ester.
3, a kind of pharmaceutical composition, it comprises as the new logical formula I compound (wherein R and n are as defined in claim 1) of active ingredient and blended commonly used carrier and/or additive in pharmaceutical industry with it.
4, the method for preparing new logical formula I benzoyl-acrylic acid di-esters:
Wherein:
R represents C
1-4Alkyl; By one or more C
1-4The phenyl that alkoxyl group replaces arbitrarily; Or 3-phenyl-3-oxo-1(E)-propenyl; And
N is 2,3 or 4,
This method comprises:
Make logical formula III alcohol:
The activity derivatives reaction of (wherein n is as defined above) and logical formula II carboxylic acid,
(wherein R as defined above); Or
Make the derivative of logical formula IV alcohol:
The activity derivatives reaction of (wherein R and n are as defined above) and formula (V) carboxylic acid.
5, according to the method for claim 4, this method comprises with acyl halide or the acid anhydrides reactive derivative as carboxylic acid.
6, the method that is used for pharmaceutical compositions; this method comprises mixes carrier and/or additive as using always in the new logical formula I benzoyl-acrylic acid dibasic acid esters (wherein R and n are as defined in claim 1) of active ingredient and the pharmaceutical industry with method preparation claimed in the claim 4, and is translated into pharmaceutical composition.
7, to therapeutic and/or the preventative-therapeutic method of the Mammals (comprising the people) that suffers from oesophagus, stomach or duodenal various ulcers, this method comprises the logical formula I benzoyl-acrylic acid dibasic acid esters (wherein R and n are as defined in claim 1) to curee's drug treatment of this treatment of needs or prevention significant quantity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU4115/92 | 1992-12-23 | ||
| HU9204115A HU210840B (en) | 1992-12-23 | 1992-12-23 | Process for preparing double esters with benzoyl acrilic acid and pharmaceutical compn.s conta. them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1094027A true CN1094027A (en) | 1994-10-26 |
Family
ID=10982767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93112995 Pending CN1094027A (en) | 1992-12-23 | 1993-12-23 | The benzoyl-acrylic acid di-esters contains their pharmaceutical composition and prepares their method |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1094027A (en) |
| AU (1) | AU5658594A (en) |
| HU (1) | HU210840B (en) |
| WO (1) | WO1994014749A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU195762B (en) * | 1986-04-01 | 1988-07-28 | Richter Gedeon Vegyeszet | Process for preparing novel butene acid derivatives and medical compositions containing them as active substance |
| IT1190340B (en) * | 1986-06-06 | 1988-02-16 | Roussel Maestretti Spa | DERIVATIVES OF 4-FENYL 4-BONE 2-BUTENOIC ACID, THEIR PREPARATION PROCEDURE AND THEIR USE AS MEDICINAL PRODUCTS |
-
1992
- 1992-12-23 HU HU9204115A patent/HU210840B/en not_active IP Right Cessation
-
1993
- 1993-12-10 AU AU56585/94A patent/AU5658594A/en not_active Abandoned
- 1993-12-10 WO PCT/HU1993/000068 patent/WO1994014749A1/en active Application Filing
- 1993-12-23 CN CN 93112995 patent/CN1094027A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994014749A1 (en) | 1994-07-07 |
| HU9204115D0 (en) | 1993-04-28 |
| HU210840B (en) | 1995-08-28 |
| AU5658594A (en) | 1994-07-19 |
| HUT65774A (en) | 1994-07-28 |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |