CN1096028A - New cyclohexyl alkylsulfonyl vinylformic acid and its derivative and preparation method thereof and purposes - Google Patents
New cyclohexyl alkylsulfonyl vinylformic acid and its derivative and preparation method thereof and purposes Download PDFInfo
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- CN1096028A CN1096028A CN93121517A CN93121517A CN1096028A CN 1096028 A CN1096028 A CN 1096028A CN 93121517 A CN93121517 A CN 93121517A CN 93121517 A CN93121517 A CN 93121517A CN 1096028 A CN1096028 A CN 1096028A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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Abstract
The present invention relates to general formula (I) but the salt of new cyclohexyl alkylsulfonyl vinylformic acid and derivative thereof, its medication, contain pharmaceutical composition of these compounds and preparation method thereof.General formula (I) compound has good antiulcer agent performance and significant anti-helicobacter pylori activity.Therefore, they can be used for the therapeutic and/or the prophylactic treatment of the various ulcer of ESD.
Description
The present invention relates to the new cyclohexyl alkylsulfonyl vinylformic acid of logical formula I and derivative thereof with and pharmacologically acceptable salt:
Wherein:
R represents hydroxyl; By C
1-4The phenoxy group that alkoxy or halogen replaces arbitrarily; 4-(C
1-4Alkoxyl group) carbonyl-1-piperazinyl; 4-[(C
1-4Alkyl) carbonyl-phenyl]-the 1-piperazinyl; 4-piperonyl-1-piperazinyl; 2-[(C
1-4Alkoxyl group) carbonyl] ethylamino; 1-ethyl-2-pyrrolidyl-amino methyl; Or by L-proline(Pro) deutero-2-carbobenzoxy-(Cbz)-1-pyrrolidyl.
The invention still further relates to the pharmaceutical composition that contains these compounds.
Another aspect of the present invention provides the preparation method of logical formula I new compound and pharmacologically acceptable salt thereof.
Logical formula I compound can E and the existence of Z configuration.
In this manual, C
1-4Alkyl and C
1-4C in the alkoxyl group
1-4Moieties is saturated, straight or branched alkyl, for example methyl, ethyl, just or sec.-propyl, just, the second month in a season or the tertiary butyl.
Found these compound biologically actives in the research process of mutual-through type (I) new compound, 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 comprises to Mammals (comprising the people) organism logical formula I compound (wherein R as defined above) or its pharmacologically acceptable salt with independent or pharmaceutical compositions drug treatment effective dose, to prevent and/or treat the various ulcers of ESD.
Pharmacologically active 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 test compound joins in the stomach of animal by stomach tube as 80% tween suspension.After 30 minutes, the acidiferous alcohol of every 100g body weight 0.5ml is administered 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 3 shows
50Value is 0.6mg/kg.
The activity of anti-helicobacter pylori
With agar diffusion and agar dilution, the activity of research logical formula I compound of the present invention on by the isolated helicobacter pylori culture of patient's various ulcer.
Minimum inhibition concentration (MIC) value that has recorded embodiment 3 compounds is 7.8 to 15.4 μ g/ml.
The result can be clear that by these pharmacology, and logical formula I compound of the present invention and pharmacologically acceptable salt thereof have significant cytoprotective performance, and the effect of significant anti-helicobacter pylori.
According to the present invention, logical formula I new compound (wherein R is as defined above) is that 3-cyclohexyl sulfenyl-the 2(Z)-vinylformic acid by the oxidation formula II prepares,
And make if desired, logical formula I compound or its reactive derivative and the following compounds reaction of resulting wherein R representation hydroxy:
A) 4-halogenated phenol, or
B) C
1-4Alkanol, or
C) bridged piperazine derivatives of logical formula III,
Wherein:
R
1Representative (C
1-4Alkoxyl group) carbonyl; (C
1-4Alkyl)-carbonyl-phenyl; 3,4-methylene-dioxy benzoyl; Or
D) sulfonamide derivatives of logical formula IV
Wherein:
R
2Representative (C
1-4Alkoxyl group) carbonyl-ethyl or 1-(C
1-4Alkyl)-2-pyrrolidyl-methyl; Or
E) L-proline(Pro) benzyl ester; Or
F) diazomethane,
And if desired, resulting wherein R is represented 4-(C
1-4Alkyl)-carbonyl-phenyl-peiperazinyl, 2-(C
1-4Alkoxyl group) the logical formula I compound of carbonyl-ethylamino or 1-ethyl-2-pyrrolidyl-amino methyl is converted into acid salt.
According to the preferred embodiment of the inventive method, wherein the logical formula I compound of R representation hydroxy is 3-cyclohexyl sulfenyl-the 2(Z)-vinylformic acid by the oxidation formula II, preferably it is heated to make in containing the glacial acetic acid solution of hydrogen peroxide.This is reflected in the Glacial acetic acid that contains 30% hydrogen peroxide and carried out under 100 ℃ 3 hours, and productive rate reaches about 80%.The formula II compound can prepare [seeing B.Weibull:Arkiv Kemi3,225-248(1951)] by currently known methods, promptly makes the reaction of stoichiometric cyclohexyl mercaptan and propynoic acid in aqueous sodium hydroxide solution.
Wherein R represents C
1-4The logical formula I compound of alkoxyl group or the phenoxy group that replaced arbitrarily by halogen be by with the known activity derivative of the formula I compound of R representation hydroxy wherein with suitable C
1-4Alkanol or the phenol acidylate that replaces arbitrarily prepare.The preferred chloride of acid of acyl halide can be used as reactive derivative.Preferably by being heated, reagent prepared chloride of acid in several hours by suitable acid and thionyl chloride.Resulting chloride of acid can be not purified and be directly used in the acidylate step after the excessive thionyl chloride of evaporation.The suitable acyl halide of using of acylation reaction with formula I compound (wherein R representation hydroxy); in the preferred anhydrous methylene chloride of inert organic solvents; in the presence of the preferred triethylamine of stoichiometric at least inactive alkali, under cooling conditions, suit under about 0 ℃ temperature, to carry out.
Wherein the carboxyl reactive derivative of the logical formula I compound of R representation hydroxy can be by preparing with the known additive method of document, for example, M.Bodanszky is (Springer Verlag described in the 9th to 52 page of the disquisition of " Principles of Peptide Synthesis " at title, Berlin, Heidelberg, New York, Tokyo(1984)).
Can be by preparing the of the present invention logical formula I compound that R wherein represents following groups like the formula I compounds of R representation hydroxy wherein:
4-(C
1-4Alkoxyl group) carbonyl-1-piperazinyl,
4-(C
1-4Alkyl) carbonyl-phenyl-peiperazinyl,
4-piperonyl-1-piperazinyl,
2-(C
1-4Alkoxyl group) carbonyl-ethylamino,
1-ethyl-2-pyrrolidyl-amino methyl or
By L-proline(Pro) deutero-2-carbobenzoxy-(Cbz)-1-pyrrolidyl,
Promptly in the preferred anhydrous methylene chloride of inert organic solvents; under cooling conditions, make preferred their chloride of acid and the following suitable alkali reaction of said derivative that carboxyl is activated: ethoxycarbonyl-piperazine, 4-Piperazino-methyl phenyl ketone, 1-piperonyl-piperazine, Beta-alanine alkyl ester, L-proline(Pro) benzyl ester or 1-ethyl-2-methylamino-tetramethyleneimine with stoichiometric ratio.
These reactions suit to carry out in the presence of the preferred triethylamine of stoichiometric at least inactive alkali.In addition, wherein R is the chloride of acid and the stoichiometric alkali reagent reaction of twice of the formula I compound of hydroxyl.
Wherein R represents C
1-4The logical formula I compound of alkoxyl group also can R be the compound of hydroxyl and suitable C in the formula I by making
1-4Diazo alkane reaction and need not preparing by any activating reagent.
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 pharmaceutical composition commonly used, 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 these compositions 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 formula I promoting agent or its pharmacologically acceptable salt 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
3-cyclohexyl alkylsulfonyl-2(Z)-acrylic acid preparation
To contain 5.55g(29.9mmol) mixture of 3-cyclohexyl sulfenyl-2-vinylformic acid, 11.9ml30% hydrogen peroxide and 60ml Glacial acetic acid stirred 3 hours down at 100 ℃.Behind the evaporating mixture, make the oily residue crystallized, obtain the purpose compound, output 5.3g(81%) by adding normal hexane.M.p.55-57 ℃; Rf value=0.27(launches system: pyridine/Glacial acetic acid/water/ethyl acetate 16: 5: 9: 70).
Embodiment 2
The preparation of 3-cyclohexyl alkylsulfonyl-2(E)-vinylformic acid (4-chloro-phenyl-) ester
A) preparation of 3-cyclohexyl alkylsulfonyl-2(E)-acrylate chloride
With 4.37g(0.02mol) boiling 3 hours that refluxes of 3-cyclohexyl alkylsulfonyl-2(Z)-acrylic acid 30ml thionyl chloride solution.After steaming excessive thionyl chloride, be dissolved in resistates in the 20ml anhydrous methylene chloride and be directly used in acylation reaction.
B) preparation of 3-cyclohexyl alkylsulfonyl-2(E)-vinylformic acid (4-chloro-phenyl-) ester
To containing 2.57g(0.02mol) add 5.6ml(0.02mol in the 30ml anhydrous methylene chloride solution of 4-chlorophenol) triethylamine, solution is cooled to 0 ℃, drip then by a) solution of described preparation of preceding step.Reaction mixture was at room temperature stirred 1 day, pour in the 300ml water then and use dichloromethane extraction.Organic solution is used 1N hydrochloric acid, water successively, is washed with 5% aqueous sodium carbonate at last.Organic solution makes the oily residue crystallized by adding ethyl acetate after anhydrous magnesium sulfate drying and evaporation, obtain the purpose compound, output 3.1g(47%), m.p.:126-128 ℃; Rf value=0.64(benzene/methyl alcohol 14: 3).
Embodiment 3
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-preparation of 4-ethoxycarbonyl-piperazine
To contain 7.9g(0.05mol) the 30ml anhydrous methylene chloride solution of ethoxycarbonyl-piperazine is cooled to 10 ℃, under agitation in 15 minutes, drip and press embodiment 2a) acyl chloride solution of described preparation.Reaction mixture was at room temperature stirred 24 hours.After being poured in the 300ml water then, separate organic phase, then with it successively with 1N hydrochloric acid, water, wash with saturated nacl aqueous solution at last.Organic solution is after anhydrous magnesium sulfate drying and evaporation, and the oily resistates is made eluent by column chromatography purifying (be with granularity 0.063 to 0.2mm Kieselgel60) with ethyl acetate.Make sublimed product crystallization by adding normal hexane, obtain 2.3g(32%) the purpose compound, m.p.92-94 ℃; Rf value=0.42(benzene/methyl alcohol 14: 3).
Embodiment 4
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-the 4-(4-acetylphenyl)-preparation of piperazine
To containing 4.08g(0.02mol) add 2.8ml(0.02mol in the 50ml anhydrous methylene chloride solution of 4-Piperazino methyl phenyl ketone) triethylamine, mixture is cooled to 0 ℃, drips and press embodiment 2a) dichloromethane solution of the chloride of acid of described preparation.Reaction mixture was at room temperature stirred 1 day, pour into then in the 500ml water, after the separation it is used twice of dichloromethane extraction.Organic solution washes with water, washs with saturated nacl aqueous solution then.Organic solution is after anhydrous magnesium sulfate drying and evaporation, and the oily resistates is by column chromatography purifying (granularity is the Kieselgel of 0.063-0.2mm), makes eluent with the mixture of 5: 1 ethyl acetate and normal hexane.Pure products obtains 5.8g(71.8% through the mixture recrystallization of methyl alcohol and normal hexane) the purpose product, m.p.156-157 ℃; Rf value=0.31(ethyl acetate/normal hexane 5: 1)
Embodiment 5
1-piperonyl-4-[3-cyclohexyl alkylsulfonyl-2(E)-acryl] preparation of piperazine
With 4.41g(0.02mol) after 1-piperonyl-piperazine is dissolved in the no Shui diox of 50ml, add 2.8ml(0.02mol) triethylamine, solution is cooled to 10 ℃ then, drips and press embodiment 2a) the chloride of acid De dioxane solution for preparing.Reaction mixture was at room temperature stirred 1 day, pour in the 500ml water then and use dichloromethane extraction.The organic solution water washs with saturated nacl aqueous solution then.After the dry also evaporation of organic phase, the oily resistates obtains 4.2g(49.9% through methyl alcohol and ether crystalline mixture) the purpose product, m.p.:129-130 ℃; Rf value=0.56(benzene/methyl alcohol 14: 3).
Embodiment 6
N-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-preparation of Beta-alanine ethyl ester
With 5.6ml(0.04mol) triethylamine joins and contains 3.08g(0.02mol) in the 50ml anhydrous methylene chloride solution of Beta-alanine carbethoxy hydrochloride.After solution is cooled to 0 ℃, drips and press embodiment 2a) dichloromethane solution of the chloride of acid for preparing, reaction mixture was at room temperature stirred 1 day, pour in the 500ml water then and use dichloromethane extraction.Organic solution successively water, 1N hydrochloric acid, water, wash with saturated nacl aqueous solution at last.Organic solution is after anhydrous magnesium sulfate drying and evaporation, and resistates is made eluent by column chromatography purifying (granularity is the Kieselgel 60 of 0.063-0.2mm) with benzene/acetone/mixture of 14: 3: 0.5 of triethylamine.Make product crystallization by adding normal hexane, obtain 3.9g(61% with this method purifying) the purpose product, m.p.100-102 ℃; Rf value=0.50(benzene/acetone/triethylamine 14: 3: 0.5).
Embodiment 7
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-2(S)-preparation of pyrrolidine carboxylic acid's benzyl ester
With 4.7g(0.02mol) L-proline(Pro) benzyl ester hydrochloride is suspended in the no Shui diox of 50ml and adds 5.6ml(0.04mol) after the triethylamine, suspension is cooled to 10 ℃, drip and press embodiment 2a) the chloride of acid De dioxane solution for preparing.With reaction mixture at room temperature stir poured in the 500ml water in 1 day then after, use dichloromethane extraction.Organic solution is successively with 1N hydrochloric acid, water and saturated nacl aqueous solution washing.Dry and the evaporation with gained solution subsequently.The oily resistates is by column chromatography purifying (granularity is the Kieselgel 60 of 0.063-0.2mm), makes eluent with the mixture of 3: 1 ethyl acetate and normal hexane.Make resulting oily matter crystallization by adding sherwood oil, obtain 2.3g(28.3%) the purpose product, m.p.:114-116 ℃, [α]
25 D=-76.7 ° (C=1, chloroform); Rf value=0.54(ethyl acetate/normal hexane 3: 1).
Embodiment 8
The preparation of 1-ethyl-2-{ [3-cyclohexyl alkylsulfonyl-2(E)-acryl] amino methyl } tetramethyleneimine dihydrochloride
With 2.56g(0.02mol) 1-ethyl-2-amino methyl-pyrrolidine hydrochloride is dissolved in the 50ml methylene dichloride, adds 5.6ml(0.04mol then) triethylamine.After mixture is cooled to 0 ℃, drips and press embodiment 2a) dichloromethane solution of the chloride of acid for preparing.Reaction mixture was at room temperature stirred 2 days, pour in the 500ml water then and use dichloromethane extraction.Organic extract liquid is with saturated nacl aqueous solution washing, dry and evaporating solvent.The oily resistates is by chromatography purification (granularity is the Kieselgel 60 of 0.063-0.2mm), makes eluent with the mixture of 9: 1 acetone and triethylamine, obtains 3.8g(52.0%) the purpose product, m.p.:139-141 ℃; Rf value=0.60(acetone/triethylamine 9: 1).
Embodiment 9
1-[3-cyclohexyl alkylsulfonyl-2(Z)-acryl]-preparation of 4-ethoxycarbonyl-piperazine
To 3.27g(0.015mol) 3-cyclohexyl alkylsulfonyl-2(Z)-acrylic acid 70ml anhydrous tetrahydrofuran solution in add 2.1ml(0.015mol) triethylamine; then solution is cooled to-15 ℃; under-15 ℃ of stirrings, drip 1.43ml(0.0156mol) Vinyl chloroformate, drip the 2.37g(0.015mol that is dissolved in the 15ml anhydrous tetrahydro furan then) 1-ethoxycarbonyl-piperazine.Stirred 1 hour down at-15 ℃, at room temperature after the restir 1 hour, mixture is poured in the 400ml water then, use twice of 50ml dichloromethane extraction at every turn.The organic phase that merges is used 10ml 1N salt acid elution again with 10ml water earlier, through anhydrous magnesium sulfate drying and evaporation.The oily resistates is by the column chromatography purifying, makes eluent with the mixture of 1: 1 acetone and normal hexane.Oily matter revaporization with purifying.By in products therefrom, adding sherwood oil, obtain 1.2g(22.3%) the purpose compound, m.p.:108-110 ℃.
Embodiment 10
The preparation of 3-cyclohexyl alkylsulfonyl-2(Z)-methyl acrylate
The dichloromethane solution that under agitation will contain the 33mmol diazomethane slowly is added drop-wise to 6.47g(30mmol) in 3-cyclohexyl alkylsulfonyl-2(Z)-acrylic acid 50ml dichloromethane solution.Under reduced pressure steam from mixture after the solvent, resistates is by the column chromatography purifying, makes eluent with the mixture of 3: 1 ethyl acetate and hexane, obtains 3.1g(44.5%) crystalloid purpose product, m.p.69-70 ℃.
Embodiment 11
The preparation of 3-cyclohexyl alkylsulfonyl-2(Z)-methyl acrylate
To containing 6.47g(30mmol) in 3-cyclohexyl alkylsulfonyl-2(Z)-acrylic acid 50ml dichloromethane solution, add 1.2ml(30mmol) methyl alcohol, 6.2g(30mmol) 4-dimethylaminopyridine of dicyclohexylcarbodiimide and catalytic amount.Reaction mixture was stirred 8 hours at 20 ℃.Organic phase successively water, 5% sodium hydrogen carbonate solution, again water, use 1N hydrochloric acid then, wash with water at last.Resulting solution is through anhydrous magnesium sulfate drying, and evaporation and crystallization obtain the purpose product, output 3.1g(46% then), m.p.69-70 ℃.
Claims (7)
1, the pharmaceutically useful salt of logical formula I compound and these compounds:
Wherein:
R represents hydroxyl; By C
1-4The phenoxy group that alkoxy or halogen replaces arbitrarily; 4-(C
1-4Alkoxyl group) carbonyl-1-piperazinyl; 4-[(C
1-4Alkyl) carbonyl-phenyl]-the 1-piperazinyl; 4-piperonyl-1-piperazinyl; 2-[(C
1-4Alkoxyl group) carbonyl] ethylamino; 1-ethyl-2-pyrrolidyl-amino methyl; Or by L-proline(Pro) deutero-2-carbobenzoxy-(Cbz)-1-pyrrolidyl.
2, be selected from following compound:
3-cyclohexyl alkylsulfonyl-2(Z)-vinylformic acid,
3-cyclohexyl alkylsulfonyl-2(E)-vinylformic acid (4-chloro-phenyl-) ester,
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-4-ethoxycarbonyl-piperazine,
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-the 4-(4-acetylphenyl)-piperazine,
1-piperonyl-4-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-piperazine,
N-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-the Beta-alanine ethyl ester,
1-[3-cyclohexyl alkylsulfonyl-2(E)-acryl]-2(S)-pyrrolidine carboxylic acid's benzyl ester,
1-ethyl-2-[3-cyclohexyl alkylsulfonyl-2(E)-acryl] amino methyl } pyrrolidine hydrochloride,
1-[3-cyclohexyl alkylsulfonyl-2(Z)-acryl]-4-ethoxycarbonyl-piperazine and
3-cyclohexyl alkylsulfonyl-2(Z)-methyl acrylate.
3, a kind of pharmaceutical composition, this pharmaceutical composition comprise as the logical formula I new compound (wherein R as defined in claim 1) of activeconstituents and with its blended pharmaceutical industry in carrier and/or additive commonly used.
4, the preparation method of the pharmacologically acceptable salt of logical formula I new compound and these compounds,
Wherein:
R represents hydroxyl; By C
1-4The phenoxy group that alkoxy or halogen replaces arbitrarily; 4-(C
1-4Alkoxyl group) carbonyl-1-piperazinyl; 4-[(C
1-4Alkyl) carbonyl-phenyl]-the 1-piperazinyl; 4-piperonyl-1-piperazinyl; 2-[(C
1-4Alkoxyl group) carbonyl] ethylamino; 1-ethyl-2-pyrrolidyl-amino methyl; Or by L-proline(Pro) deutero-2-carbobenzoxy-(Cbz)-1-pyrrolidyl,
This method comprises the 3-cyclohexyl sulfenyl of oxidation formula II-2(Z)-vinylformic acid,
And make if desired, logical formula I compound or its reactive derivative and the following compounds reaction of resulting wherein R representation hydroxy:
A) 4-halogenated phenol, or
B) C
1-4Alkanol, or
C) bridged piperazine derivatives of logical formula III,
Wherein:
R
1Representative (C
1-4Alkoxyl group) carbonyl; (C
1-4Alkyl)-carbonyl-phenyl; 3,4-methylene-dioxy benzoyl; Or
D) sulfonamide derivatives of logical formula IV
Wherein:
R
2Representative (C
1-4Alkoxyl group) carbonyl-ethyl or 1-(C
1-4Alkyl)-2-pyrrolidyl-methyl; Or
E) L-proline(Pro) benzyl ester; Or
F) diazomethane,
And if desired, resulting wherein R is represented 4-(C
1-4Alkyl)-carbonyl-phenyl-peiperazinyl, 2-(C
1-4Alkoxyl group) the logical formula I compound of carbonyl-ethylamino or 1-ethyl-2-pyrrolidyl-amino methyl is converted into acid salt.
5, according to method claimed in the claim 4, this method comprises uses the wherein reactive derivative of the logical formula I compound of R representation hydroxy of acyl halide conduct.
6, a kind of method that is used for pharmaceutical compositions; this method comprises and will mix by carrier and/or the additive as using always in the logical formula I new compound (wherein R as defined in claim 1) of activeconstituents or its pharmacologically acceptable salt and the pharmaceutical industry that uses 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 to curee's administration prevention of this treatment of needs or logical formula I compound (wherein R as defined in claim 1) or its pharmacologically acceptable salt of treatment significant quantity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU4141/92 | 1992-12-29 | ||
| HU9204141A HU210930B (en) | 1992-12-29 | 1992-12-29 | Process for producing novel cyclohexyl-sulfonyl-acrylic acid and derivatives and pharmaceutical preparations containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1096028A true CN1096028A (en) | 1994-12-07 |
Family
ID=10982776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93121517A Pending CN1096028A (en) | 1992-12-29 | 1993-12-29 | New cyclohexyl alkylsulfonyl vinylformic acid and its derivative and preparation method thereof and purposes |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1096028A (en) |
| AU (1) | AU5658694A (en) |
| HU (1) | HU210930B (en) |
| WO (1) | WO1994014765A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1557225A (en) * | 1975-07-10 | 1979-12-05 | Kao Corp | Sulphinyl compounds and processes ofr preparing same |
| DE3041154A1 (en) * | 1980-10-31 | 1982-06-09 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING 2-HALOGEN-3-SULFONYLACRYLNITRILE |
| HU203869B (en) * | 1989-07-14 | 1991-10-28 | Richter Gedeon Vegyeszet | Process for producing salts ofnew acrylic acid derivatives and pharmaceutical compositions containing them |
| HU211020B (en) * | 1991-12-12 | 1995-09-28 | Richter Gedeon Vegyeszet | Process for producing new phenylsulphonyl acrylic acid derivatives and pharmaceutical compositions containing the same |
-
1992
- 1992-12-29 HU HU9204141A patent/HU210930B/en not_active IP Right Cessation
-
1993
- 1993-12-10 WO PCT/HU1993/000069 patent/WO1994014765A1/en active Application Filing
- 1993-12-10 AU AU56586/94A patent/AU5658694A/en not_active Abandoned
- 1993-12-29 CN CN93121517A patent/CN1096028A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994014765A1 (en) | 1994-07-07 |
| HU9204141D0 (en) | 1993-04-28 |
| HUT67024A (en) | 1995-01-30 |
| HU210930B (en) | 1995-09-28 |
| AU5658694A (en) | 1994-07-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |