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WO1993012079A1 - Nouveaux derives d'ester de phenylsulfonylacrylate - Google Patents

Nouveaux derives d'ester de phenylsulfonylacrylate Download PDF

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Publication number
WO1993012079A1
WO1993012079A1 PCT/HU1992/000054 HU9200054W WO9312079A1 WO 1993012079 A1 WO1993012079 A1 WO 1993012079A1 HU 9200054 W HU9200054 W HU 9200054W WO 9312079 A1 WO9312079 A1 WO 9312079A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
optionally substituted
halogen
group optionally
Prior art date
Application number
PCT/HU1992/000054
Other languages
English (en)
Inventor
János Fischer
Ildikó BALLÓ
Tamás FODOR
Katalin SZO^'KE
E^´va PETE^´NYI GALLÓ
Ede MÁRVÁNYOS
Szilvia Wallerstein
Elemér Ezer
Judit MATÚZ
Katalin Sághy
László Szporny
György Hajós
Original Assignee
Richter Gedeon Vegye^´Szeti Gyár Rt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegye^´Szeti Gyár Rt. filed Critical Richter Gedeon Vegye^´Szeti Gyár Rt.
Publication of WO1993012079A1 publication Critical patent/WO1993012079A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
    • 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

Definitions

  • the invention relates to novel phenylsulfonyl- aerylate ester derivatives, to processes for their preparation, to pharmaceutical compostions containing them and to their medical use.
  • Ulcerative diseases of the digestive system affect a continuously increasing quote of population. In its active phase, the ulcer causes a strong pain and a bleeding may also occur. According to the traditional method of drug treatment, the primary target is to alleviate the pain and then to promote the restoration of the tissue part injured. The above target was tried to be achieved
  • the ulcer heals within 4 to 6 weeks when an appropriate treatment and diet are employed; however, the ulcer frequently relapses and the drug treatment should again be started.
  • gastrocytoprotective compounds have more and more frequently appeared in the centre of interest. Due to their capability to increase the protective ability of stomach wall, the probability of relapse can significantly be diminished or the development of an ulcer in a patient having high risk of ulceration can be prevented by using such
  • the invention relates to novel, therapeutically active phenylsulfonylacrylate ester derivatives of the formula
  • R stands for a C 1-4 alkyl group; a phenyl group optionally substituted by a C 1-4 alkoxy or a (C 1-4 alkylcarbonyl- oxy group; an aralkyl group optionally substituted by a C 1-4 alkoxy group on the aromatic ring; a phenylsulfonylvinyl or phenylcarbonylvinyl group optionally substituted by a halogen on their phenyl moiety;
  • R 1 means hydrogen or a halogen
  • n 2 or 3.
  • Alkyl groups alone or as moieties of other groups herein mean saturated, straight or branched chain hydrocarbyl groups within the above-defined range of carbon atoms such as e.g. methyl, ethyl, n- or isopropyl, n-, sec- or tert-butyl groups.
  • the compounds of formula (I) according to the invention are new and possess valuable gastric acid secretion inhibiting, gastrocytoprotective and antibacterial
  • the present invention also relates
  • a pharmaceutical composition for preventing and/or healing various inflammatory and ulcerative diseases of esophagus, stomach or duodenum comprising an amount of a compound of formula (I) effective in treating such conditions and a pharmaceutically acceptable carrier.
  • the invention relates to a method of treatment, which comprises administering a therapeutically effective amount of a compound of formula (I) to a mammal (including man) to be treated for preverting and/or healing various inflammatory and ulcerative diseases of esophagus, stomach or duodenum.
  • the invention also relates to a process for the preparation of the above compounds of formula (I)
  • the compounds of formula (I) show valuable pharmacological such as gastric acid secreto-inhibitory, gastrocytoprotective and antibacterial effects.
  • they are useful to prevent and/or heal the various inflammatory and ulcerative diseases of the esophagus, stomach and duodenum; they are especially effective in cases, where the aetiology of disease is an infection caused by the pathogenic bacterial strain Heli- cobacter pylori.
  • the gastric acid secreto-inhibitory effect of the compounds tested was determined and calculated as the ratio of their gastric acid content to the acid content measured in the gastric juice of the untreated control animals.
  • the oral ED 50 value of compound prepared according to Example 1 was found to be 7.2 mg/kg of body weight.
  • the ED 50 value of Cimetidine a known drug was found to be 50 mg/kg of body weight.
  • the compounds of formula (I) were introduced to the stomach of animals 30 minutes prior to administration of the acidic ethanol. One hour following the aministration of the acidic ethanol, the animals were killed and the average total length of longitudinal bleedings induced in the grandular part of the stomach by the acidic ethanol treatment were determined and calculated for one stomach.
  • the cytoprotective effect was characterized by the percentage of the average total length of bleedings in relation to the average total length measured in the control group (treated with acidic ethanol alone).
  • the oral ED 50 value of the compound of Example 1 was found to be 1.4 mg/kg of body weight.
  • the oral ED 50 value of Sucralfate a known active cytoprotective agent, was found to be 150 mg/kg of body weight.
  • the MIC value (i.e. the minimum inhibitory concentration) of the compound of Example 1 against the Helicobacter pylori culture proved to be 10 ⁇ g/ml.
  • the compounds of formula (I) according to the invention significantly surpass the activity of the reference drugs in tests showing the gastric acid secre- to-inhibitory, gastrocytoprotective actions and possess a strong antibacterial effect against the Helicobacter pylori culture.
  • the therapeutical dose for adults may be between 25 mg and 100 mg per day.
  • the active agents of formula (I) can be formulated in pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or auxiliaries commonly used in the therapy for parenteral or enteral administration.
  • Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vege- table oils such as peanut oil, olive oil and the like.
  • the active agent can be formulated in any usual pharmaceutical composition, particularly solid composition, e.g. rounded or edged tablet, dragee or capsule such as gelatine capsule, pill, suppository and the like.
  • the amount of the solid active ingredient may be varied within a broad range in a dosage unit of the composition (tablet, capsule, one unit of the formulated solution and the like), preferably it is between about 25 mg and 1 g.
  • these compositions may also contain other commonly used pharmaceutical auxiliaries, e.g. stabilizers, preservatives, wetting agents, emulsifying agents and the like.
  • compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the components in the case of solid compositions.
  • the compositions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization.
  • the dose to be used may be varied between wide limits depending on the body-weight and responsiveness of the person or animal to be treated, as well as on the severity of the state to be influenced, frequency and route of administration; however, the suitable dose can easily be determined by a physician skilled in the art.
  • the compounds of formula (I) contain two carboxylic acid ester moieties which are diesters of 1,2-ethylene glycol or 1,3-propylene glycol, respectively.
  • Symmetric diesters of formula (I) can be prepared also by introducing both ester groups in a
  • 1,2-ethylene glycol or 1,3- propylene glycol respectively is reacted with 2 molar equivalents of a carboxylic acid of formula wherein R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety.
  • novel compounds of formula (I) can be prepared by
  • R 1 and n are as defined above, or
  • R and n are as defined above, or
  • the reaction resulting in the compounds of formula (I) is preferably carried out in a solvent being inert to the reaction conditions, advantageously in methylene chloride, tetrahydrofuran or dioxane, in the presence of stoichiometric amount of a base, suitably triethylamine.
  • a solvent being inert to the reaction conditions, advantageously in methylene chloride, tetrahydrofuran or dioxane, in the presence of stoichiometric amount of a base, suitably triethylamine.
  • esterifying reactions are accomplished in such a way that the carboxy group of the compounds of formula (III) is firstly activated and the activated derivative obtained is brought into reaction without isolation with a hydroxyalkyl ester of formula (II).
  • Preferred activated derivatives of carboxylic acids of formula (III) are the carboxylic acid halides which may be prepared e.g. by heating the acid with an excess of
  • the acyl halide formed may be used without isolation for esterification. This reaction is carried out at a temperature between 0 °C and 20 °C.
  • the carboxy group of compounds of the formula (III) may be activated also in the form of acid anhydride.
  • compounds of the formula (II) can be acetylated or propionylated by using acetic or propionic anhydride, respectively.
  • This esterification reaction may be promoted by using catalytic amounts of pyridine bases, preferable 4-dimethylaminopyridine.
  • formula (III) may be activated also by using a coupling reagent in the reaction mixture itself.
  • Suitable coupling reagents are the carbodiimides, e.g. dicyclohexylcarbodiimide. In this case a stoichiometric amount of the
  • compound of formula (II) is mixed with the carboxylic acid of formula (III) in an inert organic solvent, preferably dry methylene chloride, then the activation and coupling are carried out by using a stoichiometric amount of dicyclohexylcarbodiimide, preferably at a temperature between 0 °C and 25 °C.
  • This reaction may be catalyzed by using a pyridine derivative, suitably 4-dimethylaminopyridine resulting in an improvement of the yield, too.
  • the compounds of formula (I) may be prepared also by reacting a hydroxyalkyl ester of formula (IV) with a carboxylic acid of formula (III) wherein R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, or with an activated derivative
  • the compounds of formula (IV) can be prepared by the direct esterification of the carboxylic acids of formula (III) with an excess of the compounds of formula (V), wherein X means hydroxy group and n is 2 or 3.
  • X means hydroxy group and n is 2 or 3.
  • proton catalysis is used and the reaction is preferably carried out in the presence of a small amount of a mineral acid at a temperature range of 60 to 120 °C.
  • the compounds of formula (IV) may be prepared by reacting "the carboxylic acids of formula (III) with a 2-haloethanol or 3-halopropanol, wherein "halo” means halogen, preferably bromine.
  • halo means halogen, preferably bromine.
  • This reaction is accomplished in an inert organic solvent, suitably a dipolar aprotic solvent, e.g. dimethylformamide in the presence of a stoichiometric amount of a base, preferably triethylamine.
  • R means phenylsulfonylvinyl group optionally substituted by halogen on its phenyl moiety, by boiling the reactants in an inert organic solvent, suitably methylene chloride while
  • the reaction may be catalyzed by a strong acid, preferably hydrochloric or p-toluenesulfonic acid.
  • reaction mixture is poured into 400 ml of water and
  • the reaction mixture is stirred at 0 °C for 2 hours, and then at 20 °C for 5 hours.
  • the dicyclohexylurea precipitated is filtered off and the filtrate is successively extracted with water, 5% sodium hydrogen carbonate solution and finally with water again.
  • the reaction mixture is stirred at 0 °C for 3 hours and then at room temperature for 2 hours.
  • the dicyclohexylure precipitated is filtered off and the filtrate is
  • Lactose 148 After wet-granulating, the powder mixtures defined above under a) or b), respectively are compressed in the usual manner to give tablets weighing 150 or 300 mg each, respectively. Each tablet contains 5 or 50 mg, respectively of the active compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouveaux dérivés d'ester de phénylsulfonylacrylate répondant à la formule (I), dans laquelle R représente un groupe alkyle C1-4; un groupe phényle éventuellement substitué par un groupe alcoxy C1-4 ou alkyle C1-4 carbonyloxy; un groupe aralkyle éventuellement substitué par un groupe alcoxy C1-4 sur le cycle aromatique; un groupe phénylsulfonylvinyle ou phénylcarbonylvinyle éventuellement substitué par un halogène sur la fraction phényle; un groupe méthylsulfonylvinyle; un groupe 4-oxo-4H-1-benzopyran-2-yle ou 4-oxo-4H-1-benzothiopyran-2-yle; R1 représente hydrogène ou halogène; et n vaut 2 ou 3. On a également prévu des compositions pharmaceutiques contenant ces composés, ainsi que les procédés de préparation des composés de la formule (I). Lesdits composés présentent une activité gastro-cytoprotectrice et antisécrétoire sur l'acide gastrique, et peuvent, de ce fait, être utilisés dans le traitement et/ou la prophylaxie des maladies inflammatoires et ulcératives de l'÷sophage, de l'estomac ou du duodénum.
PCT/HU1992/000054 1991-12-12 1992-12-11 Nouveaux derives d'ester de phenylsulfonylacrylate WO1993012079A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU3908/91 1991-12-12
HU913908A HU211020B (en) 1991-12-12 1991-12-12 Process for producing new phenylsulphonyl acrylic acid derivatives and pharmaceutical compositions containing the same

Publications (1)

Publication Number Publication Date
WO1993012079A1 true WO1993012079A1 (fr) 1993-06-24

Family

ID=10966011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1992/000054 WO1993012079A1 (fr) 1991-12-12 1992-12-11 Nouveaux derives d'ester de phenylsulfonylacrylate

Country Status (5)

Country Link
CN (1) CN1073938A (fr)
HU (1) HU211020B (fr)
IL (1) IL103938A0 (fr)
LV (1) LV10088A (fr)
WO (1) WO1993012079A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014765A1 (fr) * 1992-12-29 1994-07-07 Richter Gedeon Vegyészeti Gyár Rt. Acide cyclohexylsulfonyl-acrylique et ses derives, compositions pharmaceutiques les contenant, et leur procede de preparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109096156B (zh) * 2018-09-28 2021-01-15 吉首大学 二磺酰基间芳基二胺类尿素酶抑制剂及其制法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976668A (en) * 1972-02-22 1976-08-24 Sanitized, Inc. Aminobenzenesulfonyl-acrylamides
DE2630947A1 (de) * 1975-07-10 1977-02-03 Kao Corp Sulfinyl- und sulfonylverbindungen und verfahren zu ihrer herstellung
GB1527219A (en) * 1976-10-18 1978-10-04 Kao Corp Substituted-aryl-sulphinyl-or-sulphonyl-acrylic acids and esters thereof and their use as herbicides
EP0040358A1 (fr) * 1980-05-16 1981-11-25 Bayer Ag Procédé de préparation d'acides sulfonylcarboxyliques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976668A (en) * 1972-02-22 1976-08-24 Sanitized, Inc. Aminobenzenesulfonyl-acrylamides
DE2630947A1 (de) * 1975-07-10 1977-02-03 Kao Corp Sulfinyl- und sulfonylverbindungen und verfahren zu ihrer herstellung
GB1527219A (en) * 1976-10-18 1978-10-04 Kao Corp Substituted-aryl-sulphinyl-or-sulphonyl-acrylic acids and esters thereof and their use as herbicides
EP0040358A1 (fr) * 1980-05-16 1981-11-25 Bayer Ag Procédé de préparation d'acides sulfonylcarboxyliques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014765A1 (fr) * 1992-12-29 1994-07-07 Richter Gedeon Vegyészeti Gyár Rt. Acide cyclohexylsulfonyl-acrylique et ses derives, compositions pharmaceutiques les contenant, et leur procede de preparation

Also Published As

Publication number Publication date
HU913908D0 (en) 1992-02-28
IL103938A0 (en) 1993-05-13
HU211020B (en) 1995-09-28
HUT63381A (en) 1993-08-30
LV10088A (lv) 1994-05-10
CN1073938A (zh) 1993-07-07

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