SE445737B - PROCEDURE FOR THE PREPARATION OF N- (2-TIENYL) -2-OXO-2,3-DIHYDRO-BENZO / B / THIOFEN-3-CARBOXAMIDE - Google Patents

Description

Wherein RO represents a etherified or esterified hydroxyl group or an optionally substituted amino group and R 2 represents hydrogen, or wherein RO and R; together form a bond, or b) treat a compound of the formula _ 0 04 \ l --lC | --Da- 1 LI 1 "o (Ira), \ / \ s / \ O 'wherein R: stands for a represented or esterified hydroxy group, - with the amine of the formula H 2 N 2 / E (V 7, or S c) cycles a compound of the formula I ü ° = ° (vn, wherein Ro represents a esterified or esterified hydroxy group, or a salt thereof, or d) in a compound of the formula o H nv O: -% \ _ '_ / C NH ° \ s /' IL 'I_ | (VIII), (R) which may also be in tautomeric form and wherein R 2 represents an optionally substituted, hydrolytically transferable imino group, hydrolyzes R 2 to oxo, and optionally transfers the resulting free compound to a salt. or a salt obtained to the free compound or to another salt.

In the context of the present description, organic groups and compounds denoted by "low" contain up to 7, preferably up to 4 carbon atoms. Low alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, while lower alkenyl is e.g. allyl or metallallyl, and lower alkynyl e.g. propargyl.

Low alkoxy is e.g. methoxy, ctoxy, n-propoxy, isopropyloxy, n-butyloxy or isobutyloxy. 40 »u- 7905631-3 3 Halogen is primarily halogen with an additional atomic number, ie fluorine, chlorine or bromine.

Salts of the compound of formula I are primarily pharmaceutically usable salts with bases, in particular metal or ammonium salts. Metal salts are in particular metal salts derived from metals of groups Ia, Ib, IIa and IIb in the periodic table system, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium, calcium, zinc or copper salts. Ammonium salts are mainly salts with secondary or tertiary organic bases, e.g. morpholine, thiomorpholine, piperidine, pyrrolidine, dimethyl reps. diethylamine or triethylamine, but also salts with ammonia. The salt formation with compounds of the formula I is then likely to take place on the basis of the tautomeric 2-hydroxybenzoylthiophene form.

DE-OS 2 713 584 describes benzothiophene-2-one-3-carboxamide compounds with anti-inflammatory, analgesic, antithrombotic and uricosuric action, within the scope of which the novel compound of formula (I) and the salts thereof fall.

The new compounds surprisingly show particularly valuable pharmacological properties. At the forefront of the spectrum of action are peripheral analgesic effects, which have been demonstrated both in mice by phenyl-p-benzoquinone-Writhing test, and also in rats by acetic acid-Wríthing test analogous to that of Krupp et al., Switzerland. . with. Wsch., Bd. 105, p. 646 (1975), described the method in doses from about 1 to about 10 mg / kg per os (p.o.). In addition, the compounds I show anti-inflammatory effects, which have been demonstrated e.g. by kaolin-rat foot edema test analogous to that of Menassé o. Krupp, Toxicol.Appl. Pharmacol. bd. 29, p. 389 (1974) described methods in doses from about 10 mg / kg to about 100 mg / kg p.o. Furthermore, the compounds I show uricosuric effects, which e.g. demonstrated in phenol-red precipitation test analogous to that of Swingle o. co., Arch. int. Pharmacodyn., Vol. 189, p. 129 (1971), described the method in doses from about 30 to about 100 mg / kg p.o.

Compounds I are therefore useful as peripheral analgesics, e.g. for the treatment of pain conditions of various genesis or as antiphlogistics, e.g. for the treatment of arthritic inflammations, or for the treatment of traumatic conditions of inflammation and swelling, as well as uricosurics, e.g. for 40 7905631-3 treatment of gout.

The new compounds also show antithrombotic effects in rabbits with experimental pulmonary embolism analogous to those of Silver et al., Science, vol. l85, p. l085 (1974), described methodology in doses from about 0.1 to about 3 mg / kg p.o. In vitro, these compounds also significantly inhibit the prostaglandin synthetase system at doses of 0.1-1 pg / ml (Methodology: White and Glassman, Prostaglandins, Vol. 7, No. 2, p. 123 (1974)). They can therefore also be used as thrombolytics.

Variant a): An etherified hydroxy group RO is preferably through an optionally substituted hydrocarbon residue, such as lower alkyl, e.g. methyl or ethyl, or halo-lower alkyl, e.g. 2,2,2-trichloroethyl, and primarily by optionally substituted, such as lower alkyl, lower alkoxy, halogen and / or nitro containing phenyl, etherified hydroxy, and constitutes e.g. lower alkoxy, e.g. methoxy or ethoxy, halogenated alkoxy, e.g. 2, Z, 2-trichloroethoxy, or phenyloxy, while an esterified hydroxy group is preferably esterified by a strong mineral acid and is primarily halogen, in particular chlorine. A substituted amino group contains one or preferably two optionally substituted hydrocarbon residues, such as lower alkyl and / or optionally, e.g. as stated above, substituted phenyl as a substituent and constitutes e.g. lower alkylamino, such as methylamino or ethylamino, di-loweralkylamino, such as dimethylamino or diethylamino, or phenylamino and preferably diphenylamino, wherein the phenyl radical may be optionally substituted, e.g. with lower alkyl, such as methyl, lower alkoxy, e.g. methoxy, halogen, e.g. fluorine, chlorine or bromine, and / or nitro. However, a disubstituted amino group Ro may also represent a radical of the formula -NH-Q; The above reaction is usually carried out in the presence of a basic agent, such as a corresponding inorganic or organic agent.

Suitable inorganic bases are, in particular, salt-forming agents, in particular alkali metal salt-forming agents, such as alkali metal hydrides or amides, as well as alkali metal-organic compounds, such as the corresponding lower alkanolates, and the corresponding corresponding lower alkyl or phenyl compounds, e.g. sodium methylate, sodium ethylate, potassium tert-butylate, n-butyllithium or phenyllithium. Suitable organic bases are primarily amines, such as tertiary amines, preferably tri-lower alkylamines, e.g. triethylamine, heterocyclic tertiary bases, in particular of the pyridine type, e.g. pyridine, or quaternary bases, such as tetralgalkylammonine or trihaloalkylphonyllagalkylamines. In the presence of a base, the starting material of formula II is in anionic form, i.e. in solid form, for reaction with the starting material of formula III.

The latter are formula III corresponding to carbamic acid esters, carbamic acid halides, carbamides and isocyanates.

The reaction is carried out in the presence or absence of a solvent or diluent, and, if necessary, during cooling or heating, e.g. + 1z0 ° c, i en. closes vessel atmosphere. within a temperature range from about -10 to about and / or in an inert gas, e.g. Nitrogen b: The stepwise formation of compounds of formula I starting from starting material of formula II can be carried out in such a way that a compound of formula II is reacted with a compound of formula b - _ a Ro-C (-X) RO ester esterified hydroxy group, and that an intermediate (IV) obtainable as an intermediate wherein R 1 and R 2 independently represent a etherified or compound of the formula X Ph-cn-É-Râ (Ira) \\\ // Å = 0 S is treated with an amine of the formula HZN E? (v 3 Esterified or esterified hydroxy groups R: and R: have, for example, the meanings given above for the corresponding radical Ro and denote Lex. lower alkoxy, such as methoxy or ethoxy, further optionally substituted phenyloxy or halogen, e.g. Suitable compounds of formula IV are, for example, lower alkyl carbonates, eg diethyl or diphenyl carbonate, phosgene or haloformic lower alkyl esters, eg chloroformic isobutyl ester of the above, for example an alkali metal hydride or a tri-lower alkylumin.

The above-mentioned preliminary rounds are carried out in the absence or presence of a solvent or diluent and, if required, under cooling or heating, e.g. within a temperature range from about -10 to about + 120 ° C, in a closed vessel and / C110? in an inert gas, eg nitrogen atmosphere.

The starting materials are known or can be prepared in a manner known per se.

Starting material of the formula II can be obtained, for example, by reacting an amine 1 derivative derived from an optionally substituted cyclohexanone indicated by Ph, in the presence of sulfur with a cyanoacetic acid ester, a resulting Z-amino-4; 5,6,7- " Cof to Z-lithium compound, and oxidizes with hydrogen peroxide. Compounds of formula III may be prepared, for example, by TeHctIOD of compounds of formulas Rg-C (= O) Rg (IV) and HZMÜ (V) - The starting material of formula (IIn) may be prepared by preparing the compound of formula (II ) to react with a compound of the formula R 9 -C (= O) -R: (IV), wherein R 1 and R 9 independently represent a esterified or esterified hydroxy group.

A salt of the starting material of formula VI is e.g. an alkali metal salt.

Variant c: A group RO can.t.ex. have the meaning given above and denote e.g. lower alkoxy, such as methoxy or ethoxy, halogen lower alkoxy, e.g. 2,2, Z-trichloroethoxy, optionally substituted phenyloxy, or halogen, e.g. chlorine, and further lower alkylamino, e.g. methylamino, lower alkylamino, e.g. dimethylamino or diethylamino, phenylamino or diphenylamino, or even the group of the formula type The above cyclization reaction can be carried out in a manner known per se, when required in the presence of a customary basic condensing agent, such as a salt e.g. alkali metal salt-forming agents, i.a. also an alkali metal lower alkoxide, e.g. sodium methylate, sodium ethylate or potassium tert-butylate.

In this case, work is carried out in the absence or presence of a solvent or diluent, when required, during cooling or heating, e.g. in a temperature range from about 0 to about ISOOF, in a 7905631-3 incrtgns-, e.g. nitrogen atmosphere. Formula VI can be prepared in that in the closed vessel of the hensylic methylene group and / or in a starting material known per se, e.g. by a compound of the formula y '\ / cH2'RX ° (VII), T n \ ./ \ š_RY wherein Rx represents the group of formula (Ia) or the group of formula -C (= O) -RO and Ry represents hydrogen or preferably a mercapto protecting group, such as hydrogenolytically cleavable α-phenyl lower alkyl, e.g. benzyl, introducing a group of the formula O -c (= o) -Nn -'- ' corresponding ester, e.g. dialkyl alkyl carbonate, such as diethyl carbonate, or diphenyl carbonate, dihalide, e.g. phosgene, halogen esters, e.g. haloformic acid lower alkyl ester, urea, further isocyanate, usually in the presence of a basic agent, such as an alkali metal hydride, amide or lower alkoxide, or an organic base, e.g. triethylamine. A mercapto protection group can then be cleaved off in the usual way, e.g. by treatment with catalytically activated hydrogen and thus the mercapto group is liberated.

Variant d: In a substituted imino group wRz, a substituent is e.g. an optionally substituted hydrocarbon residue, such as lower alkyl, e.g. methyl or ethyl, or phenyl, or an acyl group derived from a carbonic acid or from a half ester of carbonic acid, e.g. lower alkanoyl, such as acetyl, or hensoyl or lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl.

The starting material of formula VIII, which may also be in tautomeric form as a corresponding 2- (H-R 2) -benzo [thiopheno compound, wherein the group -R 2 -H represents an optional in the presence of an alkaline or acidic agent, such as an inorganic base, e.g. an alkali metal hydroxide, or a mineral acid, e.g. hydrochloric acid or sulfuric acid. to a desired compound of formula I, the reaction is carried out in the presence or absence of a solvent or diluent, and, if necessary, under cooling or heating, e.g. In an empty port range from about -10 to about + 120 ° C, in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere.

The starting material of the formula VIII can be prepared in a manner known per se, by e.g. reactes a compound of the formula O E-OH / f * wherein R 2 is preferably an unsubstituted imino group and the group -R 2 -H therefore primarily represents a primary amino group, e.g. with phosgene or with a chloroformic acid lower alkyl ester, and treating such a compound of formula O (x) R 2 optionally after introduction of a substituent into a hydrogen-containing (IX) imino group R 2, e.g. by treatment with a lower alkyl halide in the presence of an alkali metal compound-forming reagent, with a. II II amine of the formula HZN's S (V) and, optionally in a starting material of formula VIII, wherein R 2 represents an unsubstituted amino group, or in a tautomer thereof, wherein -R 2 -H is an unsubstituted amino group, substituting this imino- resp. amino group, e.g. by lower alkylation or acylation, the latter reaction e.g. by treatment with an appropriate symmetrical, mixed or internal anhydride of a carboxylic acid.

The invention also relates to those embodiments of the process in which a compound is obtained as an intermediate as an intermediate process step and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or used in the form of a derivative thereof, resp. possibly a salt. In the preparation of compounds I according to the present invention, such starting paints are preferably used, which result in the compounds listed above as particularly valuable.

The pharmaceutical preparations containing compounds of the formula I are preparations for enteral, such as oral, rectal or parenteral administration or for topical resp. local use for humans resp. warm-blooded animals, which preparations contain the pharmacologically active substance I alone or together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the warm-blooded animal species, on its age and individual condition, as well as on the mode of application.

The pharmaceutical preparations contain from about 10 to about 95%, preferably from about 20 to about 90% of the active ingredient. Pharmaceutical preparations according to the invention are, for example, such preparations in elixir, aerosol or spray form or in unit dosage form, such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, e.g. by conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Preparations for oral use can-e.g. is obtained by mixing the active substance with solid carrier materials, an resulting mixture is optionally granulated and the mixture resp. the granules are worked up, if desired or required after the addition of suitable excipients, into tablets or dragee cores. Suitable carrier materials are in particular fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as strength adhesives using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above-mentioned starch products, further carboxymethyl the cross dog polyvinylpyrrolidone, ngar, alginic acid or a salt thereof, such as sodium. Aids are primarily Floating Regulator and lubricant, e.g. silicic acid, talc, stearic acid or its salts, such as magnesium or calcium cyanide, LFI 4 U 7905631-3 ID and / or polyethylene glycol. Drngé kernels are provided with suitable, even ~ tucllt gastric juice-resistant overdrugs, whereby hl.u. use concentrated sugar solutions, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or toluene solutions in suitable organic solvents or, or for the preparation of gastric nitric dioxide, solvent-resistant coatings, solutions of suitable or hydroxypropyl methylcellulose phthalate.

Tablet: or dragee coatings can be coated with dyes or pigments, e.g. for identification or for characterizing different doses of active substance.

Additional orally useful pharmaceutical preparations are gelatin operula capsules, as well as soft, closed gelatin capsules such as glycerol or sorbitol. Operulates - in the form of a graft and a plasticizer, the capsules may contain the active substance zero, e.g. in admixture with fillers such as lactose, binders, such as starch, and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active substance is preferably entrapped or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby stabilizers can also be added.

As rectally useful pharmaceutical preparations, e.g. suppositories, which are prepared from a combination of the active substance I with a suppository matrix for which e.g. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which consist of a combination of the active substance with a matrix; as matrix material, e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form, e.g. a water-soluble salt, further suspensions of the active substance, such as the corresponding oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, e.g. sodium carhoxymethylcellulose, sorhitnyl and / or dextrin or optionally stanhilisutorcr. Pharmaceutical preparations for topical and topical use are e.g. for the treatment of skin lotions and creams. A liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative); for the treatment of eye eye drops which contain the active compound in aqueous solution or oil solution, and eye ointments, which are preferably prepared in sterile form; for the treatment of nasal powders, acrosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse-grained powders which are administered by rapid inhalation into the nostrils, and nasal drops which contains the active compound in aqueous or oily solution, or for local treatment of the mouth sugars, which contain the active compound I in a mass generally formed of sugar and gum arabic or tragacanth, which may be flavored, including lozenges, which contain the active substance in an inert mass, such as gelatin and glycerol or sugar and gum arabic.

The new compounds can be used as pharmacologically active substances, in particular as anti-inflammatory agents, as analgesics, uricosurics, antiallergics and / or thromolytics, preferably in the form of pharmaceutical preparations. The daily dose, which is primarily dependent on the patient's resp. condition of warm-blooded animals to be treated and / or by the present indications, constitute for these patients resp. animals of about 70 kg from about 300 mg to about 1 g of active substance.

The following examples illustrate the invention described above; however, they do not in any way limit its scope. Temperatures are given in degrees Celsius. §§Gmpgl_L. A suspension of 2.4 g of an SO 3% sodium hydride mineral oil dispersion in 100 ml of hexamethylphosphoric triamide is added dropwise with cooling to a solution of 7.5 g of 2,3-dihydro-2-oxo-benzo [h ] thiophene in 50 ml of hexamethylphosphoric acid triamide, keeping the temperature below 150. After stirring for 0.5 hour at room temperature, 52 g of N- (2-thienyl) -carbamic acid phenyl ester dissolved in 50 ml of hexamethylphosphoric triamide are added dropwise under external cooling. The whole is stirred for 16 hours at room temperature, after which the reaction mixture is poured onto a mixture of 200 ml of Z n hydrochloric acid and 1000 ml of ice water. An oil separates, which crystallizes after about 2 hours. The crystalline product, which contains solvent, is dissolved in 2 N sodium hydroxide solution and the solution is washed four times with ethyl acetate. The organic phase is washed with water, the aqueous phases are combined, acidified to pH 1, the crude product is discarded and recrystallized from the hydrohydrofuran / etc.

There is thus obtained N- (2-thionyl] -2-oxo-2,3-dihydro-3-benzo [h] thiophinecarboxamide, m.p. 142-1440 (dec.).

Example 2. 0.8 g of N- (Z-thienyl) -Z-acetamino-benzo [h] thiophene-3-carboxamide is suspended in 5 ml of ethanol, 2.5 ml of water and 2.5 ml of concentrated hydrochloric acid and heated for 7.5 hours under reflux. The whole is left standing overnight at room temperature and the ethanol is taken up. The evaporation residue is taken up in dilute The aqueous is operated under reduced pressure. with water, aspirated, washed with water, sodium hydroxide solution and insoluble matter are filtered off. the phase is acidified and separated N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene carboxamide having a melting point of 142-1440 (decomposition) is filtered off.

The starting material can be prepared as follows: In a sulfonation flask, 3 g of magnesium turnings are introduced into 30 ml of anhydrous tetrahydrofuran and proceed to produce ethylmagnesium bromide with 13.5 g of ethyl bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophene dissolved in 60 ml of absolute tetrahydrofuran are added dropwise, then stirred for 1 hour at room temperature and then heated for a further 15 minutes under reflux. Then 8 g of 2-acetamido-benzo [b] thiophene-3-carboxylic acid ester dissolved in 100 ml of absolute tetrahydrofuran are added dropwise at room temperature, the mixture is heated under reflux for 15 minutes, stirred at room temperature for 15 minutes and the reaction solution is evaporated in vacuo. The evaporation residue is added with dilute hydrochloric acid and extracted twice with chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated in vacuo to dryness to give crude N- (2-thienyl) -2-acetamino-benzo [h] thiophene-3-carboxamide which is useful without further purification.

Example 3. 11.4 g of o-mercapto-phenylmalonic acid-N- (2-thienyl) -amide are heated in 50 ml of dimethylformamide and 1 ml of concentrated hydrochloric acid Zh at 100 °. The whole is allowed to cool, added with 100 ml of water, filtered off with suction and taken up in 100 ml of diethyl ether. From the organic phase, after washing, first with 1 N sodium hydroxide solution, then with water, drying with sodium sulphate, evaporation, chromatography and crystallization from ether N- (2-thienyl-2-oxo-2,3-benzo [h] are obtained thiophenecrboxamide with melting point 142-1440 (söndordolningl.

The starting material can be prepared, for example, in the following manner: air flow. The reaction mixture is evaporated to dryness by means of a rotary evaporator. The residue is twice infused with 50 ml of toluene and each batch is evaporated to dryness. The residue is then dried for 90 minutes under high pressure at 500 DEG C., suspended in 180 ml of dimethylformamide and stirred for 3 minutes with 7 g of dimethyl sulphate. The reaction mixture is heated for 1 hour with stirring to 1100, then cooled and poured onto ice. The suspension formed is extracted with ethyl acetate, the organic phases are combined and washed with water, dried over sodium sulphate and evaporated. The residue (18 g) is dissolved in 200 ml of dimethylformamide and added dropwise to a suspension of 4.8 g of 50% sodium hydride in 200 ml of dimethylformamide. With slight heating, stir until the hydrogen evolution is complete. Then a solution of 15 g of Z-thienyl isocyanate in 100 ml of dimethylformamide is slowly added dropwise at 0 DEG.

The solution is stirred for a further 24 hours at room temperature and then added with ice and dilute hydrochloric acid. The product which is separated off is extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated to give o, o'-bis fi 2 -methoxycarbonyl-N- (2-thienyl) -carbamylmethyl-diphenylsulfud which can be used without Purification. Crude o, o'-bis- [α & methoxycarbonyl-N- (Z-thienyl) -carbamylmethylZ-diphenyl sulphide is suspended in 300 ml of ethanol and stirred with portions of 7 g of sodium borohydride. The mixture is stirred for 4 hours at room temperature, evaporated, added with water, acidified with hydrochloric acid to a neat and even congosuric reaction and extracted with ethyl acetate. Evaporation gives crude o-mercapto-phenylmalonic acid N- (2-thienyl) -amide, which can be cyclized without further purification.

Example 4. To a stirred suspension of 2.32 g of a sodium hydride suspension (50% in mineral oil) in 60 ml of tetrahydrofuran is added dropwise 7.3 g of 2,3-dihydro-2-oxo-benzoylthiophene in 50 ml tetrahydrofuran. Allow to stir for 30 minutes, add 5 ml of pyridine and then add dropwise 7.8 g of N- (2-ticnyl) -carbamyl chloride in 20 ml of tetrahydrofuran, allow to stir for 1 hour at room temperature and 2 hours at 600, pour in 750 ml of ice water, acidify with Zn hydrochloric acid, aspirate and recrystallize from the acctone / hoxan. N- (3-thienyl) -2,3-dihydrin-2-oxo-henso [h] thiophon-3-carhoxamide is obtained, m.p. 142 DEG-1440 DEG (S). A suspension of 0.5 g of sodium hydride suspension (50% in mineral oil in 100 ml of methylphosphoric acid trinmide) is added with cooling to 10 "dropwise with a solution of 20.2 g of Z, 3-dihydro-2-oxo. bcnso [h] -thiophene. Stir for 1 hour at room temperature and then add dropwise a solution of 38.2 g of N- (2-ticnyl) urea in 100 ml of hexamethylphosphoric triamide.

Stir for 10 hours at room temperature and for 22 hours at 600, pour on a mixture of 100 ml of Zn hydrochloric acid and 1000 g of ice, extract three times with 250 ml of diethyl ether each time, dry over sodium sulphate and evaporate to dryness. The residue is recrystallized from diethyl ether. N- (Z-thienyl) -2,3-dihydro-Z-oxo-benzyl] -thiophene-3-carboxamide with a melting point of 142-144 ° (decomposition) is obtained.

Example 6. To a cooled suspension of 8.7 g of 50% sodium hydride suspension in paraffin oil in 250 ml of hexamethylphosphoric acid triamide is added dropwise the solution of 27.5 g of 2,3-dihydro-Z-oxo-benzo [h] thiophene in 100 ml. ml of hexamethylphosphoric acid triamide. Allow to stir for one hour at room temperature, cool again to 0 ° and add 31.3 g of N- (2-thienyl) -carbamic acid ethyl ester, dissolved in 50 ml of hexamethylphosphoric triamide. Stir for hours at room temperature and pour on a mixture of 1500 g of ice and 200 ml of Zn hydrochloric acid. The mixture is extracted twice with 300 ml of diethyl ether each time, the extract is washed neutral with water and evaporated to dryness. It remains N- (2-thienyl) -2-oxo-Z, 3-dihydro-benzo [h] thiophene-3-carboxamide, m.p. 142-1440 (dec.).

Example gel 7. Dissolve 16.9 g of 2,3-dihydro-3-oxo-benzo [h] thiophene in 200 ml of hexamethylphosphoric acid triamide. The solution is cooled to 0 DEG C. and added under nitrogen dropwise with a solution of 3.2 g of butyllithium in 20 ml of n-hexane. Allow to warm to room temperature and add portionwise 31 g of N- (2-thienyl) -carbamic acid ~ (2,2,2-trichloro] -ethyl ester, stir for 2 hours at 00 and i20 hours at room temperature, pour on 1000 g of ice, extract three times with 100 ml of diethyl ether each time, dry over sodium sulphate, evaporate to dryness and recrystallize from hexane / diethyl ether (125) to give N- (Z-thienyl] -2,3-dihydro-2-oxo-benzo [h7thiophene s-carboxamide melted at 14z-144 ° (sonar swelling).

Example 8. A solution of 1 g of N- (2-thienyl) -2- (formamino-henso- [thiophene-3-carboxamide in 5 ml of ethanol each and the water is added with 3 ml of hydrochloric acid and heated for about 10 hours under After removal of the alcohol, the mouthwash washes with the water, takes up diluted sodium hydroxide solution and nitrates. The hydrogen phase is acidified and N- (1-ticny1) -2-dihydro-2,3- [htlofen-3-curboxumide is recrystallized from ether, m.p. 142-1440 (dec.

The starting material can be prepared as follows: To prepare the organic compound, 10.9 g of ethyl bromide are added dropwise to a mixture of 4 g of magnesium turnings and absolute tetrahydrofuran under cooling. To the reaction product is added portionwise a solution of 9.9 g of 2-aminothiophene in absolute tetrahydrofuran and the solution is heated briefly under reflux. Then 7.5 g of 2-formamino-benzo-thiopheno-3-carboxylic acid ethyl ester, dissolved in 100 ml of absolute tetrahydrofuran, are added dropwise at room temperature. The mixture is then heated for 15 minutes under reflux and allowed to stir for 15 minutes at room temperature. After distilling off the solvent, the residue is hydrolyzed with dilute hydrochloric acid. It is then extracted with small portions of methylene chloride, the organic phase is dried from the sodium sulphate, the solvent is distilled off and the resulting N- (2-thienyl) -2-formamino-benzo [h] thiophene-3-carboxamide is used directly for a further reaction. §§Gmgel_2. 20 g of N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [thiopheno-carboxamide are suspended in 250 ml of acetone and added with 66 ml of n-sodium hydroxide solution, followed by solution. Evaporate to dryness, stir the evaporation residue first with toluene and then with diethyl ether, aspirate and dry. The sodium salt of N- (2-thienyl) -2-oxo-Z, 3-dihydro-3-benzoyl-thiophenecarboxamide, m.p. <280 °, is obtained.

Example 10. 470 mg of 2-oxo-2,3-dihydro-3-benzo [BYthiophene carboxylic acid ethyl ester (2.1 mM) and 218 mg of 2-aminothiophene (2.22 mM) are boiled in 5 ml of xylene for 5 hours. under reflux. After cooling, the product is precipitated by adding hexane (3 ml). After further dilution with 5 ml of ether and stirring, crystalline N- (2-thienyl] -Z-oxo-Z, 3-dihydro-3-benzolhiphiophenylboxamide with a melting point of 142-1440 (decomposition) is obtained and filtered off with suction.

Exemgel ll. 4.0 g of O-mercaptophenylmalonic acid phenyl ester-N- (2-thienyl) -amide are suspended in 100 ml of ethanol, added with 0.2 ml of Sn sodium hydroxide solution and stirred for 2 hours. Evaporation to dryness, evaporation in ether, washing twice with water, evaporating to incipient crystallization, adding with pnntnn, 'J1 Z0 40 7905631-3 6 1 nvkylcr to -15' and nvfiltrating the crystalline N ~ (2-thienyl- oxo-2,3-dihydro-3-hensoylthiophin-kurboxamide, m.p. 141 DEG-144 DEG C. in the presence of about equimolecular amount of N, N-dicyclohexylcarbodiimide.

Example 12. 30.0 g of bis-o- [1-methoxycarbonyl) -N- (2-thienyl) -carbamylmethyl] -diphenyl sulphide are suspended in 300 ml of ethanol and added with stirring portionwise with 7.0 g of sodium borohydride. The mixture is stirred for 4 hours at room temperature and then heated for a further 1 hour to reflux. Then it is evaporated, added with water, acidified with hydrochloric acid until a neat and uneven congo-acid reaction and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in ether and the solution is filtered through silica gel.

The filtrate is evaporated to the point of incipient crystallization, charged with an equal amount of petroleum ether and the crystallizate is collected.

N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene-carboxamide with melting point 142-1440 is obtained.

The starting material can be prepared, for example, as follows: Through a solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml of n-sodium hydroxide solution, a strong air stream is passed for 8 hours with stirring.

The reaction mixture is evaporated on a rotary evaporator to dryness. The residue is added twice with 50 ml of toluene and evaporated to dryness each time. The residue is then dried for 90 minutes at high vacuum at 500 DEG C., suspended in 180 ml of dimethylformamide and stirred for 3 minutes with 7 g of dimethyl sulphate. The reaction mixture is heated for 1 hour with stirring to 1100, then cooled and poured onto ice. The resulting suspension is extracted with ethyl acetate, the organic phases are combined and washed with water, dried over sodium sulfate and evaporated. The residue (18 g) is dissolved in 200 ml of dimethylformamide and added dropwise to a suspension of 4.8 g of SO4% sodium hydride in 200 ml of dimethylformamide. During slight heating, stir until the end of the hydrogen evolution.

Then the solution of 15 g of 2-thienylisocyanate in 100 ml of dimethylformamide is slowly added dropwise at 0 DEG. The solution is stirred for 24 hours at room temperature and soda is added with ice 7905631-3 w fl I and dilute hydrochloric acid. Separate his-o- [One-methoxycarbonyl] -N- (Z-thienyl) -carbhamylmethyl] -nyl disulfide is extracted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. It can be used without further purification.

Example Gel 13. 1 g of N- (Z-thienyl) -2-benzoylamino-benzo [fi] thiophene-3-carboxamide is dissolved in 10 ml of ethanol and added with 2.5 ml of water in 3 ml of concentrated hydrochloric acid and then heated under reflux. flow. The solution is evaporated and taken up with dilute baking soda.

The filtered aqueous solution is acidified to give the precipitated N- (2-thienyl) -2-oxo-Z, 3-dihydro-benzo [§] thiophene-3-carboxamide, m.p. 142-1440.

The starting material is prepared analogously to Example 2.

Example 14- Tablets containing 0.1 g of N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzolethiophenecarboxamide are prepared as follows: Composition (for 1000 tablets): N- (2-thienyl) - 2-oxo-2,3-dihydro-3-benzo [b] - thiophenecarboxamide 100.00 g Lactose 50.00 g Wheat starch 73.00 g Colloidal silicic acid 13.00 g Magnesium stearate 2.00 g Talc 12.00 g Water qs

The N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo / butiophenecarboxamide is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid and the mixture is passed through a sieve. An additional part of the wheat starch is pre-glued with five times the amount of water and the above-mentioned powder mixture is kneaded with the glue until a weak plastic mass is obtained. The plastic mass is pressed through a sieve with a mesh size of about 3 mm, then dried and the dry granulate is driven once more through a sieve. Then the remainder of the wheat starch, talc and magnesium stearate are mixed and the resulting mixture is compressed into tablets.

Claims (5)

7905631-3 m Qntentkrav An analogous compound for the preparation of the novel compound for use as the active substance, N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3-carboxamide of formula (I) , which may also be present in taunic 2-hydroxy-benzo / b / thiophene form, and salts thereof with bases, characterized in that a) the compound of the formula \ fi'_ 'ï oo \ II ./ \ s / \ O () In gu // \\ which may also be present in tautomeric 2-hydroxy-benzo / b / -thiophene form, to react with a compound of the formula. O = $ - N-o a (III) I wherein RO represents an etherified or esterified hydroxy group or an optionally substituted amino group and R 6 represents hydrogen, or wherein Ro and R; together form a bond, or b) treat a compound of the formula R, __ a% \ / C Ro I Q g 1 \ / U \ / 1 \ (Ira). wherein R: represents an etherified or esterified hydroxy group, with the compounds of the formula fi "" 'fi (V), H' N_ 'o or 2 \ 5 / c) includes a compound of the formula 7905631-3 °' ç = O (VI), wherein Ro represents an etherified or esterified hydroxy group, or a salt thereof, or d) 1 a compound of formula ou ° '' - c-NH-'Å L '_ / \ _ _ / \ S / - ¿| _ | i i (VIII). Which may also be in tautomeric form and wherein R 2 represents an optionally substituted, hydrolytically transferable imino group, hydrolyzes R 2 to oxo, and optionally transfers the resulting free compound to a salt or a salt obtained. 'to the free' - compound 61161 'to another salt. IN Process according to Claim 1, characterized in that a carbamic acid ester, a carbamic acid halide or the isocyanate is used as compounds of formula III according to variant a). 3. A process according to claim 1, characterized in that the reaction according to variants a) and b) is carried out in the presence of a basic agent. 4. A process according to claim 1, characterized in that the cyclization according to variant c) is carried out in the presence of a basic condensing agent. Process according to claim 1, characterized in that a compound of formula (IIa) is formed by reacting the compound of formula (II) with a compound of formula R 2 -C (= o) -R: (IV) and causes to react further without isolation.