CH634840A5 - 2-OXO-2,3-DIHYDRO-BENZO (B) THIOPHENE COMPOUND AND PHARMACEUTICAL PREPARATIONS MADE THEREOF. - Google Patents

Description

The invention relates to the 2-oxo-2,3-dihydro-benzo [b] thio-phen compound of the formula which can also be present in the tautomeric 2-hydroxy-benzo [b] thiophene form with a compound of the formula R0b -C (= X) - X

R0a (IV), wherein R0a and R0b independently of one another for 55. "/ R1

ne etherified or esterified hydroxy group, reacted, Ph ÇH — C — N (I) '

-ÇH-

and an intermediate compound of C = 0 ^ R

Formula 2

X

S

LI 3

Ph- ÇH - C - R where Ph represents a 1,2-phenylene radical, X for oxygen

Vi ° is, Ri is 2-thienyl and R2 is hydrogen, and

/ C = 0 their salts with bases, and processes for their preparation,

S as well as pharmaceutical preparations that connect the

«Contain Formula I or salts thereof.

treated with the amine of the formula R1-HN-R2 (V) and the above 2-oxo-2,3-dihydro-benzo [b] thiophene compound, if desired, a free compound obtained in a salt can also be in tautomeric form, ie as 2-hydroxy-benzo [b] -

or a salt obtained is converted into the free compound. thiophene compound present.

3rd

634 840

In connection with the present description, organic radicals and compounds denoted by “lower” contain up to 7, preferably up to 4, carbon atoms.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, while lower alkenyl e.g. Allyl or methallyl, and lower alkynyl e.g. Is propargyl.

Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy or isobutyloxy.

Halogen is primarily halogen with an atomic number up to 35, i.e. Fluorine, chlorine or bromine.

Salts of the compound of formula I are primarily pharmaceutically usable salts with bases, especially metal or ammonium salts. Metal salts are primarily metal salts derived from metals of groups Ia, Ib, IIa and IIb of the periodic element system, such as alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium *, calcium, zinc or copper salts. Ammonium salts are especially salts with secondary or tertiary organic bases, e.g. with morpholine, thiomorpholine, piperidine, pyrrolidine, dimethyl or diethylamine or triethylamine, but secondly also salts with ammonia. Salt formation with the compound of formula I is likely to take place from the tautomeric 2-hydroxy-benzo [b] thiophene form.

The new compounds show valuable pharmacological properties. In the foreground of the spectrum of activity are peripheral analgesic effects, which are analogous to that of Krupp et al., Switzerland, med. On the mouse in the phenyl-p-benzoquinone writhing test and on the rat in the acetic acid writhing test. Wsch., Vol. 105, p. 646 (1975), described method in doses of about 1 to about 100 mg / kg p.o. can be demonstrated. In addition, they have anti-inflammatory effects, e.g. in the kaolin edema test on the rat analogous to that of Menassé and Krupp, Toxicol, Appi. Pharmacol., Vol. 29, p. 389 (1974) described method in doses of about 30 mg / kg to about 100 mg / kg p.o. can be demonstrated. In vitro, these compounds also remarkably inhibit the prostaglandin synthesis system in doses of 0.1-50 yg / 5 ml [method: White and Glassman, Prostaglandins, Vol. 7, No. 2, p. 123 (1974) ]. They also have uricosuric effects, e.g. in the phenol red excretion test, analogous to the method described by Swingle et at., Arch. int. Pharmacodyn., Vol. 189, p. 129 (1971), in doses of approximately 100 mg / kg po.o. be detected. The compounds are therefore used as peripheral analgesics, e.g. for the treatment of pain conditions of various origins or as anti-inflammatory drugs, e.g. for the treatment of arthritic inflammation, or for influencing traumatic inflammation and swelling states, as well as uricosurika, e.g. used to treat gout.

The new compounds also show antithrombotic effects, which in rabbits in experimental pulmonary embolism analogous to the methods described by Silver et al., Science, Vol. 183, p. 1085 (1974), in doses of approximately 3 mg / kg to approximately 30 mg / kg po can be demonstrated. They can therefore also be used as thrombolytics.

The compounds of the present invention can be prepared in a manner known per se. For example, they can be obtained by using a compound of the formula

N

Ph- \

CH,

\

(Iii),

r;

dì),

which can also be present in the tautomeric 2-hydroxy-benzo [b] thiophene form, with a compound of the formula III

in which R0 represents an etherified or esterified hydroxy group or an optionally substituted amino group, and 10 R20 has the meaning of R2, or in which R0 and R2 ° together form a bond.

An etherified hydroxyl group R0 is preferably through an optionally substituted hydrocarbon radical, such as lower alkyl, e.g. Methyl or ethyl, or halo-lower alkyl, e.g. 2,2,2-trichloroethyl, and etherified hydroxy primarily by optionally substituted phenyl, such as lower alkyl, lower alkoxy, halogen and / or nitro, and represents e.g. Lower alkoxy such as methoxy or ethoxy, ha-log lower alkoxy, e.g. 2,2,2-trichloroethoxy, or phenyloxy 20, while an esterified hydroxy group is preferably esterified by a strong mineral acid and primarily means halogen, especially chlorine. A substituted amino group contains one and preferably two optionally substituted hydrocarbon radicals such as lower alkyl and / or 25 optionally, e.g. as indicated above, substituted phenyl as a substituent and, e.g. Lower alkylamino, such as methylamino or ethylamino, di-lower alkylamino, such as dimethylamino or diethylamino, or phenylamino and preferably diphenylamino, the phenyl radical optionally being 30, e.g. by lower alkyl such as methyl, lower alkoxy, e.g. Methoxy, halogen, e.g. Fluorine, chlorine or bromine, and / or nitro, can be substituted. However, a disubstituted amino group R0 can also represent the rest of the formula -N (Ri) (R2).

35 The above reaction is usually carried out in the presence of a basic agent such as a corresponding inorganic or organic agent. As inorganic bases there are primarily salt, in particular alkali metal salt-forming agents, such as alkali metal hydrides or amides, as well as alkali metal organic compounds, such as corresponding lower alkanolates, furthermore corresponding lower alkyl or phenyl compounds, e.g. Sodium methylate, sodium ethylate, potassium tert-butoxide, n-butyllithium or phenyllithium. Suitable organic bases are primarily amines, such as 45 tertiary amines, preferably tri-lower alkylamines, e.g. Triethylamine, heterocyclic tertiary bases, especially of the pyridine type, e.g. Pyridine, or quaternary bases, such as tetranie-deralkyl-ammonium or tri-lower alkyl-phenyl-lower alkyl - ammonium hydroxides. In the presence of the base, the starting material of formula II comes in anionic, i.e. in salt form, for reaction with the starting material of formula III.

The latter are carbamic acid esters corresponding to formula III, carbamic acid halides, ureas and isocyanates, and the corresponding sulfur compounds.

The reaction is carried out in the presence or absence of a solvent or diluent and, if necessary, with cooling or heating, e.g. in a temperature range from 60 to about -10 ° C to about + 120 ° C, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere carried out.

The compound of the formula I can furthermore be prepared by reacting the starting material of the formula II with a compound of the formula R0b-C (= X) -R0a (IV), in which R0a and R0b independently of one another represent an etherified or esterified hydroxyl group , and a compound of the formula available as an intermediate

634 840

4th

Ph

V

CH - C

I.

C = 0

(Ha)

treated with the amine of the formula Ri-HN-R2 (V).

Etherified or esterified hydroxy groups R0a and R0b have e.g. the meanings given above for the corresponding radical R0 and are e.g. Lower alkoxy such as methoxy or ethoxy, further optionally substituted phenyloxy, or halogen, e.g. Chlorine. Suitable compounds of formula IV are e.g. Lower alkyl carbonates, e.g. Diethyl or diphenyl carbonate, phosgene or lower alkyl haloformate, e.g. Isobutyl chloroformate and the corresponding sulfur compounds. The reaction of the starting material of formula IIa with a compound of formula IV is usually carried out in the presence of a base such as one of the above, e.g. an alkali metal hydride or a tri-lower alkylamine. Usually, an intermediate of formula IIa is not isolated, but is reacted directly with the amine of formula V.

The above process steps are carried out in the absence or presence of a solvent or diluent and, if necessary, with cooling or heating, e.g. in a temperature range from about -10 ° C to about + 120 ° C, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere carried out.

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

The starting material of formula II can be obtained, for example, by reacting the enamine derived from cyclohexanone with a cyanoacetic acid ester in the presence of sulfur, the 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylic acid ester obtained on the amino group acylated, the reaction product dehydrated with sulfur and the resulting 2-acylamino-benzothiophene-3-carboxylic acid ester treated with sodium hydroxide solution, or by converting an appropriate benzothiophene with butyllithium into the 2-lithium compound, oxidized with hydrogen peroxide.

Compounds of formula III can e.g. are produced by reacting compounds of the formulas R0b-C (= X) -R0a (IV) and HNR, R2 (V).

The new connection can also be obtained

if you have a compound of formula

N

/ R1

\

(VI)

R.

wherein R0 represents an etherified or esterified hydroxyl group or an optionally substituted amino group, or a salt thereof closes.

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

A group R0 can e.g. have the meaning given above and is e.g. for lower alkoxy such as methoxy or ethoxy, halogen lower alkoxy, e.g. 2,2,2-trichloroethoxy, optionally substituted phenyloxy, or halogen, e.g. Chlorine, further for lower alkylamino, e.g. Methylamino, di-deralkylamino, e.g. Dimethylamino or diethylamine, phthal

nylamino or diphenylamino, or also the group of the formula -N (Ri) (R2).

The above ring closure reaction can be carried out in a manner known per se, if necessary in the presence of a commonly basic condensing agent such as a salt, e.g. Alkali metal salt-forming agent, including also an alkali metal lower alkanolate, e.g. Sodium methylate, sodium ethylate or potassium tert-butoxide can be made. This is done in the absence or presence of a solution or diluent by means of, if necessary, cooling or heating, e.g. in a temperature range from about 0 ° C to about 150 ° C, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.

The starting materials of the formula VI can be prepared in a manner known per se, e.g. by in the ben-cyclic methylene group of a compound of the formula Ry-S-Ph-CH2-Rx (VII), wherein Rx is the rest of the formula -C (= X) -N (Ri) (R2) (Ia) or Represents the rest of the formula -C (= O) -R0, and Ry for hydrogen or preferably a Mer-20 capto protective group, such as hydrogenolytically removable a-phenyl-lower alkyl, for example Benzyl, introduces a group of formula -C (= X) -N (Ri) (R2) by reacting a compound of formula VII with a suitable derivative of carbonic acid, such as a corresponding ester, e.g. Lower alkyl carbonate, such as diethyl carbonate, or diphenyl carbonate, dihalide, e.g. Phosgene or thiophosgene, halogen esters, e.g. Lower alkyl haloformate, urea, further isocyanate, usually in the presence of a basic agent such as an alkali metal hydride, amide or lower alkanolate, or an organic base, e.g. Triethylamine. A mercapto protecting group can then be e.g.

by treatment with catalytically activated hydrogen, split off and so the mercapto group are released.

The new compound of the present invention can also be obtained by working in a compound of the formula

Ph -

\

CH -

I.

C =

X

r

N

R

[

\.

(VIII)

wherein Rz represents an optionally substituted imino group which can be hydrolytically converted into the oxo group, hydrolyzes Rz to oxo.

In a substituted imino group Rz, a substituent is e.g. an optionally substituted hydrocarbon residue such as lower alkyl, e.g. Methyl or ethyl, or phenyl, or 50 an acyl group derived from a carboxylic acid or a half ester of carbonic acid, e.g. Lower alkanoyl, such as acetyl or benzoyl, or lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl.

The starting material of the formula VIII, which can also be in the 55 tautomeric form of a corresponding 2- (H-Rz) -Benzo [b] -thiophene compound, in which the group -Rz-H stands for an optionally monosubstituted amino group, is through Hydrolysis, preferably by treatment with water in the presence of a basic or acidic agent, such as an inorganic base, for example an alkali metal hydroxide, or a mineral acid, e.g. Hydrochloric or sulfuric acid, converted into the desired compound of formula I.

The reaction is carried out in the presence or absence of a solvent or diluent and, if necessary, under 65 cooling or heating, e.g. in a temperature range from about -10 ° C to about + 120 ° C, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere carried out.

5

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The starting material of formula VIII can be prepared in a manner known per se, e.g. a compound of the formula

OH (IX)

H

wherein Rz preferably represents an unsubstituted imino group and the group -Rz-H therefore primarily represents a primary amino group, e.g. with phosgene or a chloroformic acid lower alkyl ester, and a compound of the formula so obtainable

X

II

Ph C 0

\ li I (X)

\ x'0 ~ 0

X R

z optionally after introducing a substituent into a hydrogen-containing imino group Rz, e.g. by treatment with a lower alkyl halide in the presence of an alkali metal compound-forming reagent, treated with an amine of the formula RrHN-Rz (V) and, if desired, in a starting material of the formula VIII, wherein Rz is an unsubstituted imino group, or in a Tautomers thereof, in which -Rz-H stands for an unsubstituted amino group, this imino or amino group, for example by lower alkylation or acylation, the latter e.g. by treatment with a suitable symmetrical, mixed or internal anhydride of a carboxylic acid.

The invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any process stage and carries out the missing process steps, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative thereof, optionally a salt.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable.

The present invention also relates to pharmaceutical preparations which contain the compound of the formula I. The pharmaceutical preparations according to the invention are those for enteral, such as oral, rectal or parenteral administration or for topical or local use on warm-blooded animals, which contain the pharmacologically active ingredient alone or together with a pharmaceutically usable carrier material. The dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.

The new 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, those in elixir, aerosol or spray form or in dosage unit form, such as dragées, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. produced using conventional mixing, granulating, coating, dissolving or lyophilizing processes.

5 preparations for oral use can e.g. obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable auxiliaries, to tablets or 10 dragee cores. Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch paste using e.g. of corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, also carboxymethyl starch , cross-20 networked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragée kernels are provided with 25 suitable, possibly gastric juice-resistant coatings, among other things Concentrated sugar solutions, which optionally contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used . Dyes or pigments, e.g. for identification or for labeling different doses of active ingredients.

Other pharmaceutical preparations that can be used orally are push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or Sor-40 bitol. The capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in 45 suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.

As rectally applicable pharmaceutical preparations, e.g. Suppositories into consideration, which are suitable from a combination of the active ingredient with a suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which consist of a combination of the active ingredient with a base material 55; as basic materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active ingredient in water-soluble form are suitable, e.g. a water-soluble salt, further suspensions of the active ingredient, such as 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 containing viscosity-increasing substances, e.g. Contain sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally from stabilizers.

Pharmaceutical preparations for topical and local sales

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6

are e.g. for the treatment of the skin lotions and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (which preferably contain a preservative), for the treatment of the eyes eye drops which are the contain active compound in aqueous or oily solution and eye ointments, which are preferably prepared in sterile form, for the treatment of nose powders, aerosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse powder, which can be inhaled quickly Nostrils, and nasal drops containing the active compound in aqueous or oily solution, or for local treatment of the mouth, lozenges containing the active compound in a mass generally formed from sugar and gum arabic or tragacanth, to which flavorings can be added , as well as pastilles which contain the active substance in an inert mass, e.g. made of gelatin and glycerin or sugar and gum arabic.

The new compounds can be used as pharmacologically active substances, in particular as anti-inflammatories, analgesics, uricosurics, antiallergics and / or thrombolytics, preferably in the form of pharmaceutical preparations. The daily dose, which primarily depends on the condition of the organism to be treated and / or on the indication, is from about 300 mg to about 1 g for a warm-blooded animal of about 70 kg.

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

example 1

A suspension of 2.4 g of a 50% strength sodium hydride mineral oil dispersion in 100 ml of hexamethylphosphoric acid tri-amide is added dropwise with cooling to a solution of 7.5 g of 2,3-dihydro-2-oxo-benzo [b] thiophene in 50 ml of hexamethylphosphoric triamide are added, the temperature being kept below 15 °. After stirring for half an hour at room temperature, 52 g of phenyl N- (2-thienyl) carbamate dissolved in 50 ml of hexamethylphosphoric triamide are added dropwise with external cooling. The mixture is stirred at room temperature for 16 hours and poured into a mixture of 200 ml of 2N hydrochloric acid and 1000 ml of ice water. An oil separates, which crystallizes after about 2 hours. The crystalline product, which includes solvent, is dissolved in 2N 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 and the crude product is filtered off with suction and recrystallized from tetrahydrofuran / ether. N- (2-Thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxamide with a melting point of 142-144 ° (dec.) Is obtained.

Example 2

0.5 g of ethyl 2-0x0-2,3-dihydro-3-benzo [b] thiophenecarboxylate and 0.25 g of 2-thienylamine are boiled under reflux in 10 ml of toluene for 5 hours. After cooling, the product is precipitated by adding ether in portions. The N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] -thiophenecarboxamide of mp 142-144 ° (dec.) Is obtained.

The 2-oxo-2,3-dihydro-3 - benzo [b] thiophenecarboxylic acid ethyl ester used as starting material can be prepared as follows:

To a suspension of 2 g of 2-oxo-2,3-dihydro-benzo [b] thiophene and 2.5 g of diethyl carbonate in 25 ml of hexamethyl-phosphoric acid triamide is de-oiled sodium hydride, obtained from de-oiling of 0.6 g of 50% suspension in mineral oil, added. After removing the cooling bath and stirring for 4 hours at room temperature, the mixture is poured onto a mixture of 1 liter of ice water and 10 ml of concentrated hydrochloric acid, filtered off and washed in succession with ice-5 water, diethyl ether and hexane. The residue is taken up in 50 ml of acetone, heated under reflux and cooled. It is diluted with 100 ml of diethyl ether, cooled in an ice bath for some time and filtered again. The 2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxylic acid ethyl ester is thus obtained.

10th

Example 3

11.4 g of o-mercapto-phenylmalonic acid methyl ester N- (2-thienyl) -amide are heated in 50 ml of dimethylformamide and 1 ml of concentrated hydrochloric acid at 100 ° for 2 hours. 15 is allowed to cool, 100 ml of water are added, the mixture is filtered off with suction and taken up in 100 ml of diethyl ether. After washing, first with n-sodium hydroxide solution, then with water, drying with sodium sulfate, evaporation, chromatography and crystallization from ether, the N- (2-thienyl) -2-20 -oxo-2,3-benzo is obtained from the organic phases [b] thiophene-3-carboxamide, mp 142-144 ° (dec.).

The starting material can be produced, for example, as follows:

A vigorous stream of air is passed through a solution of 9.4 g of o-mercaptophenylacetic acid 25 in 56 ml of n-sodium hydroxide solution with stirring for 8 hours. The reaction mixture is evaporated to dryness on a rotary evaporator. The residue is mixed twice with 50 ml of toluene and again evaporated to dryness. The residue is then dried under high vacuum at 50 ° for 30 minutes, suspended in 180 ml of dimethylformamide and mixed with 7 g of dimethyl sulfate within 3 minutes with stirring. The reaction mixture is heated to 110 ° with stirring for 1 hour, 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 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 50% sodium hydride in 200 ml of dimethylformamide. 40 With gentle heating, stirring is continued until the evolution of hydrogen has ended. The solution of 15 g of 2-thienyl isocyanate in 100 ml of dimethylformamide is then slowly added dropwise at 0.degree. The solution is stirred for a further 24 hours at room temperature and then ice and dilute hydrochloric acid are added. The product which separates out is extracted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The o, o'-bis- [a -methoxycarbonyl-N- (2-thienyl) -carbamylmethyl] -diphenyl disulfide is obtained, which can be used without purification. 5o 20.0 g of crude o, o'-bis- [a-methoxycarbonyl-N- (2-thienyl) carbamylmethyl] diphenyl disulfide are suspended in 300 ml of ethanol and 7 g of sodium borohydride are added in portions with stirring. The mixture is stirred for 4 hours at room temperature, evaporated, mixed with water, acidified with 55 hydrochloric acid until the Congo acidic reaction and extracted with ethyl acetate. Evaporation gives crude methyl o-mercapto-phenylmalonic acid (2-thienyl) amide, which can be cyclized without further purification.

m Example 4

0.8 g of N- (2-thienyl) -2-acetamino-benzo [b] thiophene-3-carb-oxamide are suspended in 5 ml of ethanol, 2.5 ml of water and 2.5 ml of concentrated hydrochloric acid and 7 '/ Heated to reflux for 2 hours. The mixture is left overnight at room temperature 65 and the methanol is removed under reduced pressure. The evaporation residue is taken up in water, suction filtered and washed with water. It is taken up in dilute sodium hydroxide solution and the insoluble matter is filtered off,

7

634 840

acidifies the aqueous phase and filters the precipitated N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene-carboxamide from the mp. 142-144 ° (dec.) .

The starting material can be produced as follows:

3 g of magnesium shavings with 30 ml of anhydrous tetrahydrofuran are placed in a sulfonation flask, and 13.5 g of ethyl bromide are added to produce ethyl magnesium bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophene, dissolved in 60 ml of absolute tetrahydrofuran, are added dropwise, the mixture is stirred at room temperature for one hour and then heated to reflux for a further 15 minutes. 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. Then heated to reflux for 15 minutes, allowed to stir at room temperature for 15 minutes, the reaction solution is evaporated in vacuo, the evaporation residue is mixed with dilute hydrochloric acid and extracted twice with chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated to dryness in vacuo. Crude N- (2-thienyl) -2-acetamino-benzo [b] -thiophene-3-carboxamide is obtained which can be used without further purification.

Example 5

2.75 g of N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3 - carboxamide are mixed in a mixture of 7.5 ml of 2N sodium hydroxide solution and 30 ml of water heated to about 50 °. After cooling, a crystalline precipitate is obtained, the sodium salt of N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3-carboxamide, mp above 300 °.

Example 6

5 tablets containing 0.1 g of N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxamide are prepared as follows:

Composition (for 1000 tablets): N- (2-thienyl) -2-oxo-2,3-dihydro-3 - '

10 -benzo [b] thiophenecarboxamide 100.00 g

Lactose 50.00 g

Wheat starch 73.00 g

Colloidal silica 13.00 g

Magnesium stearate 2.00 g

15 talc 12.00 g water q.s.

The N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene-carboxamide is mixed with part of the wheat starch, with the lactose and the colloidal silica and the mixture through a sieve driven. Another part of the wheat starch is gelatinized with five times the amount of water on the water bath and the above powder mixture is kneaded with this paste until a weak plastic mass has formed. The plastic mass is pressed through a sieve with a mesh size of approximately 3 mm, dried and the dry granules are again passed through a sieve. Then the remaining wheat starch, the talc and the magnesium stearate are mixed in and the mixture obtained is compressed into tablets of 0.25 g.

Claims (6)

634 840 2nd PATENT CLAIMS 6. Process for the preparation of the compound of formula I. 1. Therapeutically effective 2-oxo-2,3-dihydro-benzo [b] - and their salts with bases according to claim 1, characterized in that the thiophene compound of the formula that a compound of the formula X II a m Ph ÇH-C-R, TT, U). \ T ° (IIa)> V > 0 in which R0a is an etherified or esterified hydroxyl group in which Ph represents a 1,2-phenylene radical, X represents oxygen, is treated and stands with the amine of the formula R1-NH-R2 (V), R 1 is 2-thienyl and R 2 is hydrogen, and if desired, a free compound obtained in a salt desires its pharmaceutically acceptable salts. or a salt obtained is converted into the free compound. 2. Compound of formula I according to claim 1 in the 7. Process for the preparation of the compound of formula I tautomeric 2-hydroxy-benzo [b] thiophene form. and their salts with bases according to claim 1, characterized 3. Pharmaceutical preparations containing the compound characterized in that a compound of the formula according to claim 1 or 2 or a pharmaceutically acceptable salt thereof. X ^ 4. Process for the preparation of the compound of formula I 20 CH-Ö and their salts with bases according to claim 1, thereby / \ characterized in that the compound of the formula S '^ 9 / C = 0 ^ (yi>. «/ I TT IPÏV £ «0 <">. * SB ' S o in which R0 is an etherified or esterified hydroxy group, which is also in the tautomeric 2-hydroxy-benzo [b] thiophene form or an optionally substituted amino group, or may be present, ring-closes a salt thereof with a compound of the formula 30 and, if desired, one get- ne free compound converted into a salt or a salt obtained in the / \ free compound. X = C - 8. Process for the preparation of the compound of formula I. I R ° (HI) and its salts with bases according to claim 1, characterized 35 characterized that one in a compound of the formula ° X implements, wherein R0 for an etherified or esterified hydro II ^ R xygruppe or an optionally substituted amino group Ph ÇH — C — N (VIII) and R20 has the meaning of R2, or in which R0 and 40T R2 ° together form a bond, and if desired a /, C = R 2 obtained free compound in a salt or a salt S Z obtained transferred to the free connection. 5. A process for the preparation of the compound of formula I wherein Rz is an optionally substituted, hydrolytically imino group in and its salts with bases according to claim 1, thereby 45 imino group convertible to oxo group, Rz to oxo is characterized in that the compound of the formula is hydrolyzed and, if desired, a obtained free compound converted into a salt or a salt obtained into the free compound. (II), 50