NO151323B - ANALOGUE PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE N- (2-TIENYL) -2-OXO-2,3-DIHYDRO-BENZO (B) THIOFEN-3-CARBOXAMIDE - Google Patents

Description

The invention relates to analogous methods for the preparation of a therapeutically active N-(2-thienyl)-2-oxo-2,3-dihydro-benzo/o/thiophene-jcarboxamide of formula _

which can also exist in the tautomeric 2-hydroxy-benzo/ b/ thiophene form, as well as its salts with bases, the method being characterized by

a) a compound with formula

which can also be present in the tautomeric 2-hydroxy-benzo/~b/

thiophene form, is reacted with a compound of formula

wherein RQ means an etherified or esterified hydroxy group,

an optionally substituted amino group, and R° means hydrogen or in which RQ and R° together form a bond or

b) a compound of formula.

in which R^ means an etherified or esterified hydroxy group,

is treated with an amino of formula

or

c) a compound of formula

in which Rq means an etherified or esterified hydroxy group, or a salt thereof, - ring luttes, or

d) in a connection with formula

which can also exist in tautomeric forms, and in which Rz means

an optionally substituted hydrolytic oxo group transferable imino group, Rz is hydrolyzed to oxo,

and if desired, the formed free compound is transferred to a salt, or a formed salt to the free compound or to another salt.

Salts of compounds of formula I are primarily pharmaceutically usable salts with bases, above all metal

or ammonium salts. Metal salts are therefore above all metal salts derived from metals from the periodic table group Ia, Ib, Ila and Ilb, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium, calcium, zinc or copper salts. Ammonium salts are above all salts with secondary or tertiary bases, e.g. with morpholine, thiomorpholine, piperidine, pyrrolidine, dimethyl- or diethylamine or triethylamine, but in other cases also salts with ammonia. The salt formation with the compound of formula I thereby probably takes place from the tautomeric 2-hydroxy-benzo/bythiophene form.

DE-OS no. 2,713,584 mentions benzothiophene-2-one-3-carboxamide compounds with anti-inflammatory, analgesic, antithrombotic and uricosuric effects, under which scope the new compound of formula I and its salts fall.

The new compound shows particularly advantageous pharmacological properties to a surprising degree. In the foreground of impact

the spectrum consists of peripheral analgesic effects that can

appears as well in mice in the phenyl-p-benzoquinone Writhing test,

as also on the rat in the acetic acid Writhing test, analogous to that in Krupp et al., Schweitz. with. Wsh. volume 105, page 646 (1975) mentioned methods in doses of approx. 1 to approx. 10 mg/kg p.o. IN

in addition, it has an anti-inflammatory effect, e.g. can be detected in the kaolin paw edema test on rats analogous to that of Menassé

Croup Toxiol. Appl. Pharmacol. volume 29, page 389 (1974) re-

spoken methods in doses of approx. 10 mg/kg to approx. 100 mg/kg p.o. Furthermore, they have uricosuric effects such as is demonstrated

in phenol red excretion test analogous to that of Swingle et al.,

Arch. int. Pharmsco dyn. volume 189, page 129 (1971) mentioned methods, in doses of approx. 30 to approx. 100 mg/kg p.o. The compound is therefore used as peripheral analgesics, e.g. for the treatment of pain conditions of various genesis, or as antiphlogistics, e.g. for the treatment of tryptic inflammation

looks or to the influence of traumatic inflammatory and swelling conditions, as well as uricosurics, e.g. for the treatment of gout.

The new compound also shows antithrombotic activity

which can be detected in rabbits in the experimental pulmonary embolism analogous to that of silver et al., Science volume 183, page 1085

(1974) discussed methods in doses of approx. 0.1 to approx. 3 mg/kg p.o.

In vitro, the compound also remarkably strongly inhibits the prostaglandin synthetase system in doses of 0.1-1 pg/ml (method: White and Glassmann, Prostaglandins, vol. 7. no. 2, page 123

(1974)). It can therefore also be used as a thrombolytic.

For search report.

Comparative pharmacological studies were carried out between the compound obtained according to the invention

N-(2-thienyl)-2,3-dihydro-2-oxo-2-benzo[b]thiophene-carboxamide

I (comparison example 1)

with the compound characterized in example 3, 5 in DOS 2,713,584

N-(2-thiazolyl)-2,3-dihydro-2-oxo-3-benzo[b]thiophene-carboxamide

II.

The phenyl-p-benzo-quinone Writhing test was chosen as test model 1 for the antinociceptive effect.

Test method

The test was. carried out analogously to that of. L.C. Hendersot and J. Forsyte in J. Pharm. Exp. ■ ter.. 125 237 (1959) p blized methodology

.with the following modifications: . :>

Albino mice (MAG cf<1> 18-25 g two groups of 4 animals) that were not fed at night were intraperitoneally injected with 0.25 ml of a fresh 0.03% suspension of phenyl-p-benzo- quinone in tragacanth 0.4% 55 minutes after oral application of the comparison substance. Control animals received the carrier tragacanth 0.4% instead of the active substance. 5 minutes after the intraperitoneal injection of the irritant, the antinociceptive reaction was determined over a period of 5 minutes by counting the stretch beygels.

The antinociceptive effect (ED, Q value) of each time the test compound was determined by determining the dose at which a 50% reduction of the stretching movements was observed compared to the control animals.

Test results

N-(2-thienyl)-2,3-dihydro*-2-oxo-benzo/~b7thiophene-3-carboxamide (I) : ED5() (mgA<g>) : 0.8, N— (2- thiazolyl)-2,3-dihydro-2-oxo-benzo^~b7thiophene-3-carboxamide (II) ED50 (mg/kg): 100. ;End result ;These comparison experiments show that the effective dose leading to a 50%- ig reduction of the tensile movements by compound II in DOS 2,713,584 is by a factor of 125 higher than for compound I according to the invention. Consequently, with regard to antinociceptive effect, compound I is 125 times more active than the comparison substance II. Method variant a) An etherified hydroxy group RQ is preferably hydroxy etherified with an optionally substituted hydrocarbon residue such as lower alkyl, e.g. methyl or ethyl, or halolower alkyl, ;f. e.g. 2,2,2-trichloroethyl, and primarily with optionally substituted as lower alkyl, lower alkoxy, halogen and/or nitro-containing phenyl, and means e.g. lower alkoxy, such as methoxy or ethoxy, halogen lower oxy, e.g. 2,2,2-trichloroethoxy or phenyloxy, but an esterified hydroxy group is preferably esterified with a strong mineral acid primarily halogen, especially chlorine. A substituted amino group contains one and preferably two optionally substituted hydrocarbon residues such as lower alkyl and/or optionally, e.g. as mentioned above, substituted phenyl as a substituent, and means e.g. lower alkylamino such as methylamino, or ethylamino, dilower alkylamino such as dimethylamino, or diethylamino, or phenylamino, and preferably diphenylamino, the phenyl residue possibly e.g. may be substituted with lower alkyl, such as methyl, lower alkoxy, e.g. methoxy, halogen, e.g. fluorine, chlorine, or bromine, and/or nitro. A disubstituted amino group R can, however, also mean the residue of formula ;; The above reaction is usually carried out in the presence of a basic agent, such as a corresponding inorganic or organic agent. The inorganic base primarily includes salt, especially alkali metal salt forming agents, such as alkali metal hydrides or amides, as well as alkali metal organic compounds such as corresponding lower alkanolates, further corresponding lower alkyl or phenyl compounds, e.g. sodium methylate, sodium ethylate, potassium tert.-butylate, n-butyl lithium or phenyl lithium. Suitable organic bases are primarily amines such as tertiary amines, preferably trilower alkylamines, e.g. triethylamine, heterocyclic tertiary bases, especially of the pyridine type, e.g. pyridine or quaternary bases, such as tetralower alkylammonium or trilower alkylphenyl lower alkylammonium hydroxides. In the presence of the bases, the starting material of formula II reacts in anionic, i.e. salt form, with the starting materials of formula III. The latter are carbamic acid esters, carbamic acid halides, ureas, isocyanates corresponding to formula III. The reaction is carried out in the presence or absence of a solvent or diluent, and if necessary during cooling or heating, e.g. in a temperature range of approx. -10°C to approx. 120°C in a closed vessel, and/or in an inert gas-e.g. e.g. nitrogen atmosphere. Method variant b The step-by-step formation of the compound of formula I starting from starting material of formula II can be carried out such that a compound of formula II is reacted with a compound of formula in which R<Q> and R<q> independently of each other means an etherified or esterified hydroxy group, and is treated as an intermediate obtained compound of formula I an amine of formula ;Etherated or esterified hydroxy group) R^, R^ has e.g. those above for the corresponding residue RQ stated meaning 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. dilower alkyl carbon atoms, e.g. diethyl or diphenyl carbonate, phosgene or haloformic acid lower alkyl ester, e.g. chloroformate isobutyl ester. 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 reacted directly with amines of formula V. The above process steps are carried out in the absence or presence of a solvent or diluent, and if necessary under cooling or heating, e.g. in a temperature range from approx. -10°C to approx. 120°C, in a closed vessel, and/or in an inert gas, e.g. nitrogen atmosphere. The starting materials are known, and can be produced in a manner known per se. The starting substances with formula II can be obtained, for example, by reacting an enamine derived from an optionally substituted cyclohexanone as indicated for Ph, in the presence of sulfur with a cyanoacetic acid ester, acylating the formed 2-amine6-4,5,6,7-tetrahydro- benzothiophene-3-carboxylic acid ester at amino groups, dehydro-generate the reaction product with sulfur, and treat the formed 2-acylamino-benzothiophene-3-carboxylic acid ester with caustic soda, or while transferring a corresponding benzothiophene with butyllithium to the 2-lithium compound, oxidize with hydrogen peroxide. ;Compound with formula III can e.g. is prepared by reacting compounds of formula ;; Starting material of formula IIa can be prepared by reacting the compound of formula II with a compound of formula R^-C (=O)-R j1 (IV), in which R^ and R^ independently of each other means an etherified or esterified hydroxy group. ;Procedure variant C; That salt of starting material with formula VI is e.g. an alkali metal salt. ;A group RQ can e.g. have the above meaning, and mean ;f. e.g. 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 lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino, or diethylamino, phenylamino or diphenyl- ;amino, or also groups with formula ;; . alkali metal salt-forming agents, including also an alkali metal lavereal canolate, e.g. sodium methylate, sodium ethylate, or potassium tert.-butylate. Thereby, one works in the absence or presence of a solvent or diluent, if necessary during cooling or heating, e.g. in a temperature range from approx. 0°C to 15 0°C in a closed vessel, and/or in inert gas, e.g. e.g. nitrogen atmosphere. The starting materials with formula VI can be prepared in a manner known per se, e.g. wherein in the benzylic methylene group of a compound of formula ; in which the residue of formula Ia or the residue of formula -C(=0)-Rq means, and Ry means hydrogen or preferably a mercapto-protecting group, such as hydrogenolytically cleavable α-phenyl-lower alkyl, e.g. benzyl, introduces a group of formula ; by reacting a compound of formula VII with a suitable derivative of the carboxylic acid as a corresponding ester, e.g. dilave alkyl carbonate such as diethyl carbonate, or diphenyl carbonate, dihalide, e.g. phosgene, halogen ester, e.g. halogen formic acid lower alkyl ester, urea, further isocyanate, usually in the presence of a basic agent such as an alkali metal hydride, -amide or -lower alcohol alkanolate or an organic base, e.g. e.g. triethylamine. A mercapto-protecting group can then usually be cleaved off, e.g. by treatment with catalytically activated hydrogen, and thus the mercapto group is released. ;Procedure variant d ;In a substituted imino group Rz, a substituent is e.g. an optionally substituted hydrocarbon residue such as lower alkyl, e.g. e.g. methyl or ethyl or phenyl, or acyl group derived from a carboxylic acid or a half-ester of a carboxylic acid, e.g. lower alkanoyl, such as acetyl or benzoyl or lower alkoxycarbonyl, such as methoxy, or ethoxycarbonyl. The starting material with formula VIII, which can also exist in the tautomeric form of a corresponding 2-(H-R)-benzo/~b7thiophene compound in which the group -RZ-H means an optionally monosubstituted amino group, is transferred by means of hydrolysis, preferably by treatment with water in the presence of a basic or acidic agent, such as an inorganic base, e.g. an alkali metal hydroxide or a mineral acid, e.g. hydrochloric or sulfuric acid, to the desired compound of formula I. The reaction is carried out in the presence or absence of a solvent or diluent, and if necessary during cooling or heating, e.g. in a temperature range from approx. -10°C to approx. 120°C in a closed vessel, and/or in an inert gas, e.g. nitrogen atmosphere. Starting materials with formula VIII can be prepared in a manner known per se, as e.g. a compound of formula ; in which Rz preferably means an unsubstituted imino group, and the group -Rz-H therefore primarily means a primary amino group, reacts e.g. with phosgene or with a chloroformic acid lower alkyl ester, and a thus obtained compound of formula optionally after introduction of a substituent in a hydrogen-containing imino group Rz, is treated, e.g. by treatment with a lower alkyl halide in the presence of an alkali metal compound-forming reagent with an amine of formula ; and if desired in a starting material of formula VIII wherein Rz represents an unsubstituted imino group, or a tautomer thereof, wherein -R -H represents an unsubstituted amino group, their imino- or amino group, e.g. with lower alkylation or acylation, the latter e.g. by treatment with a suitable symmetrical mixed or internal anhydride of a carboxylic acid. The invention will be explained in more detail with the help of some examples where the temperature is indicated in degrees Celsius. ;Example 1 ;A suspension of 2.4 g of a 50% sodium hydride-mineral oil dispersion in 100 ml of hexamethylphosphoric acid triamide is mixed dropwise under cooling with a solution of 7.5 g of 2,3-dihydro-2-oxo- benzo(/<*>"b7thiophene in 50 ml of hexamethylphosphoric acid triamide, keeping the temperature below 15°C. After stirring for half an hour at room temperature, 52 g of N-(2-thienyl)-carbamic acid phenyl ester dissolved in 50 ml of hexamethylphosphoric acid triamide are added dropwise under external cooling . Stirring is continued at room temperature for 16 hours and the reaction mixture is poured onto a mixture of 200 ml of 2-N hydrochloric acid and 1000 ml of ice water. An oil separates which crystallizes after about 2 hours. The crystalline product, which contains the solvent, is dissolved in 2- N sodium hydroxide solution, the solution is washed 4 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. This gives N-(2-thienyl)-2- oxo-2,3-dihydro-3-be nzo/~b7thiophenecarboxamide of m.p. 142-144°C (under decomposition).

Example 2

0.8 g of N-(2-thienyl)-2-acetamino-benzo/~b7thiophene-3-carboxamide is suspended in 5 ml of ethanol, 2.5 ml of water and 2.5 ml of conc. hydrochloric acid, and heated for 7.5 hours under reflux. It is left overnight at room temperature, and the methanol is removed under reduced pressure. The evaporation residue is taken up with water, sucked off and washed with water. One absorbs in diluted baking soda

lye, and filters out insoluble acidifies the aqueous phase,

and filtering the precipitated N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo/ butithiophene-carboxamide of m.p. 142-144°C during decomposition.

The starting material can be prepared as follows:

In a sulphuring flask, 3 g of magnesium shavings are mixed with 30 ml of anhydrous tetrahydrofuran and mixed to produce ethylmagnesium bromide with 13.5 g of ethyl bromide. After the magnesium is dissolved, 6.1 g of 2-aminothiophene dissolved in 60 ml of abs are added dropwise. tetrahydrofuran, stir for 1 hour at room temperature, and then heat for a further 5 minutes under reflux. Then 8 g of 2-acetamido-benzo^b7thiophene-3-carboxylic acid ester dissolved in 100 ml of abs. tetrahydrofuran at room temperature. Then heat 15 minutes to reflux,

and stirring for 15 minutes at room temperature, in-

evaporate the reaction solution in vacuo, mix the evaporation residue with dilute hydrochloric acid, and extract 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 3

11.4 g of o-mercapto-phenylmalonic acid-N-(2-thienyl)-amide are heated in 50 ml of dimethylformamide and 1 ml of conc. hydrochloric acid for 2 hours at 100°C. It is allowed to cool, mixed with 100 ml of water, filtered off with suction and taken up in 100 ml of diethyl ether. From the organic phases, after washing first with n-sodium hydroxide solution, and then with water, drying with sodium sulfate, evaporation, chromatography and crystallization from ether, N-(2-thienyl)-2-oxo-2,3-benzo(b) is obtained thiophene carboxamide of m.p. 142-144°C during decomposition.

The starting material can, for example, be prepared as follows: Through a solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml of n-sodium lye, a strong air current is passed for 8 hours while stirring. The reaction mixture is evaporated to dryness on a rotary evaporator. The residue is mixed twice with 50 ml of toluene, and each time evaporated again to dryness. The residue is then dried for 90 minutes under high vacuum at 50°C, suspended in 180 ml of dimethylformamide, and mixed with stirring for 3 minutes with 7 g of dimethylsulphate. The reaction mixture is heated for 1 hour with stirring at 110°C, then cooled and poured onto ice. The resulting suspension is extracted with ethyl acetate, the organic phase is combined, 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. Continue to stir under gentle heating until hydrogen evolution is complete. The solution of 15 g of 2-thienisocyanate in 100 ml of dimethylformamide is then slowly added dropwise at 0°C. The solution is further stirred for 24 hours at room temperature, and then mixed with ice and diluted hydrochloric acid. The product which then separates is extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated. Thus, o,o'-bis/a-methoxycarbonyl-N-(2-thienyl)-carbamylmethyl-7-diphenyl disulfide is obtained, which can be used without purification.

20.0 g of crude o,o ' -/"a-methoxycarbonyl-N-(2-thienyl)-Icarbamylmethyl/- diphenyldisulfide are suspended in 300 ml of ethanol and mixed with stirring in portions with 7 g of sodium borohydride. The mixture is stirred for 4 hours at room temperature, evaporated, mixed with water, acidified with hydrochloric acid to precisely Congo acid reaction, and extracted with ethyl acetate.Evaporation yields 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% mineral oil) in 60 ml of tetrahydrofuran is added dropwise to 7.3 g of 2,3-dihydro-2-oxo-benzobthiophene in 50 ml of tetrahydrofuran.

It is left to stir for 30 minutes, mixed with 5 ml of pyri-

din, and then add dropwise 7.8 g of N-(2-thienyl)-carbamyl chloride in 20 ml of tetrahydrofuran, leave to stir for 1 hour at room temperature, and 2 hours at 60°C, rather in 750 ml of ice water, acidify with 2-n hydrochloric acid, suction, and recrystallize from acetone/hexane. One obtains N-(2-thienyl)-2,3-dihydro-2-oxo-benzo/b7thiophene-3-carboxamide of m.p. 142-144°C, with decomposition.

Example 5

Suspension of 6.5 g sodium hydride suspension (50% mineral oil)

in 100 ml of hexamethylphosphoric acid triamide is mixed dropwise with a solution of 20.2 g of 2,3-dihydro-2-oxo-benzo/b7-thio£ene while cooling to 10°C. It is left to stir for 1 hour at room temperature, and then a solution of 38.2 g of N-(2-thienyl)-urea in 100 ml of hexamethylphosphoric tri-

amide. It is stirred for 10 hours at room temperature, and 22 hours

at 60°C, rather on a mixture of 100 ml of 2-n hydrochloric acid, and 1000 g of ice, extract 3 times with 250 ml of diethyl ether each time, dry over sodium sulfate and evaporate to dryness. The residue is recrystallized from diethyl ether. One obtains N-(2-thienyl)-2,3-dihydro-2-oxo-benzo/b/thiophene-3-carboxamide of m.p. 142-144°C during decomposition.

Example 6

To a cooled suspension of 8.7 g of a 50% sodium hydride suspension in paraffin oil in 250 ml of hexamethylphosphoric acid triamide, the solution of 27.5 g of 2,3-dihydro-2-oxo-benzo1/b/thiophene in 100 ml of hexamethylphosphoric acid triamide is added dropwise. It is then allowed to stir for 1 hour at room temperature, cooled again to 0°C, and 31.3 g of N-(2-thienyl)-carbamic acid ethyl ester, dissolved in 50 ml of hexamethylphosphoric acid triamide, are added drop by drop. Mari stirs for 20 hours at room temperature, and pours on a mixture of 1500 g of ice and 200 ml of 2-N hydrochloric acid. The mixture is extracted twice with 300 ml of diethyl ether each time, the extract is washed neutrally with water,

and evaporated to dryness. N-(2-thienyl)-2-oxo-2,3-dihydro-benzo[b]thiophene-3-carboxamide of m.p. 142-144°C during decomposition.

Example 7

16.9 g of 2,3-dihydro-3-oxo-benzo[b]thiophene are dissolved in 200 ml of hexamethylphosphoric acid triamide. The solution is cooled to 0°C

and mixed under nitrogen dropwise with a solution of 3.2 g of butyllithium in 20 ml of N-hexane. It is allowed to warm to room temperature and 31 g of N-(2-thienyl)-carbamic acid-(2,2,2-trichloro)ethyl ester are added in portions, stirred for 2 hours at 0° and 20 hours at room temperature, rather at 1000 g ice, extract 3 times with 100 ml of diethyl ether each time, dry over sodium sulfate, evaporate to dryness and recrystallize from hexane/diethyl ether (1:5). The formed N-(2-thienyl)-2,3-dihydro-2-oxo-benzo[b]thiophene-3-carboxamide melts at 142-144°C with decomposition.

Example 8

A solution of 1 g of N-(2-thienyl)-2-formamino-benzo/bythiophene-3-carboxamide in each 5 ml of ethanol and water is mixed with 3 ml of hydrochloric acid and heated for approx. 10 hours in return. After removing the alcohol, the residue is washed with water, taken up in diluted caustic soda and sucked off. The aqueous phase is acidified and the precipitated N-(2-thienyl)-2-oxo-2, 3-dihydro-benzo(/-b7thiophene-3-carboxamide) is recrystallized from ether, turning at 142-144°C during decomposition.

The starting material can be produced as follows:

To prepare the organometallic compound, 10.9 g of ethyl bromide was added dropwise to a mixture of 4 g of magnesium shavings and abs. tetrahydrofuran under cooling. A solution of 10.9 g of 2-aminothiophene in abs. is added portionwise to the reaction product. tetrahydrofuran, and the solution is heated briefly under reflux. Then, at room temperature, 7.5 g of 2-formamino-benzo/b7-thiophene-3-carboxylic acid ethyl ester, dissolved in 100 ml of abs. tetrahydrofuran. It 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 hydrolysed with dilute hydrochloric acid. Small portions of methylene chloride are then extracted, the organic phase is dried over sodium sulphate, the solvent is distilled off and the resulting N-(2-thienyl)-2-formamino-benzo/b/thiophene-3-carboxamide is used directly for the further reaction.

Example 9

20 g of N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophene-carboxamide are suspended in 250 ml of acetone and mixed with 66 ml of n-sodium hydroxide solution, whereupon dissolution occurs. It is evaporated to dryness, the evaporation residue is stirred first with toluene and then with diethyl ether, filtered off with suction and dried. The sodium salt of N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo[b7]-thiophene-carboxamide is obtained, m.p. < 280°C.

Example 10

470 mg of 2-oxo-2,3-dihydro-3-benzo/b/thiophene carboxylic acid ethyl ester (2.11 mM) and 218 mg of 2-aminothiophene (2.22 mM) are boiled in 3 ml of xylene for 5 hours during reflux. After cooling, the product is precipitated by the addition of hexane (3 ml). After further dilution with 5 ml of ether and stirring, crystalline N-(2-thienyl)-2-oxo-2,3-dihydro-3-benzo/~b7thiophene-carboxamide of m.p. 142-144°C during decomposition.

Example 11

4.0 g of o-mercaptophenylmalonic acid phenyl ester N-(2-thienyl)-amide are suspended in 100 ml of ethanol, mixed with 0.2 ml of 5-normal caustic soda and stirred for 2 hours. Evaporate to dryness, take up in ether, wash twice with water, evaporate until crystallization begins, mix with pentane, cool to -15°, and filter off the crystalline N-(2-thienyl)-2-oxo-2, 3-dihydro-3-benzo/b/thiophene-carboxamide of m.p. 142-144°C.

The starting material is obtained by reacting o-mercapto-phenylmalonic acid-N-(2-thienyl)-amide with phenyl in benzene solution in the presence of the approximately equimolar amount of N,N-dicyclohexylcarbodiimide.

Example 12

3 0.0 g of bis-o-/~(α-methoxycarbonyl)-N-(2-thienyl)-carbamylmethyl/- diphenyl sulfide is suspended in 300 ml of ethanol, mixed with stirring in portions with 7.0 g of sodium borohydride. The mixture is stirred for 4 hours at room temperature, and is then heated for a further 1 hour under reflux. It is then evaporated, mixed with water, acidified with hydrochloric acid to precisely Congo acid reaction, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in ether and the solution is filtered over silica gel. The filtrate is evaporated to incipient crystallization, mixed with the same amount of petroleum ether, and the crystallized collected. One obtains N-(2-thienyl)-2-oxo-2,3-dihydro-'3-benzo[b]thiophene-carboxamide of m.p. 142-144°C.

The starting material can e.g. produced as follows:

Through a solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml of n-sodium lye, a strong air current is passed for 8 hours while stirring. The reaction mixture is evaporated to dryness on a rotary evaporator. The residue is mixed twice with 50 ml of toluene, and each time evaporated again to dryness. The residue is then dried

90 minutes under high vacuum at 50oC, -suspended in 180 ml of dimethylformamide, and mixed with stirring for 3 minutes with 7 g of dimethylsulphate. The reaction mixture is heated at 110°C for 1 hour with stirring, 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 50% sodium hydride in 200 ml of dimethylformamide. Under gentle heating until completion of hydrogen evolution, continue stirring. The solution of 15 g of 2-thienyl isocyanate in 100 ml of dimethylformamide is then slowly added dropwise at 0°C. The solution is further stirred for 24 hours at room temperature, and then mixed with ice and diluted hydrochloric acid. Bis-o-/~ (α-methoxycarbonyl)-N-(2-thienyl)-carbamylmethyl/-diphenyl disulfide which separates is extracted with ethyl acetate, washed with water, dried, over sodium sulfate and evaporated. It can be used without further purification.

Example 13

1 g of N-(2-thienyl)-2-benzoylamino-benzo[b7thio'f en.-3-carboxamide is dissolved in 10 ml of ethanol and mixed with 2.5 ml of water and 3 ml of conc. hydrochloric acid and then heated under reflux. The solution is evaporated and taken up with diluted caustic soda. The filtered aqueous solution is acidified, and the precipitated N-(2-thienyl)-2-oxo-2,3-dihydro-benzo[b7-thiophene-3-carboxamide, m.p. 142-144°C.

The starting material is prepared analogously to example 2.

Claims (1)

1. Analogy method for producing the new therapeutically active N-(2-thienyl)-2-oxo-2,3-dihydro-benzo/~b7thiophene-3-carboxamide of formula _ which can also be present in the tautomeric 2-hydroxy-benzo/ b/ thiophene form, and its salts with bases, characterized in that a) a compound of formula which can also exist in the tautomeric 2-hydroxy-benzo/b7 thiophene form, is reacted with a compound of formula wherein RQ means an etherified or esterified hydroxy group, or an optionally substituted amino group, and R° means hydrogen, or in which Rq and R° together form a bond or b) a compound of formula in which R^ means an etherified or esterified hydroxy group, is treated with the amine of formula or c) a compound of formula in which Rq means an etherified or esterified hydroxy group or a salt thereof, is ring-closed or d) in a compound of formula which can also exist in the tautomeric form, and in which Rz means an optionally substituted, hydrolytically transferable imino group to the oxo group, Rz is hydrolyzed to oxo, and if desired, the formed free connection is transferred to a salt or a formed salt in the free compound or to another salt.