FR2706899A1 - Pyrrole derivatives, their preparation and their therapeutic application - Google Patents

Abstract

The invention relates to pyrrole derivatives of general formula (I) in which R1 and R2 each represent, independently of the other, a hydrogen or halogen atom, a linear or branched C1-6 alkyl group, a C3-6 alkenyl, C1-4 alkoxymethyl, benzyl or phenyl group, optionally substituted by one or a number of halogen atoms or alkyl groups, a group COOR, in which R represents a linear or branched C1-4 alkyl group, or a group CONR'R'', in which R' and R'' each represent, independently of each other, a hydrogen atom or a linear or branched C1-4 alkyl group, and R3 represents a 2-imidazolinyl or 4-imidazolyl group, and to their addition salts with pharmaceutically acceptable acids. Application in therapeutics.

Description

The present invention relates to pyrrole derivatives,

  their preparation and their application in therapeutics.

  The compounds of the invention correspond to the general formula (I) R1

S N R3 (I

  Wherein R 1 and R 2 each independently represent a hydrogen or halogen atom, a linear or branched C 1-6 alkyl group, a C 3-6 alkenyl, C 1-4 alkoxymethyl group, benzyl, phenyl, optionally substituted by one or more halogen atoms or alkyl groups, a COOR group, in which R represents a linear or branched C1-4 alkyl group, or a group CONR'R "in which R 'and R" each represent, independently of one another, a hydrogen atom or a linear or branched C1-4 alkyl group and R3 represents a

  2-imidazolinyl or 4-imidazolyl group.

  The compounds of the invention form with the pharmaceutically acceptable acids salts which form part of the invention. The compounds of formula (I) are prepared by reacting a compound of formula (II)

R1

S + NN-H (II)

RZ

  with 2-chloromethylimidazoline or 4-chloromethyl-

  1-triphenylmethylimidazole in a solvent such as dimethylformamide, in the presence of N, N-diisopropylethylamine,

in a bath subjected to ultrasound.

  According to the invention, the compounds of formula (II) are prepared according to the reaction schemes represented in the annexes

I, II and III.

  According to the process shown in Annex I, a compound of the general formula (III) or (IV), in which R 4 represents a tosyl or (1,1-dimethyl) ethoxycarbonyl group, is reacted with bis hydride ( 2methoxyethoxy) aluminum and sodium in a solvent such as toluene at reflux temperature or with hydrochloric, hydrobromic or

  trifluoroacetic acid at a temperature of about 90 C.

  The compounds (III) are obtained by reaction of a derivative of

  general formula (VI) with a strong base such as n

  butyllithium in a solvent such as tetrahydrofuran and at a temperature in the region of -70 ° C., followed by reaction with a R7X halide in which R7 represents a methyl, ethyl, n-propyl, n-butyl, allyl, benzyl or methoxymethyl radical and X represents a chlorine atom, bromine

or iodine.

  The compounds (IV) are obtained by the action of acetic acid, in a solvent such as chloroform in the presence of calcium chloride, on a compound of formula (V), itself obtained by the action of a strong base, such as n-butyllithium, on a compound of formula (VI), in which R4 is the (1,1-dimethyl) ethoxycarbonyl group, followed by a

reaction with acetone.

  The compounds of general formula (VI) in which R 4 represents the (1,1-dimethyl) ethoxycarbonyl group or the tosyl group, are obtained by the action of ammonium formate in the presence of palladium-on-carbon in a solvent such as methanol at a temperature of temperature close to 65 C, on a compound of general formula (VII) in which R5 represents

a bromine or chlorine atom.

  The compounds of formula (VIII) are described in the application

FR 92 14065.

  The compounds of formula (II) can also be obtained, according to the process represented in annex II, by the action of trifluoroacetic acid on the compound of formula (IX) at a temperature in the region of 20 ° C., or gaseous hydrochloric acid. on the compound of formula (XI), in a solvent such

  that ethyl acetate at a temperature of 20 C.

  The compound of formula (IX) is obtained by the action of diethyl sulphate on the compound of formula (X), itself obtained by reaction of the compound of formula (VII) with a strong base such as lithium N, N-diisopropylamide in a solvent such as tetrahydrofuran followed by a reaction with

carbon dioxide.

  The compound of formula (XI) is obtained by reaction of methylamine with the mixed anhydride formed by reaction of ethyl chloroformate with the compound of formula (XIII),

  protected on nitrogen by a group (1,1-dimethyl) -

  ethoxycarbonyl in a solvent such as tetrahydrofuran

  at a temperature between 0 and 20 C.

  The compound of formula (XIII) is obtained by reaction of a strong base, such as n-butyllithium, on a compound of formula (VI), in which R4 is the tosyl group, in a solvent such as tetrahydrofuran, at a temperature of temperature close to -70 C, followed by a reaction with carbon dioxide and a deprotection reaction with the acid

  hydrobromic acid in acetic acid.

  The compounds of general formula (XII) are obtained by the action of gaseous hydrochloric acid on the compound (XIII) in ethanol or isopropanol, at a temperature

close to 70 C.

  The compounds of general formula (II) can also be obtained according to the process represented in Annex III, by the action of trifluoroacetic acid on compounds (XVI), (XVII) and

(XVIII).

  The compound (XVI) is obtained by debromination with ammonium formate, in the presence of palladium-on-carbon in a solvent such as methanol at a temperature of about 65 ° C., of the compound (XVII), itself obtained by phenylation of the compound (XIX) with phenylboronic acid, in the presence of a palladium (0) catalyst and a base such as sodium carbonate in a solvent such as a mixture

  toluene-water, at a temperature of about 90 C.

  The compound (XVIII) is obtained by selective monodebromination of the compound (XIX) using a strong base such as t-butyllithium in a solvent such as tetrahydrofuran at a temperature in the region of -70.degree. C., followed by 'a reaction

with water.

  The compound (XIX) is prepared by a known method from the compound (VIII), itself described in the patent application

FR 92 14065.

  The compounds of general formula (I) in which R 3 represents the 4-imidazolyl group, are obtained by hydrolysis of compound (XIV) with hydrochloric acid,

a temperature close to 100 C.

  The compound (XIV) is obtained by debromination of the compound (XV) by the action of ammonium formate in the presence of palladium on carbon, in a solvent such as methanol at a temperature of

temperature around 65 C.

  The following examples illustrate the invention.

  Examples 1 to 7 relate to the preparation of the compounds of formula (II) according to the processes represented in Annexes I to III.5 The analyzes confirm the structure of the compounds.

  Example 1: 1-Methyl-5,6-dihydro-4H-thienohydrobromide

[3,4-c] pyrrole.

  1.1 5-Tosyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 28.34 g (0.81 mol) of 1,3-dichloro-5-

  tosyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 800 ml of methanol is added under nitrogen atmosphere, 28 g of 10% palladium on carbon containing 50% water, then 96 g (1.52 moles) ammonium formate. The mixture is refluxed for 3 hours and then 28 g of palladium charcoal are added and the reflux is maintained for 24 hours. After diatomaceous earth filtration, the mixture is evaporated to dryness and the residue is recrystallized from methanol. We obtain 16.64 g

of a white solid.

  Yield 73%. Melting point: 125-127 C.

  1.2 1-Methyl-5-tosyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 3.5 g (12.5 mmol) of 5-tosyl-5,6-dihydro-

  4H-thieno [3,4-c] pyrrole in 40 ml of dry tetrahydrofuran is added at -70 ° C, 9.4 ml (15 mmol) of a solution of 1.6M butyllithium in hexane; after 15 minutes, 1 ml (16 mmol) of iodomethane is added and then stirred at room temperature for 30 minutes and poured into 200 ml of water. The precipitate formed is filtered and washed with hexane; after purification on silica gel using the 1/9 ethyl acetate / hexane eluent mixture, 3.16 g of a white solid are obtained.

  Yield 86%. Melting point: 158-160 ° C.

  1.3 1-Methyl-5,6-dihydro-4H-thienohydrohydrate

  [3,4-c] pyrrole. A mixture of 3.1 g (10.6 mmol) of 1-methyl-5-tosyl-5,6-dihydro-4Hthieno [3,4-h] was heated at 90 ° C. in a water bath for 3 hours. c] pyrrole and 3.1 g (32.9 mmol) of phenol in 43 ml of a 33% solution of hydrobromic acid in acetic acid, placed in a sealed tube. The reaction mixture is then filtered and poured into 150 ml of water and extracted with three times 150 ml of diethyl ether. The aqueous phase is evaporated to dryness and the residue washed with acetone. 0.64 g of a solid is obtained

pasty. Yield 27%.

  Example 2: 1- (1-methyl) ethyl-5,6-trifluoroacetate

dihydro-4H-thieno [3,4-c] pyrrole.

  2.1 1,3-Dichloro-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-

dihydro-4H-thieno [3,4-c] pyrrole.

  A suspension of 50 g (182 mmol) of 1,3-dichloro-5,6-dihydro-4H-thieno [3,4-c] pyrrole hydrobromide in 500 ml of dioxane is added dropwise at 0.degree. C, a solution of

  61.64 g (282 mmol) of di (1,1-dimethyl) dicarbonate

  ethyl in 275 ml of dioxane followed by 274 ml of 2M sodium hydroxide solution. After stirring for 1 hour at room temperature, the precipitate is filtered off, rinsed with twice 500 ml of water and dried at 70 ° C.

51 g of a white solid.

  Yield 95%. Melting point: 112-114 C.

  2.2 5 - [(1,1-Dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-

thieno [3,4-c] pyrrole.

  To a solution of 8.82 g (30 mmol) of 1,3-dichloro-5 - [(1,1

  dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 75 ml of methanol is added 17.6 g of% palladium on carbon containing 50% of water and then 41.6 g (600 mmol) ammonium formate. The mixture is refluxed for 24 hours, then cooled, filtered through a column of celite, rinsed with twice ml of dichloromethane and evaporated to dryness. The residue is taken up in 100 ml of dichloromethane, filtered and evaporated to dryness. 4.54 g of an oily product are obtained which

crystallizes slowly.

  Yield 68 %%. Melting point: 36-38 C.

  2.3 1- (2-Hydroxy-2-propyl) -5 - [(1,1-dimethyl) ethoxy] -

  carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 0.7 ml (5 mmol) of N, N-diisopropylamine in 20 ml of dry tetrahydrofuran was added at 0 ° C, 3.15 ml (5 mmol) of a solution of 1.6M butyllithium in hexane; after 30 minutes, cool to -70 ° C and add a

  solution of 0.95 g (4.2 mmol) of 5 - [(1,1-dimethyl) ethoxy] -

  carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 15 ml of tetrahydrofuran; after 1 hour at -70 ° C., 1.54 ml (21 mmol) of acetone are added and then the mixture is stirred at room temperature overnight. The reaction mixture is poured into 50 ml of water and then extracted with three times 30 ml of dichloromethane; the organic phases are dried over sodium sulphate and then evaporated to dryness. The residue is chromatographed on a column of silica gel using the ethyl acetate / cyclohexane-1/4 eluent mixture. 0.425 g of a white solid are obtained.

  Yield 36%. Melting point: 113.50C.

  2.4 1- (1-Propen-2-yl) -5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-

dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 0.81 g (2.86 mmol) of 1- (2-hydroxy-2-

  propyl) -5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4c] pyrrole in 60 ml of chloroform, 5 g of calcium chloride and 0.17 g of calcium chloride are added. ml (3 mmol) of acetic acid. The mixture is refluxed for 24 hours, filtered, washed with 5% sodium bicarbonate solution and then dried over sodium sulfate and evaporated to dryness. We obtain

0.78 g of an oily product.

  2.5 1- [1- (1-Methyl) ethyl] -5 - [(1,1-dimethyl) ethoxycarbonyl] -

  , 6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 0.78 g (2.9 mmol) of 1- (1-propen-2-yl) -5-

  [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 40 ml of methanol is added 3.7 g (59 mmol) of ammonium formate then 0.9 g of 10% palladium on carbon. The reaction mixture is heated under reflux for 8 hours, then filtered through a column of celite and evaporated to dryness. The residue is taken up in 50 ml of ethyl acetate, washed with 20 ml of water, dried over sodium sulphate and evaporated to dryness. After purification on a silica column using the eluent mixture ethyl acetate / hexane 1/4,

  obtains 0.49 g of an oily product.

Yield 63%.

  2.6 1- (1-methyl) ethyl-5,6-dihydro-4H-trifluoroacetate

thieno [3,4-c] pyrrole.

  A solution of 0.49 g (1.8 mmol) of 1- [1- (1-

  methyl) ethyl] -5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-

  4H-thieno [3,4-c] pyrrole in 0.5 ml of trifluoroacetic acid for 30 minutes at a temperature in the region of 20 ° C. After evaporation of the solvent, 0.51 g of a product is obtained.

oily. Quantitative yield.

  Example 3: 1-Chloro-3-carbethoxy-5,6-trifluoroacetate

dihydro-4H-thieno [3,4-c] pyrrole.

  3.1 1-Chloro-3-carboxy-5 - [(1,1-dimethyl) ethoxy] carbonyl

  , 6-dihydro-4H-thieno [3,4-c] pyrrole. In a 250 ml flask, it is introduced under an atmosphere

  of nitrogen, 2 g (6.8 mmol) of 1,3-dichloro-5 - [(1,1-dimethyl) -

  ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole and 48 ml of dry tetrahydrofuran; cooled to -75 ° C. and 7.24 ml (10.9 mmol) of a 1.5 M solution of (1,1-dimethyl-ethyl) lithium in pentane are added over 30 minutes. A stream of carbon dioxide is then passed for minutes, the mixture is poured at room temperature into 1 ml of saturated ammonium chloride solution and extracted with 200 ml of ethyl acetate; the organic phase is dried over magnesium sulphate, filtered and evaporated at

  dry. The product is recrystallized from ethyl acetate.

  0.63 g of a white solid is obtained.

  Yield 31%. Melting point: 218 C (with decomposition).

  3.2 1-Chloro-3-carbethoxy-5 - [(1,1-dimethyl) ethoxy] carbonyl

  , 6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a suspension of 0.63 g (2.07 mmol) of 1-chloro-3-

  Carboxy-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4c] pyrrole in 20 ml of acetone is added 0.56 g (6.6 mmol). ) of potassium carbonate and then 1.6 ml (12.4 mmol) of diethyl sulfate. After one night at room temperature, it is filtered through a column of celite, rinsed with dichloromethane and evaporated to dryness. The residue is chromatographed on silica gel using 1/30 ethyl acetate / hexane eluent. 0.42 g of a

white solid. Yield 60%.

  3.3 1-Chloro-3-carbethoxy-5,6-dihydro-trifluoroacetate

4H-thieno [3,4-c] pyrrole.

  A solution of 417 mg (1.26 mmol) of 1-chloro-3-

  carbethoxy-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-

  thieno [3,4-c] pyrrole in 5 ml of trifluoroacetic acid for 5 minutes at room temperature. After evaporation of the solvent, the residue is triturated with diethyl ether

  then dried. 417 mg of a cream solid are obtained.

  Yield 96%. Melting point: 171-172C.

  Example 4: 1- (N-Methylcarbamoyl) -5,6-hydrochloride

dihydro-4H-thieno [3,4-c] pyrrole.

  4.1 1-Carboxy-5-tosyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 3.5 g (12.5 mmol) of 5-tosyl-5,6-dihydro-

  4H-thieno [3,4-c] pyrrole in 40 ml of dry tetrahydrofuran is added under argon and at -70 ° C, 9.4 ml (15 mmol) of a solution of 1.5 M butyllithium in hexane. After 10 minutes, the mixture is poured into 200 g of solid carbon dioxide and then evaporated to dryness. 50 ml of water are added and the suspension obtained is filtered and then poured into 1M hydrochloric acid. A precipitate is obtained which is

  filtered and dried to provide 2.85 g of a cream solid.

  Yield 70%. Melting point: 234-236 C (with decomposition).

  4.2 1-carboxy-5,6-dihydro-4H-thienohydrobromide

  [3,4-c] pyrrole. The mixture is heated at 60 ° C. in a water bath for 15 minutes.

  mixture of 0.5 g (1.54 mmol) of 1-carboxy-5-tosyl-5,6-

  dihydro-4H-thieno [3,4-c] pyrrole and 5 ml of a 33% solution of hydrobromic acid in acetic acid, placed in a sealed tube. The reaction mixture is then cooled, the precipitate formed is filtered off, washed twice with diethyl ether and dried. We obtain 0.32 g of

produced in the form of hydrobromide.

  Yield 83%. Melting point: 281.3-281.7 C.

  4.3 1-Carboxy-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-

4H-thieno [3,4-c] pyrrole.

  To a suspension of 1.25 g (5 mmol) of 1-bromohydrate

  carboxy-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 20 ml of dioxane, 3.5 ml of 5M sodium hydroxide and then a solution of 1.4 g are added at 0 ° C. (6.4 mmol) di (1,1-dimethyl) ethyl dicarbonate in 5 ml of dioxane. After 2 hours at room temperature, 20 ml of water are added and acidified to pH 4 with 2M hydrochloric acid. The precipitate formed is filtered, washed with water and then dried. 1.3 g is obtained

of a white solid.

  Yield 93%. Melting point: 227 C (with decomposition).

he

  4.4 1- (N-methylcarbamoyl) -5 - [(1,1-dimethyl) ethoxy] carbonyl

  , 6-dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 0.98 g (3.6 mmol) of 1-carboxy-5 - [(1,1

  dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 15 ml of tetrahydrofuran is added at 0 C, 1.1 ml (8 mmol) of triethylamine and 0.4 ml (4.1 mmol) ethyl chloroformate. After 1.5 hours, the precipitate formed is filtered off. The filtrate is cooled to 0 ° C. and 7.5 ml of a saturated solution of methylamine in chloroform are added. After one night at room temperature, the solvent is evaporated and the residue is triturated with 15 ml of 5% sodium bicarbonate solution. The precipitate formed is washed with water and then dried to provide 0.36 g of a solid

White.

  Yield 35%. Melting point: 160.8-162.8 C.

  4.5 1- (N-Methylcarbamoyl) -5,6-dihydro-4H-hydrochloride

  thieno [3,4-c] pyrrole. A solution of 0.3 g (1.06 mmol) of

  1- (N-methylcarbamoyl) -5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6

  dihydro-4H-thieno [3,4-c] pyrrole in 4 ml of a solution of 3M hydrochloric acid in ethyl acetate. The precipitate formed is filtered and dried. 0.15 g of a

white solid. Yield 65%.

  Example 5: 1-Carbethoxy-5,6-dihydro-4H-hydrochloride

thieno [3,4-c] pyrrole.

  A stream of hydrochloric acid is passed through a suspension of 3.3 g (13.2 mmol) of 1-carboxy-5,6-dihydro- [3,4-c] pyrrole hydrobromide in 75 ml of ethanol. at reflux for 4 hours. The solvent is evaporated and the residue triturated with twice 20 ml of diethyl ether. We obtain

2.46 g of a beige solid.

  Yield 80%. Melting point: 163 C (with decomposition).

  Example 6: 1-Bromo-3-phenyl-5,6-trifluoroacetate

dihydro-4H-thieno [3,4-c] pyrrole.

  6.1 1,3-Dibromo-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-

  dihydro-4H-thieno [3,4-c] pyrrole. On a suspension of 1 g (2.74 mmol) of 1,3-dibromo-5,6-dihydro-4H-thieno [3,4-c] pyrrole hydrobromide in 6.5 ml of dioxane, dropwise by drop and at 0 C, a solution

  0.9 g (4.12 mmol) of di (1,1-dimethyl) dicarbonate

  ethyl in 3.5 ml of dioxane followed by 4 ml of 2M sodium hydroxide solution. After stirring for 1 hour at room temperature, the precipitate is filtered off, rinsed with twice 5 ml of water and dried at 70 ° C.

0.95 g of a white solid.

  Yield 91%. Melting point: 144-145C.

  6.2 1-Bromo-3-phenyl-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-

dihydro-4H-thieno [3,4-c] pyrrole.

  To a solution of 3.2 g (8.3 mmol) of 1,3-dibromo-5 - [(1,1

  dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole in 45 ml of toluene is added 0.91 g (7.5 mmol) of phenylboronic acid, 0.209 g (0.20%). 38 mmol) of dibenzylideneacetone palladium (0), 0.397 g (1.5 mmol) of triphenylphosphine and

  7.5 ml (15 mmol) of a 2M sodium carbonate solution.

  The mixture is refluxed for 5.5 hours and then cooled. The organic phase is decanted, washed with water, dried over magnesium sulphate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the eluent mixture ethyl acetate / hexane 5/95. We

0.98 g of a white solid is obtained.

  Yield 34%. Melting point: 139-1400C.

  6.3 1-bromo-3-phenyl-5,6-dihydro-4H-trifluoroacetate

thieno [3,4-c] pyrrole.

  To 0.98 g (1.32 mmol) of 1-bromo-3-phenyl-5 - [(1,1-dimethyl) -

  ethoxy] carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole, 1.5 ml of trifluoroacetic acid is added. After 10 minutes at room temperature, the solvent is evaporated to dryness. 5 ml of toluene are added and evaporated to dryness. The residue is triturated with 5 ml of diethyl ether, filtered and dried. 0.95 g of a yellowish solid is obtained.

Yield 91%.

  Example 7: 1-Phenyl-5,6-dihydro-4H-trifluoroacetate

thieno [3,4-c] pyrrole.

  7.1 1-Phenyl-5 - [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-

4H-thieno [3,4-c] pyrrole.

  To a solution of 0.5 g (1.32 mmol) of 1-bromo-3-phenyl-5-

  [(1,1-dimethyl) ethoxy] carbonyl-5,6-dihydro-4H-thieno

  [3,4-c] pyrrole in 5 ml of dry tetrahydrofuran is added

  at -70 ° C, 1.3 ml (1.95 mmol) of a solution of [1- (1,1

  1.5 M dimethyl) ethyl] lithium in pentane. After 10 minutes at -70 ° C., 5 ml of a saturated solution of ammonium chloride are added and then, at room temperature, ml of water and 50 ml of ethyl acetate are added. The organic phase is decanted, dried over magnesium sulphate and evaporated to dryness. 0.4 g of an oily product is obtained

with a quantitative yield.

  7.2 1-Phenyl-5,6-dihydro-4H-thienoic trifluoroacetate

[3,4-c] pyrrole.

  0.47 g (1.56 mmol) of 1-phenyl-5 - [(1,1-dimethyl) ethoxy] -

  carbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole, 1.5 ml of trifluoroacetic acid is added. After 10 minutes at room temperature, the solvent is evaporated and the residue is triturated with 5 ml of diethyl ether. We obtain 410 mg of a

solid cream. Yield 87%.

  Example 8: 1,3-Dibromo-5 - [(1H-imidazol-4-) dihydrochloride

  yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  8.1 1,3-Dibromo-5 - [(1-triphenylmethyl-1H-imidazol-4-)

  yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole. In a 50 ml flask, 1.5 g (4.1 mmol) of

  1,3-dibromo-5,6-dihydro-4H-thieno [3,4-c] hydrobromide

  pyrrole, 2.12 g (5.9 mmol) of 1-triphenylmethyl-4-

  chloromethylimidazole, 30 ml dimethylformamide and 1.54 ml (9 mmol) diisopropylethylamine. The reaction mixture was sonicated for 2 hours and then poured onto ice. The precipitate obtained is filtered, washed with water, taken up with 50 ml of ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified by chromatography on silica gel using the 1/1 ethyl acetate / hexane eluent mixture. 0.8 g is obtained

of a white solid. Yield 32%.

  8.2 1,3-dibromo-5 - [(1H-imidazol-4-) dihydrochloride

  yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole. A suspension of 0.7 g is refluxed for 1 hour.

  (1.15 mmol) 1,3-dibromo-5 - [(1-triphenylmethyl) -1H-

  imidazol-4-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole in 14 ml of 2M hydrochloric acid. The precipitate formed is filtered and washed with water. The combined aqueous phases are washed with ethyl acetate and then evaporated to dryness to give 0.45 g of a brown solid which is crystallized.

  in isopropanol. 0.082 g of a cream solid is obtained.

  Yield 17%. Melting point: 221 C (with decomposition).

  Example 9: 5 - [(1H-Imidazol-4-yl) methyl] dihydrochloride

  5,6-dihydro-4H-thieno [3,4-c] pyrrole.

  9.1 5 - [(1-Triphenylmethyl-1H-imidazol-4-yl) methyl] -5,6-

  dihydro-4H-thieno [3,4-c] pyrrole. In a 100 ml flask was charged with 0.88 g (1.45 mmol) of

  1,3-dibromo-5 - [(l-triphenylmethyl-lH-imidazol-4-yl) methyl] -

  6-dihydro-4H-thieno [3,4-c] pyrrole and 70 ml of methanol. To the suspension obtained was added 1.83 g (29 mmol) of ammonium formate and 0.6 g of 10% palladium on charcoal. The mixture is heated under reflux for 8 hours and then cooled and filtered on celite. The residue is washed with twice 10 ml of dichloromethane and the filtrates are evaporated to dryness. 0.34 g of a solid is obtained which is purified by chromatography on silica gel using the dichloromethane / methanol 29/1 eluent mixture. 0.14 g of compound is obtained

with a yield of 23%.

  9.2 5 - [(1H-Imidazol-4-yl) methyl] -5,6-dihydrochloride

dihydro-4H-thieno [3,4-c] pyrrole.

  0.14 g (0.3 mmol) of 5 - [(1-triphenylmethyl) -1H-

  imidazol-4-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole in 1 ml of ethanol and then 1.5 ml of 2M hydrochloric acid are added and the mixture is heated at reflux for 1 hour. The precipitate formed is filtered and the filtrate is washed with twice 1 ml of ethyl acetate and then evaporated to dryness. The residue is dissolved in 2 ml of methanol and decolorized with activated charcoal and then recrystallized from isopropanol. 0.075 g of off-white solid is obtained with a yield of 86%. Point

melting point: 260 C.

  The compounds of the invention are collected in the tables

  I and II with their physical characteristics.

R1 N

R2 H

R2 (I)

TABLE I

  ## STR2 ## ## STR13 ## wherein: ## STR2 ##

CH (CH 3) 2 H 213

  6 CH 2 CH = CH 2 H> 270 (d) 7 O-% H 196-199 (d) 8 Br H 211-213 (d) 9 Br 245-247 H 209 (d) 11 CH 2 OCH 3 H> 270 (d) 12 CO 2 C 2 H 5 H 171-174 (d) 13 C02 1 C 3 H 17 H 179-181 (d) 14 CO 2 C 2 H 5 Cl 213-215 CONHCH 3 H 220 (d) R 1 N 2 NH 2 H 2 R 2 (I)

TABLE II

  The compounds of the invention exhibit an activity.

  pharmacological a2-antagonist and have been tested in different bioassays.

  1. Antaqonism of the effects of clonidine on vas deferens

of rat.

  This determination was made on the vas deferens of the rat stimulated at a frequency of 0.1 Hz in the presence of 30 nanomoles of prazosin and one micromole of cocaine according to the method described by G.M. Drew in European Journal of Pharmacology,

42, 123-130, (1977).

  The pA2 of the compounds of the invention are between 6.5 and 9.4. 2. Antagonism of 3H-clonidine binding on

2-adrenoceptors.

  The test is performed on a preparation of rat brain membranes, according to the method described by D.A. Greenberg

  et al. in Life Sci. 19, 69, (1976).

  After incubating for 30 minutes in the presence of tritiated clonidine (0.05 to 7 nmol / l), the radioactivity of the residue is filtered and counted according to the method of P.B.M.W.M. Timmermans et al., Described in European Journal

of Pharmacology, 70, 7, (1981).

* Inhibitory concentrations 50 of the compounds of

  the invention is between 0.02 and 3.02 gmol / l.

  The results of the biological tests show that the compounds of the invention have, in vitro, antagonistic properties with respect to the adrenergic receptors of type a2. The compounds of the invention can be used, in view of their pharmacological properties, for the treatment of diabetes, obesity, hypotension, paralytic ileum

postoperative and / or asthma.

  The compounds of the invention also exhibit anagonist activity, evidenced by biological assays on

  the isolated pulmonary artery of rabbit.

  These tests were carried out under the following conditions: rabbits (Fauve de Bourgogne), weighing 2 to 3 kg, were stunned and bled, then their pulmonary arteries were removed, dissected and cut into strips from approximately 1.2 to 2 mm wide and 20 mm long. These strips of vascular tissue were immersed in a

  physiological solution (composition, expressed in mmol / l: 10 sodium chloride 137, potassium chloride 2.7;

  calcium chloride 1.8; sodium dihydrogen phosphate 0.4; sodium hydrogencarbonate 11.9; hexahydrate of magnesium chloride 1,1; dextrose 5.9; disodium salt of ethylenediaminetetraacetic acid 0.027 and ascorbic acid 0.057), oxygenated with a mixture of 95% oxygen and 5%

  carbon dioxide and maintained at a temperature of 37 C.

  They were then subjected, during 4 h, to a traction

  of 4 g, reduced to 2 g just before the start of the experiment.

  The tissue was then contracted with the test compound and the resulting voltage was recorded using a Grass model 7D polygraph and a force transducer. Two concentration-effect curves were plotted, with cumulative concentrations of compound (from 100 nmol / l to 3 mmol / l) and then a 1-antagonist, alfuzosin, was added to the bath at 1 g / ml, left in contact with the tissue for 30 minutes. Another concentration-effect curve then

  was plotted and compared with the second control curve.

  The A1-agonist effect is measured by concentration

  causing a contraction equal to 50% of the maximum effect.

  For the compounds of the invention, this concentration varies

between 1.3 and 2.6 gmol./l.

  These results show that the compounds of the invention have, in vitro, agonist properties with respect to α1-type adrenergic receptors. The compounds of the invention can therefore be used in the treatment of

urinary incontinence.

  The compounds of the invention may be presented in any suitable form, in combination with any suitable excipient, for oral or parenteral administration; for example in the form of tablets, dragees, capsules, solutions, etc .; The daily dosage can range from 0.1 to 20 mg / kg per

oral route.

  Annex I R5 S> N-H R5 = CI, Br SN - H R5

(VIII)

  (vm) R5 Rs S1N-R4 R4 = H3C-- - SO2. t-BuCO2 R5 (VII)

NH4 HCO2

Pd / C

SJIIZN-R4

  (VI) ## STR5 ## n -C4H9., 1) Ru / 2) o = 1 2) R7XCH2 = CHCH2. PhCH2, CH3OCH2 X = Cl, Br, I S N-R4 S N-R4 Br, HO R4 = CO2t-Bu R7 () (CH3OCH2CH2O) 2INaH2 1) CH3CO2H. CaCl2 HrO2 2) NH4HCO2, Pd / C R1

/ \ CF3CO2H S /

S -N-R4 S N-H

R2 '(IV) | R3CH2CI R3 = q

IF N R3

R2 (1) Annex II CI

S> <N-R4

  ci (Vil) 1) RsLi NH4HC02 2) C02 PdNH CI

> <C S () N-R4

  H02C R4 = CO2t-Bu (V) R4 = Tosyl (x) (VI) I 1) R6Li Et2SO4 2) CO2 3) HBr CI S N-R4 t>

CS N-H

  EtO 2 C (IX) HO 2 C XII) 1) (t-BuOCO) OH = C 2 H 5 i-C 3 H 7 2) CICO 2 Et, Et 3 N HCl 3) MeNH 2 CF 3 CO 2 H N -R 4 H 3 CHNOC (X 1) R 80 2 C (XII) | HCl R 1

S> N-H

R2 (I1)

R3CH2CI N

H R,

R2 (1

(I) Annex 111 Br Sg> N-H Br

(VIII)

  BBr 8 ,, CPh 3 BrBr -, CPh 3 S 9 SNCO 2t-BuS N Br Br (xIX) (XV) 1) t-BuL 1 PhB (OH) 2 NH 4 CO 2 S "N-COO 2t-Bu-CO 2

NH4HC02.

Br PhB S XN-CO2t-Bu 'SN R R3 =

(XVIII) (XVII) (XIV)

  Pd / C Rs s CO2t --BU> R3R3 N Ph (XVI) l

CF3CO2H

S XN-H NH R N R3 R3 =

R2 R2 H

(he) (1)

Claims (5)

claims   1. Pyrrole derivatives of the general formula (I) R1   in which R1 and R2 are each, independently of one another, a hydrogen or halogen atom, a linear or branched C1-6 alkyl group, a C3-6 group; alkenyl, C1-4 alkoxymethyl, benzyl, phenyl, optionally substituted with one or more halogen atoms or alkyl groups, a COOR group, wherein R represents a linear or branched C1-4 alkyl group, or a CONR'R group wherein R 'and R "each independently represent a hydrogen atom or a linear or branched C1-4 alkyl group and R3 represents a 2-imidazolinyl or 4-imidazolyl group, and that their salts   addition to pharmaceutically acceptable acids.   2. Process for preparing the compounds of formula (I) according to   claim 1, wherein R3 represents a group 2-   imidazolinyl, characterized in that a compound of formula (II) R1 is reacted S N-H (II)   Wherein R 1 and R 2 are as defined in claim 1, with 2-chloromethylimidazoline, in a   solvent such as dimethylformamide, in the presence of N, N-   diisopropylethylamine in a bath subjected to ultrasound.   3. Process for the preparation of the compounds of formula (I) according to claim 1, wherein R3 represents a group 4   imidazolyl, characterized in that a compound of formula (II) in which R1 and R2 are defined as in claim 1 is reacted with 1- (triphenylmethyl)   4 (or 5) -chloromethylimidazole, in a solvent such as dimethylformamide, in the presence of N, N-diisopropylethylamine, in a bath subjected to ultrasound, and that the compound obtained is hydrolysed with hydrochloric acid, a temperature of about 100 C.   4. Drug characterized in that it consists of a compound   of formula (I) according to claim 1.   5. Pharmaceutical composition characterized in that it contains a compound of formula (I) according to claim 1   in combination with any suitable excipient.