SK59795A3 - 5,6-dihydro-4h-thieno £3,4-c| pyrole derivatives, method of their preparation and pharmaceutical agents contained these derivatives - Google Patents

Abstract

5,6-dihydro-4H-thienoÄ3,4-cÜpyrrole derivs. of formula (I) and their acid addn. salts are new. R1 = cyano, 1-4C alkoxy, alkylthio or alkylsulphonyl, pyridyl, 3,4-dimethoxyphenyl or cyclopropyl (opt. substd. by one or two alkyl) or COR or benzyl (substd. by one or more halo and/or 1-4C alkyl or alkoxy or CO2R') or naphthylmethyl; R = 1-4C alkyl, phenyl or piperidinyl; R' = 1-4C alkyl.

Description

5,6-Dihydro-4Η-thieno [3,4-c] pyrrole derivatives, process for their preparation and pharmaceutical compositions containing them

Technical field

The invention relates to 5,6-dihydro-4H-thieno [3,4-c] pyrrole derivatives, to a process for their preparation and to their therapeutic use.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula I in which

R ¹ is either cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, pyridyl, 3,4-dimethoxyphenyl or cyclopropyl, optionally substituted with one or two alkyl groups, or a COR group in which R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a piperidinyl group, or a benzyl group substituted with one or more halogen atoms and / or linear or branched alkyl groups having 1 to 4 carbon atoms Or (C1-C4) linear or branched alkoxy groups having 1 to 4 carbon atoms or CO4R *, wherein R 'represents a linear or branched alkyl group containing 1 to 4 carbon atoms or naphthylmethyl.

The compounds of the invention form salts with the pharmaceutically acceptable acids, which also form part of the invention.

Compounds of formula (I) are prepared by a process as illustrated in the following Reaction Scheme 1.

Reaction scheme 1

PaCCQgH

(I)

According to this reaction scheme, the compound of formula (III)

(III) wherein R ¹ is as previously defined for formula I, is reacted at a temperature close to 0 ° C with trifluoroacetic acid and then the compound of formula II obtained

NH (II) is reacted with 2-chloromethyl-4,5-dihydro-1H-imidazole in a solvent such as dimethylformamide in the presence of N, N-diisopropylethylamine.

Compounds of formula III are in turn prepared from 1,1-dimethylethyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate of formula IV

(IV) by methods which depend on the nature of the general substituent R ¹ . These methods are illustrated by the following Reaction Schemes 2 and 3.

Reaction scheme

CO is ₂ t-au (PO

L) R ³ Li

2) (R ^a O) ₃ • "= alkyl, aryl) HjjO-d

S ^^ N — CO ₂ t-Su (ho) ₂ b ^/ _w

O «2 ^Ο 2

2) (R 50) ^{R 5} alkyl

ArX. Pd (O)

Ar = 2-pyridyl 3,4-dimethoxyphenyl

Reaction scheme 3 co ₂ t-au (no

1) R ³ Li 3) HOCNU «2 2) (R ^e) ₂ with ^R ₃ = alkyl, aryl

2) ^R > 0 R ^a

R ⁷ = H, alkyl, aryl

l) hb ₄ oh oxide. oxide. 2) CDI R ^e - H

alkyl

0¾

R ⁹ = H, alkyl

M— COjt-Bu

The methods illustrated in Reaction Scheme 2 relate to the preparation of compounds of formula III in which R ¹ represents an alkoxy group having 1 to 4 carbon atoms (compounds VI), a pyridyl group or a 3,4-dimethoxyphenyl group (compounds VII).

In these methods, compound IV is reacted with a strong base, such as a compound of formula R ³ Li, wherein R ³ is an alkyl group, especially an n-butyl group, in a solvent such as tetrahydrofuran at a temperature close to -70 C, and then with a trialkyl or triarylborátom, e.g., trimethyl borate, at room temperature and finally with hydrochloric acid at a temperature of about ^-40 ° C to provide

1,1-dimethylethyl-1-borono-5,5-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate of formula V, which is either reacted with hydrogen peroxide at a temperature of about 45 ° C; and then with a dialkyl sulfate of the formula (R ^a O) ₂ SO _2, wherein ^R is a linear or branched alkyl group having 1 to 4 carbon atoms, at room temperature to give a compound of formula VI, wherein R ^p is as defined above, or reacted with a halide of formula ArX in which Ar is a pyridyl or 3,4-dimethoxyphenyl group and X is a halogen atom in the presence of palladium (O) and a base such as butyltrimethylammonium hydroxide in a solvent such as methanol , at reflux temperature to give a compound of formula VII wherein Ar is as defined above.

The methods illustrated in Reaction Scheme 3 relate to the preparation of compounds of formula III wherein R ¹ is cyano (compounds IX), C 1-4 alkylthio (compounds X), C 1-4 alkylsulfonyl (compounds) XI), an RCO group in which R represents an alkyl group having 1 to 4 carbon atoms, or a phenyl group (compounds XIII) or a substituted or unsubstituted cyclopropyl group (compounds XV)

In these methods, a compound of formula IV is reacted with a strong base (such as a compound of formula R ³ Li in which R ₃ is an alkyl group, especially an n-butyl group) in a solvent such as tetrahydrofuran at a temperature of about - 70 ° C, and then the obtained compound is reacted either with dimethylformamide at ambient temperature to form a compound of formula VIII, which is reacted with hydroxylamine and then with carbonyldiimidazole at ambient temperature to form a compound of formula IX, or with a compound of formula R ⁶ S ₂ in which R ^e represents a C 1 -C 4 alkyl group at ambient temperature to form a compound of formula X, which can then be oxidized, for example, using potassium peroxymonosulfate, at ambient temperature to form a compound of formula XI, or with a compound of general formula of formula R ⁷ (R ^a ) C = O, wherein R ⁷ represents a hydrogen atom, an alkyl group or an aryl group and R ^a is H or alkyl, in a solvent such as tetrahydrofuran at room temperature to give a compound of formula XII, wherein R ⁷ and R ^a are defined as above, which, if R® is hydrogen atom, reacted with pyridinium dichromate in the presence of acetic acid at ambient temperature to form a compound of formula XIII, or, when R ^a is an alkyl group, reacted with acetic acid in the presence of calcium chloride to form a compound of formula XIV wherein R ⁷ is as defined above and R ⁹ is a hydrogen atom or an alkyl group, which is then reacted with diiodomethane to give a compound of formula XV, wherein R ⁷ and R ⁹ are as previously defined.

Compounds of formula III in which R ¹ is a substituted benzyl group are prepared in a manner analogous to that described in European patent application 93 402785.5 for the preparation of compounds of formula III comprising an unsubstituted benzyl group. The method consists in reacting a compound of formula IV with a compound of formula R ³ Li, in which R ³ is as previously defined, in a solvent such as tetrahydrofuran at a temperature close to -70 ° C and then suitably. substituted benzyl halide.

Compounds of formula III in which R ^{@ 1} is naphthylmethyl are prepared in an analogous manner, replacing the benzyl halide with naphthyl methyl halide.

The compounds of formula III, wherein ^R1 is piperidinylcarbonyl, are prepared in a manner analogous to that described in French patent application FR 93 07 538 for the preparation of compounds of formula III, comprising carbamoyl. This process consists in reacting a compound of formula III, wherein R ¹ is carboxyl, is reacted with piperidine in the presence of a coupling agent.

The preparation of compounds of formula IV is described in European patent application 93 402785.5.

In the following, the invention will be described in more detail by way of examples of a specific embodiment thereof, these examples being illustrative only and not in any way limiting the scope of the invention, which is clearly defined by the definition of the claims. Examples 2-11 relate to the preparation of compounds of formula III by the methods illustrated in Reaction Schemes 2 and 3 and the corresponding compounds of formula II. The chemical structures of the prepared compounds were confirmed by appropriate analyzes.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1 1-Methoxy-5 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole dihydrochloride

1.1. 1 _r dimethylethyl-l-boronate-5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a solution of 2.29 mL (16.23 mmol) of N, N-diisopropylamine in 66 mL of anhydrous tetrahydrofuran at 0 ° C was added

10.6 ml (17.03 mmol) of a 1.6 M solution of butyllithium in hexane. The resulting mixture was stirred for 45 minutes, then cooled to -70 ° C and a solution of 3 g (13.31 mmol) of 1,1-dimethylethyl-5,6-dihydro-4H-thieno / 3 was added to the cooled mixture. Of 4-cis-pyrrole-5-carboxylate in 26 ml of anhydrous tetrahydrofuran. The reaction mixture is kept at -70 ° C for one hour, then the solution is poured into a solution of 5 ml of trimethylborate in 10 ml of tetrahydrofuran at the same temperature. The reaction mixture is then stirred overnight at ambient temperature and then cooled to -40 ° C and 80 ml of 1N hydrochloric acid in 250 ml of ethyl acetate are added to the cooled reaction mixture. The organic phase is decanted, washed twice with 60 ml of saturated sodium chloride solution and then dried over sodium sulphate and the solvent is evaporated off. After recrystallization of the residue from ethyl acetate, 2.4 g of the desired product are obtained.

Melting point: 160-162 ° C.

1.2. 1, l-dimethylethyl-l-methoxy-5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a suspension of 4 g (14.9 mmol) of 1,1-dimethylethyl-1-borono-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 600 mL is added 80 mL of 30% hydrogen peroxide. The mixture is heated at 45 ° C for 20 minutes and then the organic phase is decanted, which is washed twice with 100 ml of 5% sodium carbonate solution and then with 200 ml of saturated sodium chloride solution and then added at 0 ° C 600 ml. toluene, 49.94 g (147 mmol) of tetrabutylammonium hydrogen sulfate, 67.8 ml (710 mmol) of dimethyl sulfate and 400 ml (800 mmol) of 2N sodium hydroxide solution. The mixture is then maintained at ambient temperature for 1.5 hours and then the organic phase is decanted, which is washed twice with 400 ml of 7% sodium bicarbonate solution, dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on a silica gel column using a 1: 9 by volume mixture of ethyl acetate and hexane. 0.95 g of product is obtained.

Melting point: 62.8-64.7 ° C.

1.3 1-Methoxy-5 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole dihydrochloride

A mixture of 0.95 g (3.72 mmol) of 1,1-dimethylethyl 1-methoxy-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate and 8.5 mL of trifluoroacetic acid After stirring at 0 ° C for 10 min, the solvent was evaporated and the residue was dissolved in DMF (21 mL). Add 1.27 ml (7.5 mmol) of N, N-diisopropylethylamine and then a solution of 0.577 g (3.72 mmol) of 2-chloromethyl-4,

Of 5-dihydro-1H-imidazole hydrochloride and 0.53 ml (3.1 mmol) of N, N-diisopropylethylamine in 21 ml of dimethylformamide. The reaction mixture is left overnight at ambient temperature, then the solvent is evaporated and 35 ml of water and 35 ml of 7% sodium bicarbonate solution are added to the residue. The mixture is extracted 6 times with 60 ml of dichloromethane, the organic phases are dried over sodium sulphate and the solvent is evaporated off. The residue is chromatographed on silica gel, eluting with a 1: 9 mixture of methanol and dichloromethane. 0.49 g of an oily product is obtained, which is converted to the hydrochloride salt by adding a saturated solution of hydrochloric acid in isopropanol. 0.31 g of product is obtained.

Melting point: 243-245 ° C (dec.).

Example 2 1- (3,4-Dimethoxyphenyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

2.1. 1, l-Dimethylethyl l- (3,4-dimethoxyphenyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

3 g (11.14 mmol) are introduced into a 250 ml flask.

1,1-dimethylethyl-1-borono-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate, 1.53 ml (12.03 mmol) of 1-bromo-3,4-dimethoxybenzene,

0.9 g (0.78 mmol) of tetrakistriphenylphosphine palladium (0), 10 ml (22.8 mmol) of a 40% solution of butyltrimethylammonium hydroxide in methanol and 60 ml of methanol. The reaction mixture was heated at reflux for 6 hours, then the solvent was evaporated. The residue is then taken up in 150 ml of dichloromethane, washed twice with 100 ml of saturated sodium bicarbonate solution, dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on silica gel, eluting with a 1: 5 by volume mixture of ethyl acetate and hexane. 1.32 g of product are obtained.

Melting point: 130-132 ° C.

2.2 1- (3,4-Dimethoxyphenyl) -5,6-dihydro-4H-thieno / 3,4-c / pyroltrifluóracetát

A solution of 1.32 g (3.65 mmol) of 1,1-dimethylethyl 1- (3,4-dimethoxyphenyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 12 mL of trifluoroacetic acid was stirred at 0 ° C for 10 minutes. Evaporation of the solvent gave 1.37 g of an oily product.

Example 3 1-Pyrid-2-yl-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

This compound is obtained in a manner analogous to that described in Example 2, starting from 2-bromopyridine.

Example 4 1-Cyano-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

4.1. 1,1-Dimethylethyl-1-formyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate

To a solution of 3.2 mL (22.7 mmol) of diisopropylamine in 84 mL of anhydrous tetrahydrofuran at 0 ° C was added 15.55 mL (24.88 mmol) of a 1.6 M solution of butyllithium in hexane. After 30 minutes, the mixture is cooled to -70 ° C and a solution of 5 g (22.2 mmol) of 1,1-dimethylethyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5 is added to the cooled mixture. -carboxylate in 34 ml of tetrahydrofuran cooled to -70 ° C. The mixture was then stirred at 0 ° C for 30 minutes and then 10 mL of dimethylformamide was added at -70 ° C. The mixture is stirred at ambient temperature for 30 minutes and then 34 ml of saturated ammonium chloride solution are added. The organic phase is decanted and the aqueous phase is extracted twice with 50 ml of ethyl acetate, then the organic phases are combined and washed with saturated sodium chloride solution and the solvent is evaporated off. The residue is chromatographed on a silica gel column using a 1:10 mixture of ethyl acetate and hexane. 4.6 g of product are obtained. Melting point: 84.3-86.6 ° C.

2.4 1, l-dimethylethyl-l / (hydroxyimino) methyl / -5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

A 500 ml flask was charged with 3.59 g (14.17 mmol)

1,1-dimethylethyl-1-formyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate, 11.56 g (85 mmol) of sodium acetate trihydrate, 4.91 g (70%) (85 mmol) of hydroxylamine hydrochloride and 180 ml of methanol. The mixture was stirred at ambient temperature for 3 hours, then the solvent was evaporated and 200 ml of saturated sodium chloride solution and 200 ml of dichloromethane were added to the residue. The organic phase is decanted and the aqueous phase is extracted twice with 150 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and the solvent is evaporated off. 1.76 g of product are obtained. Melting point: 193.8-194.9 ° C

3.4 1,1-Dimethylethyl 1-cyano-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate

To a suspension of 1.73 g (6.44 mmol) of 1,1-dimethylethyl-1 ((hydroxyimino) methyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 41 ml of chloroform at 0 ° C was added 3.12 g (19.34 mmol) of carbonyldiimidazole. The mixture was stirred at ambient temperature for hours, then poured into a mixture of 200 ml of 1N hydrochloric acid and 200 ml of dichloromethane cooled to 0 ° C. The organic phase is decanted, dried over sodium sulphate and the solvent is evaporated off. 1.58 g of product are obtained. Melting point: 106.2-107.3 ° C.

4.4 l-Cyano-5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

A solution of 1.3 g (5.19 mmol) of 1,1-dimethylethyl-1-cyano-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 11 ml of trifluoroacetic acid is stirred at at 0 ° C for 10 minutes, then the solvent is evaporated. 1.37 g of product are obtained.

Melting point: 87.5 - 89.7 ° C.

Example 5

2- (1-methylcyclopropyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

1.5 1, l-Dimethylethyl l- (l-methylcyclopropyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a suspension of 1.45 g (5.46 mmol) of 1,1-dimethylethyl-1- (1-propen-2-yl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5- of carboxylate in 80 ml of n-hexane cooled to -23 ° C was added 7.05 ml of 7.05 mmol of a 1 M solution of diethylzinc in hexane, followed by 21.96 g (82 mmol) of diiodomethane. The mixture is stirred at -23 ° C for 6 hours and then at 4 ° C for 19 hours, then 200 ml of diethyl ether and 50 ml of saturated ammonium chloride solution are added. The organic phase is decanted, dried over sodium sulphate and the solvent is evaporated off. The residue is chromatographed on a silica gel column using a 1:15 mixture of ethyl acetate and hexane as the eluent. 0.46 g of an oily product is obtained.

2.5 1- (1-Methylcyclopropyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

A solution of 0.905 g (3.24 mmol) of 1,1-dimethylethyl-1- (1-methylcyclopropyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 6 ml of trifluoroacetic acid is added. The mixture was stirred at 0 ° C for 10 minutes and then the solvent was evaporated. 0.95 g of an oily product is obtained.

Example 6 1-Methylthio-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

6.1. 1, l-dimethylethyl-l-methylthio-5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a solution of 6.5 ml (46.3 mmol) of N, N-diisopropylamine in 130 ml of anhydrous tetrahydrofuran at 0 ° C was added 30 ml (48 mmol) of a 1.6 M solution of butyllithium in hexane. After 30 minutes, the mixture is cooled to -70 ° C, then a solution of 8.7 g (38.59 mmol) of 1,1-dimethylethyl-5,6-dihydro-4H-thieno / 3,4-c is added. of pyrrole-5-carboxylate in 30 ml of anhydrous tetrahydrofuran. After one hour at -70 ° C, 4.86 ml (54 mmol) of dimethyl disulfide are added and the mixture is stirred at ambient temperature for one hour. The reaction mixture was then poured into 100 ml of saturated ammonium chloride solution and extracted twice with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and the solvent is evaporated off. 10 g of product are obtained after crystallization from hexane.

Mp .: 51-53 ° C.

2.6 l-methylthio-5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

A solution of 4,88 g (17,9 mmol) of 1,1-dimethylethyl-1-methylthio-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 10 ml of trifluoroacetic acid is stirred for one hour at at a temperature close to 0 ° C and then the solvent is evaporated. The residue is chromatographed on a column of silica gel, eluting with a 1: 9 mixture of methanol and dichloromethane. The product obtained was dissolved in 1 ml of trifluoroacetic acid and the solvent was evaporated. 5 g of an oily product are obtained.

Example 7

1-methylsulfonyl-5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

01.07 1, l-dimethylethyl 5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a solution of 2.1 g (7.8 mmol) of 1,1-dimethylethyl-1-methylthio -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 50 ml of ethanol at a temperature of near -20 ° C a solution of 9.5 g (15.5 mmol) of potassium peroximonosulfate in 50 ml of water is added. The mixture was stirred at ambient temperature for 3 hours, then filtered and ethanol was removed from the filtrate. The aqueous phase is extracted four times with 50 ml of ethyl acetate, the organic phases are dried over sodium sulphate and the solvent is evaporated off. The residue is chromatographed on a silica gel column using a 3: 7 by volume mixture of ethyl acetate and hexane. 1.1 g of product are obtained.

Melting point: 122-125 ° C.

2.7 l-methylsulfonyl-5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

A solution of 1 g (3.3 mmol) of 1,1-dimethylethyl-1-methylsulfonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 8 ml of trifluoroacetic acid is stirred for one hour at at a temperature close to 0 ° C and then the solvent is evaporated. 10 ml of diethyl ether are added and the precipitate formed is filtered off. 1 g of product is obtained.

Melting point: 172-176 ° C.

Example 8

1- (Piperidin-1-ylcarbonyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

8.1. 1,1-dimethyl-ethyl-l- (piperidin-l-ylcarbonyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a solution of 1.95 g (7.2 mmol) of 1,1-dimethylethyl-1-carboxy-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 50 ml of anhydrous tetrahydrofuran is added solution of 1.29 g (7.9 mmol) of carbonyldiimidazole in 12 ml of tetrahydrofuran. After one hour at ambient temperature, 5 ml of piperidine are added and the mixture is stirred at ambient temperature for 30 minutes. The solvent was evaporated and 40 ml of water were added to the residue and the mixture was extracted twice with 50 ml of ethyl acetate. The organic phases are dried over sodium sulphate and the solvent is evaporated. 1.89 g of an oily product are obtained.

2.8 1- (piperidin-l-ylcarbonyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

A solution of 1.86 g (5.5 mmol) of 1,1-dimethylethyl 1- (piperidin-1-ylcarbonyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 10 ml of trifluoroacetic acid is stirred for 30 minutes at a temperature in the region of 0 ° C and then the solvent is evaporated. 1.96 g of an oily product are obtained.

Example 9 1-Acetyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

9.1. 1,1-Dimethylethyl l- (1-hydroxy-ethyl) -5,6-dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate

To a solution of 0.72 g (7.2 mmol) of N, N-diisopropylamine in 10 ml of anhydrous tetrahydrofuran at 0 ° C was added 4.5 ml (7.2 mmol) of a 1.6 M solution of butyllithium in hexane. After 30 minutes, the mixture is cooled to -40 ° C, then a solution of 1.35 g (6 mmol) of 1,1-dimethylethyl-5,6-dihydro-4H-thieno / 3,4-c is added to the mixture. of pyrrole-5-carboxylate in 10 ml of tetrahydrofuran. After one hour at -40 ° C, the mixture is cooled to -70 ° C, then 1 ml (18 mmol) of acetaldehyde is added and the mixture is stirred at ambient temperature for two hours. The reaction mixture was then poured into 30 ml of saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate. The organic phases are dried over sodium sulphate and the solvent is evaporated. The residue is chromatographed on a silica gel column using a 1: 4 by volume mixture of ethyl acetate and hexane. 1.19 g of an oily product are obtained.

2.9 1,1-Dimethylethyl-1-acetyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate

To a solution of 5.39 g (20 mmol) of 1,1-dimethylethyl 1- (1-hydroxy-1-ethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 100 ml of dichloromethane are added with 1.14 ml (20 mmol) of acetic acid and then 5.64 g (15 mmol) of pyridinium dichromate. The mixture was stirred at ambient temperature for 16 hours, after which 4 g of celite was added and the mixture was filtered and the filtrate was evaporated. The residue is chromatographed on a column of silica gel, eluting with a mixture of ethyl acetate and hexane. 2.16 g of product are obtained.

Melting point: 119-121 ° C.

9.3. l-Acetyl-5,6-dihydro-4H-thieno / 3,4-c / pyrrole trifluoroacetate

A solution of 1,17 g (7 mmol) of 1,1-dimethylethyl-1-acetyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-carboxylate in 8 ml of trifluoroacetic acid is stirred for 30 minutes at near 0 ° C. The solvent was evaporated, diethyl ether (20 ml) was added and the mixture was filtered. 1.76 g of product are obtained.

M.p .: 136-138 ° C.

Example 10 1-Benzoyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

This compound was prepared in a manner analogous to that described in Example 9, substituting the benzaldehyde for acetaldehyde.

Example 11 1-Propylcarbonyl-5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate

This compound was prepared in a manner analogous to that described in Example 9, substituting butyric acid aldehyde for acetaldehyde.

The compounds of the invention are summarized in the following table together with their physical properties.

table

(I)

compound R ¹ salt MP: (° C) 1 H3CO- dihydrochloride 202-204 (D) 2 dimethanesulfonate; · 194-195 (D) 3 Cl · trimetánsulfonát. 161-162 (D) 4 NC dimethanesulfonate. 205-206 5 «h dihydrochloride 224-226 (D) 6 H3CS- dihydrochloride 227-229 (D) 7 H3CSO2- dimethanesulfonate 192-194 (D) 8 O ” ^- dihydrochloride 206-208 (D) 9 H3CCO- dihydrochloride > 270 (D) 10 O ^{- -} dihydrochloride > 270 (D) 11 H ₃ C (CH ₂ ) ₂ CO- dihydrochloride 198-200 (D) 12 dihydrochloride 246-248

Table (continued)

compound R ¹ salt MP: ( ' C) 13 dihydrochloride 235-237 14 _. "J dihydrochloride 226-227 (D) 15 W dihydrochloride 232-233 (D)

d = on decomposition

The compounds of the present invention have pharmacological alpha-antagonist activity, which has been demonstrated by various biological assays.

1) Antagonism of effects of clonidine on rat efferent vessel

This assay was performed on a 0.1 Hz rat stimulated rat efferent vessel in the presence of 30 nanomolar prazosin and micromole cocaine by the method described by GM Drew in European Journal of Pharmacology, 42, 123-130 (1977). The observed pA values _{of the} compounds of the invention and 9.4.

are between 6.5

2) Antagonism of ³ H-clonidine binding to alpha ₂ -adrenergic receptors

This assay was performed using a rat brain membrane preparation using the method described by D.A. Greenberg et al. in Life Sci. 19.69 (1976). After incubating the preparation for 30 minutes in the presence of tritiated clonidine (0.05 to 7 nmol / L), the incubation medium is filtered and the radioactivity of the residue is measured by the P.B.M.W.M. Timmermansa et al. described in European Journal of Pharmacology, 70, 7 (1981). In this test, 50% inhibitory concentrations (Cl) of the compounds of the invention were determined between 0.02 and 3.02 μιηοΐ / ΐ.

The results of the bioassays show that the compounds of the invention have in vitro antagonistic properties to adrenergic alpha receptors. In view of the aforementioned pharmacological properties, the compounds of the invention may be used for the treatment of diabetes, obesity, hypotension, postoperative paralytic ileum and / or asthma.

The compounds of the invention also have alpha -agonist activity demonstrated by biological tests on the pulmonary artery (pulmonary) of a rabbit.

These tests were performed under the following conditions.

Rabbits (Fauve de Bourgogne) with a body weight of 2-3 kg were sacrificed and dehydrated, after which a pulmonary artery was removed from which a strip of about 1.2 to 2 mm wide and about 20 mm long was cut. The obtained vascular tissue strips were immersed in saline (having the following composition, expressed in mmol / l: sodium chloride 137, potassium chloride 2.7; calcium chloride 1.8; sodium dihydrophosphate 0.4; sodium bicarbonate 11.9; chloride hexahydrate magnesium, 1.1, dextrose 5.9, disodium ethylenediaminetetraacetic acid (0.027 and ascorbic acid 0.057), which was oxidized with a mixture of 95% oxygen and 5% carbon dioxide and maintained at 37 ° C. These strips were then subjected to a 4 g traction force which was reduced to 2 g immediately before the start of the experiment. Tissue contraction caused by the test compound and the resulting tensions were recorded by a Grass Polygraph (Model 7D) and a voltage sensor. Two concentration-effect curves for cumulative concentrations of the compound (from 100 nmol / l to 3 mmol / l) were plotted, followed by alpha-α-antagonist of 1 μιηοΐ / do and added to the tissue in the test bath. 30 minutes. Next, an additional concentration-effect curve is plotted and compared to a second control curve.

The α-α-antagonizing effect was measured by a concentration inducing a contraction equal to 50% of the maximal effect. The compounds of the present invention were measured at a concentration of between 1.3 and 2.6 μπιοί / pri in this test.

These results show that the compounds of the invention have in vitro agonist properties for adrenergic alpha receptors. Thus, these compounds can be used to treat urinary incontinence.

The compounds of the invention may be formulated in combination with any suitable excipient in a form suitable for oral or parenteral administration, for example in the form of tablets, dragees, capsules and solutions.

The daily dosage may range from 0.1 to 20 mg / kg in the case of oral administration.

Claims (7)

PATENT CLAIMS CLAIMS 1. 5,6-Dihydro-4H-thieno [3,4-c] pyrrole derivatives of the general formula I in which R ^x is either cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, pyridyl, 3,4-dimethoxyphenyl or cyclopropyl, respectively; substituted with one or two alkyl groups or a COR group in which R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group or a piperidinyl group or a benzyl group substituted with one or more halogen atoms and / or linear or branched alkyl groups having 1 to 4 carbon atoms atoms, linear or branched alkoxy groups containing 1 to 4 carbon atoms or CO ₂ R *, wherein R 'represents a linear or branched alkyl group containing 1 to 4 carbon atoms, or naphthylmethyl and their addition salts with pharmaceutically acceptable acids. A compound according to claim 1 of the formula I consisting of 1-methoxy-5 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] / pyrrole dihydrochloride. A compound according to claim 1 of the formula I consisting of 1-methylthio-5 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -5,6-dihydro-4H-thieno [3,4-c] / pyrrole dihydrochloride. A process for the preparation of compounds of the formula I according to claim 1, characterized in that the compound of the formula II NH (II) wherein R ¹ is as defined in claim 1, is reacted with 2-chloromethyl-4,5-dihydro-1H-imidazole in a solvent such as dimethylformamide in the presence of N, N-diisopropylethylamine. 5. A medicament comprising a compound of formula I according to claim 1. A pharmaceutical composition comprising a compound of formula I according to claim 1 in combination with a suitable aid. Synthetic intermediate for the preparation of compounds of the formula I, in which R ¹ represents an alkoxy group having 1 to 4 carbon atoms, a pyridyl group or a 3,4-dimethoxyphenyl group, consisting of 1,1-dimethylethyl-1-borono-5,6 dihydro-4H-thieno / 3,4-c / pyrrole-5-carboxylate.