NO861802L - NEW DERIVATIVES OF TIENO (2,3-D) IMIDAZOLES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Description

The invention relates to new derivatives of thieno(2,3-d)imidazoles with the general formula

in which

means hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl,

R2 means hydrogen or lower alkyl,

, R₂ and R₂ independently mean hydrogen or

lower alkyl,

R^ means hydrogen or lower alkoxy, and

n means 0 or 1,

and their pharmaceutically acceptable acid addition salts, processes for their preparation, pharmaceutical preparations containing these compounds, as well as their use.

The term "lower alkyl" used in this description denotes straight-line or branched saturated hydrocarbon groups with 1-4 carbon atoms, such as e.g. methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl. The term "lower oxy" referred to hydroxycarbonoxy groups with 1-4 carbon atoms, e.g. methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, tert-butyloxy.

In a preferred group of compounds of formula I, means

R1 is hydrogen, acetyl, methoxycarbonyl or ethoxycarbonyl, hydrogen or acetyl being particularly preferred. R 2 is preferably hydrogen. R 3 , R 1 and R 8 preferably means hydrogen or methyl, preferably means hydrogen or methoxy.

A particularly preferred group within the compounds of the general formula I are those in which n means the number 1.

Thieno(2,3-d)imidazole derivatives with the general formula I and their salts can, according to the invention, be prepared by

a) a compound with the general formula

where R 1 and R 2 have the meaning given in formula I, are reacted

with a compound of the general formula

in which

X means chlorine or bromine, and

R 3 , R 1 , R 1 , and R 2 have the meaning given in formula I, in the presence of at least 2 equivalents of a strong base, whereupon b) optionally the thus formed compounds of the general formula I, in which n = 0, are reacted with equivalent amounts of

an organic peracid or hydrogen peroxide to a compound of the general formula I, in which n means the number 1, and

c) if desired, one formed in step a) or b) is transferred for binding with the general formula I to a pharmaceutically acceptable acid addition salt.

Reaction according to method step a) is advantageously carried out such that the compounds of formula II and III are suspended in an inert organic solvent, for example a lower-boiling aliphatic alcohol, such as methanol, ethanol, isopropanol, etc., preferably in methanol, since due to better workability, the compound of formula II is used suitably in excess, and then at least 2 equivalents of a strong base, preferably NaOH or KOH, dissolved in some water, at room temperature, are added dropwise. The reaction time is 2-4 hours.

According to method step b), the sulphoxy compound in which n in the general formula I means the number 1 can be obtained starting from the sulphide compound formed after method step a) with the meaning for n = 0 by partial oxidation of suitable oxidizing agents. As such oxidizing agents equivalent amounts of an organic peracid such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid are preferably used in a reaction-inert solvent, e.g. methylene chloride or chloroform, suitably at temperatures between -5°C and -50°C, or equivalent amounts 30% ^ 2®2 ^ ^- se^^ > f°r_ stepwise at room temperature.

The compounds of the general formula I are subject to tautomerism and can therefore also exist in all of the formula I tautomeric forms.

The starting compounds of the general formula III are known. The starting compounds of the general formula II used for the method are either known or can be prepared from

in and of itself a known way as it is based on known products. In particular, they must be prepared according to the following reaction core, and according to the specific indications in the examples. They i-:reak-

starting compounds with formulas IVa, IVb, V and VI are known from the literature. Reaction nucleus I

refers to the preparation of the compound of formula II, in which R^ is hydrogen, lower alkyl, chlorine or bromine, and R 2 is hydrogen, or lower alkyl, and the reaction nucleus II for the preparation of the compound of formula II, in which R^ is acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, and R2 again means hydrogen or lower alkyl.

Reaction nucleus I

Reaction nucleus II

The compounds of the general formula I have strongly basic properties. They can therefore be easily transferred in process step c) to crystalline, pharmaceutically acceptable acid addition salts, which can be purified as e.g. the hydrochlorides well by recrystallization. For this, the raw base is suitably dissolved in a suitable solvent, e.g. a lower alcohol, add an equivalent amount of protonic acid, evaporate the solvent in vacuo, and recrystallize the residue from methanol or ethanol, optionally with the addition of ether.

Suitable examples for such pharmaceutically acceptable salts are, in addition to the salts of hydrochloric acid, for example the salts of sulfuric acid, nitric acid, phosphoric acid, of sulphonic acids, benzoic acid, of maleic acid, of tartaric acid or citric acid.

The compounds of the general formula I and their pharmaceutically acceptable acid addition salts show valuable pharmacological properties in animal experiments. In particular, they cause a blockade of (H<+>+ K<+>) - ATP -ase, and can therefore for example be used for the treatment or prophylaxis of gastric and duodenal ulcers and other diseases caused by increased gastric secretion in human medicine. To investigate the pharmacological properties, the following test methods were used: The substances were dissolved in 20% dimethylsulfoxide and orally applied to adult female rats (strain: Charles River CD) in increasing doses of 125, 250 and 500 ymol/kg with the uniform dosing volume of 2 0 ml/kg. 60 minutes later, the animals were subjected to a pyloric ligature. 4 hours after setting the pylorus ligature, the acid concentration was determined and the total acid content in the animals' stomach volume was collected. The control group received 20 ml/kg dimethyl sulphoxide resp. 20 ml/kg distilled water.

In this standard test, the compounds with the general formula I such as 5-acetyl-2-((4-methoxy-3,5-dimethyl-2-pyridyl)-methylsulfenyl)-3H-thieno(2,3-d)imidazole ( connection ■

A) or 2-((4-methoxy-2-pyridyl)methylsulfinyl-3H-thieno(2,3-d)imidazole (compound B), a clear dose-dependent inhibition of gastric secretion (Tables I and II).

Compounds with the general formula I as well as their salts can find use as healing agents, e.g. in the form of pharmaceutical preparations containing the compounds according to the invention in mixtures with a pharmaceutical, organic or inorganic carrier material suitable for enteral or parenteral application, for example water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycols, vaseline etc. Pharmaceutical preparations may be available in solid form, e.g. as tablets, dragees, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliaries such as preservatives, stabilizers or emulsifiers, salts, for changing the osmotic pressure or buffers. They can also be administered in combination with other therapeutically valuable substances.

The following examples shall explain the invention in more detail.

Example 1

5-methyl-2-(2-pyridylmethylthio)-3H-thieno(2,3-d)imidazole (formula I: R± = CH3, R2 - Rg = H, n = 0).

1.56 g (9.162 mmol) of 1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-thione (formula II: R1 = CH3, R2 = H) and 1.33 g (8.108 mmol) of 2-chloromethylpyridine, hydrochloride, is suspended in 40 ml of methanol and, while stirring, 8.64 ml of 2-n NaOH (17.28 mmol) is slowly added dropwise over 20 minutes. Thereby the temperature increases up to 29°C, and the formed a clear solution, from which the product already falls out after about 30 minutes.

stirred for a further 2.5 hours at room temperature, then the solvent is removed as best as possible under vacuum, the residue is taken up in 30 ml of water and adjusted by adding 0.5 ml of glacial acetic acid, pH 4.5. It is shaken four times with 25 ml of chlorine each time, the combined organic phases are dried over sodium sulfate and evaporated. The product (2.0 g, 94% of theory) is recrystallized from acetonitrile.

Yield: 1.56 g of colorless crystals (73.6% of theory).

Sm.p. 171 - 172°C (CH 3 CN).

The starting material can be prepared as follows: 2-acetylamino-5-methyl-3-thiophenecarboxylic acid ethyl ester (Xla: R = CH3,<R>2<=>H).

284.0 g (1.659 mol) of 2-amino-5-methyl-3-thiophenecarboxylic acid methyl ester (IVa, known from the literature) is stirred portionwise into 600 ml of acetic anhydride, while the temperature during ice cooling is kept between 18° and 25°C. After stirring for 2.5 hours, the mixture is evaporated in vacuo and the brownish, crystalline residue is recrystallized from diisopropyl ether.

Yield: 277.5g of yellowish crystals (78.5% of theory).

Sm.p. = 100 - 101°C (diisopropyl ether).

2-acetylamino-5-methyl-3-thiophenecarboxylic acid

(XII: R ± = CH 3 , R 2 = H).

200.0 g (0.938 mol) of 2-acetylamino-5-methyl-3-thiophenecarboxylic acid methyl ester is stirred in 1400 ml of methanol at 50°C. Under mechanical stirring, a solution of 37.6 g (0.940 mmol) of NaOH in 970 ml of water is added dropwise over a period of 3.5

hours. It is still heated for 30 minutes at reflux and

the solution is best evaporated after cooling. The remaining residue is taken up in 1800 ml of water and 200 ml of saturated sodium bicarbonate solution, extracted three times with 250 ml of methylene chloride each time. The aqueous phase is released with concentrated hydrochloric acid to pH 1, the formed precipitate is suctioned off, washed three times with water, dried for 3 hours in a circulation drying cabinet at 70°C.

Yield: 121.8 g of colorless crystals (65.2% of theory).

Sm.p. = 197-198°C (MeOH).

3,6-dimethyl-4H-thieno(2,3-d)-(1,3)-oxazin-4-one

(XIII: R-1 = CH 3 , R 2 = H).

170.0 g (0.853 mol) of 2-acetylamino-5-methyl-3-thiophenecarboxylic acid (XII) is suspended in 800 ml of acetic anhydride and heated for 2.5 hours under reflux. The solution is then cooled and completely evaporated in vacuo. The remaining residue is recrystallized from carbon tetrachloride.

Yield: 128.0 g of colorless crystals (82.8% of theory).

Sm.p. = 140°C (diisopropyl ether).

2-acetylamino-5-methyl-3-thiophenylcarboxylic acid azide

(XIV): R x =CH 3 , R =H).

72.0 g (0.397 mol) of 3,6-dimethyl-4H-thieno(2,3-d)-(1,3)-oxazin-4-one are dissolved in 1100 ml of dioxane and sublayered with a solution of 51 .7 g (0.795 mol) of sodium azide in 170 ml of water. This is stirred slowly for 50 hours at room temperature and added at intervals of 8-12 hours to a total of 23.8 ml (0.397 mol) of glacial acetic acid in four portions.

The phase is then separated, and the organic phase is evaporated at a bath temperature of 40°C. The remaining dark oil is taken up in 600 ml of methylene chloride and combined with the aqueous phase and 150 ml of saturated sodium bicarbonate solution. The phases are separated, and the aqueous phase is shaken twice more, each time with 200 ml of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated.

Yield: 72.0 g of yellow crystals (80.8% of theory).

The crude product can be recrystallized from methanol.

Sm.p. 78 - 79°C (MeOH).

3-Acetyl-1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-one (XV: R1 = CH3, R = H).

16.3 g (72.2 mmol) of 2-acetylamino-5-methyl-3-thiophenecarboxylic acid azide was dissolved in 250 ml of abs. dioxane and heated for 4.5 hours at 100°C. The dark solution is cooled overnight, the formed precipitate is suctioned off, the mother liquor is evaporated to half the volume, allowed to crystallize and again suctioned off.

Yield: 9.92 g of colorless crystals (69.6% of theory).

Sm.p. about. 200 o C during decomposition <,> (dioxane).

1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-one

(XVI: R 1 = CH 3 , R 2 = H).

34.7 g (0.177 mol) of 2-acetyl-1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-one are introduced at room temperature into 420 ml of 2-n NaOH, and stirred until complete solution still for 15 minutes. The darker solution is acidified with conc. HC1 dropwise to pH = 2.5, cooled shortly after an ice bath, the formed precipitate is suctioned off, and washed 2 times with cold water. The residual water is dried at 70°C/20 mbar.

Yield: 26.5 g of colorless crystals (97.2% of theory).

Melting point: 275-278°C during decomposition.

1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-thione (II: R1= CH3, R2= H),

To 700 ml abs. pyridine, 25.0 g (0.162 mol) 1,3-dihydro-5-methyl-thieno(2,3-d)imidazol-2-one and 27.0 g (0.122 mol) P„z Sbr are placed at room temperature under mechanical stirring. The suspension is stirred under nitrogen in an oil bath, since at approx. 100°C a clear, red solution occurs. It is heated for 3 hours under reflux. The solvent is then cooled and distilled off in a vacuum. The dark tough oily residue is dissolved in 300 ml of 2-n NaOH, this solution is slowly poured into a well-stirred mixture of 1100 ml of ethyl acetate in 400 ml of 3-n HC1.

It is stirred for a further 10 minutes, filtered off with suction over a filter aid, the phases are separated. The aqueous phase is shaken a further 4 times with a total of 800 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate/activated carbon and evaporated. The dark residue (12.4 g, 45% of theory) is dissolved in 90 ml of 2-n NaOH, filtered with activated carbon, and the clear, red solution is acidified with conc. HC1 and pH 2. The precipitated crystals are suctioned off, washed twice with water and dried in vacuum at 60°C.

Yield: 9.8 g of light brown crystals (34.5% of theory).

Sm.p. greater than 330°C, during continuous decomposition.

Example 2

5-methyl-2-((4-methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d) imidazole

(In: R x = CH 3 , R 2 , R 3 , R 1 , and R 8 = H, R 4 = OCH 3 , n = 0).

3.46 g (20.3 mmol) 1,3-dihydro-5-methyl-thieno(2,3)imidazol-2-thidn and 3.35 g (17.3 mmol) 2-chloromethyl-4-methoxypyridine- hydrochloride is suspended in 70 ml of ethanol and 18.8 ml (47.6 mmol) of 2-n NaOH is slowly added dropwise while stirring. The temperature increases to

29°C, and a clear solution forms. It is still being stirred

for 2 hours at room temperature, and then the solution is best evaporated in a vacuum. The remaining residue is taken up in 70 ml of water, and with the addition of 1 ml of glacial acetic acid, a pH value of 4.5 is set. It is shaken four times with a total of 300 ml of chloroform, the combined organic phases are dried over sodium sulphate and evaporated. The remaining oily residue is expelled with acetonitrile and dissolved at boiling temperature in 280 ml of acetonitrile. It is filtered after adding activated charcoal, the solution is evaporated to 60 ml, crystallized overnight in a refrigerator, filtered off with suction and washed with cold acetonitrile.

Yield: 3.62 g of light brown crystals (71.9% of theory).

Sm.p. = 173°C (CH 3 CN).

Oak Sempe1 3

2-(2-pyridyl)methylthio-311-thieno(2,3-d)imidazole

(In: R x - R 6 = H, n = 0).

1.20 g (7.68 mmol) 1,3-dihydro-thieno(2,3-d)imidazol-2-thione (II: Rx and R = H), and 1.13 g (6.91 mmol) 2-Chloromethylpyridine hydrochloride is dissolved in 15 ml of methanol, 7.4 ml (14.8 mmol) of 2-n HaOH are added dropwise with stirring over the course of 20 minutes.

It is stirred for a further 1 1/2 hours at room temperature,

then pesed on a rotavapor. The residue is distributed between 60 ml of water and 80 ml of methylene chloride. For phase separation, filter over a filter aid, and the aqueous phase is extracted three more times with 70 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate and evaporated.

The crude product (1.52 g brown crystals, 92.4% of theory) is recrystallized from acetonitrile with the addition of activated carbon.

Yield: 1.10 g of colorless crystals (64.3% of theory),

Sm.p. = 155 - 156°C (CH 3 CN).

Starting materials can be prepared as follows:

1,3-dihydro-thieno(2,3-d)imidazol-2-thione.

(II: R x and R 2 = H).

20.0 g (0.143 noi) of 1,3-dihydro-thieno(2,3-d)imidazol-2-one (known from the literature) is introduced at room temperature with mechanical stirring in 500 ml abs. pyridine. Then 23.8 g (0.107 mol) ?2S5 °9 are added, the mixture is heated for 5.5 hours under reflux. It is cooled, and the solvent is distilled off as much as possible in a vacuum. The dark residue is dissolved in 500 ml of 2-n NaOH and emptied with good stirring into a mixture of 370 ml of 2-n HCl and 400 ml of ethyl acetate. The two-phase mixture is sucked off over a filtration aid and the phases are separated. The aqueous phase is extracted a further six times with 150 ml of ethyl acetate each time, the combined organic phases are dried over sodium sulphate and evaporated.

Yield: 8.81 g of brown crystals (39.5% of theory).

Melting point: continuous cleavage.

Example 4

2-((4-Methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d)imidazole (I: R-j^, R2, R3, R5 and Rg = H, R4=OCH3, n = 0).

4.65 g (29.76 mmol) 1,3-dihydro-thieno(2,3-d)imidazol-2-thione and 4.91 g (25.30 mmol) 2-chloromethyl-4-methoxy-pyridine- hydrochloride is suspended in 60 ml of methanol and, while stirring, 27.6 ml (55.2 mmol) of 2-n KOH is slowly added dropwise over 25 minutes. The temperature thereby increases to 32°C. After finishing

addition is stirred for a further 4 hours at room temperature, then the reaction mixture is evaporated in vacuo, the residue is taken up in 50 ml of water, and by adding glacial acetic acid "a pH value of 4.5 is set. The precipitate formed is dissolved in 80 ml of chloroform, the mixture is shaken well and for phase separation is aspirated over a filter aid. The phases are separated, the aqueous is further extracted three times with 40 ml of chloroform each time. The combined organic phases are dried over sodium sulfate and evaporated. The crude product (5.8 g) 82.2% of theory) is dissolved in 400 ml of acetonitrile at boiling temperature, filtered hot with activated carbon, evaporated to 150 ml and crystallized.

Yield: 4.34 g of brownish crystals (61.8% of theory).

Melting point: 140 - 141°C (CH3CN).

Example 5

5-Acetyl-2-((4-methoxy-3,5-dimethyl-2-pyridyl)-methylthio)-3H-thieno (2/.3-d) imidazole.

(In: Rx = COCH3, R2 and Rg = H, R3 and R5 = CH3, R4 = OCH3, n=0).

5.64 g (28.4 mmol) 5-acetyl-1,3-dihydro-thieno(2,3-d)imidazol-2-thione and 6.00 g (27.0 mmol) 2-chloromethyl-4- Methoxy-3,5-dimethylpyridine hydrochloride is suspended in 250 ml of methanol, and with stirring, 28 ml of 2-n NaOH (56.0 mmol) is added dropwise over the course of 15 minutes as the temperature increases to 27°C. From the formed solution, the product already falls out after a short time.

It is then stirred for a total of 4 hours at room temperature,

and then the reaction mixture is evaporated as best as possible. The residue is taken up in 200 ml of water, and by adding approx. 2 ml of glacial acetic acid is set to a pH value of 4.5. The suspension is then shaken 4 times with a total of 350 ml of chloroform, and the combined organic phases are dried over sodium sulphate/activated carbon and evaporated.

The remaining dark oil is crystallized with 80 ml of acetonitrile, cooled and the precipitate filtered off with suction. It is washed three times with cold acetonitrile and dried at 40 oC in a vacuum.

Yield: 8.92 g of slightly yellowish crystals (95.0% of theory).

Melting point: 177 - 180°C (CH3CN).

The starting material can be prepared as follows:

1-(5-chloro-4-nitro-2-thienyl)-1-ethanone

(VIII: = COCH 3 , R 2 = H).

In 180 ml conc. H 2 SO 4 is introduced at -20°C 30.0 g (0.1868 mol) finely ground 1-(5-chloro-2-thienyl)-1-ethanone (Vila: R.^ = COCH 3 ,

R2= H) with stirring. To the red-colored solution drip-es during 3 5 minutes at a temperature between -2 0°C and

-25°C a nitration mixture of 7.8 ml fuming HN03 (0.1868 mol)

and 30 ml conc. H2SO4.

It is stirred for a further 30 minutes at -20°C and then the reaction mixture is poured into 1400 ml of ice water. The precipitated product is taken up in 500 ml of methylene chloride, and the aqueous phase is shaken twice more with 250 ml of methylene chloride each time. The combined organic phases are washed once with 300 ml of water, dried over sodium sulphate and evaporated.

The raw product (36.0 g, 93.8% of the theoretical) contains approx. 10% of an impurity (in DC upstream), which does not interfere with the further conversion, can, however, be removed by recrystallization from ethanol.

Yield: 26.0 g of slightly yellowish crystals (67.7% of theory).

M.p.: 80°C (EtOH).

1-(5-amino-4-nitro-2-thienyl)-1-ethanone.

(IX: R = COCH 3 , R = H).

Into a solution of 22.0 g (0.108 mol) 1-(5-chloro-4-nitro-2-thienyl)-1-ethanone in 250 ml of dry dioxane, dry NK2 gas is introduced while increasing the temperature to 45 C. After the end of the exothermic reaction, the temperature is maintained by heating in a water bath at 50°C, and in addition a further 1 1/2 hours of NH3 gas is introduced.

It is then filtered off from a formed precipitate and discarded. The filtrate is stirred at 50<Q>C with activated carbon, filtered again

and evaporated. The remaining residue is recrystallized from acetonitrile.

Yield: 11.9 g of yellow needles (59.2% of theory).

Sm.p. = 224 - 225°C (CH 2 CN).

5-acetyl-1,3-dihydro-thieno(2,3-d)imidazol-2-thione.

(II: R x = COCH 3 , R 2 =H).

10.0 g (0.0537 mol) 1-(5-amino-4-nitro-2-thienyl)-1-ethanoh

(IX: R1= COCH3, R2 = H)/o<p>issolved in a mixture of 150 ml methanol and 150 ml dioxane and hydrogenated with 3 spoons of W2~

Raney nickel as catalyst in a Parr medium-pressure hydrogenation apparatus at room temperature until calculated hydrogen uptake for 2 1/2 hours. The catalyst is sucked off over a filtration aid, and washed well with methanol and dioxane. The filtrate (consisting of X: R-j^ = COCH 3 , R 2 = H) is mixed with 8.39 g (0.0644 mol) of sodium ethyl xanthogenate and heated for 4 hours with stirring and reflux. (temperature approx. 70°C). After cooling, evaporate as best as possible and dissolve the residue in 250

ml of water. The solution is stirred for 10 minutes with 2 teaspoons of activated charcoal and then suctioned off over a filtration aid. The filtrate is acidified with conc. HCT while stirring slowly

to pH = 1, stir again briefly, and the yellow precipitate formed is suctioned off. The crystals are dried for 2 hours at 90°C/20 mbar.

Yield: 8.2 g of crystals (77.0% of theory).

Sm.p. = 302°C during decomposition.

Example 6

2-((4-Methoxy-3,5-dimethyl-2-pyridyl)-methylthio)3H-thieno(2,3-d)imidazole-5-carboxylic acid methyl ester.

(In: R x = COOCH 3 , R 2 and R 8 = H, R 3 = CH 3 , R 4 = 0CH 3 , n = 0).

The above-mentioned compound with the general formula I is prepared analogously to the working method indicated in example 5 by reacting 1,3-dihydro-thieno(2,3-d)imidazole-5-carboxylic acid methyl ester-2-thione with 2-chloromethyl -4-methoxy-3,5-dimethyl-pyridine hydrochloride.

Yield: 89% of the theoretical.

M.p.: 173 - 174.5°C (CH 3 CN).

The starting material was prepared following the reaction of 5-chloro-4-nitro-thiophene-2-carboxylic acid methyl ester (VIII: R1= C00CH3, R2= H, known from the literature) over 5-amino-4-nitro-2- thiophene carboxylic acid methyl ester (IX: R^= COOCH3, R2 = H, m.p.: 271°C during decomposition) reduction 4,5-diamino-2-thiophene carboxylic acid methyl ester (X: R^= COOCH3,

R2= H) and reaction of this compound with sodium methyl xanthogenate. In this way we get essl,3-dihydro-thieno(2,3-d) imidazole-5-carboxylic acid methyl ester-2-thione (II: R-^ = COOCH3, R2= H, m.p.: 279°C during decomposition) .

Example 7

5-acetyl-2((4-methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d)-imidazole

(In: R 1 = COOCH 2 , R 2 , R 3 , R 5 and R 8 = H, R 4 = 0CH 3 /n = 0).

1.30 g (6.567 mmol) of 5-acetyl-1,3-dihydro-thieno(2,3-d)imidazol-2-thione and 1.08 g (5.565 mmol) of 2-chloromethyl-4-methoxy-pyridine-

hydrochloride is suspended in 15 ml of methanol while stirring, 6.2 ml of 2-n NaOH (12.4 mmol) is added dropwise over the course of 10 minutes

as the temperature increases to 27°C. It is stirred for a further 1 1/2 hours at room temperature.

The reaction mixture is then evaporated as best as possible, the residue is taken up in 50 ml of water, and brought to pH = 4 by the addition of 1 ml of glacial acetic acid. It is shaken three times, with each time 40

ml of chloroform, the combined organic phases are dried over sodium sulphate and evaporated.

The crude product (1.52 g brown oil) is treated with acetonitrile and recrystallized from acetonitrile with the addition of activated charcoal.

Yield: 0.76 g of colorless crystals (42.8% of the theoretical .

Melting point: 192 - 194°C (CH3CN).

Example 8

5-acetyl-2-(2-pyridyl)methylthio-3H-thieno(2,3-d)imidazole

(I: R, = COCH-, R- - R, = H, n = 0).

1.50 g (7.565 mmol) of 5-acetyl-1,3-dihydro-thieno(2,3-d)imidazole-2-thione and 1.12 g (6.809 mmol) of 2-chloromethylpyridine hydrochloride are suspended in 60 ml of methanol and in the course of 8 minutes, 7.2 ml of NaOH (14.4 mmol) are added dropwise with stirring as the temperature rises to 26°C. It is stirred for a further 2 hours at room temperature.

The formed clear solution is evaporated as best as possible, the residue is taken up in 80 ral of water and by adding 1.2 ml of glacial acetic acid, a pH value of 4.5 is set. It is extracted three times with a total of 150 ml of chloroform, the organic phase is dried over sodium sulphate and evaporated. The remaining crystals are recrystallized from acetonitrile.

Yield: 1.85 g of colorless crystals (84.5% of theory).

Sm.p. 171-173°C (CH 3 CN).

Example 9

5-methyl-2-(2-pyridyl)-methylsulfinyl-3H-thieno(2,3-d)imidazole

(I: Rx = CH3, R2~R6 = H'n = 1)'

1.0 g (3.826 mmol) of 5-methyl-1-(2-pyridyl)methylthio-3H-thieno (2,3-d)imidazole is dissolved in 20 ml of chloroform at room temperature and the solution is cooled to -10°C. At a temperature between -12°C and -9°C, a solution of 0.76 g (3.749 mmol) of 85% 3-chloroperbenzoic acid in 10 ml of chloroform is added dropwise during 10 minutes with stirring. After completion of instillation, stir for a further 10 minutes at -10°C.

The reaction mixture is shaken twice with 10 ml of saturated sodium bicarbonate solution each time, and the combined organic phases are dried over sodium sulphate and evaporated.

The crude product (0.96 g, 90.5% of theory) is recrystallized from acetonitrile.

Yield: 0.76 g of colorless crystals (71.6% of theory).

Melting point: 175 - 176°C with decomposition (CH3CN).

Example 10

5-methyl-2-((4-methoxy-2-pyridyl)methylsulfinyl)-3H-thieno(2,3-d)imidazole,

(In: R 1 = CH 3 , R 2 , R 3 , R 5 and R 8 = H, R 4 = OCH 3 , n = 1).

6.0 g (20.59 mmol) of 5-methyl-2-((4-methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d)imidazole are dissolved in 120 ml of chloroform at room temperature. The solution is cooled to -12°C, and during 20 minutes a solution of 4.10 g (20.80 mmol) is added dropwise

85% 3-chloroperbenzoic acid in 60 ml of chloroform at a temperature between -12°C and -8°C with stirring. After finishing the

The mixture is stirred for a further 10 minutes at -10°C.

The mixture is then extracted twice with 25 ml of saturated sodium bicarbonate solution each time, the aqueous phase is washed twice with a little chloroform, the combined organic phases are dried over sodium sulphate and evaporated.

The remaining residue (approx. 6 g of reddish oil) is crystallized with a little acetonitrile and dissolved in 40 ml of DMF at 80°C. It is filtered hot with activated charcoal, poured into 220 ml of 60°C hot acetonitrile, and cooled slowly. The crystallization is fully stabilized overnight in a refrigerator. Then suction off and wash with cold acetonitrile.

Yield: 4.81 g of colorless crystals (76% of theory).

M.p.: 183-184°C (DMF/CH₂CN).

Example 11

2-(2-pyridyl)methylsulfinyl-3H-thieno(2,3)imidazole (I: R1-R6 = H, n = 1).

0.45 g (1.82 mmol) of 2-(2-pyridyl)methylthio-3H-thieno(2,3-d)imidazole is dissolved in 10 ml of chloroform and at a temperature between -11° and -6°C is added dropwise under stirring a solution of 0.37 g (1.82 mmol) of 85% 3-chloroperbenzoic acid in 5 ml of chloroform. It is stirred for a further 30 minutes at a temperature below 0°C, the solution is diluted with a little methylene chloride. and washed twice with each time 5 ml of saturated sodium bicarbonate solution.

The aqueous phase is extracted twice with 5 ml of methylene chloride each time, the combined organic phases are dried over sodium sulphate and evaporated.

Those after expulsion with acetonitrile crystalline residue

(0.42 g 87.7% of theory), recrystallized from aceto-

nitrile/activated carbon.

Yield: 0.33 g of colorless crystals (68.9% of theory).

Melting point: 151-152°C with decomposition (CH-jCN) .

Example 12

2-((4-methoxy-2-pyridyl)methylsulfinyl)-3H-(2,3-d)imidazole,

(In: R1-R3, R5 and Rg = H, R4 = OCH3, n = 1).

4.30 g (15.50 mmol) of 2-((4-methoxy-2-pyridyl)methylthio)-3H-thieno (2,3-d)imidazole are dissolved in 90 ml of chloroform at room temperature, and the solution is cooled to -10 °C. A solution of 3.08 g (15.19 mmol) of 85% 3-chloroperbenzoic acid in 35 ml of chloroform is then added dropwise with stirring at a temperature between -11° and -8°C over the course of 30 minutes. The mixture is then stirred for another 15 minutes at -10°C. The solution is extracted twice with a total of 30 ml of saturated sodium bicarbonate solution, the aqueous phase is shaken three times with 20 ml of chloroform each time, and the combined organic phases are dried over sodium sulphate and evaporated.

The crude product (5.2 g red oil) is extracted with a little acetonitrile

and the brownish crystals are dissolved in 22 ml of DMF at 80°C.

It is mixed with activated carbon, filtered hot and emptied into 130 ml of 60°C hot acetonitrile. It is cooled slowly, and the crystallization is completed in a refrigerator overnight.

Yield: 4.03 g of colorless crystals (88.6% of theory).

Melting point: 157-159°C with decomposition (CH3CN).

Example 13

5-acetyl-2((4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl)-3H-thieno(2,3-d)imidazole.

(In: R-j^ = COCH 3 , R 2 and R 3 = H, R 3 and R 5 = CH 3 , R 4 = OCH 3 , n = 1).

4y.5 g (12.95 mmol) of 5-acetyl-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio)-3H-thieno(2,3-d)imidazole is dissolved almost completely in 120 ml of chloroform at room temperature, the solution is cooled to -10°C at a temperature between -8°C and -0°C a solution of 2.58 g (12.69 mmol) 85% 3-chloroperbenzoic acid in 40 ml of chloroform.

It is stirred for a further 10 minutes at -10°C, and the now completely clear solution is extracted three times with a total of 60 ml of saturated sodium bicarbonate solution. The aqueous phase is washed three times with a little chloroform, the combined organic phases are dried over sodium sulphate and evaporated.

The remaining residue (approx. 5 g of red oil) is dissolved in 50 ml of DMF at 80°C and filtered with activated carbon. The solution is emptied

in 300 ml of 60°C hot acetonitrile, is cooled slowly, and the crystallization is completed overnight in a refrigerator. It is suctioned off and washed three times with acetonitrile.

Yield: 3.30 g of colorless crystals (70.1% of theory).

Melting point: 190-191°C (DMF/CH3CN).

Example 14

4-acetyl-2-((4-methoxy-2-pyridyl)methylsulfinyl)-3H-thieno(2,3-d)imidazole,

(In: R x =COCH 3 , R 2 , R 3 , R 3 and R 3 = H, R 3 = OCH 3 , n = 1).

0.53 g (1.628 mmol) of 5-acetyl-2-(4-methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d)imidazole is suspended in 15 ml of chloroform at a temperature between -12° and -8°C, a solution of 0.33 g (1.628 mmol) of 85% 3-chloroperbenzoic acid in 6 ml of chloroform is added dropwise with stirring over the course of 7 minutes, as a clear solution is formed. It is stirred for a further 10 minutes at -10°C. It is then extracted twice with 6 ml of saturated sodium bicarbonate solution each time, and the aqueous phases are subsequently shaken twice with 5 ml of chloroform each time, the combined or

ganic phases are dried over sodium sulfate and evaporated. The oily crude product is recrystallized from acetonitrile/activated carbon.

Yield: 0.37 g of colorless crystals (67.8% of theory),

sm.p. 159-162°C with decomposition (CH3CN).

Example 15

5-acetyl-2-((4-methoxy-2-pyridyl)methylsulfinyl)-3H-thieno(2,3-d)imidazole.

(In: R1 = COCH3, R2, R3, R5 and Rg = H, R4 = OCH3, n = 1).

0.53 g (1.628 mmol) of 5-acetyl-2-(4-methoxy-2-pyridyl)methylthio)-3H-thieno(2,3-d)imidazole is taken up in 15 ml of glacial acetic acid, mixed slowly at 5-10° C with a solution of 181 mg (1.628 mmol) 30% H2^2'^et a clear solution occurs. It is stirred for a further 30 minutes at room temperature. It is then diluted with 100 ml of water, shaken three times with 20 ml of chloroform each time, and the combined organic phases are washed neutrally with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The oily crude product is crystallized from acetonitrile/activated carbon.

Yield: 0.28 g of colorless crystals (51.3% of theory).

Melting point: 159-162°C with decomposition (CH3CN).

Example 16

5-Acetyl-2-(2-pyridyl)methylsulfinyl-3H-thieno(2,3-d)imidazole (I: R±= COCH3, R2-R6 = H, n = 1).

1.0 g (3.46 mmol) of 5-acetyl-2-(2-pyridyl)methylthio-3H-thieno-(2,3-d)imidazole is dissolved almost completely at room temperature in 15 ml of chloroform, the solution is cooled to -12 °C. At a temperature of -14° and -9°C, drip during 10

minutes a solution of 0.69 g (3.39 mmol) 85% 3-chloroperbenzoic acid in 10 ml of chloroform.

It is stirred for a further 10 minutes at -10°C, in the meantime

completely clear solutions are diluted with chloroform, and extracted twice with each time 7 ml of saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated. The remaining residue is crystallized with acetonitrile and recrystallized from acetonitrile while adding activated carbon.

Yield: 0.78 g of colorless crystals (73.9% of theory).

M.p.: 194-197°C (CH3CN).

Example 17

2-((4-Methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl)-3H-thieno (2,3-d)imidazole-5-carboxylic acid methyl ester.

(In: R±= COOCH3, R2 and Rg = H, R3 and R4= OCH3, n = 1).

The above-mentioned compounds with the general formula I are obtained analogously to the method indicated in example 16 by partial oxidation of 2-((4-methoxy-3,5-dimethyl-2-pyridyl)-methylthio)-3H-thieno(2,3- d) imidazole-5-carboxylic acid methyl ester with perbenzoic acid in methylene chloride as solvent.

Yield: 72.5% of the theoretical.

M.p.: 179-179.5°C (CH3CN).

Claims (6)

1. Derivatives of thieno(2,3-d)imidazoles of the general formula in which means hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopro alkylcarbonyl, methoxycarbonyl or ethoxycarbonyl, R2 means hydrogen, or lower alkyl, R 1 , R 1 , and R 8 independently mean hydrogen or lower alkyl, R 1 means hydrogen or lower alkoxy, and n means 0 or 1, and their pharmaceutically acceptable acid addition salts. 2. Compounds with the general formula I stated in claim 1, where n means the number 1. 3. Compounds with the general formula I according to one of claims 1 or 2, while R^ means hydrogen, acetyl, methoxycarbonyl, ethoxycarbonyl, R2 means hydrogen, R^, R^ and Rg mean hydrogen, or methyl, and R 1 means hydrogen or methoxy. 4. Process for the preparation of compounds of the general formula I specified in claim 1, characterized by ata) a compound of the general formula in which R-^ and when ^en under formula I has the meaning indicated, is reacted with a compound of the general formula wherein X means chlorine or bromine, and R^ , R^ , R^ and Rg have the meaning given under formula I in the presence of at least two equivalents of a strong base, whereupon b) optionally, the thus formed compounds of the general formula I in which n = 0, are reacted with equivalent amounts of an organic peracid or hydrogen peroxide to a compound of the general formula I, in which n means the number 1, and c) if desired, a formed compound of the general formula I is transferred to a pharmaceutically acceptable acid addition salt. 5. Pharmaceutical preparations containing compounds of the general formula I according to claim 1 or their acid addition salts in combination with usual excipients and carriers. 6. Compounds according to claim 1 for use as active substances for pharmaceuticals for the treatment of prophylaxis and diseases produced by increased gastric secretion, such as gastric or duodenal ulcers.