DD258608A1 - PROCESS FOR THE PREPARATION OF NEW THIENO (2,3-ALPHA) IMIDAZOLE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel derivatives of thieno (2,3-d) imidazoles of the general formula I of the formula sheet, in which R 1 is hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, R 2 is hydrogen or lower Alkyl, R3, R5 and R6 are independently hydrogen or lower alkyl, R4 is hydrogen or lower alkoxy and n is 0 or 1 and their pharmaceutically acceptable acid addition salts, by reacting a compound of general formula II of the formula sheet, with a compound of general formula III of the formula sheet, wherein X is chlorine or bromine, in the presence of a strong base. The compounds of the formula I cause blockade of the (H K) ATPase and possess gastro-intestinal activity. Formulas I to III

Description

a) a compound of the general formula II of the formula sheet,

wherein R ₁ and R _{2 have} the meaning given in formula I with a compound of general formula III of the formula sheet,

X is chlorine or bromine and

R ₃ , R _4, R ₅ and R _{6 have} the meaning given for formula I, in the presence of at least 2 equivalents of a strong base, whereupon

b) optionally reacting the thus obtained compounds of the general formula I, wherein η = 0, with equivalent amounts of an organic peracid or hydrogen peroxide to give a compound of the general formula I in which η is 1, and

c) if desired, converting a compound of general formula I obtained in stage a) or b) into a pharmaceutically acceptable acid addition salt.

2. The method according to claim 1, characterized in that compounds of general formula I are prepared in which η is the number 1.

3. The method according to any one of claims 1 or 2, characterized in that a compound of general formula II, wherein R _{1 is} hydrogen, acetyl, methoxycarbonyl or ethoxycarbonyl and R _{2 is} hydrogen, with a compound of general formula III, wherein R ₃ , R ₅ and R _{6 are} hydrogen or methyl and R _{4 is} hydrogen or methoxy.

4. The method according to any one of claims 1 to 3, characterized in that one carries out the reaction in step a) in a low-boiling alcohol, preferably methanol.

5. The method according to any one of claims 1 to 4, characterized in that one uses in step a) the compound of the general formula II in excess.

6. The method according to any one of claims 1 to 5, characterized in that one carries out the oxidation in step b) with equivalent amounts of 3-chloroperbenzoic acid, perbenzoic acid or peracetic acid.

7. The method according to claim 6, characterized in that one carries out the oxidation in step b) in methylene chloride or chloroform at -5 ⁰ C to -50 ⁰ C.

8. The method according to any one of claims 1 to 5, characterized in that one carries out the oxidation in step b) with equivalent amounts of hydrogen peroxide.

9. The method according to claim 8, characterized in that one carries out the oxidation in step b) with 30% hydrogen peroxide in glacial acetic acid.

For this 1 sheet of formulas.

Field of application of the invention

The invention relates to a process for the preparation of novel derivatives of thieno (2,3-d) imidazoles of the general formula I of the formula sheet,

in the

R _{1 is} hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, R _{2 is} hydrogen or lower alkyl,

R ₃ , R ₄ and R ₆ independently of one another are hydrogen or lower alkyl,

R _{4 is} hydrogen or lower alkoxy and

η is 0 or 1, j

and their pharmaceutically acceptable acid addition salts.

The compounds which can be prepared according to the invention are biologically highly active and are used in medicaments.

Field of application of the invention is therefore the chemical or pharmaceutical industry.

Characteristic of the known technical solutions

EP-A-5129 and EP-A-74341 describe the preparation of pyridylmethylthiobenzimidazole derivatives which inhibit gastric acid. The preparation of ATPase inhibitors based on pyridylmethylthio-thieno (2,3-d) imidazole derivatives has not previously been described in the literature.

Object of the invention

The aim of the invention is the development of a suitable method for the preparation of new, suitable as ATPase inhibitors chemical substances.

Explanation of the essence of the invention

The invention is therefore based on the object, by choosing suitable starting materials and chemical methods, to enable the preparation of compounds of the general formula I in good yields and with the purity necessary for use as medicaments.

According to the invention, the thieno (2,3-d) imidazole derivatives of general formula I and their salts are prepared by

a) a compound of the general formula II of the formula sheet,

wherein Ri and R _{2 have} the meaning given in formula I, with a compound of general formula III of

Formula sheet, ·

X is chlorine or bromine and

R3, R4, R5 and R _{6 have} the meanings given in formula I, in the presence of at least 2 equivalents of a strong base, whereupon

b) optionally reacting the thus obtained compounds of the general formula I, wherein η = 0, with equivalent amounts of an organic peracid or hydrogen peroxide to give a compound of the general formula I in which η is 1, and

c) if desired, converting a compound of general formula I obtained in stage a) or b) into a pharmaceutically acceptable acid addition salt.

The term "lower alkyl" as used in this specification designates straight-chain or branched saturated hydrocarbon groups having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl The term "lower alkoxy" refers to on hydrocarbonoxy groups having 1-4 carbon atoms, eg Methoxy, ethoxy, propyloxy, isopropylaxy, butyloxy, tert -butyloxy.

In a preferred group of compounds of the formula I, R is hydrogen, acetyl, methoxycarbonyl or ethoxycarbonyl, hydrogen or acetyl being particularly preferred. R ₂ is preferably hydrogen. R ₃ , R ₅ and R ₆ are preferably hydrogen or methyl. R ₄ is preferably hydrogen or methoxy.

A particularly preferred group within the compounds of general formula I is that in which η is 1.

The reaction according to process step a) is advantageously carried out by suspending the compounds of the formula II and III in an inert organic solvent, for example a low-boiling aliphatic alcohol such as methanol, ethanol, isopropanol and the like, preferably in methanol For reasons of better workability, the compound of formula II expediently used in excess and then at least 2 equivalents of a strong base, preferably NaOH or KOH, dissolved in a little water, drops at room temperature. The reaction time is 2-4 hours.

According to process step b), the sulfoxide compounds in which η in the general formula I is 1, starting from the obtained according to process step a) sulfide compounds having the meaning of η = 0 by partial oxidation with suitable oxidizing agents. As such oxidizing agents are preferably equivalent amounts of an organic peracid such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid, in a reaction-inert solvent, for. As methylene chloride or chloroform, conveniently at temperatures between -5 ° C and -50 ⁰ C, or equivalent amounts of 30% H ₂ O ₂ in glacial acetic acid advantageously used at room temperature.

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

The starting compounds of general formula III are known. The starting compounds of the general formula II used for the process are either known or can be prepared starting from known products in a manner known per se. In particular, they can be synthesized according to the following reaction schemes and according to the specifics in the examples. The starting compounds of the formulas IVa, IVb, V and VI given in the reaction schemes are known from the literature.

Scheme I relates to the preparation of compounds of formula II in which Ri is hydrogen, lower alkyl, chloro or bromo and R _{2 is} hydrogen or lower alkyl and Reaction Scheme II refers to the preparation of compounds of formula II wherein R _{1 is} acetyl, cyclopropylcarbonyl , Methoxycarbonyl or ethoxycarbonyl, and R _{2 is} again hydrogen or lower alkyl.

Rg Action Scheme I

, COOCH ₃

DTa (Rp (Ac) ₂ O

COXH,

^ S ^ "NHAc XIa (R ₁ = H, alkyl)

, COOH

H -N

C = O

rl

23 "

ac

C = O

TVT

, COOCH.

'NH-

GTb

1. (Ac) ₂ O

2. SO ₂ Ct ₂ , Br ₂

, COOCH.

R ₁ ^ ^ S ^ ^ NHAc Sib (R _<= C

0 Il, CN ₃

NHAC

TTV

(R, = H, alkyl, Cl, Br)

Reaction scheme II

 S "

COOH * Cl

3ΖΓ

CH ₃ COCl t> -COCl /

alch

1. SOCI ₂

2. CH ₃ OH / C ₂ H ₅ OH

W. a (R ₁ = COCH ₃ , CO- <j)

b (R ₁ -COOCH ₃₇ COOC ₂ H ₅ )

Cl

R-R,

W (R ₁ = COCH ₃ , CO- <], COOCH ₃ , COOC ₂ H ₅ j 2

NH ₂

NH-

(R, "COCH ₃ , CO - <!, COOCH ₃ COOC ₂ H ₅ ) (R ₂ = H, alkyl)

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The compounds of the general formula I have strongly basic properties. It can therefore be easily converted into crystalline, pharmaceutically acceptable acid addition salts according to process step c, which can be such. B. the hydrochlorides can be cleaned well by recrystallization. For this purpose, the crude base is conveniently dissolved in a suitable solvent, for. B. in a lower alcohol, an equivalent amount of protic acid added thereto, the solvent is evaporated off in vacuo and the residue is crystallized from methanol or ethanol, optionally with the addition of ether.

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

The compounds of 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 ⁺ ) -ATPase and can therefore be used, for example, for the treatment or prophylaxis of gastric and duodenal ulcer and other diseases caused by increased gastric secretion in human medicine. To investigate the pharmacological properties, the following test method was used:

The substances were dissolved in 20% dimethyl sulfoxide and monitored female rats (strain: Charles River CD) in increasing doses of 125.250 υηαδΟΟμπιοΙ / ^ with the uniform dose volume of 20ml / kg administered orally. 60 minutes later, the animals were subjected to a pylorus ligation. 4 hours after setting the pylorus ligature, the acid concentration and the total acid content in the stomach volume of the animals was determined. The control group received 20 ml / kg of dimethyl sulfoxide or 20 ml / kg of distilled water.

In this standard test, compounds of the general formula such as, for example, 5-acetyl-2 - ((4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl) -3H-thieno (2,3-d) iridazole (Comp A) or 2 - ((4-methoxy-2-pyridyl) methylsulfinyl-3H-thieno (2,3-d) imidazole (Compound B), a significant, dose-dependent inhibition of gastric secretion (Tables I and II).

Table I.

Gastric secretion in rats with pylorus ligature after application of compounds of general formula I.

amount acid concentration Total acid (Ml) (Meq / ml) (MEq) water 4.7 + 0.7 0.12 + 0.005 0.56 + 0.09 (Control) OMSO 3.8 + 0.5 0.08 + 0.008 0.34 + 0.07 (Carrier) Connection A 125μηηοΙ ^ 4.7 + 0.4 0.08 + 0.008 0.37 + 0.06 250μΓηοΙ ^ 3,4 + 0,3 0.04 + 0.006 0.16 + 0.03 500μηηοΙ ^ 3.1 + 0.4 0.04 + 0.005 0.13 + 0.03

Table II

Gastric secretion in rats with pylorus ligature after application of compounds of general formula I.

amount acid concentration Total acid (Ml) (Meq / ml) (MEq) water 4.9 + 0.6 0.13 + 0.003 0.62 + 0.08 (Control) DMSO 5.1 + 0.4 0,10 + 0,006 0.50 + 0.05 (Carrier) Compound B 125μηιοΙ ^ 4.5 + 0.6 0.08 + 0.007 0.37 + 0.07 250μηιοΙ ^ 5.0 + 0.6 0.05 + 0.004 0.27 + 0.05 500μηιοΙ ^ 4.5 + 0.4 0.03 + 0.004 0.14 + 0.02

The compounds of the general formula I and their salts can be used as medicaments, for. B. in the form of pharmaceutical preparations use.

Such pharmaceutical preparations can be prepared by reacting compounds according to the invention with a suitable for enteral or parenteral administration, pharmaceutical, organic or inorganic carrier material, for example with water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline or the like mixed and solid dosage forms z. As to tablets, dragees, suppositories, capsules or liquid dosage forms z. B. processed into solutions, suspensions or emulsions. If appropriate, they are sterilized and / or mixed with auxiliaries, such as preservatives, stabilizers or emulsifiers, salts for varying the osmotic pressure or buffers. They can also be processed with other therapeutically valuable substances to combined preparations.

The following examples illustrate the invention.

embodiments example 1

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

(Formula I: R ₁ = CH ₃ , R ₂ -R ₆ = H, η = 0)

1.56 g (9.162 mmol) of 1,3-dihydro-5-methylthieno (2,3-d) imidazole-2-thione (Formula II: R ₁ = CH ₃ , R ₂ = H) and 1.33 g ( 8.108 mmol) of 2-chloromethylpyridine, hydrochloride are suspended in 40 ml of methanol and 8.64 ml of 2N NaOH (17.28 mmol) are slowly added dropwise with stirring over 20 minutes. The temperature rises to 29 ⁰ C and it forms a clear solution, from which after approx.

30 minutes already the product fails. The mixture is stirred for a further 2.5 hours at room temperature, then the solvent is largely removed under reduced pressure, the residue is taken up in 30 ml of water and adjusted to pH 4.5 by addition of 0.5 ml of glacial acetic acid. It is shaken four times with 25 ml of chloroform, the combined organic phases dried over sodium sulfate and evaporated. The crude product (2.0 g, 94% of theory) is crystallized from acetonitrile.

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

Mp = 171-172 ⁰ C (CH ₃ CN)

The starting material can be prepared as follows:

2-acetylamino-5-methyl-3-thiophenecarboxylate

(XIa: R ₁ = CH ₃ , R ₂ = H)

284.0 g (1.659 mol) of methyl 2-amino-5-methyl-3-thiophenecarboxylate (IVa, known from the literature) are stirred in portions in 600 ml of acetic anhydride, the temperature being maintained between 18 ° C and 25 ° C by intermediate ice-cooling. After stirring for 2.5 hours, it is evaporated in vacuo and the brownish crystalline residue is recrystallized from diisopropyl ether.

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

Fp = 100-101 ⁰ C (diisopropyl ether)

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

(XII: R ₁ = CH ₃ , R ₂ = H)

200,0g (0,938 mol) of 2-acetylamino-5-methyl-3-thiophencarbonsäuremethylesterwerden in 1400ml methanol at 5O ⁰ Ceingerührt.

With mechanical stirring, a solution of 37.6 g (0.940 mmol) of NaOH in 970 ml of water is added dropwise in the boiling heat over 2.5 hours. The mixture is refluxed for a further 30 minutes and the solution is largely evaporated after cooling. The remaining residue is taken up in 1800 ml of water and 200 ml of saturated sodium bicarbonate solution and extracted three times with 250 ml of methylene chloride each time. The aqueous phase is treated with conc. Hydrochloric acid acidified to pH = 1, the precipitate filtered off with suction, washed three times with water and dried for 3 hours in a convection oven at 7O ⁰ C.

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

Mp = 197-198 ⁰ C (MeOH)

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

(XIII: R ₁ = CH ₂ R ₂ = H)

170.0 g (0.853 mol) of 2-acetylamino-5-methyl-3-thiophenecarboxylic acid (XII) are suspended in 800 ml of acetic anhydride and refluxed for 2.5 hours. 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)

Mp = 140 ° C (diisopropyl ether) '

2-acetylamino-5-methyl-3-thiophencarbonsäureazid

(XIV: R ₁ = CH ₃ , R ₂ = 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 treated with a solution of 51.7 g ( 0.795 mol) of sodium azide in 170 ml of water. The mixture is stirred slowly at room temperature for 50 hours and a total of 23.8 ml (0.397 mol) of glacial acetic acid in 4 portions are added at intervals of 8-12 hours.

Subsequently, the phases are separated and the organic phase evaporated at a bath temperature of 40 ⁰ 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 extracted twice 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.

Mp = 78-79 ⁰ C (MeOH)

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

(XV: R ₁ = CH ₃ , R = H)

16.3 g (72.7 mmol) of 2-acetylamino-5-methyl-3-thiophencarbonsäureazid be in 250ml absol. Dissolved dioxane and heated at 100 ⁰ C for 4.5 hours. The dark solution is allowed to cool overnight, the precipitate was filtered off with suction, the mother liquor concentrated to half the volume, left to crystallize and again filtered with suction.

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

Mp = 200 ⁰ C dec. (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-methylthieno (2,3-dHmidazol-2-one are added at room temperature in 420 ml of 2N NaOH and stirred after complete dissolution for 15 minutes Deep red solution is acidified dropwise with concentrated HCl to pH = 2.5, cooled briefly in an ice bath, the precipitate is filtered off with suction and washed twice with cold water The crystals are dried at 70 ° C./20 mbar.

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

Mp = 275-278T Zers.

1,3-Dihydro-5-methyl-thieno (2,3-d) imidazol-2-thione

(II: R ₁ = CH ₃₁ R ₂ = H)

To 700ml abs. Pyridine, 25.0 g (0.162 mol) of 1,3-dihydro-5-methylthieno (2,3-d) imidazol-2-one and 27.0 g (0.122 mol) of P ₂ S _{6 are added} at room temperature with mechanical stirring , The suspension is heated under nitrogen in an oil bath, at about 100 ⁰ C, a clear red solution is formed. It is heated under reflux for 3 hours.

It is then cooled and the solvent is distilled off in vacuo. The dark viscous-oily residue is dissolved in 300 ml of 2N NaOH and this solution is poured slowly into a vigorously stirred mixture of 1100 ml of ethyl acetate and 400 ml of 3N HCl.

The mixture is stirred for 10 minutes, filtered with suction through a filter aid and the phases separated. The aqueous phase is shaken out a further four times with a total of 800 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate / activated charcoal and evaporated. The dark residue (12.4 g, 45% of theory) is dissolved in 90 ml of 2N NaOH, with charcoal

filtered and the clear red solution mitkonz. HCI acidified to pH = 2. The precipitated crystals are filtered off, washed twice with water and dried in vacuo at 60 ⁰ C.

 Yield: 9.8g light brown crystals (35.5% of theory) Fp = greater than 330 ° C, continuous decomposition.

Example 2

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

(I: R ₁ = CH ₃ , R ₂ , R ₃ , R ₅ and R ₆ = H, R ₄ = OCH ₃ , η =. 0)

3.46 g (20.3 mmol) of 1,3-dihydro-5-methylthieno (2,3) imidazole-2-thione and 3.35 g (17.3 mmol) of 2-chloromethyl-4-methoxypyridine hydrochloride are dissolved in 70 ml Ethanol and slowly added dropwise with stirring 18.8 ml (37.6 mmol) of 2N NaOH. The temperature rises to 29 ⁰ C and it forms a clear solution. It is stirred for 2 hours at room temperature and then the solution is largely evaporated in vacuo. The remaining residue is taken up in 70 ml of water and adjusted by adding about 1 ml of glacial acetic acid, a pH of 4.5. It is shaken out four times with a total of 300 ml of chloroform, the combined organic phases dried over sodium sulfate and evaporated.

The remaining oily residue is triturated with acetonitrile and dissolved at the boiling point in 280 ml of acetonitrile. It is filtered hot after addition of activated carbon, the solution was concentrated to 60ml, allowed to crystallize overnight in the refrigerator, filtered off with suction and washed with cold acetonitrile.

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

Mp = 173 ^° C (CH ₃ CN)

Example 3

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

(I: R ₁ -R ₆ = H, n = 0)

1.20 g (7.68 mmol) of 1,3-dihydro-thieno (2,3-d) imidazole-2-thione (II: R ₁ and R ₂ = H) and 1.13 g (6.91 mmol) 2- Chiormethylpyridine hydrochloride are dissolved in 15 ml of methanol and 7.4 ml (14.8 mmol) of 2N NaOH are added dropwise with stirring within 20 minutes. It is stirred for 1.5 hours at room temperature and then concentrated on a Rotavapor. The residue is partitioned between 60 ml of water and 80 ml of methylene chloride. For phase separation is filtered through a filter aid and the aqueous phase extracted three times with 70 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated.

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

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

Mp = 155-156 ⁰ C (CH ₃ CN)

The starting material can be prepared as follows:

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

(II: R ₁ and R ₂ = H)

20.0 g (0.143 mol) of 1,3-dihydro-thieno (2,3-d) imidazol-2-one (known from the literature) at room temperature with mechanical stirring in 500ml abs. Pyridine registered. Thereafter, 23.8 g (0.107 mol) of P ₂ S _{5 are} added and the mixture is refluxed for 5.5 hours. It is cooled and the solvent is largely distilled off in vacuo. The dark residue is dissolved in 300 ml of 2N NaOH and emptied with vigorous stirring into a mixture of 370 ml of 2N HCl and 400 ml of ethyl acetate. The biphasic mixture is filtered off with suction through a filter aid and the phases are separated. The aqueous phase is extracted six times with 150 ml of ethyl acetate, the combined organic phases dried over sodium sulfate and evaporated.

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

Fp = continuous decomposition

Example 4

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

(I: R ₁ , R ₂ , R ₃ , R ₅ and R ₆ = H, R ₄ = OCH ₃ , η = 0)

4.65 g (29.76 mmol) of 1,3-dihydro-thieno (2,3-d) imidazole-2-thione and 4.91 g (25.30 mmol) of 2-chloromethyl-4-methoxy-pyridine hydrochloride are dissolved in 60 ml of methanol are suspended and, with stirring, 27.6 ml (55.2 mmol) of 2N KOH are slowly added dropwise over the course of 25 minutes. The temperature rises to 32 ° C. After completion of the addition is stirred for 4 hours at room temperature.

The reaction mixture is then evaporated in vacuo, the residue taken up in 50 ml of water and adjusted by the dropwise addition of glacial acetic acid, a pH of 4.5. The precipitate is dissolved in 80 ml of chloroform, the mixture is shaken vigorously and filtered with suction through a filter aid for phase separation. The phases are separated and the aqueous extracted three more times with 40 ml of chloroform. 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 in the boiling heat, filtered hot with activated charcoal, concentrated to 150 ml and allowed to crystallize out.

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

Mp = 140-141 ⁰ C (CH ₃ CN)

Example 5

5-Acetyl-2 - ((4-methoxy-3,5-dimethyl-2-pyridyl) methylthio) -3H-thieno (2,3-d) imidazole (I: R ₁ = COCH ₃ , R ₂ and R ₆ = H, R ₃ and R ₅ = CH ₃ , R ₄ = OCH ₃ , η = 0)

5.64g (28.4mmol) of 5-acetyl-1,3-dihydro-thieno (2,3-d) imidazole-2-thione and 6.00g (27.0mmol) of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride are suspended in 250 ml of methanol and 28 ml of 2N NaOH (56.0 mmol) added dropwise with stirring over 15 minutes, the temperature rises to 27 ⁰ C. From the resulting solution precipitates the product after a short time.

It is stirred for a total of 4 hours at room temperature and then the reaction mixture is largely evaporated. The residue is taken up (in 200 ml of water and by addition of about 2 ml of glacial acetic acid, a pH of 4.5

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set. The suspension is shaken four times with a total of 350 ml of chloroform, the combined organic phases dried over sodium sulfate / charcoal and evaporated.

The remaining dark oil is crystallized with 80 ml of acetonitrile, cooled and the precipitate is filtered off with suction. It is washed three times with cold acetonitrile and dried at 40 ⁰ C in a vacuum.

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

Mp = 177-18O ⁰ C (CH ₃ CN)

The starting material can be prepared as follows:

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

(VIII: R ₁ = COCH ₃ , R ₂ = H)

In 180ml conc. H ₂ SO ₄ at -2O ⁰ C 30.0 g (0,1868mol) finely ground 1- (5-chloro-2-thienyl) -1-ethanone (Vila: Ri = COCH _3, R ₂ = H) with stirring entered. To the red-colored solution at a temperature between -2O ⁰ C and -25 ° C, a nitration mixture of 7.8ml fuming HNO ₃ (0.1868mol) and 30ml conc. H ₂ SO ₄ added dropwise within 35 minutes.

The mixture is stirred for 3QMinuten at -20 ⁰ C and then emptied the reaction mixture to 1400 ml of ice water. The precipitated product is taken up in 500 ml of methylene chloride and the aqueous phase extracted twice with 250 ml of methylene chloride. The combined organic phases are washed once with 300 ml of water, dried over sodium sulfate and evaporated.

The crude product (36.0 g, 93.8% of theory) contains about 10% of an impurity (higher in the TLC), which does not interfere with the further reaction, but can be removed by recrystallization from ethanol.

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

Fp = 8O ⁰ C (EtOH)

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

(IX: R ₁ = COCH ₃ , R ₂ = H)

In a solution of 22.0 g (0.108 mol) of 1- (5-chloro-4-nitro-2-thienyl) -1-ethanone in 250 ml of dry dioxane dry NH ₃ -GaS is introduced, the temperature up to 45 ° C. increases. After the exothermic reaction, the temperature is maintained by heating on a water bath at 5O ⁰ C and another 1.5 hours NH ₃ gas introduced.

It is then sucked off a precipitated precipitate, which is discarded. The filtrate is stirred at 50 ^° C. with activated charcoal, filtered again and evaporated. The remaining residue is recrystallized from acetonitrile.

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

Mp = 224-225 ° C (CH ₃ CN)

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

(II: R ₁ = COCH ₃ , R ₂ = H)

10.0 g (0.0537 mol) of 1- (5-amino-4-nitro-2-thienyl) -1-ethanone (IX: R ₁ = COCH ₃ , R ₂ = H) are dissolved in a mixture of 150 ml of methanol and 150 ml Dissolved dioxane and hydrogenated with 3 spoons of W ₂ -Raney nickel catalyst in a PARR medium pressure hydrogenation apparatus at room temperature to the calculated hydrogen uptake in 2.5 hours. The catalyst is filtered off with suction through a filter aid and washed well with methanol and dioxane.

The filtrate (consisting of X: R ₁ = COCH ₃ , R ₂ = H) is mixed with 8.39 g (0.0644 mol) of sodium methylxanthogenate and heated for 4 hours with stirring and reflux (temperature about 70 ° C). After cooling, it is largely evaporated and the residue dissolved in 250 ml of water. The solution is stirred for 10 minutes with two teaspoons of activated carbon and then filtered with suction through a filter aid. The filtrate is treated with conc. HCl slowly acidified with stirring to pH = 1, stirred briefly and the precipitated yellow precipitate was filtered off with suction. The crystals are dried for 2 hours at 90 ° C / 20mbar.

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

Mp = 302 ° C (decomp.)

Example 6

2 - ((4-methoxy-3,5-dimethyl-2-pyridyl) methylthio) -3H-thieno (2,3-d) imidazole-5-carboxylic acid methyl ester (I: R ₁ = COOCH ₃ , R ₂ and R ₆ = H, R ₃ = CH ₃ , R ₄ = OCH ₃ , η = 0)

The abovementioned compound of general formula 1 was analogously to the procedure described 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% d. Th.

Mp = 173 to 174.5 ⁰ C (CH ₃ CN)

The starting material was prepared by the reaction sequence indicated in Example 5 from δ-chloro-nitro-thiophene - carboxylic acid methyl ester (VIII: R ₁ = COOCH ₃ , R ₂ = H, known from the literature) via the 5-amino-4-nitro-2-thiophencarbonsäuremethylester (IX: R ₁ = COOCH ₃ , R ₂ = H, mp = 271 ° C dec.), Reduction to 4,5-diamino-2-thiophenecarboxylic acid methyl ester (X: R ₁ = COOCH ₃ , R ₂ = H) and reaction this compound prepared with sodium methylxanthogenate. This gives the 1,3-dihydro-thieno (2,3-d) imidazole-5-carboxylic acid methyl ester 2-thione (II:

R ₁ = COOCH ₃ , R ₂ = H; Mp = 279 ⁰ C, dec.).

Example 7

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

(I: R ₁ = COCH ₃ , R ₂ , R ₃ , R ₅ and R ₆ = H, R ₄ = OCH ₃ , η = 0)

1,30g (6,567mmol) of 5-acetyl-1,3-dihydro-thieno (2,3-d) imidazole-2-thione and 1,08g (5,565mmol) of 2-chloromethyl-4-methoxypyridine hydrochloride are dissolved in 15ml Methanol was added dropwise with stirring 6.2 ml of 2N NaOH (12.4 mmol) within 10 minutes, the temperature rises to 27 ° C. It is stirred for 1.5 hours at room temperature.

Subsequently, the reaction mixture is largely evaporated, the residue taken up in 50 ml of water and brought to pH = 4 by adding about 1 ml of glacial acetic acid. It is shaken three times with 40 ml of chloroform each, the combined

dried organic phases over sodium sulfate and evaporated. -

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

Yield: 0.76 g of colorless crystals (42.8% of theory)

Fp = 192-194 ⁰ C (CH ₃ CN)

Example 8

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

(I: R ₁ = COCH ₃ , R ₂ -R ₆ = H, η = 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 7 , 2 ml of 2N NaOH (14.4 mmol) added dropwise with stirring within 8 minutes, the temperature rises to 26 ° C. It is stirred for 2 more hours at room temperature.

The resulting clear solution is largely evaporated, the residue taken up in 80 ml of water and adjusted by addition of 1.2 ml of glacial acetic acid, a pH of 4.5. It is extracted three times with a total of 150 ml of chloroform, the organic phase dried over sodium sulfate and evaporated. The remaining crystals are recrystallized from acetonitrile.

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

Mp = 171-173 ⁰ C (CH ₃ CN)

Example 9:

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

(I: R ₁ = CH ₃ , R ₂ -R ₆ = H, η = 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 ⁰ C a solution of 0.76 g (3,749mmol) 85% ige3-Chlorperbenzoesäurein 10ml chloroform is added dropwise in 10 minutes under stirring. After complete addition 10 minutes is stirred at-1O ⁰ C.

The reaction mixture is washed twice with 10ml each. Shaken out sodium bicarbonate solution and the combined organic phases dried over sodium sulfate 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)

Mp = 175-176 ⁰ C dec. (CH ₃ CN)

Example 10

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

(I: R ₁ = .CH ₃ , R ₂ , R ₃ , R ₆ and R ₆ = H, R ₄ = OCH ₃ , η = 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 added dropwise within 20 minutes, a solution of 4.10 g (20.18 mmol) of 85% 3-chloroperbenzoic acid in 60 ml of chloroform at a temperature between -12 ° C and -8 ° C with stirring ,

After completion of the addition, stirring is continued at -1O ⁰ C for 10 minutes.

Then it is washed twice with 25ml each. Sodium bicarbonate extracted, the aqueous phases washed twice with a little chloroform, the combined organic phases dried over sodium sulfate and evaporated.

The remaining residue (about 6 g of reddish oil) is crystallized with a little acetonitrile and dissolved in 40 ml of DMF at 80 ⁰ C. It is filtered hot with charcoal, emptied into 220 ml of 60 ° C warm acetonitrile and allowed to cool slowly. The crystallization is completed overnight in the refrigerator. It is then filtered off with suction and washed with cold acetonitrile.

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

Mp = 183-184 ° C (DMF / CH ₃ CN) ,

Example 11

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

(I: R ₁ -R ₆ = Kn = D

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

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

The residue which crystallizes after trituration with acetonitrile (0.42 g, 87.7% of theory) is recrystallized from acetonitrile / activated carbon.

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

Mp = 151-152 ° C dec. (CH ₃ CN)

Example 12.

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

(I: R ₁ -R ₃ , R ₅ and R ₆ = H, R ₄ = OCH ₃ , η = 1)

4,30g (15,50mmol) 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 to -10 ⁰ C. cooled. Thereafter, a solution of 3.08 g (15.19 mmol) of 85% strength 3-chloroperbenzoic acid in 35 ml of chloroform is added dropwise with stirring at a temperature between -11 ⁰ C and -8 ° C within 30 minutes. The mixture is then stirred for 15 minutes at -10 ° C.

The solution is saturated twice with a total of 30 ml. Sodium bicarbonate extracted, the aqueous phase extracted three times with 20 ml of chloroform and the combined organic phases dried over sodium sulfate and evaporated.

The crude product (5.2 g of red oil) is triturated 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 warm acetonitrile. It is allowed to cool slowly and the crystallization in the refrigerator is completed overnight.

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

Mp = 157-159 ⁰ C dec. (CH ₃ CN)

Example 13

5-Acetyl-2 - ((4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl) -3H-thieno (2 _/ 3-d) imidazole (I: R ₁ = COCH ₃ , R ₂ and R ₆ = H, R ₃ and R ₆ = CH ₃ , R ₄ = OCH ₃ , η = 1)

4.5 g (12.95 mmol) of 5-acetyl-2- (4-methoxy-3,5-dimethyl-2-pyridyl) -nethylthio) -3H-thieno (2,3-d) -imidazole are dissolved in 120 ml of chloroform at room temperature almost completely dissolved and the solution cooled to -10 ⁰ C. At a temperature between -8 ° C and -10 ⁹ C, a solution of 2.58 g (12.69 mmol) of 85% 3-chloroperbenzoic acid in 40 ml of chloroform is added dropwise with stirring within 25 minutes.

It is stirred for 10 minutes at -1O ⁰ C and the now completely clear solution three times with a total of 60 ml sat.

Sodium bicarbonate solution extracted. The aqueous phase is washed three times with a little chloroform, the combined organic phases dried over sodium sulfate and evaporated.

The remaining residue (about 5 g of red oil) is dissolved in 50 ml of DMF at 80 ⁰ C and filtered with activated charcoal. The solution is emptied into 300 ml of 60 ^° C. acetonitrile, allowed to cool slowly, and the crystallization is completed overnight in the refrigerator. It is filtered off with suction and washed three times with acetonitrile.

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

Mp = 190-19I ⁰ C (DMFZCH ₃ CN)

Example 14

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

(I: R ₁ = COCH ₃ , R ₂ , R ₃ , R ₅ and R ₆ = H, R ₄ = OCH ₃ , η = 1)

0.53 g (1,628mmol) 5-Acetyl-2- (4-methoxy-2-pyridyl) methylthio) -3H-thieno (2,3-d) imidazole are suspended in 15ml chloroform and at a temperature between -12 ⁰ C and -8 ° C is added dropwise a solution of 0.33 g (1.628 mmol) of 85% 3-chloroperbenzoic acid in 6 ml of chloroform with stirring in 7 minutes to give a clear solution. It is stirred for 10 minutes at -10 ° C. It is then washed twice with 6ml each. Sodium bicarbonate extracted, the aqueous phases shaken twice with 5 ml of chloroform, the combined organic phases dried over sodium sulfate and evaporated. The oily crude product is recrystallised from acetonitrile / activated carbon.

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

Mp = .159-162 ⁰ C dec. (CH ₃ CN)

Example 15

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

(I: R ₁ = COCH ₃ , R ₂ , R ₃ , R ₆ and R ₆ = H, R ₄ = OCH ₃ , η = 1)

0.53 g (1.628 mmol) of 5-acetyl-2- (4-methoxy-2-pyridyl) methylthio) -3H-thieno (2,3-d) imidazole are taken up in 15 ml of glacial acetic acid and at 5 to 10 ⁰ C with a Solution of 181 mg (1.628 mmol) of 30% H ₂ O ₂ slowly added, resulting in a clear solution. It is stirred for 20 minutes at room temperature. The mixture is then diluted with 100 ml of water, extracted by shaking three times with 20 ml of chloroform and the combined organic phases washed neutral with sodium bicarbonate solution, dried over sodium sulfate and concentrated. The oily crude product is recrystallized from acetonitrile / activated carbon.

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

Mp = 159-162 ° C dec. (CH ₃ CN)>

Example 16

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

(I: R ₁ = COCH ₃ , R ₂ -R ₆ = H, η = 1)

1.0 g (3.46 mol) of 5-acetyl-2- (2-pyridyl) methylthio-3H-thieno (2,3-d) imidazole is almost completely dissolved at room temperature in 15 ml of chloroform and the solution is cooled to 12 ° C. cooled. At a temperature between -14 ⁰ C and -9 ° C, a solution of 0.69 g (3.39 mmol) of 85% 3-chloroperbenzoic acid in 10 ml of chloroform is added dropwise within 10 minutes.

It is stirred for 10 minutes at -10 ⁰ C, the meanwhile completely clear solution diluted with a little chloroform and extracted twice with 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 with addition of activated carbon.

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

Mp = 194-197 ⁰ C (CH ₃ CN)

Example 17

2 - ((4-Methoxy-3,5-dimethyl-2-pyridyl) -methylsulfinyl) -3H-thieno (2,3-d) imidazole-5-carboxylic acid methyl ester (I: R ₁ = COOCH ₃ , R ₂ and R ₆ = H, R ₃ and R ₄ = OCH ₃ , η = 1)

The abovementioned compound of the general formula 1 is prepared analogously to the procedure described 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 the solvent.

Yield: 72.5% d. Th.

Mp = 179 to 179.5 ⁰ C (CH ₃ CN)

H H

XCH I

HX

Claims (1)

1. A process for preparing new derivatives of thieno (2,3-d) imidazoles of the general formula of the formula sheet, in the R _{1 is} hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, R _{2 is} hydrogen or lower alkyl, R ₃ , R ₅ and R _{6 are} independently hydrogen or lower alkyl, R _{4 is} hydrogen or lower alkoxy and η is 0 or 1, and of their pharmaceutically acceptable acid addition salts, characterized in that