HRP940853A2 - Process for the preparation of new thienyloxyactic acid derivatives - Google Patents

Description

The invention relates to a process for the preparation of new 2-thienyloxyacetic acids, which can be used in medicines for the treatment of thrombotic diseases.

Substances with antithrombotic effect have been known for a long time. Thus, for example, acetylsalicylic acid (aspirin) in high doses is also antithrombotic effective. At this high dosage, it can cause gastritis in many cases. And sulfated polysaccharides, such as heparins, have antithrombotic efficacy. Since these substances can cause bleeding, their use in human medicine is problematic.

It is also known that substances that inhibit the synthesis of thromboxane-A2, that is, block the thromboxane-A2 receptor, are antithrombotically effective. Such substances are, for example, described in US-PS 4,602,016, where phenoxyalkylimidazoles with an antithrombotic effect are described. Given that the pharmacological profile of the effect of this substance has not yet been fully verified and therefore it is not clear whether these substances can be used purposefully in human therapy, there is still a need for new compounds with antithrombotic effect.

We have now established that certain derivatives of 2-thienyloxyacetic acid can block thromboxane-A2 receptors.

The subject of the invention is therefore a process for the preparation of new derivatives of 2-thienyloxyacetic acid of formula I

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in which R means in the given example a phenyl or thienyl group substituted once or more with halogen, trifluoromethyl or C1-C4-alkyl, as well as pharmaceutically usable salts of compounds with formula I; thienyloxyacetic acid derivatives with the formula I and their salts are prepared according to the invention in such a way that the compound with the formula II

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in which R has the above meaning.

a) in an aqueous alkaline medium we oxidize with silver oxide into acid i

b) as desired in step a) of the process, convert the obtained free acid with formula I into a pharmaceutically acceptable salt with inorganic or organic bases.

As a halogen, fluorine, chlorine or bromine, especially chlorine, is primarily meant.

The term "C1-C4-alkyl" used in the description means straight or branched carbon groups with 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl.

Among the compounds with the general formula I, priority is given to those where R is phenyl or 4-chlorophenyl.

Particularly priority individual compounds are:

5-(2-(benzenesulfonylamino)-ethyl-2-thienyloxyacetic acid,

5-(2-(4-chloro-benzenesulfonylamino))-ethyl-2-thienyloxyacetic acid.

The easiest way to exchange matter according to the process according to the invention is to dissolve sulfonamide alcohol with formula II in 0.5-4.0 n, preferably in 2n alkaline hydroxide solution, add at least 2 equivalents of Ag2O and heat the suspension with stirring to a temperature of about 75 - 85°C. The reaction time lasts 2 - 3 hours.

Acids of formula I can be converted in the usual way with organic or inorganic bases into their pharmaceutically usable salts.

Salts are created, for example, by adding the cited compounds with formula I in a suitable solvent, e.g. in water or a lower aliphatic alcohol, e.g. methanol, ethanol, propanol or isopropanol, adding the equivalent amount of the desired base, ensuring good mixing and after completion of formation salt, we distill the solvent in a vacuum. In the given example, we can recrystallize the salts after isolation.

Pharmaceutically used salts are, for example, metal salts, especially alkaline or alkaline earth salts, such as sodium, potassium, magnesium or calcium salts. Other pharmaceutically usable salts are, for example, also ammonium salts, which crystallize very easily. The following are formed from ammonia or organic amines, for example mono-di- or ti-lower (alkyl, cycloalkyl or hydroxyalkyl)-amines, lower alkylenediamines or (hydroxy-lower alkyl or aryl-lower alkyl)-lower alkylammonium bases, such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)-aminomethane, benzyl-trimethyl ammonium hydroxide, etc.

For the process in terms of the invention, the used starting material with formula II can be prepared from known products in a manner known per se. We can especially synthesize them according to the following reaction scheme and according to the specific data in the examples.

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New compounds with formula I block thromboxane-A2 receptors in vitro and in vivo.

On the basis of these pharmacological properties, we can use the new compounds as medicine alone or in a mixture with other effective substances in the form of ordinary galenic preparations in diseases caused by thromboxane-A2, such as, for example, thrombosis, inflammation, high blood pressure, stroke, asthma , shock and angina pectoris.

To determine the antithrombotic effect, we compared the substance from example 1, 5-(2-benzenesulfonylamino)-ethyl)-2-thienyloxyacetic acid with dazoxiben (hydrochloride of 4-(2-(1H-imidazol-1-yl)ethoxy)benzoic acid ), an antithrombotic, which is clinically investigated, as described in example A. In this comparison, it was shown that the antithrombotic effect of the substance from example 1 greatly exceeds the effect of dazoxiben.

The compounds of formula I are intended for use in humans and can be administered in the usual manner, eg orally or parenterally. They are primarily given orally, where the daily dose is around 0.5 to 2 mg/kg of body weight. Depending on the general condition and age of the patient, the treating physician may also prescribe higher or lower doses of the appropriate substance with formula I, the type of disease and the type of preparation.

If we use substances according to the invention for prophylaxis, the doses range approximately in the same range as in the case of treatment. Oral administration is a priority also in the case of prophylaxis.

Compounds of formula I can be administered alone or together with other pharmaceutically active substances, where the content of compounds of formula I is between 0.1 and 99%. In general, the pharmaceutically active compounds are in a mixture with suitable inert excipients and/or carriers or diluents, such as, for example, pharmaceutically suitable solvents, with gelatin, with gum arabic, with milk sugar, with starch, with magnesium stearate, with talc, with vegetable oil , with polyalkylene glycol, with vaseline, etc.

Pharmaceutical preparations can be in a solid form, eg tablets, dragees, suppositories, capsules and others, in a semi-solid form eg ointments, or in a third form, eg as solutions, suspensions or emulsions. In the given example, they are sterilized and contain auxiliary substances, such as preservatives, stabilizers or emulsifiers, salt for changing the osmotic pressure and the like.

In particular, pharmaceutical preparations may contain the compounds of the invention in combination with other therapeutically useful substances. With them, we can formulate the compounds in terms of the invention, for example, together with the aforementioned auxiliary substances and, that is, carriers and diluents into combination preparations.

Example 1

5-(2-Benzolsulfonylamino)-ethyl)-2-thienyloxyacetic acid

Dissolve 19.3 g (0.1136 mol) of silver nitrate in 120 ml of distilled water and slowly add a solution of 4.54 g (0.1136 mol) of sodium hydroxide in 50 ml of distilled water while stirring. The resulting suspension of silver oxide is stirred for another 10 minutes, the precipitate is filtered and washed several times with distilled water.

9.3 g (0.028 mol) of amide N-(2-(2-(5-(2-hydroxy)-ethoxy)thienyl)-ethyl)-benzenesulfonic acid (II) are dissolved in 90 ml of 2 normal sodium alkali, add more moist silver oxide and heated to 80°C with mechanical stirring. After three hours at that temperature, cool, and filter the suspension through HYFLO. The clear sodium lye solution is acidified with approx. 6 ml of concentrated hydrochloric acid and extracted three times with 100 ml of ether each. The ether phase is shaken three times with 100 ml of saturated sodium bicarbonate solution, washed once and acidified with 50 ml of ether and acidified with concentrated hydrochloric acid. The aqueous phase is extracted twice with 150 ml of ether, the combined ether phases are dried over sodium sulfate, filtered and evaporated. The crystalline residue is digested with 30 ml of diisopropylether and filtered.

Result: 2.6 g of colorless crystals (26.4% theoretical.)

Melting point: 110-113°C (ether/diisopropylether)

1H-NMR: (CDCl3)

delta (ppm): 7.81; 7.71; 7.51; 7.42 (AB; 4H; Bz-H; JAB=8.0 Hz), 6.39; 6.35; 6,10; 6.06 (AB; 2H; Th-H3; Th-H4; JAB=3.8 Hz), 4.85 (t; 1H; -NH-), 4.61 (s; 2H; -O-CH2- COO-), 3.13 (t; 2H; N-CH2-; J=6Hz), 2.80 (t; 2H; Th-CH2-; J=6Hz)

13C-NMR: (DMSO)

delta (ppm); 169.0 (s; -COOH), 161.9 (s; Th-C2), 139.3 (s; Bz-C1), 137.1 (s; Bz-C4), 1291, (d; Bz- C3, B-C5), 128.2 (d; Bz-C2, Bz-C6), 127.4 (Th-C5), 122.4 (d; Th-C4), 105.1 (d; Th- C3), 69.4 (t; O-CH2-CO), 43.8 (t; -NH-CH2-), 29.9 (t; Th-CH2)

We can prepare the starting material as follows:

2-(2-thienyloxy)-ethanol

To 1600 ml of absolute ethylene glycol, add 323.7 ml of 5.4 m sodium methylate solution (1.75 moles). The relative mixture is heated and the resulting methanol is distilled off while blowing nitrogen through the reflux divider, until the temperature on the floor reaches 130°C. After the complete removal of methanol, add 187.5 g (1.15 moles) of 2-bromothiophene, 55.5 g of finely ground copper oxide and 5.6 g of sodium iodide, flush the apparatus briefly with nitrogen, close with a balloon and stir for 175 hours at 80 °C.

Then the reaction mixture is cooled and dried over HYFLO. Dilute the filtrate with 800 ml of water and slightly acidify with concentrated hydrochloric acid.

We extract four times with 400 ml of methylene chloride each (1600 ml in total). Shake the combined organic phases once with 200 ml of water, dry with sodium sulfate, filter and evaporate. We distill the rest.

Result: 102.7 g of colorless oil (62% theoretical)

Boiling point: 90.95°/0.6 mbar.

N-(2-(2-(5-(2-hydroxy)-ethoxy)-thienyl)-ethyl)-benzenesulfonic acid amide

Put 30 g (0.208 moles) of 2-(2-thienyloxy)-ethanol in 300 ml of absolute tetrahydrofuran and dissolve 50 mg of p-toluenesulfonic acid in it. Add 18.37 g (0.218 moles) of 3,4-dihydropyran to the solution and stir for 8 hours.

Cool to -20°C and, while stirring, slowly add 83.2 ml (0.208 moles) of a 2.5 m solution of n-butyllithium in n-hexane drop by drop, so that the temperature does not rise above -10°C. After that, let it warm up to room temperature and stir for 1 hour.

The reactive mixture is cooled to 10°C and after 30 minutes, a solution of 19.5 g (0.104 moles) of N-benzenesulfonylaziridine (DRP, 698597 (1939)) in 100 ml of absolute tetrahydrofuran is added dropwise at 10-15°C. Warm to room temperature. and mix for another 2 hours.

The mixture is emptied into 200 ml of 2N aqueous HCl and extracted three times with 120 ml of methylene chloride. The organic phases are dried over sodium sulfate and combined, filtered and evaporated. Transfer the residue to 300 ml of absolute methanol, add 2 ml of 30% methanolic hydrochloric acid and mix for 10 minutes at room temperature. After adding 2 g of sodium carbonate, evaporate in a vacuum.

Divide the residue between 250 ml of 1N aqueous sodium hydroxide solution and 200 ml of ether and wash the ether phase once with 50 ml of 1N sodium hydroxide solution. Combine the aqueous phases and wash twice with 100 ml of ether, acidify with about 25 ml of concentrated hydrochloric acid and extract three times, each time with 150 ml of methylene chloride. Dry the phase with methylene chloride over sodium sulfate, add 3 g of activated carbon, filter and evaporate.

Result: 33.3 g of dark red oil (97%,8 theoretical), which we use directly in the next stage.

Example 2

5-(2-(4-chloro-benzenesulfonylamino)-ethyl-2-thienyloxyacetic acid

Dissolve 15 g (0.099 moles) of silver nitrate in 90 ml of distilled water and slowly add a solution of 3.5 g (90.088 moles) of sodium hydroxide in 45 ml of distilled water drop by drop while stirring. The resulting suspension of silver oxide is stirred for another 10 minutes, the precipitate is filtered and washed several times with distilled water.

4.0 g (0.011 moles) of amide 4-chloro-N-(2-(2-/5-(2-hydroxy-ethoxy)-thienyl)ethyl)-benzenesulfonic acid (II) is dissolved in 40 ml of 2N aqueous sodium alkali, add wet silver oxide and heat to 80°C with mechanical stirring. After 3.5 hours at that temperature, let it cool down, suck off the suspension through HYFLO and wash with 2N aqueous sodium hydroxide solution. The clear solution of sodium lye is acidified with concentrated hydrochloric acid and extracted three times with 80 ml of ether.

The ether phase is shaken twice with 50 ml of saturated sodium bicarbonate solution, washed once with 50 ml of ether and acidified with concentrated hydrochloric acid. The aqueous phase is extracted twice with 150 ml of ether, the ether phases are combined and dried with sodium sulfate, filtered and poured. The crude product is recrystallized from toluene.

Result: 1.3 g of colorless crystals (31.7% of theory)

Melting point: 125 - 127 °C (toluene)

1H-NMR: (CDCl3)

delta (ppm): 7.81; 7.71; 7.51; 7.42 (AB; 4H; Bz-H; JAB=8.0 Hz), 6.39; 6.35; 6,10; 6.06 (AB; 2H; Th-H3; Th-H4; JAB=3.8 Hz), 4.85 (t; 1H; -NH-), 4.61 (s; 2H; -O-CH2- COO-), 3.13 (t; 2H; N-CH2-; J=6Hz), 2.80 (t; 2H; Th-CH2-; J=6Hz)

13C-NMR: (DMSO)

delta (ppm); 169.0 (s; -COOH), 161.9 (s; Th-C2), 139.3 (s; Bz-C1), 137.1 (s; Bz-C4), 1291, (d; Bz- C3, B-C5), 128.2 (d; Bz-C2, Bz-C6), 127.4 (Th-C5), 122.4 (d; Th-C4), 105.1 (d; Th- C3), 69.4 (t; O-CH2-CO), 43.8 (t; -NH-CH2-), 29.9 (t; Th-CH2)

We can prepare the output material as follows:

4-chloro-(2-(2-(5-(2-hydroxy)-ethoxy)-thienyl)-ethyl)-benzenesulfonic acid amide

We put 18.9 g (0.137 moles) of 2-(2-thienyloxy)-ethanol in 200 ml of absolute tetrahydrofuran and dissolve about 50 mg of p-toluenesulfonic acid in it. Add 14.2 g (0.169 moles) of 3,4-dihydropyran and stir for 8 hours.

Cool to -20°C and, while stirring, add dropwise 66 ml (0.165 moles of a 2.5m solution of n-butyllithium in n-hexane, so that the temperature does not rise above -15°C. Slowly let it warm to room temperature and we stir for another hour. Now we add dropwise a solution of 18 g (0.083 moles) of N-(4-chloro-benzenesulfonyl)-azaridine (V.I. Markov and D.A. Danileiko, Zh. Org. Khin 1973 (6), 1357) in 100 ml of absolute THF at -5 to 0°C. The reaction mixture is warmed to room temperature and stirred for another 30 minutes. The reaction mixture is placed in 200 ml of 2N aqueous HCl and extracted three times with 250 ml of methylene chloride each. The organic phases are collected, dried with sodium sulfate, filtered and evaporate. Place the residue in 100 ml of absolute methanol, add 10 ml of 30% methanolic hydrochloric acid and stir for 10 minutes at room temperature. Add a spoonful of sodium carbonate and distill off the methanol. Divide the residue between 100 ml of 1N aqueous sodium hydroxide solution and 100 ml of ether and the ether phase is then washed once with 100 ml 1n sodium lye. The collected aqueous phases are washed twice with 50 ml of ether, acidified with concentrated hydrochloric acid and extracted three times each time with 100 ml of methylene chloride. After that, dry with sodium sulfate, add activated carbon, filter and evaporate. We get 10.15 g of thick dark oil. This heavily polluted raw product is filtered through Kieselgel 60 (180 quartz gel, eluent: ethyl acetate: petroleum ether).

Result: 4.5 g of colorless crystal (15% theoretical)

Melting point: 85 - 87°C (benzene).

Example A

Investigation of antithrombotic efficacy

Male Wisttar rats (SPF) weighing 200 to 300 g were anesthetized with pentobarbital sodium (60 mg/kg i.p.). After that, the animals are intravenously initiated with the substance of example 1 ("substance A"), or dazoxiben (4-(2-(1H-imidazol-1-yl)ethoxy)benzoic acid hydrochloride) ("substance B"). We prepare the venule of the mesentery, attach it to the table for microscope objects with connectors and wash it with a constant 2.5 ml/min physiological saline solution. The laser beam of the Coherent CR 2 supergraphite ion laser (argon laser) is aimed half an hour after the injection of the test substance through the interference contrast objective of a 50 x Leitz Orthoplan microscope at a time of 1/30 sec. at the venule. The output energy under the microscope objective is 0.18 Watt. If after the first laser lesion (=laser hit) not a single flat thrombus is formed or if the thrombus does not match the diameter of the vessel in terms of length and width, we make new laser hits with the intention of creating a thrombus, which corresponds in length and width to the diameter of the vessel.

The number of laser hits is the benchmark for the antithrombotic effectiveness of the tests. The greater the number of laser hits for one vessel diameter, the stronger the antithrombotic effect.

Animals that did not receive the test are used as controls.

We perform the tests with regard to the test substance and concentration on five animals, where three vessels with a diameter between 20 and 30 μm were damaged on each animal. We make a statistical evaluation according to the Kruskal and Wallis test and according to Dunn's cumulative rank test.

The results:

The results of the experiment are summarized in table 1.

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Discussion:

The onset of the antithrombotic effect is for substance A at 1 mg/kg of body weight and reaches a maximum at 5 mg/kg. With a further increase in concentration, we do not achieve a further increase in effect. In order to achieve an effect comparable to the maximum effect of substance A with substance B, an injection of 20 mg/kg is required, i.e. four times the amount.

Claims (11)

1. Process for the preparation of new derivatives of 2-thienyloxy-acetic acid with formula I [image] in which R means, in the given example, a phenyl or thienyl group substituted one or more times with halogen, trifluoromethyl or C1-C4-alkyl, as well as pharmaceutically usable salts of compounds with formula I, indicated by the fact that a) compound with formula II [image] in which R is defined as above, is oxidized in an aqueous alkaline medium with silver oxide in acid i b) in the given example, in step a) of the process, the obtained free acid with formula I is converted into a pharmaceutically acceptable salt with inorganic or organic bases. 2. The method according to claim 1, characterized in that the compound with formula II is dissolved in a 0.5-4n alkaline hydroxide solution and oxidized to acid with at least 2 equivalents of Ag2O at a temperature of 75 to 85° for two to three hours. 3. The process according to one of claims 1 or 2, characterized by dissolving the compound of formula II in 2n NaOH or KOH. 4. The process according to one of the requirements from 1 to 3, indicated by the fact that the Ag2O required for oxidation is prepared before the oxidation itself by dissolving silver nitrate in distilled water and adding equimolar amounts of NaOH solution. 5. New derivatives of 2-thienyloxyacetic acid with general formula I [image] characterized by the fact that in the given example a phenyl or thienyl group substituted one or more times with halogen, trifluoromethyl or C1-C4-alkyl, as well as their pharmaceutically usable salts. 6. Compounds with general formula I, in claim 1 indicated by R meaning phenyl. 7. Compounds according to one of claims 1 or 2, characterized in that it means an unsubstituted phenyl nucleus. 8. Pharmaceutical preparations, characterized in that they contain compounds with the general formula I according to claim 1 or their salt in combination with ordinary galenic auxiliary substances and/or carriers. 9. Preparations, characterized in that they contain compounds with the general formula I according to claim 1 or their salt in combination with other therapeutically valuable and effective substances as well as with usual auxiliary substances and/or carriers. 10. Compounds according to claim 1, characterized in that they are thromboxane-A2 receptor blockers. 11. Compounds according to claim 1, characterized in that they are for use as active substances for drugs both for the treatment and for the prophylaxis of diseases caused by thromboxane-A2.