DK172258B1 - Thienyloxyacetic acid derivatives, a process for preparing them, pharmaceutical preparations which comprise such derivatives, and their use - Google Patents

Description

in DK 172258 B1

The invention relates to novel 2-thienyloxyacetic acid derivatives, a process for their preparation and pharmaceutical compositions containing these substances as well as their use.

Substances with antithrombotic effects have long been known. Thus, for example, acetylsalicylic acid (aspirin) at high doses is also antithrombic. However, these high doses can in many cases cause inflammation of the gastric mucosa (gastritis).

Also, sulfated polysaccharides such as heparin have an antithrombotic effect.

However, as these substances can cause bleeding, their use as a human medicine 10 is problematic.

It is also known that substances which inhibit thromboxane A2 synthesis, for example by blocking the thromboxane A2 receptor, are antithrombotic. Such substances are described, for example, in U.S. Patent No. 4,602,016, in which phenoxyalkylimidazole having an antithrombotic effect is disclosed. However, as the pharmacological efficacy profile of these substances has not yet been fully tested, and it is not clear whether these substances are also truly applicable in human therapy, there is a need for new compounds with antithrombotic effects in the future.

It has now been found that certain 2-thienyloxyacetic acid derivatives can block thromboxane A2 receptors.

The invention therefore relates to novel derivatives of 2-thienyloxyacetic acid of general formula I 25 ΓΥ

R-IT ^ COOH I

Wherein R is a phenyl or thienyl group, which is optionally substituted one or more times with halogen, trifluoromethyl or C 1 -C 4 alkyl, and their pharmaceutically acceptable salts, a process for their preparation, pharmaceutical compositions containing these compounds, as well as their use. In the case of halogen, fluorine, chlorine or bromine, especially chlorine, is preferably proposed. The term "C 1 -C 4 alkyl" used in this specification refers to straight or branched hydrocarbon groups having 1-4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl.

Of compounds of the general formula I, those in which R is as phenyl or 4-chlorophenyl are preferred.

Particularly preferred single compounds are: 5- (2- (benzenesulfonylamino) ethyl) -2-thienyloxyacetic acid and 5- (2- (4-chlorobenzenesulfonylamino) ethyl) -2-thienyloxyacetic acid.

The compounds of general formula I and their salts are prepared according to the invention in that a) a compound of formula II: 20 R-SO 2 N 2 nf n in which R has the above meaning is oxidized in aqueous alkaline medium with silver oxide to acid and, b) if desired, a free acid obtained in the preparation step a) of the general formula I with inorganic or organic bases is converted into a pharmaceutically acceptable salt.

30

The reaction of the process according to the invention is most advantageously carried out so as to deposit the sulfonamide alcohol of formula II, dissolved in 0.5-4.0 N, preferably 2N alkali hydroxide solution, with at least two equivalents of Ag2O and heat the suspension with stirring to a temperature of about 75-85 ° C. Reaction time 35 amounts to approx. 2-3 hours.

3 DK 172258 B1

The acids of general formula I can be transferred in their usual manner with inorganic or organic bases into their pharmaceutically acceptable salts. The salt bond can be carried out, for example, by dissolving said compounds of formula I in a suitable solvent, eg water or a lower aliphatic alcohol, for example methanol, ethanol, propanol or isopropanol, adding an equivalent amount of the desired base, providing good mixing and after completion of salt bonding, the solvent distills off in vacuo. Where appropriate, the salts may be recrystallized after isolation.

Pharmaceutically acceptable salts are, for example, metal salts, especially alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts. Other pharmaceutically acceptable salts, for example, are also easily crystallizable ammonium salts. The latter is derived from ammonia or organic amines, e.g., mono-, di- or tri-low (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkyl diamine or (hydroxy-low alkyl or aryl-low alkyl) -lavalkylammonium bases, such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine.

tris (hydroxymethyl) aminomethane, benzyl trimethylammonium hydroxide and the like.

The starting compounds of formula II 20 used in the process of the invention can be prepared in a manner known per se from known products. In particular, they can be synthesized according to the following reaction scheme and the specific indications in the examples.

4 DK 172258 B1

Scheme

R-SO 2 Cl + Hif-CttrCHrOH III VI

V

SQR-R ^ H-CH-CHrOH

ζΚ— », n |

IV

R-SQ? -KH "CH * CHrCl

VIII

Q - 1

^ o ^ R-SOr-N

V —IX

R - SO?

H

X

''

II

5 DK 172258 B1

The novel compounds of formula I block in vitro and in vivo thromboxane A2 receptors.

Because of these pharmacological properties, the new compounds can be used as drugs alone or in admixture with other active substances in the form of usual 5 galenic preparations for diseases caused by thromboxane-A2, such as thrombosis, inflammation, high blood pressure, cerebral haemorrhage, asthma, shock and angina pectoris (angina pectoris).

To determine the antithrombotic effect, the substance of Example 1, 5- (2-10 (benzenesulfonylamino) ethyl) -2-thienyloxyacetic acid, compared to dazoxibene, (4- (2- (1H-imidazol-1-yl) ethoxy) benzoic acid hydrochloride, an antithrombotic drug included in the clinical trial, as described in Example A. By this comparison, it was found that the antithrombotic effect of the substance of Example 1 is clearly superior to that of dazoxibene.

15

Compounds of general formula I are intended for use in humans and may be administered in the usual manner, for example, orally or parenterally. Preferably, they are administered orally, whereby the daily dose amounts to approx. 0.05 to 20 mg / kg, preferably 0.5 to 5.0 mg / kg body weight. However, depending on the general condition and age of the patient, the particular compound of formula 1, the nature of the disease and the type of formulation, the treating physician may also prescribe doses above or below.

In case the compound of the invention is used for prophylaxis, the doses move approximately in the same ranges as in the case of treatment. Oral administration 25 is also preferred in the case of prophylaxis.

The invention also relates to pharmaceutical compositions which are characterized in that they contain compounds of the general formula I according to claim 1 or salts thereof in combination with other therapeutically active substances as well as conventional galenic adjuvants, carriers and / or diluents.

Compounds of formula I can be administered alone or in conjunction with other pharmaceutically active substances, the content of compounds of formula I being between 0.1 and 99%. In general, the pharmaceutically active compounds are in admixture with suitable inert auxiliaries and / or carriers or antifouling agents, such as, for example, pharmaceutical solvents considered to be harmless, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, vaseline and the like.

The pharmaceutical compositions may be in solid form, for example, as tablets, coated tablets, suppositories, capsules and the like, in semi-solid form, for example as ointments or in liquid form, for example as solutions, suspensions or emulsions. They are optionally sterilized and contain adjuvants such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or the like.

10

In particular, pharmaceutical compositions may contain compounds of the invention in combination with other therapeutically valuable substances. With these, the inventive compounds can be formulated, for example, together with the above adjuvants and / or carriers or diluents for combination preparations.

In a further aspect, the invention relates to compounds of formula I for use as active substances in drugs for the treatment and prophylaxis of diseases caused by thromboxane-A2.

20

Example 1 5- (2- (Benzenesulfonylamino) ethyl) -2-thienyloxyacetic acid 19.3 g (0.1136 mol) of silver nitrate is dissolved in 120 ml of distilled water and slowly added dropwise with a solution of 4.54 g (0.1136 mol) sodium hydroxide in 50 ml of distilled water. The resulting suspension of silver oxide is stirred for another 10 minutes, the precipitate is filtered off and washed several times with distilled water.

Dissolve 9.3 g (0.028 mol) of N- (2- (2- (5- (2-hydroxy) ethoxy) thienyl) ethyl) benzenesulfonic acid amide (II) in 90 ml of 2N aqueous sodium hydroxide solution, add the still moist silver oxide and heat. with mechanical stirring to 80 ° C. After 3 hours at this temperature, the suspension is cooled and filtered over HYFLO. The clear aqueous sodium hydroxide solution is acidified by ca. 6 ml of concentrated hydrochloric acid and extracted three times with 100 ml of ether. The ether phase is shaken three times with 100 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 combined ether phase is dried over sodium sulfate, filtered and evaporated. The crystalline residue 5 is dissolved and filtered off with 30 ml of diisopropyl ether.

Yield: 2.6 g of colorless crystals (26.4% of theory); mp: 110-113 ° C (ether / diisopropyl ether).

1 H NMR: (DMSO) delta (ppm): 9.16 (s; broad; 1H; -COOH), 7.67 - 7.80 (m; 2H; B-H2> BH +), 7.47 -7.55 (m; 3H; B-H3, B-H4, B-H5), 7.27; 7.33; 7.47 (t; 1H; -NH-) 6.02; 6.06; 6.33; 6.38 (AB; 2H; Th-H 2; Th-H 3; 34 = 3.7 Hz), 4.51 (s; 2H; O-CH 2 -CO), 2.57 - 2.99 (m 4 H; -CH 2 -CH 2 -) 1 C NMR: (DMSO) delta (ppm): 169.1 (s; -COOH), 162.0 (s; Th-C 2), 140.3 (s) ; Β-Οχ), 131.8 (s;

B-C4), 128.5 (d; B-C3.B-C5), 127.7 (s; Th-C5), 126.3 (d; B-C2, B-C6), 122.0 ( d; Th-C 4), 105.3 (d; Th-C 3), 69.5 (t; O-CH 2 -CO), 43.8 (t; -NH-CH 2 -), 30.2 (t; Th-CH 2 -X

The starting material can be prepared as follows: 2- (2-thienyloxy) ethanol

To 1600 ml of absolute ethylene glycol is added 323.7 ml of 5.4 M sodium methylate solution 30 (1.75 mol). The reaction mixture is heated and the methanol formed is distilled off under nitrogen over a reflux divider until the mixture temperature rises to 130 ° C. After methanol removal is complete, 187.5 g (1.15 mole) of 2-bromothiophene, 5.5 g of finely ground copper oxide and 5.6 g of sodium iodide are added again briefly with nitrogen, closed with a balloon and stirred for 275 hours. 80 ° C. Then, the reaction mixture is cooled and suctioned over HYFLO. The filtrate is diluted with 800 ml of water and slightly acidified with concentrated hydrochloric acid. Extract four times with 400 ml of methylene chloride (1600 ml in total). The combined organic phase is shaken with 200 ml of water, dried over sodium sulfate, filtered and evaporated. The residue is distilled.

Yield: 102.7 g of colorless oil (62% of theory) boiling point: 90-95 ° C / 0.6 mbar.

N- (2- (2- (5- (2-hydroxy) ethoxvHhienvnethvPbenzensulfonsvreamid.

30 g (0.208 mol) of 2- (2-thienyloxy) ethanol are added to 300 ml of absolute tetrahydrofuran and 50 mg of p-toluenesulfonic acid is dissolved therein. The solution is added 18.37 g (0.218 mol) of 3,4-dihydropyran and stirred for 8 hours. It is cooled to -20 ° C and, with stirring, 83.2 ml (0.208 mole) of 2.5M solution of n-butyllithium in n-hexane are dropped so that the temperature does not exceed -10 ° C. It is allowed to warm to room temperature and stirred for 1 hour.

The reaction mixture is cooled to 10 ° C and, over 30 minutes, a solution of 19.05 g (0.104 mol) of N-benzenesulfonylaziridine (DRP. 698597 (1939)) in 100 ml of absolute THF at 10-15 ° C is dropped. Heat to room temperature and stir for another 2 hours.

20

The mixture is poured into 200 ml of 2N aqueous HCl and extracted three times with 120 ml of methylene chloride each. The combined organic phase is dried over sodium sulfate, filtered and evaporated. The residue is taken up in 300 ml of absolute methanol, left with 2 ml of 30% methanolic hydrochloric acid and stirred for 10 minutes at room temperature. After adding 25 g of sodium carbonate, evaporate in vacuo.

The residue is partitioned between 250 ml 1N aqueous sodium hydroxide solution and 200 ml ether and the ether phase is washed once with 50 ml 1N sodium hydroxide solution.

The combined aqueous phase is washed twice with 100 ml of ether each, extracted with ca.

25 ml of concentrated hydrochloric acid and extracted three times with 150 ml of methylene chloride each. The methylene chloride phase is dried over sodium sulfate and left with 3 g of activated carbon, filtered and evaporated.

9 DK 172258 B1

Yield: 33.3 g of dark red oil (97.8% of theory), which is used directly in the next step.

Example 2 5- (2- (4-Chlorobenzenesulfonylamino) ethyl) -2-thienyloxyacetic acid.

15 g (0.088 mole) of silver nitrate was dissolved in 90 ml of distilled water and a solution of 3.5 g (0.088 mole) of sodium hydroxide in 45 ml of distilled water was added dropwise. The resulting suspension of silver oxide was stirred for another 10 minutes and the precipitate was filtered off and washed several times with distilled water.

4.0 g (0.011 mol) of 4-chloro-N- (2- (2- (5- (2-hydroxy) ethoxy) thienyl) ethyl) -benzenesulfonic acid amide (II) was dissolved in 40 ml of 2N aqueous sodium hydroxide solution, added the still moist silver oxide and heated under mechanical stirring to 80 ° C. After 3.5 hours at this temperature, it was cooled and the suspension was aspirated over HYFLO and washed with 2N aqueous sodium hydroxide solution. The clear sodium hydroxide solution was extracted with concentrated hydrochloric acid and extracted three times with 80 ml of ether each.

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

Yield: 1.3 g of colorless crystals (31.7% of theory) freezing point: 125-127 ° C (toluene).

1 H-NMR: (CDCl 3) 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-Hz,; JAB =?> 8 Hz), 4.85 (t; 1H; -NH-), 4.61 (s; 2H; -O-CH 2 -COO-), 3.13 (t; 2H; N-CH 2 -; J = 6Hz), 2.80 (t; 2H; Th-CH 2 -; J = 6Hz); : (DMSO) delta (ppm): 169.0 (s; -COOH), 161.9 (s; Th-C 2), 139.3 (s; Bz-C *), 137.1 (s; Βζ- ϋή), 129.1 (d; BZ-C3, B-C3), 128.2 (d; Bz-C2. Bz-C6>. 127> * (Th-Cj), 122.4 (dj Th-Czj ), 103.1 (d; Th-C 3), 69.4 (t; O-CH 2 -CO), 43.8 (t; -NH-CH 2 -), 29.9 (t; Th-CH 2)

The starting material can be prepared as follows: 4-chloro- (2- (2- (5- (2-hydroxy) ethoxy) thienyl) ethylene benzenesulfonic acetic acid.

18.9 g (0.137 mol) of 2- (2-thienyloxy) ethanol were pre-loaded in 200 ml of absolute tetrahydrofuran and ca. 50 mg of p-toluenesulfonic acid dissolved therein. 14.2 g (0.169 mol) of 3,4-dihydropyran was added and stirred for 8 hours.

It was cooled to -20 ° C and, with stirring, 66 ml (0.165 mol) of 2.5M solution of n-butyllithium in n-hexane was added dropwise so that the temperature did not exceed -15 ° C. Heating was allowed to warm slowly to room temperature and further stirred for 1 hour.

Next, a solution of 18 g (0.083 mole) of N- (4-chlorobenzenesulfonyl) aziridine (V.I.

Markov & D.A. Danileiko, Zh.Org.Khim 1973 (6), 1357) in 100 ml of absolute THF at -5 to 0 ° C. The reaction mixture was warmed to room temperature and stirred for another 30 minutes.

The reaction mixture was poured into 200 ml of 2N aqueous HCl and extracted three times with 250 ml of methylene chloride each. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue was taken up in 100 ml of absolute methanol, added with 10 ml of 30% methanolic hydrochloric acid and stirred for 10 minutes at room temperature. A spoonful of sodium carbonate was added and the methanol distilled off. The residue was partitioned between 100 ml 1N aqueous sodium hydroxide solution and 100 ml ether and the ether phase was washed once with 100 ml 1N sodium hydroxide solution. The combined aqueous phase was washed twice with 50 ml of ether, acidified with concentrated hydrochloric acid and extracted three times with 100 ml of methylene chloride each. Next, dried over sodium sulfate, with activated charcoal, filtered and evaporated. 10.15 g of a cool dark oil were obtained. This highly contaminated crude product was filtered over silica gel 60 (180 g silica gel, 35 eluent: ethyl acetate / petroleum ether).

n DK 172258 B1

Yield: 4.5 g of colorless crystals (15% of theory) freezing point: 85-87 ° C (benzene).

Example A:

Investigation of the antithrombotic effect.

Male Wistar rats (SPF) weighing 200-300 g were anesthetized with pentobarbital sodium 10 (60 mg / kg i.p.). Next, the substance of Example 1 was 5- (2- (benzenesulfonylamino) -ethyl-2-thienyloxyacetic acid ("Substance A") or dazoxibene (4- (2-1H-imidazol-1-yl) ethoxy) benzoic acid hydrochloride ("Substance") B ") intravenously injected into the animals. A mesentery vein was freely operated, clamped to a microscope object and rinsed with a constant 2.5 ml / min physiological saline solution. passed through the interference contrast lens, 50 x Leitz Orthoplan Microscope, with a duration of 1/30 s, on the venol The output energy under the microscope lens amounted to 0.18 W. When no thrombus spot is formed after the first laser lesion (= laser shot) or when the length is reached and the width of the thrombus not 20 corresponded to the average tissue, additional laser shots were inserted to produce a thrombus that in length and width corresponded to the average tissue.

The number of laser shots is thereby a measure of the antithrombotic effect of the test substance: the greater the number of laser shots at the same card diameter, the stronger the antithrombotic effect.

As control animals, those who received no test substance served.

The tests were performed for each test substance and concentration of 5 animals, with each animal 30 being damaged three vessels with diameters between 2 to 30 mm. The statistical calculations then followed the Kruskal and Wallis tests and after Dunn.

Result: 35 The results of the experiment are summarized below: 12 DK 172258 B1

Concentration Number of laser shots (mean)

mg / ml Subst. A Subst. B

0 (control) 2.93 ± 0.36 2.93 ± 0.36 5 1 3.12 ± 0.52 3.07 ± 0.47 5. 6.40 ± 0.56 2.89 ± 0.57 10 6.13 ± 0.30 3.14 ± 0.66 6.33 ± 0.53 4.46 ± 0.48 6.42 ± 0.41 6.35 ± 0.55 10

Discussion:

The onset of antithrombotic activity is at substance A at 1 mg / kg body weight and reaches a maximum effect at 5 mg / kg. A further increase of 15 concentrations brings no further increase in effect. In order to achieve an effect for substance B comparable to the maximum effect of substance A, an injection of 20 mg / kg, ie the four-fold amount, is necessary.

Claims (9)

1. 2-thienyloxyacetic acid derivatives of the general formula I in which R is a phenyl or thienyl group optionally or once substituted with halogen, trifluoromethyl or C1-C4 alkyl, or their pharmaceutically acceptable salts. 15 Compounds according to claim 1, characterized in that R is phenyl. Compounds according to claim 1, characterized in that R is 4-chlorophenyl. Compound according to claim 1, characterized in that it is 5- (2- (benzenesulfonylamino) ethyl) -2-thienyloxyacetic acid. Compound according to claim 1, characterized in that it is 5- (2- (4-chlorobenzenesulfonylamino) ethyl) -2-thienyloxyacetic acid. 25 Process for the preparation of compounds according to claim 1 of the general formula I or their salts, characterized in that (a) a compound of formula II 30 ΓΛ - R - SOpN n in which R is defined as above, is oxidized in aqueous alkaline medium with silver oxide to acid and, if desired, a free acid obtained in preparation step a) of the general formula I (with inorganic or organic bases) is transferred into a pharmaceutically acceptable salt. Pharmaceutical compositions, characterized in that they contain compounds of the general formula I according to claim 1 or salts thereof in combination with conventional galenic adjuvants, carriers and / or diluents. Pharmaceutical preparations, characterized in that they contain compounds of the general formula I according to claim 1 or salts thereof in combination with other therapeutically active substances as well as conventional galenic adjuvants, carriers and / or diluents. 15 Compounds according to claim 1 for use as active substances in drugs for the treatment and prophylaxis of diseases caused by thromboxane-A2.