NO144794B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE BENZOFURAND DERIVATIVES - Google Patents

Description

The present invention relates to an analogous method for the production of pharmacologically active acetamidoxime derivatives of benzofuran, which may occur in racemic form or in the form of their optically active isomers and which have the following general formula:

where means a branched or linear alkyl group having from 1 to 4 carbon atoms and

R2 means a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino or heptamethyleneimino group or a 1-piperazino group substituted in the 4-position by a linear alkyl group with 1 to 4 carbon atoms,

X means a hydrogen or chlorine atom,

and pharmaceutically acceptable acid addition salts thereof,

and where the method is characterized by calling

opening of a 3,4-disubstituted-1,2,4-A-oxadiazol-5-one of the general formula:

or an acid addition salt thereof, where R^, and X have the same meanings as in formula I, and the compound obtained about-

is optionally formed into an acid addition salt thereof. The ring opening can be carried out using known methods, e.g.

by heating the compound in an aqueous alcoholic medium in the presence of a base, e.g. sodium hydroxide.

The compounds of formula II can be prepared by reaction in an organic medium such as e.g. anhydrous acetone containing a small amount of methyl alcohol, and in the presence of a base such as e.g. anhydrous potassium carbonate, of a 3-substituted 1,2,4-A<2->oxadiazol-5-one of the general formula: where R^ and X have the same meanings as in formula I, with a chloroalkylamine, preferably in form of its hydrochloride salt, represented by the general formula:

where R_ has the same meanings as in formula I.

The connections; with formula IV is already known. The compounds of formula III can be prepared using known methods, e.g. by reacting, in absolute ethanol containing a base such as e.g. sodium ethylate, an amidoxime derivative with the general formula:

or an acid addition salt thereof, where R, and X have the same meanings as in example I, with anhydrous diethyl carbonate.

The compounds of formula V can be prepared using methods that are described in many places in the literature. A particularly advantageous method consists in reacting, in an alcoholic medium containing a base such as e.g. sodium methylate or sodium ethylate, a compound with the general formula:

where and X have the same meanings as in formula I, with hydroxylamine hydrochloride. • ■

The compounds of formula VI are already known and are described by Areschka et al., in Chimie Thérapeutique 7, 3 37

(1972), or can be produced by the method described in the aforementioned publication. - The compounds produced according to the invention have been found to have useful pharmacological properties which give them considerable value in the treatment of disturbances in the cardiovascular system, which are expressed in too high or too low blood pressure. Pathological disturbances of blood pressure, especially hypertension, can thus be treated by administering at least one compound of formula r or a pharmacologically acceptable acid addition salt thereof to the sick person. The predominant types of high blood pressure are essential and malignant high blood pressure, and there is no specific therapy for these diseases, as individual cases vary greatly in response to different medications. There are therefore many blood pressure lowering agents that are used to treat different types of high blood pressure.

Among these, ganglion blocking agents are known for

to exert a ganglioplegic effect in that they interrupt the sympatho-cotonic impulses and thus cause relaxation of the vessel walls. This phenomenon can be dangerous in cases where the patient needs increased tonicity in the vessel walls as a result of, for example, a change in position. As can be seen later, the compounds prepared according to the invention are free from ganglioplegic effects.

Other blood pressure-lowering agents, such as e.g. the veratrum alkaloids, are characterized by a rather narrow margin between their therapeutic and toxic doses. Overdosing can be dangerous and the doctor must choose the dosage carefully and continuously adjust it according to the needs and the patient's response. In contrast, the compounds prepared according to the invention have toxic doses that are far above the amounts needed to produce a pharmacological effect and thus have a wide margin of safety.

Other known agents exert such a rapid and powerful blood pressure-lowering effect that it is difficult to regulate their effect. The compounds produced according to the invention do not have these disadvantages. It has been observed that the blood pressure-lowering effect of the compounds produced according to the invention is easy to regulate, even though they have a noticeable effect.

A compound which may also be mentioned is the preferred compound in the series described in the British patent. 1,380,145, namely 2-(2-ethyl-3-benzofuranyl)-N,N-(3-n-propyl-3-aza-pentamethylene)-acetamidine dihydrochloride..

This compound is chemically related to the compounds produced according to the invention and has been found to be pharmacologically active in the treatment of induced high blood pressure. However, it will appear that the compounds produced according to the invention are not only more active but also significantly less toxic than said preferred compound.

Furthermore, the blood pressure-lowering effect of the compounds produced according to the invention is associated with very few or no unwanted side effects, while no signs of loss of activity due to habituation have so far been observed.

Finally, it is well known that a diuretic effect combined with a blood pressure-lowering effect is very useful in the treatment of high blood pressure, especially when the diuretic effect does not induce excretion of potassium ions. but instead induces excretion of sodium ions.

The compounds produced according to the invention have been found

to have a very favorable sodium excretion index, so that said compounds can be expected to constitute valuable blood pressure-lowering agents.'

Pharmacological tests have been carried out with a view to

to show the blood pressure-lowering effects of the compounds prepared according to the invention on different types of experimentally induced high blood pressure.

The first tests were carried out on male rats weighing approx. 120 g in which chronic renal hypertension is induced by the Grollman technique (Proe. Soc. exp. Biol. Med., 57, 102

(1944)).

According to this technique, the animals are anesthetized with ether and one kidney is moved from its place without being removed from the body, the secondary kidney being first freed from the kidney but otherwise kept intact. The kidney is then tied with twists in the shape of a figure eight, just tight enough to change the ellipsoidal shape of the organ slightly. Ten days later, the other kidney is completely removed along with its adrenal gland. About. four weeks after the second operation, most of the animals (60-70%) developed very high blood pressure, systolic pressure in the majority of cases exceeding 180 mm Hg.

Groups of rats thus treated received the compounds, prepared according to the present invention, in a dose of 25 mg/kg intragastrically. Arterial pressure was measured just before and 1, 2, 3, 4, 5 and 6 hours after administration. The following compounds produced the indicated results:

In the same test, performed with a well-known blood pressure-lowering agent, namely α-methyl-(3,5-dihydroxy-phenyl)-alanine, it was found that an intragastric dose of 400 mg/kg was required to achieve a fall in arterial pressure of between 20 and 30 mm Hg. Another agent known to have blood pressure-lowering properties, namely hydrochlorothiazide, was found to be inactive in this test at a dose of 200 mg/kg given intragastrically. •

The same test was also carried out with the preferred compound from British Patent 1,380,145, namely 2-(2-ethyl-3-benzofuranyl)-N,N-(3-n-propyl-3-aza-pentamethylene)-acetamidine- dihydrochloride.

At a dose of 50 mg/kg given intragastrically, a drop in arterial pressure of 14 mm Hg was achieved, while a drop of 24 mm Hg was recorded at a dose of 200 mg/kg in the same way.

2-(2-Ethyl-3-benzofuranyl)-N-(2-morpholino-ethyl)-acetamidoxime gave the best results and this is why this compound is considered the preferred compound.

Further pharmacological tests were carried out in order to determine the antihypertensive effect of the preferred compound prepared according to the invention, namely: 2-(2-ethyl-3-benzofuranyl)-N-(2-morpholino-ethyl)-acetamidoxime (or L 9552) .

All these tests were performed on rats that had hypertensive blood pressure. Each test was divided into two series. In the first series, a single dose of the test product was administered intragastrically to each animal and the arterial pressure of the latter was measured hourly for six hours after administration. In the second series, the investigated product was given in the same way every day for eleven consecutive days and the arterial pressure was measured daily during this period. The amount of product administered varied from one animal to another.

The following are the results of the tests thus carried out..

1) Rats that developed high blood pressure according to the Groilman method

When the method described above was applied, the following results were recorded:

2) High blood pressure of endocrine origin

This test was performed according to the technique of Stanton and White (Arch. Int. Pharmacodyn. 154, 351, 1965).

Female rats weighing 90 + 10 g were anesthetized with ether and hypertension was obtained by removal of one kidney and the corresponding adrenal gland, after which a dose of 50 mg/kg desoxycorticosterone acetate (DOCA) was administered subcutaneously five times a week for a period.of-four weeks. During this period, the rats' drinking water contained 1% NaCl. This was replaced with plain tap water when the administration of desoxycorticosterone ceased.

Under these circumstances, the arterial pressure rose to approx.

200 mm Hg.

3) Salt- caused high blood pressure

This test was performed according to the technique of Dahl, Knudsen, Heine and Lei ti..,

Male rats weighing 55 + 5 g were fed with feed containing 8% NaCl, but which was otherwise normal.

After six weeks on this diet, the arterial pressure had increased to approx. 180 mm Hg.

The following results were recorded:

4) Neurogenic high blood pressure

This test was performed according to the technique of Krieger and imbs (Circul. Res. 15, 511, 1964 and CR. Soc. Biol. 162, 778, 1968).

Male rats weighing from 200 to 250 g were anesthetized with ether and 0.5 mg of atropine sulfate was administered to them intra-peritoneally.

The rats were restrained in a supine position and an incision was made in the front of the neck to expose the neuromuscular bundle comprising the sympathetic and vagus nerves and the common carotid arteries.

The vagus nerves and carotid arteries were then carefully isolated while 1 centimeter was cut away from the sympathetic nerves. The upper laryngeal nerves were split. The area there. The caroT times divide was exposed by pulling aside the appropriate neck muscles (sternocleidomastoid and omohyoid). The vessels that were thus freed were painted with 10% phenol. in ethanol. in this way complete sympathetic denervation was achieved. ■

A marked increase in arterial pressure was obtained after 5 to 8 days.

The following results were recorded:

5) Genetic high blood pressure

This test was performed according to the technique of Okamoto and Aoki (Jap. Circul. J. , 27, 282, 1963), using male rats belonging to a breed specially bred to produce animals with high blood pressure. The animals used were approx. 10-week-old <p>g had blood pressure readings in the range of 180 mm Hg.

The following results were obtained:

According to <p>lummer (Anti-hypertensive agents, p. 67, published by Schlittler, Academic Press N.Y. and London, 196 7) and many other authors, any substance active against various types of experimentally induced high blood pressure can be considered potentially blood pressure-lowering in humans.

Furthermore, it is now recognized that genetic hypertension constitutes the model of experimental hypertension that is most closely related to essential hypertension in humans (representing 80% of cases of pathological hypertension).

L 9552 has been found to be active in the five cases of experimentally induced hypertension discussed above and is particularly active in genetic hypertension.

It can thus be concluded that it is very likely that L 9552 is active against high blood pressure in humans.

Additional pharmacological tests were performed to determine the diuretic properties of L 9552: 1 - Volumetric urinary excretion

This test was performed according to the technique of Lipschitz et al., (j. <p>harmacol. exp. Therap. 79, 97, 1943), using groups of 20 male albino rats weighing from 150 to 200 g and having no got.food or drink in 18 hours.

The test substance was given intragastrically just after intragastric administration of 50 ml/kg of a 9% NaCl solution.

A control group of 20 rats received only the saline solution.

The total amount of urine excreted during the 6 hours following administration was collected and measured.

The results are expressed as a percentage of the volume of salt solution that was administered and are listed in the following table:

The maximum excretion among the control animals is 50%, which means that results above this value can be considered significant for a diuretic effect.

2 - Ionic ratio in urinary excretion

This test was performed according to the technique of Ambrosili et

al., (Minerva Nepol. 11, 56, 1964).

The test substance was given intragastrically immediately after intragastric administration of 50 ml/kg of distilled water to groups of 20 male albino rats weighing 140 + log and which had fasted for 18 hours.

A control group, which also included .20 animals, only received

distilled water.

The total amount of urine excreted during the 4 hours following administration was collected and measured and the total Na -f - and K + ion excretion values determined.

These values were then converted into milliequivalents per liters (mEq/1) to achieve the correct Na<+> and K<+->ion excretion numbers regardless of the increase in the amount of urine.

The ionic ratio was obtained according to the formula below:

The following results were recorded:

These figures show that L 9552 exhibits a very beneficial sodium excretion index, which is very important when it comes to the treatment of high blood pressure.

Pharmacological tests were also performed to show that L 9552 is free of ganglioplegic activity: 1) The arterial pressure and tone of the blink membrane of an anesthetized cat were first noted, after which the contractile response of the membrane to an intravenous injection of epinephrine and to electrical stimulation of the preganglia -the fiber of the cervical sympathetic nerve was tested. It was found that two intravenous doses of 5 mg/kg of L 9552 did not modify the intensity of the contractions of the membrane elicited as described above. 2) An intravenous dose of 5 mg/kg L 9552 administered to a dog initially anesthetized with sodium pentobarbital and atropinized did not alter the hypertensive effect of 1 mg/kg acetylcholine injected into the animal's veins, in contrast to this res. a ganglioplegic substance such as plutonium the pressure-increasing effect of acetylcholine.

Finally, toxicity tests were carried out on rats and mice which were kept under observation for 12 days after a single administration.

The following results were recorded:

These figures compare very favorably with the intragastric active doses of 50 and 100 mg/kg whose effects are described above and show that there is a very wide margin of safety between the toxic and the therapeutic dose.

It will be understood that for therapeutic use the compounds produced according to the invention will normally be administered in the form of a pharmaceutical preparation containing as active substance at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof in connection with a pharmaceutical carrier and/or binder therefore.

For clinical use, the preparation is advantageously prepared in

a dosage unit form suitable for the desired mode of administration, e.g. a tablet or capsule for oral administration.

The following example illustrates the invention.

Example

2-(2-ethyl-3-benzofuranyl)-N-(2-morpholiho-ethyl)-acetamidoxime sesquioxalate.

(a) Preparation of 2-(2-ethyl-3-benzofuranyl)-acetamidoxime.

To 350 ml of methanol containing 37.4 g (0.55 mol) of sodium ethylate was added 38.2 g (0.55 mol) of hydroxylamine hydrochloride and the reaction medium was stirred until complete dissolution.

Stirring was continued for 16 hours after the addition of

200 ml of methanol containing 92.6 g (0.50 mol) of 2-ethyl-3-cyano-methylbenzofuran and the solution was finally refluxed for 3 hours.

The solvent was evaporated under reduced pressure and the residue was taken up in ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and made colorless with activated charcoal.

By adding an ether solution of hydrochloric acid, 99.7 g of 2-(2-ethyl-3-benzofuranyl)-acetamidoxime hydrochloride was obtained, which was recrystallized from a mixture of ethyl acetate and methanol. Yield: 78.3%, m.p. 158-161°C.

By following the procedure described above and using appropriate starting products, the compounds listed below were prepared:

(b) Preparation of 3-(2-ethyl-3-benzofuranyl-methyl)-1,2,4- A 2-oxadiazol-5-one

With stirring, 25.47 g (0.1 mol) of 2-(2-ethyl-3-benzofuranyl)-acetamidoxime hydrochloride was added to a solution of 13.6 g (0.2 mol) of sodium ethylate in 250 ml of absolute ethanol.

After addition of 23.6 g (0.2 mol) of anhydrous diethyl carbonate, the reaction medium was refluxed for 24 hours.

The resulting solution was evaporated to dryness under reduced pressure and the residue taken up in water.

The aqueous solution thus formed was treated with ether and the phases obtained were separated. The aqueous phase was acidified with a dilute hydrochloric acid solution. The precipitate obtained was washed with water and dried under vacuum to obtain 20 g of 3-(2-ethyl-3-benzofuranyl-methyl)-1,2,4-A-oxadiazol-5-one which was recrystallized from a mixture of ether and petroleum ether (4o/60°C).

Yield: 81.9%, m.p. 156-159°C.

By following the method described above and using appropriate starting products, the compounds listed below were prepared:

c) Preparation of 3-(2-ethyl-3-benzofuranyl-methyl)-4-(2-morpholino-ethyl)-1,2,4-A-oxadiazol-5-one

In a flask equipped with a stirrer and a Soxhlet

apparatus assembled together with a cooler, a solution of 10.5 g (0.043 mol) 3-(2-ethyl-3-benzofuranyl-methyl)-1,2,4- Δ<2->oxadiazol-5-one was introduced in a mixture of 250 ml of anhydrous acetone and 50 ml of methanol, and 7.1 g (0.051 mol) of finely ground anhydrous potassium carbonate.

9.3 g (0.05 mol) of 1-chloro-2-morpholino-ethane hydrochloride were introduced into the Soxhlet apparatus.

Under stirring, the reaction medium was refluxed for 18 hours. After filtering off the salts, the solution was evaporated under reduced pressure. The obtained residue was taken up in water and extracted with ether so that 15 g of 3-(2-ethyl-3-benzofuranyl-methyl)-4-(2-morpholino-ethyl)-1,2,4-A 2 were obtained -oxadiazol-5-one,.-which melted at 105-106°C. Yield: 97.6%.

The melting point of the hydrochloride. was 181-183°C after recrystallization from a mixture of isopropanol and ethanol.

By following the method described above and using appropriate starting products, the compounds listed below were prepared:

(d) Preparation of 2-(2-ethyl-3-benzofuranyl)-N-(2-morpholino-ethyl)-acetamidoxime

To a solution of 7.9 g (0.02 mol) 3-(2-ethyl-3-benzofuranyl-methyl)-4-(2-morpholino-ethyl)-1,2,4-A<2->oxadiazole -5-one hydrochloride in 70 ml of methanol was added to a solution of 3.2 g (0.08 mol) of sodium hydroxide in 32 ml of water.

The reaction medium was then refluxed for 30 min. and was evaporated under reduced pressure until 3 quarters of the volume was eliminated.

The resulting residue was taken up in 200 ml of water and

The pH of the reaction medium was adjusted to 8.

The solution thus formed was extracted with ether so that 5.89 g of 2-(2-ethyl-3-benzofuranyl)-N-(2-morpholino-ethyl)-acetamidoxime were obtained, which represented a yield of 89%. The crude product was taken up in a small amount of methanol and, with stirring, was acidified using a methanol solution containing 3 g (0.33 mol) of oxalic acid so that 8 g of 2-(2-ethyl-3-benzofuranyl)-N were obtained -(2-morpholirio-ethyl)-acetamidoxime-sesquioxalate. Yield: 85%, m.p. 163 - 164°C.

By following the procedure described above and using appropriate starting products, the compounds listed below were prepared:

Claims (2)

1. Analogous method for the preparation of pharmacologically active benzofuran derivatives with the general formula: and pharmaceutically acceptable acid addition salts thereof, wherein Rj^ means a branched or linear alkyl group having from 1 to 4 carbon atoms, R 2 means a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino, heptamethyleneimino group or a 1-piperazino group substituted in the 4-position with a linear alkyl group containing from 1 to 4 carbon atoms, and X means a hydrogen or chlorine atom, characterized by ring opening of a 3,4-disubstituted-1,2,4-A 2-oxadiazol-5-one with the general formula: or an acid addition salt thereof, where R 1 , R 2 and X have the meanings given above, and optionally converts the obtained compound into an acid addition salt thereof. 2. Process as stated in claim 1 for the production of 2-(2-ethyl-3-benzofuranyl)-N-(2-morpholino-ethyl)-acetamidoxime, characterized in that a starting material of formula II is used where R is ethyl, R 1 is morpholino and X is hydrogen.