FI60395B - FRAME FOR THE PREPARATION OF 2-BENZOFURANYL-N-SUBSTITUTES ACETAMIDOXIMDERIVAT MED HOEGT BLODTRYCK FOERHINDRANDE VERKAN - Google Patents

Description

M (11) ANNOUNCEMENT 60TOC fO & jQ U 1 '/ UTLAGGNINGSSKRIFT OU070 • β /' τδ C Patent granted 11 01 1932

Patent pending (51) Kv.ik.3 / int.a.3 C 07 D 307/81

FINLAND-FINLAND C ») Patanttlhaktmus - PatantansOknlng T6 360U

(22) H »k * ml * ptlvi— An * eknlngtdag 15.12.76 (23) Alkupilvt — Glklghatadag 15.12.76 (41) Tullut (ulklMkal - Blhrtt offentllg 23.06. 77

Patent and Registration Board ... ......,. . .....

_. (44) Date of issue and date of issue. - oa aa Oi

Patent · och registerstyrelsen Anaökan uttagd och utl. * Krift «n publicerad Jy.oi (32) (33) (31) Pyydetty utudkuu * —Buglrd priorct 22.12.75

England-England (GB) 52 ^ 75/75 (71) Sanofi, Uo, avenue George V, 75008 Paris, France-France (FR) (72) Alex Areschka, Brussels, Marcel Descamps, Rosieres, Belgium-Belgium (BE) (7b) Oy Borenius & Co Ab (5I +) Method for the preparation of 2-benzofuranyl-N-substituted acetamidoxime derivatives for the treatment of hypertension

The present invention relates to a process for the preparation of novel antihypertensive 2-benzofuranyl-N-substituted acetamidoxime derivatives or pharmaceutically acceptable acid addition salts thereof having the general formula? I) in which formula denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms and R 1, which are identical, denotes a straight-chain alkyl group having 1 to 4 carbon atoms or together with an adjacent nitrogen atom morpholine group and X represents a hydrogen or chlorine atom.

The process according to the invention is characterized in that 3,4-disubstituted 2 1,2,4-Δ-oxadiazol-5-one of the general formula 60395. ^ N 0

X is -CHCH- -C ^ I

II 2 NC = 0 R (II) I | Ju.R '2 \ c ^ 1 CH 2 -CH 2 -N r 3 and wherein, R 2, R 3 and X are as defined above, are heated to reflux in aqueous alcohol and in the presence of sodium hydroxide to form a compound of formula I which, if desired, is reacted with an organic or inorganic acid to produce a pharmaceutically acceptable acid addition salt.

Preparation of starting material

The starting materials of formula (II) can be prepared by reacting 2,3-substituted-1,2,4-β-oxadiazol-5-one of the general formula N-O-rH2'c ^% A0> R1 h <m) in which formula R 1 and X have the same meaning as in formula (I), to react in an organic medium, e.g. anhydrous acetone with a small amount of methyl alcohol and in the presence of a base, e.g. anhydrous potassium carbonate, with chloroalkylamine, suitably used as its hydrochloride salt, and the formula is R2

Cl - CH2 - CH2N (IV) · wherein R2 and R3 have the same meaning as in formula (I).

3 60395

The compounds of formula (IV) are known in the art.

Compounds of formula (III) may be prepared by applying methods known in the art, e.g. by reacting an amidoxime derivative of general formula

"_0H

X ~ v 1 -r-CHO-C-NH 9 I 2 2 (V) ^ / \ / ~ R 1 or an acid addition salt thereof, wherein A and X have the same meaning as in formula (I), to react with anhydrous diethyl carbonate in absolute ethanol containing a base , e.g. sodium ethylate.

Compounds of formula (V) may be prepared by applying methods widely described in the literature. A particularly preferred process is based on reacting a compound of the general formula X - ch2-cn (VI) in which formula and X have the same meaning as in formula (I) with hydroxylamine hydrochloride in an alcoholic medium containing a base, e.g. sodium methylate or sodium ethylate.

The compounds of formula (VI) are known in the art and have been described by Areschka et al. Chimie Therapeutique 7> 337, (1972) or can be prepared by applying the methods described in this publication.

- 60395

The compounds according to the invention have been found to have valuable pharmacological properties which make them extremely valuable in the treatment of cardiovascular disorders.

The compounds according to the invention can thus be used in the treatment of pathological diseases of arterial pressure by administering to a person suffering from high arterial pressure at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

There are numerous antihypertensive agents used to treat different types of hypertension. Among these substances, mention should be made of neuronal blocking agents, the blocking effect of which interrupts the pulses which excite the sympathetic and thus causes the walls of the vasculature to loosen. This phenomenon can be dangerous in cases where the patient needs increased tension from the vessel wall, e.g. due to a change of position. As will be seen below, the compounds of the invention do not have neuronal blocking effects.

Other antihypertensive compounds, such as Veratrum alkaloids, are characterized by a relatively narrow margin between their drug doses and toxic doses. Overdose can be dangerous, and the physician must carefully select the dosage and continuously adjust it according to the patient's needs and reactions. In contrast, the toxic doses of the compounds according to the invention are clearly higher than those required to produce a pharmacological effect, so that they have a wide safety margin.

Some other substances known in the art cause such a sudden and severe drop in blood pressure that their effect is difficult to control. The compounds of the invention do not have this disadvantage. In fact, it has been found that the antihypertensive effect of these new compounds is easily controllable, although quite significant.

From GB 1,380,145, the most potent compound is known to be chemically close to 2- (2-ethyl-3-benzofuranyl) -5,60395 N, N-C3-n-propyl-3-aza-pentamethylene) -acetamidine dihydrochloride, which is pharmacologically effective in the treatment of experimentally induced hypertension. However, the novel compounds prepared according to the invention have proven to be both more effective and much less toxic than this known compound.

In addition, the compounds of the invention have an antihypertensive effect while having little or no side effects, and it has not been found that the effect decreases as the patient becomes accustomed to the drug.

It is already known that the increase in urinary excretion combined with the antihypertensive effect is a very useful property in an antihypertensive drug, especially since the increase in urinary excretion does not cause the removal of potassium ions but instead causes the removal of sodium ions. The novel compounds according to the invention have been found to have a very favorable sodium excretion index, so that the compounds have been found to be valuable as antihypertensive drugs.

Pharmacological experiments

Pharmacological experiments have been performed to demonstrate the antihypertensive effects of the compounds of the invention on various types of experimentally induced hypertension disorders.

The first experiment was performed on male rats weighing approximately 120 g and in which chronic renal hypertension was induced by the method described by Grollman Proc. Soc. exp. Biol. Med., 57, 102 (1944).

According to this method, the animals are anesthetized with ether and the second kidney is removed without being removed from the body, with the adrenal gland first being removed from the kidney but otherwise left intact. The kidney is then tied with a thread number eight shape just so tightly that the ellipsoidal shape of the organ changes slightly. After ten days, the second kidney is completely removed, as is its adrenal gland. Approximately four weeks after surgery, most animals (60,.,. 70%) 6 60395 developed severe hypertension with a systolic pressure greater than 180 mm Hg in most cases.

Groups of rats thus treated were administered the compounds of the invention intraperitoneally at a dose of 25 mg / kg. Arterial pressure was measured immediately before and 1, 2, 3, 4, 5, and 6 hours after administration. The following compounds gave the results shown in the table.

Table I

artery pressure

Compound_decrease, mm Hg_ 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime_36- 2- (2-methyl-3-benzofuranyl) -N- (2-morpholinoacetamidoxime_25_ 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime_21- 2- (2-ethyl-3-benzofuranyl) -N- (2-di-n-butyl- amine-ethyl) -asetamidoksiimi_27_

Comparison

A similar experiment was performed using a previously known antihypertensive compound, α-methyl- (3,5-dihydroxy-phenyl) -alanine, which found that an intramuscular dose of 400 mg / kg was required to reduce arterial pressure by 20-30 mm Hg. . Another known compound, hydrochlorothiazide, which has antihypertensive properties, was found to be ineffective in this experiment when administered at a dose of 200 mg / kg intraperitoneally.

The same experiment was also performed with the most preferred compound of GB Patent 1,380,145 with 2- (2-ethyl-3-3-benzofuranyl) -N, N- (3-propyl-3-aza-pentamethylene) -acetamidine dihydrochloride.

Intravenous administration of 50 mg / kg resulted in a reduction in arterial pressure of 14 mm Hg, whereas a similar dose of 200 mg / kg resulted in a reduction of 24 mm Hg.

7 60395

A particularly preferred compound prepared according to the invention, 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime, was subjected to other pharmacological tests to determine the antihypertensive effect of this compound. This preferred compound prepared according to the invention is hereinafter abbreviated as L 9552.

All experiments were performed on rats with hypertension.

Each experiment was divided into two series. In the first series, a single dose of test compound was administered intraperitoneally to each animal, and arterial pressure was measured every hour for six hours after compound administration. In the second series of experiments, the test compound was administered in the same manner every day for eleven consecutive days, and arterial pressure was measured daily during this period. The amount of compound administered varied according to the weight of the animal.

The following are the results of the experiments performed.

1) Rats with hypertension using the Grollman method

Applying the method described above, the following results were obtained:

Table II

Treatment Dose Arterial pressure Type of arterial pressure mg / kg maximal decrease - maximal decrease _in (mm Hg) _timate_

Single 10 14 4th hour dose 25 36 4th hour _50_55_3, hour_ Daily 10 18 6th day doses 25 32 5th day (11 days) _50_47_4. day_s 60395 2) Hypertension of endocrine or endocrine origin This experiment was performed using the method of Stanton and White (Arch. Int. Pharmacodyn. 1 5 * 4, 3 51, 1 965).

Female rats weighing 90-10 g were anesthetized with ether and hypertension was induced by removal of the second kidney and the corresponding adrenaline gland, followed by subcutaneous administration of a dose of 50 mg / kg deoxycorticosterone acetate (DOCA) five days per week for four weeks. During this period, the rats were given drinking water with 1% CaCl. This water was replaced with ordinary tap water when the administration of deoxycorticosterone was stopped.

Under these conditions, arterial pressure rose to about 200 mm Hg. The following results were achieved:

Table III

Arterial Pressure Treatment Maximum decrease in arterial pressure ^ Dose at time of maximum decrease type_mg / kg_nen (mm Hg) _

Single 25 18 hour dose 50 26 4th hour 100 45 4th hour Daily 25 15 Day 5 doses 50 30 Day 4 (11 days) 100 49 Day 4 3) Saline-induced hypertension This experiment was performed using a method that by Dahl, Knudsen, Heine and Leitl.

• ··· · # * Φ * | · | 4

Male rats weighing 55-5 g were fed a diet containing 8¾ NaCl but otherwise normal.

After six weeks with this diet, the arterial pressure had risen to about 180 mm Hg.

9 60395

The following results were achieved:

Table IV

Treatment Dose Arterial pressure Type of arterial pressure mg / kg maximal decrease maximal decrease _ mm (Hg) _time_

Single 10 14 4th hour dose 25 27 4th hour 50 54 4th hour Daily 10 13 7th day * ™ ° to> ** 25 26 4th day (11 days) 50 53 3rd day 4) Neurogenic hypertension This experiment was performed using the method of Krieger and Imbs (Circul. Res. Ijj, 511, 1964 CR Soc. Biol. 162, 778, 1968).

Male rats weighing 200-250 g were anesthetized with ether and 0.5 mg of anthropin sulfate was administered intraperitoneally.

The rats were fixed in a supine position, and an incision was made in the front of the neck so as to expose a bundle of nerves and muscles that included sympathetic and circulating nerves and a common head-artery.

The circulating nerves and the artery of the head were then carefully isolated and 1 cm was excised from the sympathetic nerve. The nerves above the larynx were severed. The area where the common head artery divides was revealed by pulling aside the corresponding neck muscles (head nodule muscle and omohyoideus muscle). The blood vessels thus exposed were stained with a 10% ethanol solution of phenol. In this way, the sympathetic nerves were completely anesthetized.

A marked increase in arterial pressure was achieved after 5 to 8 days. The following results were obtained: 10 60395

Table V

Treatment Dose Arterial Pressure Arterial Pressure 'Type mg / kg Maximum Decrease - Maximum Decrease _in (mm Hg) _time_

A single ΛΟ 10 18 3rd hour dose no nr? «,,.

25 37 4th hour 50 56 3rd hour Daily 10 17 Day 5 doses 25 35 Day 5 (11 days) __________ 5) Genetic hypertension This experiment was performed using the method 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 10 weeks old and had blood pressure in the range of 180 mm Hg.

The following results were achieved:

Table VI

Treatment Dose Arterial pressure Type of arterial pressure mg / kg maximal decrease- maximal decrease _then (mm Hg) _timate_

Single 5 16 2nd hour dose 10 35 2nd hour 20 52 3rd hour Daily 5 0 doses 10 26 Day 4 (11 days) 20 47 Day 5

According to Plummer (Anti-hypertensive agents, p. 67, Edited by Schlittler, Academic Press N.Y. Adn London, 1967) and numerous other authors, any substance that affects various types of experimentally induced hypertension can be considered a potential antihypertensive agent in humans.

ιι 6 O 3 9 5

In addition, it is now recognized that genetic hypertension serves as a model for experimental hypertension, which is mainly related to human independent hypertension (representing 80% of pathological hypertension cases).

Compound L 9552 has been found to be effective in the five types of experimentally induced hypertension used and particularly effective in genetic hypertension.

From this, it can be concluded that L 9552 is more likely to be effective in human hypertension.

Other pharmacological experiments were performed to determine the diuretic, i.e., urinary excretion, properties of L 9552.

1) Volumetric urinary excretion This experiment was performed using the method of Lipschitz et al. (J. Pharmacol, exp. Therap. 79, 07, 1943) and using groups of 20 male albino rats weighing 150-200 g that had been without food and drink for 18 hours.

The test compound was administered intraperitoneally immediately after administration of 50 ml / kg of 9% NaCl solution by the same route.

The control group, which also had 20 rats, was given saline only.

t

The total amount of urine excreted within 6 hours of administration was collected and measured.

The results are expressed as a percentage of the volume of saline administered and are listed in the following table: 12 60395

Table VII ς ° y D

Dose Urinary excretion mg / kg _% _ O 20. ... 50 10 84 20 102 50 118 100 138 200 165

The maximum excretion in control animals is 50%, which means that higher values can be considered as an indication of an increase in urinary excretion.

2) Ion ratio in urinary excretion This experiment was performed using the method of Amhrosili et al. (Minerva Nepol. 1J_, 56, 1964).

The test compound was administered intraperitoneally immediately after administration of 50 ml / kg of distilled water by the same route to groups of 20 male albino rats weighing 140-10 g and fasted for 18 hours.

The control group, which also had 20 animals, was given only distilled water.

The total amount of urine excreted within 4 hours after administration was collected and measured, and the total excretion value of Na + and K + ions was determined.

These values were then converted to milliequivalents / l (mEq / 1) in order to obtain the correct Na + and K + ion excretion numbers regardless of the increase in urine volume.

The ionic ratio was calculated from the following formula: 60395 13 / -Na + _7 »ratio of treated animals £ Lä_ = L K J *" "+ —— -— /“ Na _7> control animals / ”k + _7" "

The following results were achieved:

Table VIII

Dose Urinary Na + K + Na + / K + (mg / kg) excretion% m.equ./l m.equ./l ratio_

Reference animals_4Ό_27.3 18.5 1 10 55 24.8 15.3 1.09 20 80 43.0 17.5 1.66 50 95 55.6 15.0 2.50 100 137 71.3 14.3 3.37 200 124 78.0 15.8 3.34 These numbers indicate that compound L 9552 has a very favorable sodium secretion index, which is very important. , when it comes to treating hypertension.

Pharmacological experiments were also performed to demonstrate that L 9552 did not have any neurotubic-blocking effects: electrostimulation. It was found that two intravenous doses of 1 9552 of 5 mg / kg did not alter the intensity of the contractions induced by the membrane as described above.

2) A dose of 5 mg / kg of Compound L 9552 was administered intravenously to a dog first anesthetized with sodium pentobartol and atropinated, and this dose did not alter the pressure-increasing effect produced by intravenous injection of 1 mg / kg of acetylcholine. In contrast, a neurotransmitter such as pentonium reversed the antihypertensive effect of acetylcholine.

Finally, acute toxicity was tested in rats and mice, with the animals being inspected for 12 days after a single administration.

The following results were recorded:

Table IX

Animals Method of administration LD (mer / w) _ ^ 0 Ko Cf.

Mouse Intraperitoneal 30 70 110

Intestinal 250 250 1,250

Rat Intraperitoneal 80 200 350

Intraperitoneally 1,100 1,900 2,500 These numerical values are highly advantageous compared to intravenously administered doses of 50 mg / kg and 100 mg / kg, the effects of which have been explained above, and show that there is a fairly wide safety margin between the toxic dose and the therapeutic dose.

It should be noted that for pharmaceutical use, the compounds of the invention are normally administered as pharmaceutical compositions containing as active ingredient at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier and / or diluent.

For pharmaceutical use, the composition is preferably presented in unit dosage form suitable for the desired route of administration, e.g., as a tablet or capsule for oral administration.

The following examples illustrate the invention.

1 5

Example 1 60395 Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime

To a solution of 7.9 g (0.02 mol) of 3- (2-ethyl-3-benzofuranyl-2-methyl) -4- (2-morpholino-ethyl) -1,2,4-Δ-oxadiazole-5 -one hydrochloride in 7C ml of methanol, a solution of 3.2 g (0.08 mol) of sodium hydroxide in 32 ml of water was added.

The reaction mixture was refluxed for 30 minutes, then evaporated under reduced pressure until three-quarters of the volume was removed. The resulting residue was taken up in 200 ml of water, and the pH of the reaction mixture was adjusted to 8.

The solution thus obtained was extracted with ether to give 5.89 g of 2- (C 2 -ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime, corresponding to 89% of yield. The crude product was taken up in a small amount of methanol and acidified with stirring by the addition of a methanolic solution of 3 g (0.33 mol) of oxalic acid to give 8 g of 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -asetamidoksiimi-Sesqui-oxalate. Yield 85%, melting point 163 ... 154 ° C.

Example 2 Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-dimethylaminoethyl) acetamidoxime dihydrochloride 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-diethylamino) -ethyl) -2,2,4-Δ-oxadiazol-5-one hydrocarbon was heated at reflux in the presence of methanol and sodium hydroxide. The product was reacted with hydrochloric acid to give the desired product in 66% yield.

Melting point 161-163 ° C (recrystallization from methyl ethyl ketone / isopropanol).

Example 3 Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-diethylaminoethyl) acetamidoxime sesquioxalate 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-diethyl -amino-ethyl) -2,2,4-Δ-oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with oxalic acid to give the desired product in 31% yield.

Melting point: 159-161 ° C (recrystallization from ethanol; decomposes). Example 4 Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-di-n-propylaminoethyl) -acetamidoxime dihydrochloride 3- (2-ethyl-3-benzofuranyl) -N- (2-di -n-propylaminoethyl) -2,2,4-Δ-oxadiazol-5-one hydrocarbon was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with hydrochloric acid to give the desired product in 60% yield.

Melting point: 180-184 ° C (recrystallization from ethyl acetate / methanol); decomposition).

Example 5 Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-di-n-butylaminoethyl) acetamidoxime dihydrochloride 3- (2-ethyl-3-benzofuranyl) -N- (2-di -n-butylamino-ethyl) -1,2,4-2. . . .

Δ-Oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with hydrochloric acid to give the desired product in a yield of 43%.

Melting point: 165-168 ° C (recrystallization from ethyl acetate / methanol).

Example 6 Preparation of 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime 3- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2 -morpholinoethyl) -2. . .

1.2.4-Δ-Oxadiazol-5-one hydrochloride was heated to reflux to give the desired product in 83% yield. Melting point: 110-112 ° C (recrystallization from petroleum ether 60/80 ° C).

n 60395

Reaction of the title product thus obtained with hydrochloric acid gives the corresponding dihydrochloride salt in 44% yield.

Melting point: 122-126 ° C (recrystallization from ethyl acetate / methanol); decomposition).

Example 7 Preparation of 2- (2-methyl-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime sesquioxalate 2 3- (2-methyl-3-benzofuranyl) -N- (2-morpholinoethyl) -1,2,4-Δ-Oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with oxalic acid to give the desired product in 68% yield.

Melting point: 148-150 ° C (recrystallization from methanol / ethyl ether; decomposes).

Example 8 Preparation of 2- (2-n-propyl-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime sesquioxalate 3- (2-n-propyl-3-benzofuranyl) -N- (2-morpholino ethyl) -1,2,4-2 Δ-oxoaziazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with oxalic acid to give the desired product in 62% yield.

Melting point: 162-164 ° C (recrystallization from methanol; decomposes). Example 9 Preparation of 2- (2-isopropyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime dihydrochloride 2,3- (2-isopropyl-3-benzofuranyl) -N- (2-morpholinoethyl) -1,2,4-Δ-Oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with hydrochloric acid to give the desired product in 86% yield.

18 60395

Melting point: 196-199 ° C (recrystallization from acetone / isopropanol, decomposes).

Example 10 Preparation of 2- (2-n-butyl-3-benzofuranyl) -N- (2-morpholino-ethyl) -acetamidoxime dihydrochloride 3- (2-n-butyl-3-benzofuranyl) -N- (2- morpholinoethyl) -1,2,4-Δ-oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with oxalic acid to give the desired product in 69% yield.

Melting point 115 ° C (recrystallization from methanol; decomposes)

Example 11 Preparation of 2- (2-isobutyl-3-benzofuranyl) -N- (2-morpholino-ethyl) -acetamidoxime dihydrochloride 3- (2-isobutyl-3-benzofuranyl) -N- (2-morpholino-ethyl) ) -1,2,4-Δ-oxadiazol-5-one hydrochloride was heated to reflux in the presence of methanol and sodium hydroxide. The product was reacted with hydrochloric acid to give the desired product in 88% yield.

Melting point: 172-174 ° C (recrystallization from ethanol / ethyl ether).

Claims (1)

A process for the preparation of antihypertensive 2-benzofuranyl-N-substituted acetamidoxime derivatives or pharmaceutically acceptable acid addition salts thereof having the general formula N-OH X Tch2c ^ nh-ch9-ch9-n in R Ro SAo ^ "1 (I) wherein means a straight or branched chain alkyl group having 1 to 4 C atoms, R2 and R3, which are identical, denote a straight chain alkyl group having 1 to 4 · C atoms or together with an adjacent nitrogen atom form morpholine - a group and X represents a hydrogen or chlorine atom, characterized in that .... 3,4-disubstituted-1,2,4-Δ -oxadiazol-5-one of the general formula X —✓x N ._________ - CH9-C ^ I | I ^ "NC = O ch? -Ch9-n ^ R2 (ii) ^ R3 and wherein R1, R2, R3 and X have the same meaning as above, are heated to reflux in aqueous alcohol and in the presence of sodium hydroxide to give a compound of formula I which, if desired, is is reacted with an organic or inorganic acid to produce a pharmaceutically acceptable acid addition salt. *