DE2657902A1 - HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF - Google Patents

Description

Dlpl.-lng. P. WIRTH Dr. V. SCHMIED-KOWARZIK Dlp! .- lng. G. DANNENBERG Dr. P. WEINHOLD - Dr. D. GUDEL

335024 * 1 ^ SIEGFRIEDSTRASäE 8 TELEPHONE: C0893 J

335025 ^W 6000 MUNICH 40

SA LABAZ
Avenue de Bejar 1

B-1120 Brussels, Belgium Case: Br.176

Wd / Sh

Heterocyclic compounds, processes for their preparation and pharmaceutical containing them Compositions.

709826/1 093

The present invention relates to heterocyclic compounds, and more particularly to acetamidoxime derivatives of benzofuran, as well as pharmaceuticals containing them Compositions and a method for making these derivatives.

The compounds according to the invention, which can exist in racemic form or in the form of the optically active isomers, can be represented by the following general formula:

N-OH

wherein R ^ is a branched or straight chain alkyl group with 1 to about 4 carbon atoms or a phenyl group; A one of the groups:

Rp is an optionally substituted amino group, such as, for example, a dimethylamine, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino or heptamethyleneimino group, or a 1-piperazino group, which is in the 4th Position is substituted by a straight-chain alkyl group having 1 to 4 carbon atoms; X represents a hydrogen or chlorine atom or a methoxy group; and η is the integer 2 or 3 .

The present invention also covers the pharmaceutically usable acid addition salts of the compounds of the formula I _v If the substituent (s) on the amino group are alkyl radicals, they preferably contain 1 to 6 carbon atoms.

The compounds of the formula I can be prepared by adding the ring of a 3 »4-disubstituted 1,2,4- & -oxadiazol-5-one of the general formula:

709826/1093

II

wherein R ₁ , R ₂ , A, X and η have the same meaning as in formula I,

or an acid addition salt is opened by this. The ring opening can be carried out according to known methods, for example by heating the compound in an aqueous alcoholic medium in the presence of a base such as Sodium hydroxide.

The compounds of formula II can be prepared

by a 3-substituted 1,2,4-A -oxadiazol-5-one of the general Formula:

III

A and X have the same meaning as in formula I,

in an organic medium such as anhydrous acetone containing a small amount of methyl alcohol and in the presence a base such as anhydrous potassium carbonate with a chloroalkylamine, preferably in the form of its hydrochloride salt, the general formula:

Cl- (CH ₂ ) _n -R ₂

IV

in which R ₂ and η have the same meaning as in formula I, is reacted.

709826/1093

-Jk-

The compounds of the formula IV are already known.

The compounds of the formula III can by known processes be prepared, for example by reacting an amidoxime derivative of the general formula:

wherein R ₁ , A and X have the same meaning as in formula I,

or an acid addition salt thereof with anhydrous diethyl carbonate in absolute ethanol which is a base such as Sodium ethylate.

The compounds of Formula V can be prepared by a wide variety of methods described. A particularly beneficial one Method consists in that a compound of the general formula:

VI

wherein R ₁ , R ₂ and X have the same meaning as in formula I,

in an alcoholic medium containing a base such as sodium methylate or sodium ethylate, with hydroxylamine hydrochloride is implemented.

The compounds of the formula VI in which A is group - ₂ are already known; they are from ARESCHKA et al. in "Chimie Therapeutique" 7, 337 (1972) or can be prepared by the methods described therein.

709826/1093

The compounds of the formula VI in which A is the group:

means, can be prepared by adding a compound of the formula VI, in which A is the group -CHp-, with a group of the formula CH ^ -HaI, in which Hai is a chlorine, bromine or iodine atom represents, is implemented.

The compounds of the formula VI in which A is the group:

or

means can be made by connecting the general formula:

VII

where R ₁ and X have the same meaning as in formula I and R * denotes a methoxy or ethoxy group,

in liquid ammonia, which contains sodium amide produced in situ, alkylated with methyl iodide or ethyl iodide and the Ester group of the compound obtained is reduced to a nitrile group, the reduction being carried out by known methods will.

The compounds of the formula VII can be prepared by known processes from the compounds of the formula VI, in which A is the group -CHp, getting produced.

709826/1093

It has been found that the compounds according to the invention have valuable pharmacological properties which they do suitable for the treatment of disorders of the circulatory system characterized by high or low blood pressure do.

The compounds according to the invention can therefore be used for the treatment of pathological disorders of arterial blood pressure, in particular Hypertension, can be used by giving the patient at least one compound of formula I or a pharmaceutically acceptable one Acid addition salt is administered by this.

The predominant types of hypertension are essential and malignant hypertension and there is no specific therapy for these diseases; the reaction to different preparations is very different in each individual case.

There are therefore many different antihypertensive agents that are used to treat the different types of hypertension will.

Among them there are ganglion blockers which are known to have a ganglion-inhibiting effect by being. interrupt the sympatheticotonic impulses, which leads to a relaxation of the vessel walls. This phenomenon can occur in in such cases where the patient - for example as a result of a change in situation - an increased Tonicity of the vessel walls is required. The compounds according to the invention, on the other hand, are free from ganglia-inhibiting Effect.

Other antihypertensive compounds, such as the veratrum alkaloids, have only a very narrow margin between their therapeutic and their toxic dose. Overdosing can be dangerous, and the doctor must choose the dose carefully and constantly according to the needs and response of the patient adjust. In contrast, the compounds according to the invention are

709826/1093

the toxic doses far exceed those used to generate them a pharmacological effect are necessary, so that these connections thus have a large margin of safety.

Other known agents have such a sudden and strong antihypertensive effect that the effect is difficult to achieve control is. The compounds according to the invention do not have this disadvantage. It has been shown that the antihypertensive effect of the compounds according to the invention considerable, but easy to control.

A compound that can be named is the preferred one Compound of the series described in British Patent No. 1,380,145, namely 2- (2-ethyl-3-benzofuranyl) -N, N- (3-n-propyl-3-aza ~ pentametia ylene) acetamidine dihydrochloride.

This connection is with the compounds of the invention chemically related and has been found to be pharmacological in the treatment of experimental hypertension is effective. However, as can be seen from the experiments, the compounds according to the invention are not only more effective, but also because less toxic than that. named preferred connection.

In addition, when the antihypertensive compounds of the invention are used, little or no occur unwanted side effects and no signs of deterioration as a result of Getting used to it.

Finally, it is also known that a diuretic effect, which is coupled with an antihypertensive effect, for The treatment of hypertension is very beneficial, especially when the diuretic effect does not excrete the Potassium ion, but rather a secretion of the sodium ion.

709826/1093

It has been found that the compounds according to the invention give a very advantageous sodium secretion index, so that one can assume that they are valuable antihypertensive agents represent.

Pharmacological tests have been carried out to improve the antihypertensive effect of the compounds according to the invention Detect different types of experimental hypertension.

The first experiment was with male rats with a body weight carried out by about 120 g, in which by the Grollman method (Proc, Soc. exp. Biol. Med., 57, 102 (19 ^ 4)) chronic kidney hypertension had been caused.

In this procedure, the animals are anesthetized with ether and a kidney is removed from its place without severing it from the body, with the adrenal gland previously removed from the kidney but left intact. The kidney is then tied off with an 8-shaped thread, just tight enough to slightly change the ellipsoidal shape of the organ. Ten days later, the other kidney along with the adrenal gland is completely removed. About four weeks after the second operation, most animals (60-70 %) develop severe hypertension, with systolic pressure in the majority of cases greater than 180 mm Hg.

Then, groups of rats treated in this way were given a dose of 25 mg / kg of the compounds of the invention administered by the intragastric route. Arterial pressure was measured immediately before and 1, 2, 3, 4, 5 and 6 hours after administration measured.

The following results were obtained with the compounds listed below:

709826/1093

Tabel

link Sinking of the Arte
pressure (mm Hg) 2- (2-ethyl-3-benzofuranyl) -N-
(2-morpholinoethyl) acetamidoxime 36 2- (2-methyl-3-benzofuranyl) -N-
(2-morpholinoethyl) acetamidoxime 25th 2- (2-ethyl-5-chloro-3-benzofuranyl) -N-
(2-morpholinoethyl) acetamidoxime 21 2- (2-ethyl-3-benzofuranyl) -N-
(2-di-n-butylamineethyl) acetamidoxime 27

When the same experiment was carried out with a known antihypertensive agent, namely cc-methyl- (3 »5-dihydroxyphenyl) -alanine it was found that an intragastric dose of 400 mg / kg of this compound was required for a decrease of arterial pressure to reach 20 to 30 mm Hg. Another remedy, which has antihypertensive properties attributed to, namely hydrochlorothiazide, it was found in this experiment that at a dose of 200 mg / kg, administered by the intragastric route was ineffective.

The same experiment was also carried out with the preferred compound of British Patent No. 1,380,145, namely 2- (2-ethyl-3-benzofuranyl) -N, N- (3-n-propyl-3-aza-pentamethylene) -acetamidine dihydrochloride , carried out.

When administered intragastrically, 50 mg / kg was used achieved a decrease in arterial pressure of 14 mm Hg while a decrease of 24 mm Hg was observed at a dose of 200 mg / kg administered in the same manner.

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-W-

Further pharmacological tests were carried out to determine the antihypertensive efficacy of the preferred compounds of the present invention Connection, namely:

2- (2-Ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime (or L 9552)

to determine.

All of these experiments were carried out with rats, the apparitions of hypertension. Each trial was divided into two series. In the first row, each animal got one single dose of the product to be tested was administered by the intragastric route and it was administered over a period of 6 hours After administration, the arterial pressure of the animal was measured every hour * The product to be examined was measured in the second row on the same route of administration daily on 11 consecutive days Days, and arterial pressure was measured daily during that time. The amount of product administered was different from animal to animal.

A summary of these attempts is given below.

1) Rats in which hypertension according to the GROLLMAN method was generated.

When the procedure described above was used, the following results were obtained:

Table II

Treatment
art dose
mg / kg max sink
of the arteries
Drucksimm Hg) Time of
max. sinking of the
Arterial pressure a single one
dose 10
25th
50 14th
36
55 4th hour
4th hour
3rd hour daily dose
(For 11 days) 10
25th
50 18th
32
47 6th day
5th day
4th day

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2) hypertension of endocrine origin

This experiment was carried out according to the method of STANTON and WHITE (Arch. Int. Pharmacodyn. ^ H, 351, 1965).

Female rats with a body weight of 90 + 10 g were used anesthetized with ether, and hypertension was created by removing a kidney and its adrenal gland, then a dose of 50 mg / kg deoxycorticosterone acetate five times a week for a period of 4 weeks (DOCA) was administered subcutaneously. During this time, the drinking water given to the rats contained 196 NaCl. When the administration of deoxycorticosterone was finished, this drinking water was replaced with plain tap water.

Under these circumstances, the arterial pressure increased to about 200 mm Hg.

The following results were obtained:

Table III

Type of
treatment dose
mg / kg max sink
of the arteries
Drucksimm Hg) Time of
max. sinking of the
Arterial pressure a single one
dose 25th
50
100 18th
26th
45 4th hour
4. »
4. » daily
dose
(For 11 days) 25th
50
100 15th
30th
49 5th day
4th day
4th day

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3) Hypertension caused by salt

This experiment was carried out according to the method of DAHL, KNUDSEN, HEINE and LEITL carried out.

Male rats with a body weight of 55 + 5 g were fed with food which contained 8% NaCl, but was otherwise normal.

After 6 weeks of this diet, the arterial pressure had risen to about 180 mm Hg.

The results were as follows:

Table IV

Type of
treatment dose
mg / kg max sink
of the arteries
pressure (mm Hg) Time de3
max.sink de3
Arterial pressure one
only one
dose 10
25th
50 14th
27
54 4th hour
4. »
4. « daily
dose
(For 11 days) 10
25th
50 13th
26th
53 7th day
4th day
3rd day

4) Neuro-open hypertension

This experiment was carried out according to the method of KRIEGER and IMBS (Circul. Res. Jj ?, 5111 1964 and CR. Soc. Biol. 162, 778, 1968) carried out.

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

709826/1093

The rats were fixed lying on their backs and an incision was made in the front of the neck, around the neuromuscular bundle, which includes the sympathetic and vagus nerves, and the common carotid arteries to expose.

The vagus nerves and carotid arteries were then carefully secreted while 1 cm was excised from the sympathetic nerves. The upper nerves of the larynx were severed. The point at which the carotid arteries divide was exposed by pulling aside the corresponding neck muscles (sternocleidomastoideus and omohyoideus). The exposed vessels were coated with 10% phenol in ethanol. In this way a complete sympathetic denervation was obtained.

After 5 to 8 days there was a marked increase in arterial pressure observed.

The following results were obtained:

Table V

Type of
treatment dose
mg / kg max sink
of the arteries
pressure (mm Hg) Time of
max. sinking of the
Arterial pressure one-time
dose 10
25th
50 18th
37
56 3rd hour
4th hour
3rd hour daily dose
(For 11 days) 10
25th 17th
35 5th day
5th day

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5) Genetic hypertension

This experiment was carried out according to the method of OKAMOTO and AOKI (Jap. Circul. J., 221, ²⁸² »1963) using male rats of a breed specially bred to obtain high blood pressure animals. The animals used were about 10 weeks old and had a blood pressure of about 180 mm Hg.

The following results were obtained:

Table VI

Type of
treatment dose
mg / kg max sink
of the arteries
pressure (mm Hg) Time of
max. sinking of the
Arterial pressure one-time
dose 5
10
20th 16
35
52 2 hours
2. ^dd
3rd ^M daily
dose
(For 11 days) 5
10
20th 0
26th
47 4th day
5. ^w

After PLUMMER (Anti-hypertensive agents, p. 67, edited by SCHLITTLER, Academic Press N.Y. and London, 1967) and Many other authors suggest any substance that is useful in different types of experimental hypertension effective to be viewed as a potential means of treating hypertension in humans.

However, it is now generally accepted that genetic hypertension is the type of experimental hypertension which is most closely related to essential hypertension in 'humans (80 96 of the cases of pathological hypertension).

709826/1093

It was found that L 9552 was tested on five types of generated hypertension was effective and particularly effective in genetic hypertension.

It can therefore be assumed that L 9552 in hypertension most likely to be effective in humans.

Further pharmacological tests were carried out, to determine the diuretic properties of L 9552:

1 - Volumetric urine excretion

This experiment was carried out according to the method of LIPSCHITZ et al. (J. Pharmacol, exp. Therap. 72 * 97, 19 ^ 3) using groups of 20 male albino rats each with a body weight of 150-200 g, which had not been given anything to eat or drink for 18 hours, carried out.

The substance under investigation became intragastric immediately after Administration of 50 ml / kg of a 9% NaCl solution administered by the intragastric route.

A comparison group of 20 rats also received the saline solution.

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

The results are in percent by volume of the saline solution administered and are listed in the following table:

709826/1093

Tabel

VII

dose Urinary excretion mg / kg % O 20 - 50 10 84 20th 102 50 118 100 138 200 165

The maximum excretion in the reference animals is 50 %, which means that all results above this value indicate a diuretic effect.

2 - ion ratio in excreted urine

This experiment was carried out according to the method of AMEROSILI et al. (Minerva Nepol. ^ L, 56, 1964).

The substance to be investigated was grouped with 20 male albino rats weighing 140 pounds 10 g, the 18 Fasted for hours immediately after intragastric administration of 50 ml / kg of distilled water also administered by the intragastric route.

A comparison group, which also included 20 animals _t was only administered the distilled water.

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

These values were then converted into milliequivalents per liter (meq. / L) in order to obtain the exact values for the Na ⁺ and K ⁺ ion excretion - independent of the increase in the amount of urine.

^hold * 709826/1093

The ion ratio was obtained from the following formula:

/ ~ Na__7 of the treated animals

relationship

^ 7 of the animals for comparison

/ "XL7" "

The following results were obtained:

Table VIII

dose
(mg / kg) Urinary discharge
divorce % N / A*
(mEq. / l) K ⁺ ..
(mEq. / l) Na ⁺ / K ⁺ -
relationship Comparison
animals 40 27.3 18.5 1.00 10 55 24.8 15.3 1.09 20th 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 figures show that L 9552 gives a very favorable sodium excretion index, which is useful for the treatment of Hypertension is extremely important.

Pharmacological tests have also been carried out to demonstrate that L 9552 is free from a ganglion-inhibiting effect:

709826/1093

1) First, the arterial pressure and the tone of the nictitating membrane of an anesthetized cat were measured, followed by the contractile Response of the nictitating membrane to an intravenous injection of adrenaline and to electrical stimulation of the preganglionic membrane Cervical sympathetic nerve fiber was tested. It was found that the intensity of the contractions of the nictitating membrane evoked in the manner described above by two intravenous doses of 5 mg / kg L 9552 has not been modified.

2) By an intravenous dose of 5 mg / kg L 9552 given to a dog previously treated with sodium pentobarbital After being anesthetized and atropinized, the hypertensive effects of 1 mg / kg acetylcholine, which was in the animal's vein was not changed. On the other hand, a ganglion-inhibiting substance such as penthonium hypertonic effects of acetylcholine abolished.

Finally, acute toxicity tests were carried out with rats and mice, which followed a one-off Administration for 12 days.

The following results were obtained:

Table IX

animal administration LD value (only / k ^) LD ₀ ^LD 50 LD ₉₅ mouse intraperitoneally
intragastric 30th
250 70
700 110
1,250 rat intraperitoneally
intragastric 80
1,100 200
1,900 350
2,500

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These figures offer a very favorable comparison with the intragastric doses of 50 mg / kg and 100 mg / kg, the effect of which has been described above, and they show that there is a large margin of safety between the toxic dose and the therapeutic dose.

The compounds according to the invention are used for therapeutic purposes usually administered in the form of a pharmaceutical composition containing as active ingredient at least one compound of the formula I or a pharmaceutically usable acid addition salt thereof together with a pharmaceutical Contains carrier and / or excipient.

For clinical use, the composition is conveniently located in the form of dosage units that are suitable for the desired mode of administration, e.g. in the form of Tablets or capsules for oral administration.

709828/1093

The following examples serve to explain the invention in more detail.

example 1

2- (2-Ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime sesquioxalate. _u

a) Production of 2- (2-Äthvl-3-benzofuranyl) -acetamidoxinu

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

After adding 200 ml of methanol, the 92.6 g (0.50 mol) of 2-ethyl-3-cyanomethylbenzofuran was stirred for 16 hours, and finally the solution was under for 3 hours Heated to reflux.

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

By adding an ethereal solution of hydrochloric acid, 99.7 g of 2- (2-ethyl ~ 3-benzofuranyl) acetamidoxime hydrochloride were obtained was recrystallized from a mixture of ethyl acetate and methanol.

Yield: 78.3 %, melting point 158-161 ° C.

Following the procedure described above, but using of the corresponding starting materials, the compounds listed below were made:

709826/1093

-2W-

link Melting point C.

2- (2-methyl-3-benzofuranyl) acetamidoxime

2- (2-methyl-3-benzofuranyl) acetamidoxime hydrochloride

2- (2-n-propyl-3-benzofuranyl) acetamidoxime hydrochloride)

2- (2-1sopropyl-3-benzofuranyl) acetamidoxime hydrochloride

2- (2-n-Butyl-3-benzofuranyl) acetamidoxime hydrochloride

2- (2-1sobutyl-3-benzofuranyl) acetamidoxime hydrochloride

2 - / "" 2- (2-butyl) -3-benzofuranyljacetamidoxime hydrochloride

2- (2-Ethyl-5-chloro-3-benzofuranyl) acetamidoxime hydrochloride

2- (2-phenyl-3-benzofuranyl) • acetamidoxime

2- (2-phenyl-3-benzofuranyl) ■ acetamidoxime hydrochloride 131 - 133 (ethyl acetate / petroleum ether 3O / 4O ° C)

190 - 194 (decomposition) (isopropanol / ethyl ether)

146 - 150 (methyl ethyl ketone / ethyl ether)

160-162

128 - 131 (methyl ethyl ketone / ethyl ether)

143-145
(Ethyl acetate / ethanol)

182 - 185 (decomposition)

(Methyl ethyl ketone / ethanol /

Ether)

196 - 199 (decomposition) (isopropanol)

143-145

203 - 205 (decomposition) (isopropanol)

b) Preparation of 3- (2-ethyl-3-benzofuranylmethyl) -1,2,4-Δ. ~ oxadiazol-5-one

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

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

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

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- ae - • TH *

The aqueous solution obtained was treated with ether and the phases obtained were separated. The aqueous phase was acidified with a dilute hydrochloric acid. The resulting precipitate was washed with water and dried under vacuum, and 20 g of 3- (2-ethyl-3-benzofuranylmethyl) -1,2,4-Δ-oxadiazol-5-one, obtained from a mixture of ether and Petroleum ether (40/60 ⁰ C) was recrystallized.

Yield: 81.9% i melting point 156-159 ⁰ C.

Following the same procedure, but using the appropriate one Starting materials, the compounds listed below were made:

link Melting point C.

3- (2-methyl-3-benzofuranylmethyl) - 162-164

112,4-Δ-oxadiazol-5-one

3- (2-n-Propyl-3-benzofuranylmethyl) -1,2,4- / ± -oxadiazol-5-one

3- (2-Isopropanol-3-benzofuranylmethyl) -1,2,4-Δ -oxadiazol-5-one

3- (2-1sobutyl-3-benzofuranylmethyl) -1,2,4-Δ -oxadiazol-5-one

3- / ~ 2- (2-butyl) -3-benzofuranylmethyl / -1 , 2, 4- Δ -oxadiazol-5-one

3- (2-Ethyl-5-chloro-3-benzofuranylmethyl) -1,2,4-Δ -oxadiazol-5-one

3- (2-phenyl-3-benzofuranylmethyl) -1,2,4-Δ -oxadiazol-5-one

155-157

162-164

3- (2-n-Butyl-3-benzofuranylmethyl) - 157-159

1,2,4-Δ-oxadiazol-5-one

134 - 136 (ethyl ether / petroleum ether 40 / 8O ⁰ C)

117 - 120 (ethyl ether / petroleum ether 40/80 ⁰ C)

169 - 172 (ethyl ether)

200 - 203 (ethanol)

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c) Preparation of 3- (2-ethyl-3-benzofuranylmethyl) -4-

(2-morpholino.utyl) -1,2,4 - »/ S ~ -oxacliazol-5-one

In a flask of _t, equipped with a stirrer and a Soxhlet apparatus, which was connected to a condenser, a solution of 10.5 g (0.043 mole) of 3- (2-ethyl-3-benzofuranylmethyl) -1,2, 4-A -oxadiazol-5-one, mixed with 250 ml of anhydrous acetone and 50 ml of methanol, and 7.1 g (0.051 mol) of finely ground anhydrous potassium carbonate are added.

9.3 g (0.05 mol) of 1-chloro-2-morpholinoethane-hydro were in the Soxhlet apparatus Give chloride.

The reaction medium was stirred and refluxed for 18 hours. After filtering off the salts, the solution was evaporated under reduced pressure. The residue obtained was taken up with water and extracted with ether, and 15 g of 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -i, 2,4-Ä ² -oxadiazole-5- were obtained on. Melting point: 105-106 ^° C., yield: 97.6 %.

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

Following the same procedure, but using the appropriate one Starting materials, the compounds listed below were made:

Compound melting point, ⁰ C

3- (2-ethyl-3-benzofuranylmethyl) - 200 - 204 (methylethyl-4- (2-dimethylaminoethyl) -1,2,4-ketone / isopropanol) Δ. -oxadiazol-S-one hydrochloride

3- (2-ethyl ~ 3-benzofuranylmethyl) - 166 - 169 (methylethyl-4- (2-diethylarainoethyl) -1,2,4-ketone / isopropanol) Δ-oxadiazol-5-one hydrochloride

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3- (2-ethyl-3-benzofuranylmethyl) 4- (2-di-n-propylaminoethyl) -1,2,4-

A, -oxadiazol-5-one hydrochloride

3- (2-ethyl-3-benzofuranylmethyl) 4- (2 ~ di-n-butylaminoethyl) -1,2,4- Δ ² -

oxadiazol-5-one oxalate monohydrate

3- (2-ethyl-3-benzofuranylmethyl) -4- (2-pyrrolidinoethyl) -1,2,4- / 5? - oxadiazol-5-one hydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- (3-pyrrolidino-n-propyl) -1,2, k-Jx oxadiazol-5-one hydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-piperidinoethyl) -1.2 _T 4- ² -oxadiazol-5-one hydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- (3-piperidino-n-propyl) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3- (2-ethyl-3-benzofuranylmethyl) -4- (3-morpholino-n-propyl) -1,2,4-

Δ-oxadiazol-5-one hydrochloride

3- (2-ethyl-3-benzofuranylmethyl) -4- (2-heptamethyleneiminoethyl) -

1,2,4-A-oxadiazol-5-one

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-heptamethyleneiminoethyl) -1,2,4-

ö
Δ-oxadiazol-5-one hydrochloride salt

3- (2-ethyl-3-benzofuranylmethyl) -4- (3-di-n-propylamino-n-propyl) -

1,2,4-Δ-oxadiazol-5-one oxalate

164 - 166 (ethyl acetate / acetone)

108 - 112 (ethyl acetate)

188 - 190 (decomposition) (isopropanol)

169 - 171 (methyl ethyl ketone)

177 - 180 (isopropanol)

172 - 175 (isopropanol / ethyl ether)

119 - 122 (acetone / ethyl ether)

74 - 75 (isopropyl ether)

199 - 201 (ethyl acetate / methyl alcohol)

122 - 125 (ethyl acetate / methyl alcohol)

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- TJ-

3- (2-Ethyl-3-benzofuranylmethyl) -4- / ~ 2- (4-n-propylpiperazine p) -ethyl7-1,2,4-Δ -oxadiazol-5-one dihydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- / ~ 2- (4-methylpiperazino) ethyl7-1,2,4-Δ -oxadiazol-5-one dihydrochloride

3- (2-Ethyl-5-chloro-3-benzofuranylmethyl) -4- (2-pyrrolidinoethyl) -1,2,4-

Δ-oxadiazol-5-one hydrochloride

3- (2-Ethyl-5-chloro-3-benzofuranylmethyl) -4- (2-piperidinoethyl) -1,2,4 Δ. -oxadiazol-S-one hydrochloride

3- (2-Ethyl-5-chloro-3-'benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4-Δ -oxadiazol-5-one hydrochloride

3- (2-methyl-3-benzofuranylmethyl) -

4- (2-morpholine ^{ethyl) -1,2,4-Δ 2} -oxadiazol-5-one

3- (2-n-propyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -

1,2,4-Δ. oxadiazol-5-one oxalate

3- (2-Isopropyl-3-benzofuranylmethyl) -4- (2-pyrrolidinoethyl) ~ 1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3 ~ (2-Isopropyl-3-benzofuranylmethyl) -4- (2-piperidino-ethyl) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3- (2-isopropyl-3-benzofuranylraethyl) -4- (2-morpholine-ethyl) -1,2,4-

p
Δ. -oxadiazol-S-one hydrochloride

228 - 232 (decomposition) (isopropyl alcohol / Methyl alcohol)

230 - 233 (decomposition) (methyl alcohol)

211 - 214 (decomposition) (isopropyl alcohol / methanol)

205 - 208 (ethyl acetate / methanol)

225 - 229 (decomposition) (ethyl acetate / methanol)

130-132
(Ethyl ether)

145-148

(Isopropyl alcohol)

220 - 223 (isopropyl alcohol / ethanol)

217 - 221 (decomposition) (methanol / ethyl ether)

211 - 214 (decomposition) (methanol)

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3- (2-n-Butyl-3-benzofuranylmethyl) -4- (2-piperidinoethyl) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3- (2-n-Butyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4- Δ. ² - oxadiazol-5-one hydrochloride

3- (2-Isobutyl-3-benzofuranylmethyl) 4- (2-morpholinoethyl> 1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3- (2-phenyl-3-benzofuranylmethyl ) -4- (2-morpholinoethyl) -1,2,4-A ~ -oxadiazol-5-one

3- (2-Phenyl-3-benzofuranylmethyl) -4- (2-piperidinoethyO) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride

3- / ~ 2- (2-n-butyl) -3-benzofuranylmethylJ-4- ( 2-morphol inö ät hyl) -1,2,4-

p
Δ-oxadiazol-5-one hydrochloride

174 _ 176 (isopropanol / ethyl ether)

185 - 188 (isopropanol / ethyl ether)

185 - 189 (methanol / ethyl ether)

140 - 142 (ethanol)

208 - 211 (ethanol)

211 - 215 (decomposition) (isopropanol / methanol)

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

A solution of 7.9 g (0.02 mol) of 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -i, 2,4-Δ -oxadiazol-5-one hydrochloride in 70 ml of methanol was a solution of 3.2 g (0.08 mol) Sodium hydroxide in 32 ml of water was added.

The reaction medium was refluxed for 30 minutes and evaporated under reduced pressure to 3/4 des Volume were removed.

The residue obtained was taken up in 200 ml of water and the pH of the reaction medium was adjusted to 8.

709826/1093

The solution thus formed was extracted with ether, and 5.89 g of 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) acetamidoxime were obtained, which corresponded to a yield of 89 % . The crude product was taken up in a small amount of methanol and acidified with stirring with the aid of a methanol solution containing 3 g (0.33 mol) of oxalic acid, to give 8 g of 2- (2-ethyl-3-benzofuranyl) -N - (2-morpholine, acetamidoxime rsesquioxalate.

Yield: 85 %, melting point 163-164 ° C.

Following the same procedure, but using the appropriate starting materials, the following were made Connections made:

link Melting point C.

2- (2-Ethyl-3-benzofuranyl) -N- (2-dimethylaminoethyl) acetamidoxime dihydrochloride

2- (2-1thyl-3-benzofuranyl) -N- (2-diethylaminoethyl) acetamidoxime sesquioxalate

2- (2-Ethyl-3-benzofuranyl) -N- (2-di-n-propylaminoethyl) -acetamidoxime dihydro chlo rid

2- (2-Ethyl-3-benzofuranyl) -N- (2-di-n-butylaminoethyl) -acetamidoxime dihydrochloride

2- (2-rethyl-3-benzofuranyl) -N- (2-pyrrolidinoethyl) -acetamidoxime-dihyaxO chloride

2- (2-Ethyl-3-benzofuranyl) -N- (3-pyrrolidino-n-propyl) -acetamidoxime

2- (2-ethyl-3-benzofuranvl) -N-

(2-piperidinoethyl) ₇ acetamidoxime dihydrochloride

161 - 163 (methyl ethyl ketone / isopropanol) 159 - 161 (decomposition) (ethanol)

180-184 (decomposition) (ethyl acetate / methanol;

165-168
(Ethyl acetate / methanol)

184 - 187 (decomposition)

(Methyl ethyl ketone /

Isopropanol)

79 - 82 (n-hexane / petroleum ether 40/60 ° C) 181 - 183 (decomposition)

(Ethyl acetate / iso-

propanol)

709826/1093

-3B-

■ IO ·

2- (2-Ethyl-3-benzofuranyl) -N- (3-piperidino-n-propyl) -acetamidoxime hydrochloride

2- (2-ethyl-3-benzofuranvl) -N- (3-morpholino-n-propyl) -acetamidoxime dihydrochloride

2- (2-Ethyl-3-benzofuranyl) -N- (2-heptamethyleneiminoethyl) -acetamidoxime

2- (2-ethyl-3-benzofuranyl) -N- (3-di-n-propylamino-n-propyl) -acetamidoxime-dioxalate

2- (2-Ethyl-3-benzofuranyl) -N- [2- (4-methylpiper az ino) * ethyl / acetamidoxime ""

2- (2-Ethyl-3-benzofuranyl) -N- / ~ * 2- (4-n-propylpiperazino) -äthylJ7 * acetamidoxime trihydrο chloride

2- (2-ethyl-5-chloro-3-benzo-

furanyl) -N- (2-pyrrolidinoethyl) acetamidoxime dihydrochloride

2- (2-ethyl-5-chloro-3-benzo-

furanyl) -N- (2-piperidinoethyl) -acetamidoxime

2- (2-! Ethyl-5-chloro-3-benzo-

furanyl) -H- (2-piperidinoethyl) -acetamldoxime dihydrochloride

2- (2-ethyl-5-chloro-3-benzo-

furanyl) -N- (2-morpholinoethyl) -acetamidoxime

2- (2-ethyl-5-chloro-3-benzo-

furanyl) -N- (2-morpholinoethyl) -acetamidoxime dihydrochloride

2- (2-methyl-3-benzofuranvlUN-

(2-morpholinoethyl] acetamidoxime sesquioxalate

2- (2-n-Propyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoximesesquioxalate

2- (2-1sopropyl-3-benzofuranyl) -N-

(2-pyrrolidino5th2 /]) - acetarnidoxime dihydrochloride

171 - 173 (decomposition) (isopropanol / ethyl ether)

199 - 202 (isopropanol / ethyl ether)

79-81 (n-hexane)

123 - 126 (decomposition) (ethyl acetate / methanol)

121-123
(Ethanol / water)

161-165
(Ethanol / ethyl ether)

210 - 213 (decomposition) (isopropanol)

118 - 120 (petroleum ether 40/80 ⁰ C)

157 - 160 (decomposition) (ethyl acetate / methanol)

110 - 112 (petroleum ether 60/80 ⁰ C)

122 - 126 (decomposition) (ethyl acetate / methanol)

148 - 150 (decomposition) (ethanol / ethyl ether)

162 - 164 (decomposition) (methanol)

201 - 202 (decomposition) (isopropanol)

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2- (2-Isopropyl-3-benzofuranyl) -N- (2-piperidinoethyl) -acetamidoxime-dihydrochioria

2- (2-Isopropyl) -3-benzofuranyl) -N- (2-morpholinoethyi) -acetamidoxime dihydrochloride

2- (2-n-Butyl-3-bp ^ 7.ofuranyl) -N- (2-piperidinoethyl) -acetamidoxime

2- (2-n-Butyl-3-benzofuranvl) -N- (2-morpholinoethyl) -acetamidoxime sesquioxalate

2- (2-Isobutyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxiradihydrochloride

2 - / "2- (2-n-butyl) -3-benzofuranyl7-N-T2-morpholinoethyl) -acetamide- "" oxime dihydrochloride

2- (2-Phenyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime-sesquioxalax

2- (2-Phenyl-3-benzofuranyl) -N- (2-piperidinoethyl) -acetamidoxira

180 - 184 (ethyl acetate / isopropanol)

196 - 199 (decomposition) (acetone / isopropanol)

72-74

(Petroleum ether 40 / 8O ⁰ C)

115 (decomposition) (methanol)

172 - 174 (ethanol / ethyl ether)

197 - 199 (decomposition) (isopropanol)

157 - 159 (ethanol)

162 - 164 (ether)

Example 2

2- (2-Ethyl-3-benzofuranyl) -2,2-dimethyl-N- (2-morpholinoethyl) acetamidoxime

a) Preparation of 2- (2-ethyl-3-benzofuranyl) -2-methyl propionitrile

A solution of 37 g (0.2 mol) of 2-ethyl-3-cyanomethylbenzofuran in 200 ml of anhydrous ethyl ether was added dropwise with stirring to a suspension of 17.2 g (0.44 mol) of sodium amide in 250 ml of anhydrous ethyl ether are added.

It was stirred for 2 hours at room temperature; then a solution of 85.2 g (0.6 mol) of methyl iodide in 200 ml anhydrous ethyl ether was added dropwise. A possible one

709826/1093

Excess sodium amide was removed by adding a little water decomposed, and the resulting solution was poured into water.

The aqueous solution obtained was extracted with ether, and 22.45 g of 2- (2-ethyl-3-benzofuranyl) -2-methylpropionitrile were obtained.

Yield: 52.7 % boiling point 95-10O ⁰ C (0.03 mm Hg)

b) Preparation of 2- (2-ethyl-3-benzofuranyl) -2,2-dimethyl ^i- acetamidoxime

This compound * was prepared from 2- (2-ethyl-3-benzofuranyl) -2-methylpropionitrile by the method described in Example 1 a) produced, but 1.5 moles of Hydroxylamin.-hydrοChlorid and sodium methylate per mole of 2- (2-ethyl-3-benzofuranyl) -2-methylpropionitrile were used and the reaction was continued for 72 hours.

Yield: 41 %; Melting point 118-120 ° C after recrystallization from a mixture of ethyl acetate and light petroleum ether.

Melting point of the hydrochloride: 189-192 ⁰ C after recrystallization from a mixture of ethyl acetate, isopropanol and ethyl ether.

c) Preparation of 3- / ~ 1- (2-ethyl-3-benzofuranyl) -1-methyl- 1-ethyl ^{-7-1,2,4-A. 2} -oxadiazol-5-one

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) -2,2-dimethylacetamidoxime hydrochloride by the method described in Example 1 b) manufactured.

Melting point: 153-156 ° C.

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d) Preparation of 3- / ~ "i ~ (2-ethyl-3-benzofuranyl) -1-methyl- 1-ether7-4- (2-morpholinoethvl) -1» ^{2,4-A 2} -oxadia2ol-3 -on

This compound was made according to that described in Example 1 c) Process from 3- / ~ "i - (2-ethyl-3-benzofuranyl) -1-methyl-1-ethyl / 1,2,4-Δ-oxadiazol-5-one prepared.

Melting point of the hydrochloride: 215-219 ° C after the recrystalline lize from a mixture of methyl ethyl ketone, isopropyl alcohol and ethyl ether.

Following the same procedure, but using the appropriate one Starting products, the following connection was made:

/ - (2-Ethyl-3-benzofuranyl) -1-methyl-1-ethyl7-4- (2-piperidi «O-ethyl) -1 _f 2,4-A ² -oxadiazol-5-one.

Melting point of the hydrochloride: 209 - 213 ° C (decomposition) after recrystallization from a mixture of acetone and isopropanol and ethyl ether.

e) Production of 2- (2-ethyl-3-benzofuranyl) -2,2 ~ dimethyl-

N- (2-morpholinoethyl) acetamirtoxime

This compound was prepared by the method described in Example 1 d) from 3- / ~ 1- (2-ethyl-3-benzofuranyl) -1-methyl-1-ethyl7-4- (2-morpholinoethy: i) - »1, 2,4-A -oxadiazol-5-one hydrochloride produced. Melting point: 110-112 ° C after recrystallization from n-hexane.

Following the same procedure, but using the corresponding one Starting product, the following connection was made:

2- (2-Ethyl-3-benzofuranyl) -2,2-dimethyl-N- (2-piperidinoethyl) acetamidoxime.

Melting point: 94 - 97 ° C after recrystallization from a mixture of ethyl ether and petroleum ether (boiling point 40 - 60 ° C).

709826/1093

Example 3

2- (2-ethyl-3-benzofuranyl) -2-ethyl-N- (2-morpholinoethyl) -acet amidoxime ; .

a) Preparation of 2- (2-ethyl-3-benzofuranyl) -butvronitrile

8.3 g (0.106 mol) of a 50% suspension were obtained with stirring of sodium amide in toluene, which were taken up with 50 ml of ethyl ether, dropwise to a solution of 18.52 g (0.1 mol) of (2-ethyl-3-benzof uranyl) acetonitrile in 200 ml of dry ether was added. The mixture was refluxed for 1 hour, then allowed to cool at room temperature. The stirring was continued and a solution of 23 g became dropwise (0.1475 mol) of ethyl iodide in 100 ml of ethyl ether was added. The reaction medium was refluxed for 3 hours after which time it was allowed to cool.

Any excess of sodium amide that was present was carefully decomposed by adding a little water, and the medium was poured into water. The nitrile was extracted with ether and separated.

Yield: 75 %. Boiling point: 115-117 ⁰ C (0.5 mm Hg).

b) Preparation of 2- (2-ethyl-3-benzofuranvl) -butvr & midoxime

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) butyronitrile by the method described in Example 1 a). Melting point of the hydrochloride: 160 - 163 ° C after Recrystallize from ethyl acetate.

c) Preparation of 3- / ~ 1- (2-ethyl-3-benzofuranyl) -i-propyl / - 1,2,4-Δ-oxadiazol-5-one

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) butyramidoxime according to the method described in Example 1 b).

709826/1093

crystallize ethyl ether and petroleum ether (40/60 °).

Melting point: 130-132 ⁰ C after recrystallization from

d) Preparation of 3- / ~ 1- (2-ethyl-3-benzofuranyl) -1-propyl7-

4- (2-morpholinoethvl) -1,2,4-Δ-oxadiazol-5-one

This compound was prepared by the method described in Example 1 c) from 3 - / "~ 1- (2-ethyl-3-benzofuranyl) -1-propyl7-1,2,4-Δ -oxadiazol-5-one produced.

Melting point of the hydrochloride: 185-188 ⁰ C after recrystallization from isopropanol.

e) Preparation of 2- (2-ethyl-3-benzofuranyl) -2-ethyl-N- (2-morpholinoäthvl) -acetamidoxini

This compound was made according to that described in Example 1d) Process from 3- / ~ 1- (2-ethyl-3-benzofuranyl) -1 «propyl7-4- (2-morpholinoethyl) -1,2,4-Δ -oxadiazol-5-one produced.

Melting point of the sesquioxalate: 139-141 ° C. (decomposition) after recrystallization from isopropanol.

Example 4

2- (2-Ethyl-3-benzofuranyl) -2-methyl-N- (2-morpholinoethyl) acetamidoxime

a) Preparation of 2- (2-ethyl-3-benzofuranyl) -methanol-propionate

With stirring, 1 g of iron (III) nitrite and then Put 6.35 g (0.276 g-atom) of sodium in 500 ml of liquid ammonia. Stirring was continued for 30 minutes and it a solution of 54.5 g (0.25 mol) (2-ethyl-3-benzofuranyl) methyl acetate in 50 ml of dry ethyl ether was added dropwise. It was stirred for an additional 2 hours and it became a solution of 39 g (0.275 mol) of methyl iodide in 50 ml of dry Ether added dropwise.

7098 2 6/1093

- 34 -

The reaction medium was allowed to cool with stirring at room temperature for 2 hours.

100 g of ammonium chloride were added to the brownish residue and the medium was extracted four or five times with ethyl ether. The organic phases were collected, washed with water and dried over anhydrous sodium sulfate. The ether was evaporated to give 21.4 g of 2- (2-ethyl-3-benzofuranyl) methyl propionate _r.

Yield: 37%. Boiling point: 100 ^° C. (0.4 mm Hg).

b) Preparation of 2- (2-ethyl-3-benzofuranyl) propionic acid

41.6 g (0.179 mol) of 2- (2-ethyl-3-benzofuranyl) methyl propionate were added to a solution of 12 g (0.215 mol) of potassium hydroxide in a mixture of 240 ml of water and 120 ml of methanol. The reaction medium was heated in a water bath for 3 hours and the methanol was evaporated. The watery Solution was acidified with hydrochloric acid and extracted with ether. The essential solution was anhydrous over Sodium sulfate was dried, the solvent was evaporated, and 39 g of 2- (2-ethyl-3-benzofuranyl) propionic acid were obtained.

Yield: 90%. Melting point: 62 - 64 ° C after recrystallization from petroleum ether (40 - 60 °).

c) Preparation of 2- (2-ethyl-3-benzofuranyl) proplonamide

A solution of 35.1 g (0.161 mol) 2- (2-ethyl-3-benzofuranyl) propionic acid in 100 ml of thionyl chloride was for 12 hours at room temperature and then for another 1 hour at that temperature of the water bath.

The excess thionyl chloride was evaporated off under reduced pressure, and the 2- (2-ethyl-3-benzofuranyl) propionic acid chloride which formed was dissolved in 100 ml of dry ether. the

709826/1093

The resulting solution was added dropwise to 500 ml of ethyl ether saturated with dry ammonia.

The reaction medium was stirred for 1 hour and then allowed to stand for 12 hours. The essential solution was made with water washed, dried over anhydrous sodium sulfate and the solvent evaporated to give 35 g of 2- (2-ethyl-3-benzofuranyl) propionamide.

Yield: 100%; Melting point: 84-87 ⁰ C after recrystallization from n-hexane.

d) Preparation of 2- (2-ethyl-3-benzofuranyl) propionitrile

A solution of 35 g (0.16 mol) of 2- (2-ethyl-3-benzofuranyl) propionamide in 500 ml of toluene was refluxed for 18 hours in the presence of PpOc. The organic Phase was decanted off and the residue was carefully decomposed with ice water and extracted with ether.

The organic phase was washed with water over sodium sulfate dried and added to the toluene phase.

The solvents were evaporated under reduced pressure, and the residue was fractionated, yielding 23 »8 g 2- (2-ethyl-3-benzofuranyl) propionitrile was obtained.

Yield: 74.4 %, boiling point: 105 ^° C. (0.2 mm Hg).

e) Preparation of 2- (2-ethyl-3-benzofuranyl) propionamidoxime

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) propionitrile by the method described in Example 2 b). Melting point of the hydrochloride: 152-155 ° C after recrystallization from acetone-ethyl ether.

709826/1093

f) Preparation of 3- / ~~ 1- (2-ethyl-3-benzofuranyl) -i-äthylj-

1,2,4-Δ-oxadiazol-5-one

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) propionamidoxime according to the method described in Example 1b). Melting point: 11C-113 ⁰ C after recrystallization from ethyl ether-petroleum ether (40-60 °).

g) Preparation of 3- / ~ 1- (2-räthyl-3-benzofuranyl) -1-ethyl7-4- (2-morphollnoäthy]) - 1,2,4-Δ-oxadiazol-5-one

This compound was prepared from 3-Z ~ 1- (2-ethyl-3-benzofuranyl) -1-ethyl7-1,2,4-A ² -oxadiazol-5-one by the method described in Example 1 c).

Melting point: 132 to 135 ⁰ C after recrystallization from isopropyl · propanol-isopropyl ether.

h) Preparation of 2- (2-ethyl-3-benzofuranyl) -2-methyl-N- (2- morpholinoät hy l) -acetamidoxime

This compound was made according to that described in Example 1d) Process from 3- / ~ 1- (2-ethyl-3-benzofuranyl) -1-ethyl7-4- (2-morpholinoethyl) -1,2,4-Δ -oxadiazol-5-one produced.

Melting point: 112-115 ⁰ C after recrystallization from acetone-petroleum ether (40 - 60 °).

Melting point of the sesquioxalate: 132-135 ° C (decomposition) after recrystallization from methanol-ethyl ether.

Example 5

Hard gelatin capsules were made according to known pharmaceutical processes manufactured:

709826/1093

- if - Components m R per 2657902 '%%' 2- (2-ethyl-3-benzofuranyl) -N- capsule (2-morpholine ethyl) acetamidoxime 20th -2. Sequioxalate 10 Cornstarch 194 , 3 colloidal silicon oxide 0 , 7 204 0, , 3 , 7

215.0 mg 215.0 mg

709826/1093

Claims (9)

Patent claims:
M.yCombination of the general formula: :-OH wherein R ^ is a branched or straight chain alkyl group with 1 to about 4 carbon atoms or a phenyl group, A one of the groups: H CH-, H ^ r _c r ^ or R _{2 is} an optionally substituted amino group, X is a hydrogen or chlorine atom or a methoxy group and η is the integer 2 or 3, or a pharmaceutically acceptable acid addition salt thereof. 2. A compound according to claim 1, characterized in that Rp is a dimethylamino, diethylamino, di-n-propylamino, Di-η-butylamino, pyrrolidino, morpholino, piperidino or heptamethyleneimino group or a 1-piperazino group substituted in the 4-position by a straight chain alkyl group is substituted by 1 to 4 carbon atoms. 3. 2- (2-Ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime and the pharmaceutically acceptable acid addition salts of this. 709826/1093 4. Process for the preparation of a compound of formula I, characterized in that a 3,4-disubstituted 1,2,4- & -oxadiazol-5-one of the general formula: wherein R ₁ , Rp, A, X and η have the same meaning as in formula I, a ring opening is made. 5. The method according to claim 4, characterized in that the ring opening is carried out by heating the compound of formula II in an aqueous alcoholic medium in the presence of a base. 6. The method according to claim 5, characterized in that sodium hydroxide is used as the base. 7. Pharmaceutical composition, characterized in that it as active ingredient at least one compound of the formula I or a pharmaceutically acceptable acid addition salt of this together with a pharmaceutical carrier. 8. Pharmaceutical composition, characterized in that it contains as active ingredient 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholirP-ethyl) -acetamidoxime or a pharmaceutically acceptable acid addition salt of this together with a pharmaceutical excipient. 9. Composition according to claim 7-8, characterized in that it is in the form of dosage units for oral Administration are suitable, is present. 709826/1093