HU176557B - Process for producing acetamidoxime derivatives of benzofurane - Google Patents

Abstract

1508210 Benzofuran-derived amidoxines LABAZ 30 Nov 1976 [22 Dec 1975] 52475/75 Heading C2C The invention comprises compounds of formula and their pharmaceutically acceptable acid addition salts wherein R 1 is C 1-4 alkyl or Ph, A is CH 2 , CMe 2 , CHMe or CHEt; R 2 is substituted amino; X is H, Cl or MeO; and n is 2 or 3. These compounds are prepared by heating the oxadiazolones of formula in an aqueous alcohol medium, in the presence of a base. Starting materials otherwise prepared are the analogues of (I) and (II) in which H replaces (CH 2 ) n -R 2 ; and compounds of formulµ ZCHMeCO 2 R, ZCHMeCOCI, ZCHMeCONH 2 and Z-A<SP>1</SP>-CN, wherein Z is 2-ethylbenzo-3-furyl and A<SP>1</SP> is CHMe, CHEt or CMe 2 . Therapeutic compositions having cardiovascular, antihypertensive and diuretic activity comprise compounds of the above Formula (I) and are preferably administered orally.

Description

The present invention relates to a process for the preparation of novel derivatives of benzofuran-acetamidoxime and to pharmaceutical compositions containing the above-mentioned acetamidoxime derivative as an active ingredient.

The compound of the present invention, which may exist in racemic or optically active form, is represented by formula (I) wherein

R 1 is a linear or branched alkyl group containing from 1 to 4 carbon atoms or a phenyl group,

A is -CH ₂ -, = C (CH 3) ₂ , = CH-CH ₃ , and = CH-C ₂ H _5.

R ₂ is a lower dialkylamino group, preferably dimethylamino, dimethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino, or heptamethyleneimino, or a 1-piperazino group. which is substituted at the 4-position by a straight-chain alkyl group containing from 1 to 4 carbon atoms,

X is a hydrogen atom, a chlorine atom or a methoxy group, and n is 2 or 3.

The preparation of pharmaceutically acceptable acid addition salts of a compound of formula (I) is also within the scope of this invention.

The compounds of formula (I) are prepared by ring opening of 3,4-disubstituted-1,2,4-Δ ² -oxadiazol-5-one or acid addition salts thereof, wherein R 1, R ₂ , A, X and n is as defined above. Ring opening may be accomplished by known methods, for example, by heating the compound in an aqueous alcoholic medium in the presence of an alkali such as sodium hydroxide.

The prepared compound of general formula (II) where (III) 3-substituted-l formula, A ^{1 2} 2,4-oxadiazol-5-one, wherein R _3, A and X are as defined above, With chloroalkylamine of formula (IV) in which r ₂ and n are as defined above, or preferably its hydrochloride, in an organic medium such as anhydrous acetone containing a small amount of methyl alcohol in the presence of a base such as anhydrous potassium carbonate.

Compounds of formula IV are already known.

Compounds of formula (III) may be prepared by known methods, for example, by reacting an amidoxime derivative of formula (V) wherein R ₃ , A and X are as defined above or an acid addition salt thereof with an anhydrous diethyl carbonate, e.g. in anhydrous ethanol containing ethylate.

Preferably, the compound of formula (V) is prepared by reacting a compound of formula (VI) wherein R ₁ , R ₂ and X are as defined above with hydroxylamine hydrochloride in an alcoholic medium containing a base such as sodium methylate or sodium ethylate.

Compounds of formula VI wherein A is CH ₂ are already known in ARESCHKA et al. Chimie Therapeutique 7, 337 (1972), and may be prepared according to the procedure described in this publication.

Compounds of formula VI wherein A is = C (CH ₃ ) _{2 can be} prepared if compounds of formula VI wherein A is = CH _{2 are} CH _{3 -} Hal wherein Hal is chlorine, bromine or iodate.

Compounds of formula VI wherein A is = CH-CH ₃ or = CH-C ₂ H _{5 can be} prepared by reacting a compound of formula VII wherein R 1 and X are as defined above, R ₃ is the methoxy or ethoxy group, in liquid ammonia containing sodium amide produced in situ, is alkylated with methyl iodide or ethyl iodide and the ester group of the resulting compound is reduced to the nitrile group by a known method.

Compounds of formula (VII) may be prepared from compounds of formula (VI) in which A is = CH ₂ by any of the known methods.

The compounds of the present invention have useful therapeutic properties and, as such, are useful in the treatment of cardiovascular disorders, i.e., high and low blood pressure.

Majority of the types of hypertension are constituted by essential and malignant hypertension and there is no specific cure for these diseases. Individual cases may respond in different ways to different medications.

Therefore, many anti-hypertensive agents are known which are used to treat various types of hypertension.

Among them, ganglion blocking agents are known to exert a ganglioplegic effect by interrupting sympathicotonic impulses and thereby relaxing vascular walls. This report can be dangerous if the patient is in need of a greater tone of the vessel walls, for example due to a change in position. It will now be seen that the compounds of the invention have no ganglioplegic activity at all.

Other antihypertensive compounds, such as veratrum alkaloids, are characterized by a very small difference between therapeutic and toxic doses. An overdose can be dangerous and the doctor should choose the dosage carefully and keep up to date with patient needs and reactions. In contrast, the toxic dose of the compounds of the invention is many times the amount required to achieve the therapeutic effect, and thus has a wide margin of safety.

Other known agents have rapid and potent anti-hypertensive effects and are therefore difficult to control. The compounds of the invention do not have this disadvantage. In contrast, it has been observed that the compounds of the invention have significant and easily controllable anti-hypertensive activity.

Among the known compounds are 2- (2-ethyl-3-benzofuranyl) -N, N- (3-n-propyl-3-aza-pentamethylene) -acetamide dihydrochloride, which is disclosed in British Patent Application No. 1,380,145. of the compounds disclosed herein are the most preferred.

This compound is chemically related to the compounds of the invention and has proved to be an effective drug for the treatment of experimentally induced hypertension. It will be appreciated, however, that the compounds of the invention are not only more active but also less toxic than the compound recommended in that patent.

Furthermore, the anti-hypertensive activity of the compounds of the invention is associated with little or no side effects. At the same time, there is no reduction in activity due to habituation.

Finally, it is well known that the diuretic effect associated with the anti-hypertensive action is very beneficial in the treatment of hypertension, especially when the diuretic action does not induce potassium ion secretion but rather sodium secretion.

The compounds of the present invention have been found to exhibit very favorable sodium ion secretion and thus may be very valuable antihypertensive agents.

Therapeutic studies were performed to illustrate the anti-hypertensive activity of the compounds of the invention in experimentally induced hypertension.

The first studies were performed on male rats weighing 120 g, which induced renal function-related hypertension using the Grollmann method. [Proc. Soc. Exp. Biol. Med., 57, 102 (1944).]

In this method, the animals were anesthetized with ether and one of their kidneys was removed without being removed from their bodies, and the adrenal gland was removed from the kidney but otherwise intact. The kidney was then tied with a twine in shape 8, strong enough to slightly deform the ellipsoidal body. After ten days, the other kidney and its adrenal gland were completely removed. About 4 weeks after the second surgery, most animals (approximately 60-70%) developed severe hypertension. The systolic pressure in most cases exceeded 180 mmHg.

One group of rats so treated was treated with a compound of the invention at a dose of 25 mg / kg by gastric tube. Arterial pressure was measured immediately before treatment, and 1, 2, 3.4, 5 and 6 hours after dosing.

The compounds listed in Table I gave the results reported there:

Table I

Compound arterial pressure decreases MmHg 2- (2-ethyl-3-benzofuranyl) -N- - (2-morpholinoethyl) -acetamidoxime 36 2- (2-methyl-3-benzofuranyl) -N- - (2-morpholinoethyl) -acetamidoxime 25 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- - (2-morpholinoethyl) -acetamidoxime 21 2- (2-ethyl-3-benzofuranyl) -N- - (2-di-n-butylamine-ethyl) -acetamidoxime 27

In the same study, a well-known antihypertensive agent, namely, α-methyl- (3,5-dihydroxyphenyl) -?

Under these conditions, arterial pressure increased to about 200 mmHg. The following data were recorded:

A dose of mg / kg was required to maintain the arterial pressure drop between 20 and 30 mmHg. Another agent with anti-hypertensive properties, hydrochlorothiazide, was found to be inactive in this study at a dose of 200 mg / kg by gavage.

The same test was 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.

At a dose of 50 mg / kg by gastric tube, a reduction in arterial pressure of 14 mmHg was obtained, whereas at a dose of 200 mg / kg the decrease was 24 mmHg.

Further pharmacological studies were conducted with the most preferred compound of the invention, 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime (or L 9552), to determine its antihypertensive efficacy.

All studies were conducted in rats that were hypertensive. Each study was divided into two series. In the first series, the test product was administered in a single dose by gavage to each animal, and their arterial pressure was measured every hour for 6 hours after dosing. In the second series, the test product was administered daily in the same manner for 11 consecutive days, and arterial pressure was measured daily during that period. The amount of product administered was different for each animal.

The results of these tests are summarized below.

1. Rats hypertonic with GROLLMAN

Using the above method, we obtained the following result:

II. spreadsheet

Treatment type Dose in mg / kg The arterial pressure is max. reduced. Hg The max. harms. pressure drop time One dose 10 14 4 o'clock 25 36 4 o'clock 50 55 3 hours Daily 10 18 6 days dosage 25 32 5 days (For 11 days) 50 47 4 days

2. Endocrine hypertension

This assay was performed by the method of STANTON and WHITE (Arch. Int. Pharmacodyn. 154, 351, 1965).

Female rats (± 10 g) were anesthetized with ether. Hypertension was induced by subcutaneous administration of 50 mg / kg of deoxycorticosterone acetate (DOCA) for 5 weeks per week, with ether. During this period, the rats' drinking water contained 1% sodium chloride. This was later replaced by plain tap water when deoxycorticosterone treatment was discontinued.

III. spreadsheet

Treatment type. Dose in mg / kg A2 arterial pressure max. reduced. Hg The max. harms. pressure drop time one 25 18 4 o'clock dose 50 26 4 o'clock 100 45 4 o'clock Daily 25 15 5 days dosage 50 30 4 days (For 11 days) 100 49 4 days

3. Hypertension induced by salt intake

This study was performed by DAHL, KNUDSEN, HEINE and

This was done by the LEITL method (Circulation Research, 22.11 - 18.1968).

Male rats weighing + 5 g were fed with otherwise normal food containing 8% sodium chloride.

After six weeks, arterial pressure rose to 180 mmHg 25.

The following results were obtained:

ARC. spreadsheet _____________________________.__

Treatment type Dose in mg / kg The arterial pressure is max. reduced. Hg The max, art. pressure drop time one 10 14 4 o'clock dose 25 27 4 o'clock 50 54 4 o'clock Daily 10 13 7 days dosage 25 26 4 days (For 11 days) 50 53 3 days

4. Neurogenic hypertension

This assay was performed by the method of KRIEGER and IMBS 45 (Circul. Res. 15, 511, 1964 and C. R. Soc.

162,778,1968).

Male rats (200-250 g) were anesthetized with ether and 0.5 mg atropine sulfate was administered intraperitoneally.

Rats were supine and anteriorly incised to allow access to a neuromuscular bundle that includes sympathetic and sciatic nerves and common carotid arteries.

The cutaneous nerves and carotid arteries were carefully separated, while 1 cm from the sympathetic nerves was excised.

Upper laryngeal nerves were isolated. The area in which the carotid arteries divide was dissected by dissecting the appropriate neck muscles (sternocleidomastoid and omohyoide) 60. The blood vessels thus released were stained with 10% phenol in ethanol. In this way, complete sympathetic denervation was achieved.

The increase in arterial pressure after 5 to 8 days was 65.

The control group, also consisting of 20 rats, received only saline.

Within 6 hours of dosing, all selected urine was collected and weighed.

The result obtained, expressed as a percentage of the volume of saline administered, is given in the following table.

ι

The following results were obtained:

Table V.

Time of treatment Dose in mg / kg The arterial pressure is max. reduced. Hg The max. harms. pressure drop time one 10 18 3 hours dose 25 37 4 o'clock 50 56 3 hours Daily 10 17 5 days dosage (for 11 days) 25 35 5 days

5. Inherited hypertension

This assay was performed by OKAMOTO and AOKI (Jap. Cireul. J., 27, 282, 1963). Male rats of the species specifically bred to obtain high blood pressure animals were used. The animals used in the study were 10 days old and had a blood pressure of about 180 mmHg.

The following results were obtained:

VI. spreadsheet

Treatment type Dose in mg / kg The arterial pressure is max. reduced. Hg The max. harms. pressure drop time one 5 16 2 o'clock dose 10 35 2 o'clock 20 52 3 hours Daily 5 0 - dosage 10 26 4 days (For 11 days) 25 35 5 days

According to PLUMMER (Anti-hypertensive agents, p. 67, Edited by SCHLITTLER, Academic Press, N.Y. and London, 1967) and many other authors, any substance that is effective in various types of experimentally induced hypertension can be used in human medicine as an antihypertensive agent.

Furthermore, it is also known that hereditary hypertension is the closest to the so-called essential hypertension in humans (which accounts for 80% of hypertensive diseases).

Compound L 9552, which was used in all five types of experimentally induced hypertension, was found to be effective in all cases, but was particularly effective in hereditary hypertension.

Thus, it can be concluded that L 9552 is also likely to be useful in the treatment of hypertension in humans.

Further experiments were performed to investigate the diuretic effect of L 9552.

1. Volume measurement of selected urine

This study was performed by LIPSCHITZ et al. (J. Phamacol. exp. Therap. 79, 97, 1943) 20 male albino rats weighing 150-200 g were kept without food and water for 18 hours.

The test substance was administered directly to the animals by gavage at a dose of 9% o 50 ml / kg. sodium chloride solution by gavage.

VII. spreadsheet

Dose in mg / kg Selected urine. 0 20-15 10 84 20 102 50 118 100 138 200 165

The maximum secretion observed in control animals is 50%, which means that the diuretic effect can be considered very good in comparison.

2, Ion ratio in selected urine

This study was performed by AMBROSILI et al. (Minerva Nepol. 11,56,1964).

Immediately after administration of 50 ml / kg of distilled water via gavage, the test substance was administered to 20 male albino rats weighing 140 ± 10 g, from which food and water were withdrawn for 18 hours.

The control group of 20 rats was administered only distilled water.

Within 4 hours of dosing, all urine excreted was collected and weighed, and all Na ⁺ and K ' ^{1 were} assayed.

The values obtained were converted to milliequivalents per liter (mEq / liter) to obtain the correct excretion of Na ' ^- and K ⁺ ions, which is independent of urine volume.

The ion ratio is calculated using the formula:

₊ [Na ⁺ ] in treated animals ^a , [K ⁺ ] in treated animals gold = --- v ---- [Na ^4- ] in control animals [K ⁺ ] in control animals

The following results were obtained:

VIII. spreadsheet

Dose in mg / kg Urine Select% na + (MEq / L) K + (mEq / liter) Na + / K + ratio Control animals 40 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

According to the table, L 9552 has a very favorable sodium secretion index, which is very important for the treatment of hypertension.

Pharmacology! tests have also been performed to show that L 9552 has no ganglionic effect:

1. The arterial pressure and the tone of the blinking membrane of an anesthetized cat were recorded. Next, we examined the contraction of the membrane by intravenous injection of adrenaline and electrical simulation of the preganglionic fiber of the cervical sympathetic nerve. It was found that two injections of L 9552 intravenously at 5 mg / kg did not affect the intensity of the membrane contraction produced as described above.

2. In a dog anesthetized with sodium pentobarbital and then atropinised, L 9552 administered intravenously at a dose of 5 mg / kg does not alter the hypertensive effect of acetylcholine in mg / kg administered intravenously. In contrast, ganglionic blocking agents, such as pentonium, eliminate the hypertensive effect of acetylcholine.

Finally, acute intoxication studies were performed in rats and mice, which were observed for 12 days after a single administration.

The following results were recorded:

IX. spreadsheet

Animals Method of administration LD (mg / kg) LDO i-Djo LDps Mouse intraperitoneally delivered to the onial stomach 30 250 70 700 110 1250 Rat delivered intraperitoneally 80 1100 200 1900 350 2500

Comparing these doses with the active doses of 50 mg / kg and 100 mg / kg, respectively, administered to the stomach at which the effects described above were tested, gives a very favorable picture and we see that there is a very wide margin of therapeutic and toxic doses. between. 40

It will also be appreciated that, for therapeutic treatment, the compounds of the invention may normally be administered in the form of a pharmaceutical composition containing at least 45 of the compounds of formula I or pharmaceutically acceptable acid addition salts thereof as an active ingredient in admixture with conventional carriers and / or excipients. .

For clinical use, the composition is conveniently administered in unit dosage form, for example, for oral administration in the form of tablets or capsules.

The invention is illustrated by the following examples.

Example 1 55

2- (2-ethyl-3-benzofuranyl> N- (2-morpholinoethyl) acetamidoxime sesquioxalate

a) Preparation of 2- (2-ethyl-3-benzofuranyl) -acetamidoxime 60

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 mixture was stirred until completely dissolved. 65

200 ml of methanol containing 92.6 g (0.50 mole) of 2-ethyl-3-cyanomethylbenzofuran were added and stirring was continued for 16 hours and finally the solution was heated under reflux for 3 hours.

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

Addition of a solution of hydrochloric acid in ether gave 99.7 g of 2- (2-ethyl-3-benzofuranyl) -acetamidoxime hydrochloride which was recrystallized from a mixture of ethyl acetate and methanol.

Yield: 78.3%, m.p. 158-161 ° C.

According to the above procedure, using the appropriate starting materials, the following compounds can be prepared:

Compound 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-isopropyl-3-benzofuranyl) acetamidoxime hydrochloride

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

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

2- [2- (2-butyl) -3-benzofuranyl] acetamidoxime 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 30/40 ° C) 190-194 (decomposes) (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 (decomposed) (methyl ethyl ketone / ethanol / ether) 196-199 (decomposed) (isopropanol)

143-145

203-205 (decomposes) (isopropanol)

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

2- (2-Ethyl-3-benzofuranyl) -acetamidoxime hydrochloride (25.47 g, 0.1 mol) was added to 13.6 g (0.2 mol) of sodium ethylate in 250 ml of anhydrous ethanol.

Anhydrous diethyl carbonate (23.6 g, 0.2 mol) was added and the reaction mixture was heated under reflux for 24 hours.

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

The resulting solution is treated with ether and the phases are separated. The aqueous phase is acidified with dilute hydrochloric acid. The precipitate formed is washed with water and dried in vacuo. 20 g of 3- (2-ethyl-3-benzofuranylmethyl) -1,2,4-Δ ² -oxadiazol-5-one are obtained, which is recrystallized from ether / petroleum ether (40/60 ° C fraction). .

Yield: 81.9%, m.p. 156-159 ° C.

Using the above procedure and using the appropriate starting materials, the following compounds can be prepared:

Compound

M.p.

Compound Melting point ° C

3- (2-methyl-3-benzofuranylmethyl) -1,2,4-A ² -oxadiazol-5-one 3- (2-n-propyl-3-benzofuranylmethyl) -1,2,4- ^2- Oxadiazol-5-one 3- (2-isopropyl-3-benzofuranylmethyl) -1,2,4-A ² -oxadiazol-5-one 3- (2-n-butyl-3-benzofuranyl) methyl) -1,2,4-A ² -oxadiazol-5-one 3- (2-isobutyl-3-benzofuranylmethyl) -1,2,4-A ² -oxadiazol-5-one 3- [2- (2-Butyl) -3-benzofuranylmethyl] -1,2,4-Δ ² -oxadiazol-5-one 3- (2-ethyl-5-chloro-3-benzofuranylmethyl) -1,2,2; 4-A ² -oxadiazol-5-one 3- (2-phenyl-3-benzofuranylmethyl) -1,2,4-A ² -oxadiazol-5-one

c)

162-164

155-157 5

162-164

157-159

134-136 (ethyl ether / petroleum ether 40/80 ° C) 15

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

169-172 (ethyl ether) 20

200-203 (ethanol)

Preparation of 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one

oxalate monohydrate

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-pyrrolidinethyl) -1,2,4-A ² -oxadiazol-5-one hydrochloride

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

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-piperidinethyl) -1,2,4-A ² -oxadiazol-5-one hydrochloride

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

3- (2-Ethyl-3-benzofuranylmethyl) -4- (3-morpholino-M-propyl) -1,2,4-A ² -oxadiazol-5-one-one hydrochloride

3- (2-ethyl-3-benzofuranylmethyl) -4- (2-heptamethyleniminoethyl) -1,2,4-A ² -oxadiazol-5-one 3- (2-ethyl-3-benzofuranylmethyl) ) -4- (2-Heptamethylenimino188-190 (decomposes) (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)

In an anhydrous flask fitted with a stirrer and a Soxhlet flask equipped with a condenser, 10.5 g (0.043 mol) of 3- (2-ethyl-3- benzofuranylmethyl) -1,2,4-Δ ² -oxadiazol-5-one.

To the Soxhlet was added 9.3 g (0.05 mol) of 1-chloro-2-morpholino-35-ethane hydrochloride.

While stirring, the reaction mixture was heated under reflux for 18 hours. After filtration of the salt, the solvent is evaporated under reduced pressure. The resulting residue was taken up in water and extracted with ether 40, 15 g of 3- (2-ethyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one. t get.

105-106 ° C. Yield: 97.6%.

181-183 ° C, after recrystallization from isopropanol and benzene. 45

According to the above procedure, using the appropriate starting materials, the following compounds can be prepared:

ethyl) -1,2,4-A-oxadiazol-5-one · hydrochloride salt

3- (2-Ethyl-3-benzofuranylmethyl) -4- (3-di-n-propylamino-n-propyl) -1,2,4-A ² -oxadiazol-5-one oxalate

3- (2-Ethyl-3-benzofuranylmethyl) -4- [2- (4-n-propyl-piperazinyl) -ethyl] -1,2,4-A ² -oxadiazol-5-one dihydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- [2- (4-methylpiperazinyl) ethyl] -1,2,4-A ² -oxadiazol-5-one dihydrochloride

122-125 (ethyl acetate / methanol)

228-232 (decomposes) isopropyl alcohol (methanol)

230-233 (decomposes) (methanol)

Compound

Melting point ^Ö C

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

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-diethylaminoethyl) -1,2,4-A ² -oxadiazol-5-one hydrochloride

3- (2-Ethyl-3-benzofuranylmethyl) -4- (2-di-n-propylaminoethyl) -1,2,4-A ² -oxadiazole-5-hydrochloride

3- (2-ethyl-3-benzofuranyl) methyl-4- (2-di - «- ^J butiÍamino ethyl) -l, ^{2,4-oxadiazol-5-2} on50

200-204 (methyl ethyl ketone) isopropanol

166-169 (methylethyl 55

ketone) isopropanol

164-166 (ethyl acetate / acetone) 60

108-112 (ethyl acetate)

3- (2-Ethyl-5-chloro-3-benzofuran-211- 214 (decomposed) methyl) -4- (2-pyrrolidinethyl) - (isopropyl alcohol / methyl-2,4- ^2- Oxadiazol-5-ontanol)

hydrochloride

3- (2-ethyl-5-chloro-3-benzofuran-205-208 n-methyl) -4- (2-piperidinethyl) - (ethyl acetate / methanol) -1,2,4-A ² -oxadiazole; 5-one hydrochloride

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

225-229 (dec.) (Ethyl acetate / methanol)

3- (2-Methyl-3-benzofuranyl-methyl-130-132 (ethyl ether) ethyl) -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one

3- (2-n-propyl-3-benzofuranyl-145-148)

-methyl) -4- (2-morpholyrioethyl) - (isopropyl alcohol)

-1,2,4-A ² -oxadiazol-5-one oxalate

3- (2-isopropyl-3-phenyl benzofura- 220-223) methyl-4- (2-pyrrolidin-ethyl) - (isopropyl alcohol / ethanol-l, ^2,4-z oxadiazol-5-one - nol)

hydrochloride

Compound ____________ Melting point ° C

Compound

M.p.

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

3- (2-Isopropyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride 3- (2-n-butyl) 3-Benzofuranylmethyl) -4- (2-piperidinethyl) -1,2,4-A 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-A ² -oxadiazol-5-one hydrochloride 3- (2-phenyl-3-benzofuranylmethyl) -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazole- 5-one 3- (2-phenyl-3-benzofuranylmethyl) -4- (2-piperidinethyl) -1,2,4-Δ ² -oxadiazol-5-one hydrochloride 3- [2- (2) -n-butyl) -3-benzofuranylmethyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one hydrochloride

217-221 (decomposed) methanol (ethyl ether)

211-214 (decomposes) (methanol)

174-176 (isopropanol / ethyl ether)

185-188 (isopropanol) methanol / ethyl ether)

185-189 (methanol / ethyl ether)

140-142 (ethanol)

208-211 (ethanol)

211-215 (decomposes) (isopropanol / methanol)

d) Preparation of 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -35-acetamidoxime

7.9 g (0.02 mol) of 3- (2-ethyl-3-benzofuranyl-ethyl) -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one hydrochloride To a solution of 70 ml of methanol is added 3.2 g (0.08 mol) of sodium hydroxide in 32 ml of water.

The reaction mixture was heated at reflux for 30 minutes and then heated under reduced pressure until three quarters of its volume evaporated.

The resulting solution was extracted with ether to give 2.89 g of 2- (2-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxy.

Yield: 89%.

The crude product was taken up in a small amount of methanol and acidified with stirring with a solution of 3 g (0.33 mol) of oxalic acid in methanol. 8 g of 2- (Z-ethyl-3-benzofuranyl) -N- (2-morpholinoethyl) -acetamidoxime sesquioxalate are obtained.

Yield: 85%; mp 163-164 ° C.

According to the above procedure, using the appropriate starting materials, the following compounds can be prepared: Melting point C 161-163 (methylethylketone) isopropanol

- (2-Di-n-propylaminoethyl) -acetamidoxime dihydrochloride 2- (2-ethyl-3-benzofuranyl) -N- (2-di-n-butylaminoethyl) -acetamidoxime dihydrochloride

2- (2-ethyl-3-benzofuranyl) -N- (2-pyrrolidinoethyl) acetamide oxime dihydrochloride (ethyl acetate / methanol)

165-168 (ethyl acetate / methanol)

184-187 (decomposed) (methylethylketone) iso-propanol

2- (2-Ethyl-3-benzofuranyl) -N-x- 79-82 (n-hexane / petroleum (3-pyrrolidino-n-propyl) ether 40/60 ° C) -acetamidoxime

2- (2-ethyl-3-benzofuranyl) -N- (2-piperidinoethyl) acetamidoxime dihydrochloride 2- (2-ethyl-3-benzofuranyl) -N- (3-piperidino-n-propyl) acetamidoxime 2- (2-ethyl-3-benzofuranyl) -N- (3-morpholino-n-propyl) -acetamidoxime dihydrochloride 2- (2-ethyl-3-benzofuranyl) -N- (2-heptamethylenimino-ethyl) -hydrochloride ) -acetamidoxime 2- (2-ethyl-3-benzofuranyl) -N- (3-di-n-propylamino-n-propyl) -acetamidoxime dioxalate 2- (2-ethyl-3-benzofuranyl) -N- [2 - (4-Methyl-piperazino) -ethyl] -acetamidoxime 2- (2-ethyl-3-benzofuranyl) -N- [2- (4-n-propyl-piperazino) -ethyl] -acetamidoxime trihydrochloride 2- (2- ethyl 5-chloro-3-benzofuranyl) -N- (2-pyrrolidinoethyl) acetamidoxime dihydrochloride 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2-piperidinoethyl) - acetamidoxime 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2-piperidinoethyl) acetamide oxime dihydrochloride 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2 -morpholinoethyl) acetamide oxime 2- (2-ethyl-5-chloro-3-benzofuranyl) -N- (2-morpholinoethyl) acetamide oxime dihydrochloride

181-183 (decomposed) (ethyl acetate / isopropanol)

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

199-202 (isopropanol / ethyl ether)

79-81 («-hexane)

123-126 (decomposes) (ethyl acetate)

121-123 (ethanol / water)

161-165 (ethanol / ethyl ether)

210-213 (decomposes) (isopropanol)

118-120 (petroleum ether 40/80 ° C)

157-160 (dec.) (Ethyl acetate / methanol)

110-112 (petroleum ether 60/80 ° C)

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

Compound

2- (2-ethyl-3-benzofuranyl) -N- (2-dimethylaminoethyl) acetamidoxime dihydrochloride 2- (2-ethyl-3-benzofuranyl) -N- (2-diethylaminoethyl) acetamidoxime sesquioxalate 2- (2-ethyl-3-benzofuranyl) -N159-161 (decomposes) (ethanol)

180-184 (decomposes)

2- (2-methyl-3-benzofuranyl) -N-148-150 (decomposed)

- (2-morpholinoethyl) - (methanol / ethyl ether)

-acetamidoxime sesquioxalate

2- (2-rt-propyl-3-benzofuranyl) -162-164 (decomposed) -N- (2-morpholinoethyl) - (methanol)

-acetamidoxime sesquioxalate

2- (2-Isopropyl-3-benzofuran-201-202 (decomposed) nyl) -N- (2-pyrrolidinoethyl) - (isopropanol) acetamide oxime dihydrochloride

2- (2-Isopropyl-3-benzofuran-180-184 nyl) -N- (2-piperidinoethyl) (ethyl acetate / isopropanol) acetamidoxime dihydrochloride

2- (2-Isopropyl-3-benzofuran-196-199 (decomposed) nyl) -N- (2-morpholinoethyl) - (acetone / isopropanol) acetamide oxime dihydrochloride

Compound Melting point ° C

2- (2-M-Butyl-3-benzofuranyl) -72-74-N- (2-piperidinoethyl) - (petroleum ether 40/80 ° C)

-acetamidoxime

2- (2-n-Butyl-3-benzofuranyl) -115 (decomposed) -N- (2-morpholinoethyl) - (methanol)

-acetamidoxime sesquioxalate

2- (2-Isobutyl-3-benzofuranyl) -172-174-N- (2-morpholinoethyl) - (ethanol / ethyl ether)

-acetamidoxime dihydrochloride

2- [2- (2-n-Butyl) -3-benzofuran-197-199 (decomposed) nyl] -N- (2-morpholinoethyl) (isopropanol) acetamide oxime dihydrochloride

2- (2-phenyl-3-benzofuranyl) -N-157-159 (ethanol) - (2-morpholinoethyl) -

-acetamidoxime sesquioxalate

2- (2-phenyl-3-benzofuranyl) -N-162-164 (ether) - (2-piperidinoethyl) -

-acetamidoxime

Example 2

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

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

While stirring, a solution of 2-ethyl-3-cyanomethylbenzofuran (47 g, 0.2 mole) in 200 ml of anhydrous ethyl ether was added dropwise to a mixture of 17.2 g (0.55 mole) of sodium amide and 250 ml of anhydrous ethyl ether.

Stirring was continued at room temperature for a further 2 hours and then 85.2 g (0.6 mol) of methyl iodide in 200 ml of anhydrous ethyl ether was added dropwise. Any excess sodium hydroxide was quenched by adding a little water and the solution was poured into water.

The resulting aqueous solution was extracted with ether to give 22.45 g of 2- (2-ethyl-3-benzofuranyl) -2-methylpropionitrile.

Yield: 52.7%. Boiling point: 95-100 ° C (0.03 mm Hg).

b) Preparation of 2- (2-ethyl-3-benzofuranyl) -2,2-dimethylacetamidoxime

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) -2-methylpropoxonitrile by the method of Example 1a, but using 1.5 moles of hydroxylamine hydrochloride and sodium methylate in 2- (2-ethyl-3 benzofuranyl) -2-methylpropionitrile, and the reaction is performed for 72 hours.

Yield: 41%. 118-120 ° C after recrystallization from ethyl acetate / light petroleum.

189-192 ° C, after recrystallization from ethyl acetate / isopropanol / ethyl ether.

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

This compound was prepared from the hydrochloride of 2- (2-ethyl-3-benzofuranyl) -2,2-dimethylacetamidoxime according to the method of the horse example.

153-156 ° C.

d) 3- [1- (2-Ethyl-3-benzofuranyl) -1-methyl-1-ethyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one production

This compound was prepared using 3- [1- (2-ethyl-3-benzofuranyl) -1-methyl-1-ethyl] -1,2,4-a- ^2- oxadiazol-5-one according to the procedure described in Example le. .

The hydrochloride m.p. 215-219 ° C after recrystallization from a mixture of methyl ethyl ketone, isopropyl alcohol and ethyl ether.

Following this procedure and using the appropriate starting material, the following compound can be obtained: 3- [1- (2-ethyl-3-benzofuranyl) -1-methyl-1-ethyl] -4- (2-piperidinoethyl). -1,2,4-α ² -oxadiazol-5-one.

M.p. 209-213 ° C (dec.) After recrystallization from acetone / isopropyl alcohol / ethyl ether.

e) Preparation of 2- (2-ethyl-3-benzofuranyl) -2,2-dimethyl-N- (2-morpholinoethyl) acetamide oxime

The above-named compound is 3- [l- (2-ethyl-3-benzofuranyl) -l-methyl-ethyl] -4- (2-morpholinoethyl) -l, 2,4 ^-oxadiazol-2 5-On hydrochloride was prepared according to the procedure described in Example 1d.

110-112 ° C, after recrystallization from n-hexane.

Following the same procedure and using the appropriate starting materials, 2- (2-ethyl-3-benzofuranyl) -2,2-dimethyl-N- (2-piperidinoethyl) acetamide oxime can be prepared.

94-97 ° C, after recrystallization from a mixture of ethyl ether and petroleum ether boiling at 40-60 ° C.

Example 3

2- (2-ethyl-3-benzofuranyl) -2-ethyl-N- (2-morpholinoethyl) -acetamidoxime

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

A suspension of 8.3 g (0.106 mol) of sodium amide and sulfuric acid is prepared in 5% w / v solution, taken up in 50 ml of ethyl ether, and 18.52 g (0.1 mol) of (2-ethyl-3) are added dropwise with stirring. benzofuranyl) acetonitrile in 200 ml of anhydrous ethereal solution. The mixture was heated to reflux for one hour and then cooled to room temperature. While stirring, a solution of ethyl iodide (23 g, 0.1475 mol) in ether (100 ml) was added dropwise. The reaction mixture was heated at reflux for 3 hours and then cooled.

Any excess sodium amide is decomposed by adding a little water and the whole mixture is poured into water. The nitrile is extracted with ether and recovered.

Yield: 75%. Boiling point 115-117 ° C.

b) Preparation of 2- (2-ethyl-3-benzofuranyl) butyramidoxime

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) butyronitrile according to the procedure of Example 1a. 160-163 ° C, after recrystallization from ethyl ether.

176 657

c) Preparation of 3- [1- (2-ethyl-3-benzofuranyl) -1-propyl] -1,2,4-Δ ^{1 2} -oxadiazol-5-one

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) -butyramamidoxime according to the procedure described in Example 1b. Melting point: 130-132 ° C after recrystallization from petroleum ether-ether boiling point 40-60 ° C.

d) Preparation of 3- [1- (2-ethyl-3-benzofuranyl) -1-propyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one

This compound was prepared using 3- [1- (2-ethyl-3-benzofuranyl) -1-propyl] -1,2,4-A ² -oxadiazol-5-one according to the procedure described in Example 1b.

185-188 ° C, after recrystallization from isopropanol.

e) Preparation of 2- (2-ethyl-3-benzofuranyl) -2-ethyl-N- (2-morpholinoethyl) acetamide oxime

This compound was prepared using 3- [1- (2-ethyl-3-benzofuranyl) -1-propyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one as described in Example 14. process. The sesquioxalate had a melting point of 139-141 ° C (dec.) After recrystallization from isopropanol.

Example 4

2- (2-ethyl-3-benzofuranyl) -2-methyl-N- (2-morpholino-methyl-ethyl acetamidoxime

a) Preparation of 2- (2-ethyl-3-benzofuranyl) -methyl propionate g g of iron nitrite was added under stirring to 500 ml of liquid ammonia followed by 6.35 g (0.276 mol) of sodium. Stirring is continued for another 30 minutes and then 2-ethyl-3-benzofuranylmethyl acetate (54.5 g, 0.25 mol) in anhydrous ether (50 ml) is added dropwise. Stirring was continued for a further 2 hours and methyl iodide (39 g, 0.275 mol) dissolved in anhydrous ether was added dropwise.

The reaction mixture was cooled to room temperature, where it was stirred for a further 2 hours.

To the resulting brownish mixture was added 100 g of ammonium chloride and the mixture was extracted with ethyl ether 4-5 times. The organic layer was collected, washed with water and dried over anhydrous sodium sulfate. Evaporation of the ether gave 21.4 g of 2- (2-ethyl-3-benzofuranyl) methyl propionate.

Yield: 37%; boiling point: 100 ° C (0.4 mm Hg).

b) Preparation of 2- (2-ethyl-3-benzofuranyl) propionic acid Sodium hydroxide (g, 0.215 mol) was dissolved in a mixture of water (240 ml) and methanol (120 ml) and added thereto.

2- (2-Ethyl-3-benzofuranyl) -methyl-propionate (41.6 g, 0.179 mol) was heated in a water bath for 3 hours while the methanol was evaporated, acidified with hydrochloric acid and extracted with ether, dried over anhydrous sodium sulfate. and evaporating the solvent to give 39 g of 2- (2-ethyl-3-benzofuranyl) -propionic acid.

Yield: 90%. 62-64 ° C, after recrystallization from petroleum ether 40-60 ° C.

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

35.1 g (0.161 mol) of 2- (2-ethyl-3-benzofuranyl) -propionic acid in 100 ml of thionyl chloride were stirred for 12 hours at room temperature and then for 1 hour on a water bath.

The excess thionyl chloride was evaporated under reduced pressure, and the resulting 2- (2-ethyl-3-benzofuranyl) -propionic acid chloride was dissolved in 100 ml of anhydrous ether and the resulting solution was added dropwise to 500 ml of ammonium-saturated ether.

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

Yield: 100%. 84-87 ° C after recrystallization from n-hexane.

d) Preparation of 2- (2-ethyl-3-benzofuranyl) -propionitrile 2- (2-ethyl-3-benzofuranyl) -propionamide (g) (0.16 mol) was dissolved in toluene (500 mL) and heated to reflux for 18 hours. in the presence of phosphorus pentoxide. The organic phase is decanted and the residue is carefully decomposed with ice-cold water and extracted with ether.

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

The solvents were evaporated under reduced pressure and the residue was fractionated to give 23.6 g of 2- (2-ethyl-3-benzofuranyl) -propionitrile.

Yield: 74.4%. Boiling Point! 105 ° C (0.2 Hgmmen).

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

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) -propionitrile according to the procedure of Example 2b. 152-155 ° C, after recrystallization from acetone / ether.

f) Preparation of 3- [1- (2-ethyl-3-benzofuranyl) -1-ethyl] -1,2,4-A ² -oxadiazol-5-one

This compound was prepared from 2- (2-ethyl-3-benzofuranyl) -propionamidoxime according to the procedure of Example 1b. 110- 113 ° C, after recrystallization from a mixture of ethyl ether and petroleum ether 40-60 ° C.

g) Preparation of 3- [1- (2-ethyl-3-benzofuranyl) -1-ethyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one

This compound was prepared using 3- [1- (2-ethyl-3-benzofuranyl) -1-ethyl] -1,2,4-A ² -exadiazol-5-one according to the procedure described in Example 1b. 132-133 ° C after recrystallization from isopropanol / isopropyl ether.

h) Preparation of 2- (2-ethyl-3-benzofuranyl) -2-methyl-N- (2-morpholinoethyl) acetamide oxime

This compound was prepared using 3- [1- (2-ethyl-3-benzofuranyl) -1-ethyl] -4- (2-morpholinoethyl) -1,2,4-A ² -oxadiazol-5-one. , using the procedure described in Example 14. op .:

112-155 ° C, recrystallized from acetone-petroleum ether (40-60 ° C).

The sesquioxalate had a melting point of 132-135 ° C (decomposition) recrystallized from methanol-ethyl ether.

Example 5

A hard gelatin capsule is prepared by a method known in the pharmaceutical art:

Components in mg per capsule

2- (2-ethyl-3-benzofuranyl) -N-12

- (2-morpholinoethyl) acetamide oxime sesquioxalate 2010 maize starch 194,3204,3 colloidal silicon dioxide 0,70,7

215.0 215.0 mg

Claims (4)

Patent claims A process for the preparation of the compounds of the formula I and their pharmaceutically acceptable acid addition salts comprising: Rj is a straight or branched alkyl or phenyl group having from 1 to 4 carbon atoms, A is -CH ₂ -, == C (CH ₃ ) ₂ , = CH-CH ₃ and -CH-C ₂ H ₅ , R ₂ is a lower dialkylamino group, preferably dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino, furthermore pyrrolidino, morpholino, piperidino or heptamethyleneimino, or in the 4-position 1-piperazino substituted with C 1-4 straight-chain alkyl, X is hydrogen, chlorine, or methoxy, n is 2 or 3, characterized in that it is a 3,4-disubstituted-1,2,4-Δ ² -oxadiazol-5-one molecule of formula (II) wherein R _x , R ₂ , X and n are the same as ring opening, and the resulting compound of formula I is optionally converted into the acid addition salt. 2. The process of claim 1, wherein the ring opening is carried out by heating the compound of formula II in an aqueous alcoholic medium in the presence of a base. 3. A process according to claim 2, wherein the base is sodium hydroxide. The process for the preparation of a pharmaceutical composition according to claim 1, wherein the compound of formula (I) wherein R 1, A, R ₂ , X and n are as defined in claim 1, preferably 2- (2-ethyl) -3-benzofuranyl) -N- (2-morpholinoethyl) acetamide oxime or a pharmaceutically acceptable acid addition salt thereof is mixed with a conventional excipient and optionally with other excipients. 1 picture page