IE44753B1 - Benzofuran-derived amidoximes - 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-A1-CN, wherein Z is 2-ethylbenzo-3-furyl and A1 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

Thin invention relates to heterocyclic compoundc and ic concerned with, acctnraidoxime derivatives of bensofuran and phnrraaceutical compositions containing them and with a process for preparing tho card aeetamidoxime dorivativec.

The compoundc of the invention, which can exist in racemic form or in the form of their optically active isomers, can be represented hy the general formula : wherein R^ represents a branched- or straight-chain alkyl group containing from 1 to 4 carbon atoms or a phenyl group ; A represents one of the groupG : Rg represents a substituted smino group, such as fcr example a dimethylamino, diethylamino, di-n-prqpylamino, di-n-butylamino, pyrrolidin-l-yl, morpholino piperidino or heptamethyleneirrtino group or a 1-piperazinyl group substituted in tne 4-position by a straight-chain alkyl group containing frcm 1 to 4 carbon atans; X represents a hydrogen or chlorine atan or a methoxy group; and n is the integer 2 or 3.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are included within the scope of the invention.

The compounds of formula I can be prepared by ring opening of a 2,A-disubGtitutod-1,2,l|-Z\ -oxadazol-5-one represented by the general formula : .

X//' -a-o; M-i 'H-C=0 -R1 (k,)a-R2 II or of an acid addition salt thereof, in which formula R^, Rg, A, X and π have the same meanings as in formula I, The ring opening can be accomplished using s. known procedure, for example by refluxing the compound in an aqueous alcoholic medium in the presence of a base, -- 2 •j4753 for example sodium hydroxide.

The compound.'.: of formula II can he prepared by reacting, in, an organic medium such as, for example, anhydrous acetone containing a email quantity of methyl alcohol, and in the presence of a base such as, for example, anhydrous potassium carbonate, a 3-substitutcd 1,2, -oxadiazol-5-one of tho general formula : X- III in which 1?^, A and X have the same meanings as in formula I, with a chloroalkylamine, preferably in the form of itc hydrochloride salt, represented by the general formula : IV in which end n have the came meanings as in formula I.

The compounds of formula IV are already known. , The compounds of formula III can be prepared using known procedures, for example by reacting, in absolute ethanol containing a base such as sodium ethylate, an nmidoxime derivative represented by the general formula : N-OH II or· an acid addition salt thereof, in which formula E^, A and X have the same meanings as in formula I, with anhydrous diethyl carbonate.

The compounds of formula V can be prepared by using methods widely described in the literature. One particularly advantageous method consists of reacting, in an alcoholic medium containing a base, such as sodium methylate or sodium ethylate, a compound represented by the general formula ! X· A-CN •R, VI - 3 in which K^, R^ and X have the name meanings as in formula 1, with hydroxylamine hydrochloride.

The compounds of formula VI in which A rcprcGcnts the group -CH2~ are already known,having been described by ARHCCHKA et al in Chimie Therapoutique γ, 327 (1972), or may be prepared by the proc^sccE described in the eaid publication.

The compounds of formula VI in which A represents the group : can be prepared by reacting a compound of formula VI in which A represents the group -CH ~ with a group of the formula CK7-Hol in which C J Hal represents an atom of chlorine, bromine or iodine.

The compounds of formula VI in which A represents either of the groups : can be prepared by alkylating, in liquid ammonia containing sodium amide prepared in situ, a compound of the general formula : in which and X have the came meanings as in formula I and Rj represents a methoxy or ethoxy group, by means of methyl iodide or ethyl iodide and converting the ester function of the compound so obtained to a nitrile function, the conversion being carried out using a known procedure.

The compounds of formula VII can be prepared by known procedures from the compounds of formula VI in which A represents the group -CH^-.

The compounds of the invention have been found to possess useful pharmacological properties capable of rendering them of considerable value in the treatment of disorders of tho cardiovascular system, characterized by high blood pressure or low blood pressure.

Another object of the inventi6n io therefore a method of treating - 4 pathological. disorders of arterial pressure and, in particular hypertension in a non-human subject in need of such treatment by administering to the said subject at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

The predominant types of hypertension are essential and malignant hypertension and there is no specific therapy for these diseases, individual cases varying widely in response to various drugs.

There are therefore many anti-hypertensive agents v/hich are used to treat the different types of hypertension. •jO Amongst them, ganglionic blocking agents are knov/n to exert a ganglioplegic effect in that they interrupt the sympathicotonic impulse/ thus causing relaxation of the vascular walls. This phenomenon may be dangerous in cases where the patient requires increased tonicity of the vascular walls as a result of, for example, a change of position.

As may be seen further on, the compounds ox the invention are devoid of any ganglioplegic effects.

Other anti-hypertensive compounds, such as the veratrum alkaloids, are characterized by a rather narrow margin between their therapeutic and toxic doses. Overdosage may be dangerous and tho physician must select the dosage carefully and continually adjust it in accordance v/ith the needs and response of the patient. As opposed to this,the compound of the invention have toxic doses v/hich are far in excess of the amounts required to produce a pharmacological effect and present therefore a wide safety margin, Other knov/n agents exert such a sudden and pov/erful anti-hypertensive effect that their action is difficult to control. The compounds of the invention do not present this disadvantage. It has, in fact, been observed that the anti-hypertensive action of the compounds of the invention, while being very appreciable, is easy to control.

One compound v/hich may also be cited is the preferred compound of the series described in British Patent No 1,280,145, namely 2-(2-ethyl3-benzofuranyl)-N,N-(3-n-propyl-3-aza-pentamothylcne)-acetamidine dihydro chloride.

This compound is chemically related to the compounds of the invention and has been found to bo pharmacologically active in the treatment of experimentally induced hypertension. However, it will be - 5 4 4758 Been that· the compounds of the invention are not only more active but also far less toxic than the Raid preferred compound.

Moreover, the anti-hypertensive action of compounds of the invention io exerted with little oi' no undesirable side-effects while no signs of loss of activity due to habituation have so far been observed.

Finally, it io well known that a diuretic action coupled with an anti-hypertensive action is very useful in the treatment of hypertension, especially when the diuretic action does not provoke excretion •jq of the potassium ion but rather induces excretion of the sodium ion. .

Die compounds of the invention have been found to present a very favourable sodium-excretion index co that said compounds may be expected to constitute valuable anti-hypertensive agents.

Pharmacological tests have been undertaken with a view to 15 demonstrating the anti-hypertensive effects of the compounds of the invention on different types of experimentally induced hypertension.

The first test was carried out on male rats weighing about l20g in which chronic renal hyportcnc.! -in had been induced by the Grollman technique [Proc. Soc. exp. Biol. ed., 57, 102 According to this technique, the animals are anaesthetized with ether and one kidney is displaced from its site without being detached from the body, the suprarenal gland having been first liberated from the kidney hut otherwise left intact. The kidney is then bound with twine in the form of a figure eight, just tightly enough to alter slightly the ellipsoid shape of the organ. Ten days later, the other kidney is completely removed together with its suprarenal gland.

About four weeks after the second operation, most of the animals (60 to 70S?) develop severe hypertension, systolic pressure in the majority of cases exceeding 180 mm.Kg.

Groups of rats so treated received compounds of the invention in a dose of 25 mg/kg by intragastric route. Arterial pressure was measured immediately before and 1,2,5,^,5 and 6 hours after administration.

The following compounds gave the results indicated : - 6 TABLE I : Compound • · Fall in A.P. : (itun.llg) .: : 2-(2-Ethyl-3-L'?!iBofuranyl)-N- : : (2-raorpholino-i.ihy]J-acetamidoximc : 36 ’ i 2-(2-Kethyl-3-beuzofuranyl)-W- : : (2-morpholiriO-cthjT)--ncetamidoxime : 25 . s 2- (2-Ethyl-5“Cliloro-3-bcnzofuranyl) -K-: : (2-raorpholino-cthyl)-acetamidoxirae : 21 : 2-(2-Ethyl-3-benzofuranyl)-N- : : (2~di~n-butylamine-eihyl)~acetaraidoxircc 27 ’ I» the same test, performed with a well-known anti-hypertensive agent, namely a-methyl-(3,5-d.ihydroxy-phenyl)-alanine, it was found that an intragastric dose of 400 nig/kg of the latter was required to obtain a fall in arterial pressure of between 20 and 3θ mm.Hg.

Another agent recognised as possessing anti-hypertensive properties, namely hydrochlorothiazide proved to be inactive in thin test at a dose of 200 mg/kg given by intrngastric route.

The some test was also performed with the preferred compound of British Patent Ko 1,380,1¾] namely 2-(2-ethyl-3-benzofuranyl)-K,H·'’b (5-n-propyl-3-asa-pentamethylene)-acctamidine dihydrochloride.

At a dose of 50 mg/kg by intragastric route, a fall in arterial pressure of 14 mm.Hg was obtained vrhilc a fall of 24 ram.Hg was registered at a dose of 200 mg/kg by the same route.

Further pharmacological tests were carried out with a view to 25 determining the anti-hypertensive activity of the preferred compound of the invention, namely : 2-(2-ethyl-3-benzofuranyl)-N-(2-mprpholino-ethyl)-acetamidoxime (or 1 9552).

All of theee tests were performed on rats which wore in a state 30 of hypertension. Each test was divided into two series. In the first eeries, one single dose of the product under study was administered by intragastric route to each animal and the arterial pressure of the latter was measured every hour for six hours after administration.

In the second series the product under study was given by the same route every day for eleven consecutive days xmd arterial pressure was measured daily throughout this period. The amount of product administered varied from one animal to another. “ 7 “ Tho following in ah account £ tho teats ao performed. 1) Rata rendered hypertensive hy Hie GBOLLKAH method Vihen'the procedure described above vac applied tho following results were recorded : TABLE II Type of Treatment Dose mg/kg Maximum fall in A.P. (mm.Hg) Moment of maximum fall in A.P.

Single dose 10 25 50 14 36 55 4th hour 4th » 3rd Daily doses (11 days) 10 25 50 18 32 47 6th day 5th 4th '· 2) Hypertension of endocrine origi;i Thia test was performed in accordance with the technique of STAHTON and WHITE (Arch. Int. Pharuacodyn. 154, 351, 1965).

Female rgts weighing 90 + 10g were anaesthetized with ether and hypertension was produced by ablation of one kidney and the corresponding adrenal gland, after which a dose of 5° mg/kg of desoxycorticosterone acetate (DOCA) was administered subcutaneously five days a week over a period of. four weeks. Throughout this period the drinking-water given to the rats contained 1$ί of WaCl. This was replaced by ordinary tap-water when administration of the desoxycorticosterone ceased.

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

The following results were registered : TABLE III : Type of • Treatment : Dose : mg/kg Maximum fall : in A.P. : (mm.Hg)- : Moment of ; maximum : fall in A.P.: Single 25 18 : 4th hour done 50 26 ! 4th : 100 45 ! 4th : ~ 8 5 »3 i Daily : 25 : 15 : 5th day : : doses : 50 : 50 : 4th : : (11 days) : 100 ί 49 : 4th ) Saline hypertension This test iras performed in accordance with the technique of DAHL, KNUDSEN, HEINE and LEITL.

Hale rats weighing 55 + 5g were fed on food containing 8% of NaCl but which was otherviise normal.

After six weeks of this diet, arterial pressure had risen to about 18O mm.Hg.

The following results were registered : TABLE IV : Type of Dose : Maximum fall: Moment of : : Treatment mg/kg : in A.P. : maximum fall: : (mm.IJg): in A.P, : : Single 10 : 14 : 4th hour : ί dose 25 : 27 : 4th hour : 50 : 54 : 4tii hour : : Daily 10 : 15 : 7th day : j doses 25 : 26 ί 4 th : : (11 days) 50 s 55 ·· 5rd : 4) Neurogenic hypertension This test was performed in accordance with the technique of KRIEGER and IMBS (Cireul. Res. 15, 511, 1964 and C.R. Soc. Biol. 162, 778, 1968).

Hale rats weighing from 200 to 250g were anaesthetized with ether and 0.5mg of atropine sulphate was administered to them intraperitoneally.

The rats were fixed in a supine position and an incision Was made in the front of the neck to expose the neuromuscular bundle comprising the sympathetic and vagus nerves and the common carotid arteries, The vagus nerves and the caroti.d arteries were then carefully isolated while one centimetre was cut out of the sympathetic nerves. ι 4723 The superior laryngeal nerves \icre severed. The area in which the carotids divide was exposed by pulling aside the appropriate neck muscles (sternocleidomaotoideus and omohyoideus). The vessels thus liberated were painted with 10# phenol in ethanol. In this way, complete sympathetic denervation was obtained. Λ marked rise in arterial pressure was obtained after 5 to 8 days.

The following results were registered : TABLE V Type of Treatment : Dose : mg/kg il aximum fall : Moment of : in A.P. : (mra.Hg) : maximum fal : in A.P. Single : 10 : 18 i3rd hour dose 25 : 37 :4th » 50 : 56 :3rd ·' Daily ί 10 : 17 :5th day doses (11 days) : 25 35 :5th ) Genetic hypertension This test was performed in accordance with the technique of OKAMOTO and AOKI (Jap. Circul. J., 27, 282, 1965), using male rats belonging to a race which has been specially bred to produce animals having high blood pressure. The animals employed were about ten weeks old and had a blood pressure reading in the region of 180 ma.Hg.

The following results were obtained : TABLE VI : Type of : Treatment : Dose : mg/kg :Maximum fall : in A.P. : (mm. Jig) : Moment of : : maximum : : fall in A.P.: : Single : . 5 : 16 : 2nd hour : : dose : 10 : 35 : 2nd : : 20 : 52 : 3rd ·' : : Daily 5 ί 0 s : doses 10 : 26 : 4th day s ί (11 days) 20 : 47 : 5th : According to PLUMBER (Anti-hypertensive agents, p. 67, Edited 5 by SCIILITTLER, Academic Press II,Y, and London, 19^7) and many other authors, any substance v/hich is active on the various typos of experimentally induced hypertension may be considered as potentially anti-hypertensive in humans.

Moreover, it ic now admitted that genetic hypertension 10 constitutes tho model of experimental hypertension v/hich is the most closely related to human essential hypertension {which represents 8θ{5 of cases of pathological hypertension).

L 9552 has been found to be active in the five types of experimentally induced hypertension employed and especially active in -(5 genetic hypertension.

Thun, it may be concluded that L 9552 is most probably active against human hypertension.

Further pharmacological tests were performed in order to determine the diuretic properties of I 9552 : <>0 1 ” Volumetri c urinary excretion This test v/as performed according to the technique of LIPSCHXTZ et al. (J. Pharmacol, exp. Therap. 79, 97, 194-3), by using groups of 20 male albino rats weighing from 150 to 200g which had been deprived of food and drink for 18 hours. ?5 The substance to be tested v/as given by intragastric route immediately after the intragastric administration of 5θ ml/kg of a 9°/0 solution of NaCl.

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

The total amount of urine excreted during the 6 hours following 30 administi'ation v/as collected and measured.

The results are expressed in percentage of the volume of saline solution administered and are listed in the following Table ; _ 4 7 5 3 TABLE VII : Dose’ . mg/kg Urinary excretion : % : · O 20 to 50 : 10 84 . · : . 20 102 i : 50 118 : : 100 138 ί : 200 165 s The maximum excretion amongst the control animals is 5055, which means that results superior to this value may he considered as signifying a diuretic effect.

- Ionic ratio in urinary excretion This t,est was performed according to the technique of AKBROSILI et al. (Minerva Hepol. 11.,56, 1964).

The Substance to be tested was given by intragastric route immediately after the intragastric administration of 50 ml/kg of distilled water to groups of 20 albino male rats weighing 140 + 10g which had been fasting for 18 hours, A control group,also comprising 20 animals, only received the distilled water.

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

These values were then converted to mill!equivalents per litre (raEq/1.) in order to obtain the correct Ha+ and K+ ion excretion figures independently of tho increase in the amount of urine.

The ionic ratio was obtained according to the following formula : Ha ratio = K+ Qfa 3 of the treated animals LK+] fHa*] of the control animals [K+] Tho following results were registered : 12TABLE VIII : Dose , (mg/kg) : Urinary excretion Ji a · I!;/ (mKq/l.) : R* (mEq/1.) : Na+/K+ : Ratio : Control eanimals • · • · 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 : These figures show that L 3552 presents a very favoux'ahlo sodium-excretion index, which is extremely important as far as treatment of hypertension is concerned.

Pharmacological tests were also carried out with a view to showing that L 9552 is devoid of ganglioplegic activity : 1) The arterial pressure and the tonus of the nictitating raembrsxie of an anaesthetized cat was first noted, after which the contractile reaction of the membrane to an intravenous injection of adrenaline and to electric stimulation of the preganglionic 2Q fibre of the cervical sympathetic nerve was tested. It was found that tvzo intravenous doses of 5 mg/kg of L 9552 did not modify the intensity of the contractions of the membrane provoked as described -above. 2) An intravenous dose of 5 mg/kg of L 9552 administered to a dog, which was first anaesthetized with sodium pentobarbital and atropinized, did not alter the hypertensive effect of 1 mg/kg of acetylcholine injected into the vein of the animal. As opposed to this, a ganglioplegic substance such as penthonium annulled the hypertensive effect of acetylcholine, Finally, acute toxicity trials were carried out on rats and mice which were kept under observation for 12 days following one single administration.

The following results were registered : 4 7 5 3 TABLE IX : Animal ί Administration : LD (mg/kg) : • :LD50 : LD95 : Mouse : intraperitoneal : 30 : ?0 : 110 : : intragastric : 250 : 700 :1,250 : : intraperitoneal : 80 : 200 : 350 : Rat : intragastric :1,100 :1,900 :2,500 : These figures compare very favourably with the intragastric active doses of 50 mg/kg and 100 mg/kg of which the effects are described above and show that there is a very wide safety margin between tbe toxic dose and the therapeutic dose.

It will bo appreciated that, for therapeutic use, the compounds of the invention will normally be administered in the form of a pharmaceutical composition containing as active principle at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier and/or excipient therefor.

Advantageously, for clinical use the composition will be made up in a dosage unit form appropriate to the desired mode of administration for example a tablet or capsule for Oral administration. (c) Freuaratj on r> 5-(2--pl;):yl··'·' methyl- ·';·· X^-aprphoXu.u-rLijj-j )-1,,. -oxaca azol--3-one.

In a flask equipped with n stirrer and a Doxlilot mounted with n condcncex- were introduces a. solution of 10.5 i> (0.013 mol) of >-(2-etljyl-3-ben:'.ofnrany3}methyl - 1,2/b-/V~ oxadiozol-5-one in a mixture of 250 ml. of anhydrous acetone and 50 u>l· of methanol, and 7.1 £. (0.051 mol) of finely ground anhydrous potassium carbonate.

In the Soxhlet were introduced 9.3 g, (0.05 mol) of 1-chloro-2-iaorpholino-ethane hydrochloride.

While stirring, the reaction medium was refluxed foils hours. After filtration of the salts, the solution was evaporated off under reduced pressure. The residue obtained was taken up in water and extracted with ether to give 15 C» of 3-(2-ethyl-3-benzofuranyl)methyl - 4-(2~norpholino~othyl)~· t2t4-A^-oxadiazoI-5-one melting at 105 - 10S°C. field : W.G%. t The melting point of the hydrochloride was 181 - 18J°C. after.recrystallization from a mixture of isopropanol and ethanol.

By following the procedure the appropriate starting products, under were prepared: Compound 3- (2~ethyl-3-benzcfurariyl) methyl4- L 2-dj methylamino-t>thyl)-1,2,4Δτ -oxadiazol-5-one hydrochloride 3~(?-ethyl-3-benzofuranyl) methyl 4 ~ ( 2-e i ethy 1 ani no- et j ijH J -1,2,4A^-oxadiazol-5-one hydrochloride described above and using the compounds listed here· Koltjj-.g Point °C. 200 - 204 (methyl ethyl ketone/i copropanol) 166 - 169 (Diethyl ethyl ketone/isopropanol) •Ϊ4 733 . • 25 (the aqueous solutxou oo formed was treated with ether and the phases obtained wore separated. The aqueous phase was acidified'with a dilute solution of hydrochloric acid.

The precipitate which was obtained was washed with water and dried under vacuum to Give 20 g. of 3-(2-etbyl-3-beuzop furanyl) methyl - 1,2,4-A -oxadiazol-5-one which was recrystallizcd from a mixture of ether and petroleum ether (/+0/60¾.). field: 81.9^} m.p. 156 - 159¾.

By following the procedure ( the appropriate starting products, under were prepared: Compound 3-(2-)nethyi-3-berzofuran.5rl) methyl1.2.4- /\^-oxadiazol~5-one 3-( 2-n-pi’opy!-3-£enz of uranyl) methyl - 1,2,4—Ag>Oxadiazol-5-oue 3-(2-inopropyl-3~benzofuranyl) methyl - 1,2,4-A^-oxadiazol-5-one » 3-(2-n-butyl-3-benzofuranyl) methyl - -1,2,4-A2— oxadiazol-5-one 3-(2-isobutyl-3-benzofuranyl) j methyl “1,2,4-/\2-oxadiazol-5- one 3-[2-(2-butyl)-3-benzofuranyl) methyl - -1,2,4—A.-oxadiazoI-5- one 3-(2-ethyl-5-chloro-3-bcnzofuranyl) methyl --1,2,4-A.^-oxadiazol-5-one 3-(2~phcnyl-3~bcnzofuranylj me1 hyl1.2.4- A^-oxadiazol-5-one described abox'e and using the compounds listed hcreMelting Point °C. 16£ - 164 155 - 157 162 - 16/+ 157 - 159 134 - 136 (ethyl ether/ petroleum ether 40/80°C.) 11? -120 (ethyl ether·/ petroleum ether 40/80¾.) 169 - 172 ’ (ethyl ether) 200 - 203 . (ethanol) -1,6 „ Compound Helt?np. Point °C. 2-(2-met)jyl-3“be/izofuranyl)- acetamidoxime 131 - 153 (ethyl acetate/ petroleum etiier 5 2-(2-methyl- 9-benzofuranyl)acetamidoxin.c hydrochloride 790 - 194 (wit)/ decomposition) (isopropanoi/ethyl ether) 2-(2-n-propyJ-9-benzofuranyl)acetar/iidoxirae hydrochloride 746 - 15θ (methyl ethyl ketone/ethyl ether) 10 2-(8-1 sopropyl -3-bcn:: of uranyl )acctanidoxirac hydrochloride 760 - 762 2-(?-n-1 ·υ ty1-J-hanz ofuranyl)occtomidox irac hydrochloride 726 - 737 (methyl c-thyl ketone/ethyl ether) 2- ( 2-i: -, ol ai ty 1- 5-hcn z ofur enyl) acetamidoxime hydrochloride 745 „ 1.-,5 (ethyl acelate/ethan ol) 15 2-(2-(2-butyl)-3-benzofuranyl3acetamidoxime hydrochloride 782 - 785 (v/ith decomposition)· (methyl,ethyl ketone/ ethanol/ether) 20 2-(2-ethyl-5'-chloro-3-benzofuranyl)-acetanidoxine hydrochloride 796 - 799 (with decomposition) (isopropanoi) 2-(2-phenyl-3-benzofuranyl)acetamidoxime 743 - 745 2-(?-plienyl-3-benzofuranyl)acetamidoxime hydrochloride 203 - 209 (v/ith decomposition) (isopropanoi) · 75 Cb) Preparation of 3-(?-etkyl~5· 7, 2,4-/\^-oxaciazol--5One. -benzofuranyl) methyl - While stirring, 25.47 g. (0·Ί mol) of 2~(2~ethyl~3benzofuranyl)-acetanidoxine hydrochloride were added to a solution of 15.6 g. (0.2 mol) of sodium ethylate in 250 El. of absolute ethanol.

After adding ?3-6 g. (0.2 Eol) of anhydrous diethyl carbonate, the reaction medium was refluxed for 24 hours. 1’toe resulting solution v/as evaporated to dryness under reduced pressure and the residue obtained was taken 35 up in water. - 17The following Examples illustrate the invention.

. EXAMPLE 1 g-fg-Ethjfl-^-hcny.ofxirnnifl )-E-(2-mm>nhelino-ethyl)-ticeta;..idoxiirte sesouloxnlate. · (a) Preparation of ?-(2-ethyl-5-benzofurpnyl)-acetamidoxjKe.

To 350 ml. of methanol containing 37·4 g. (0.55 mol) of sodium ethylate were added 38.2 E· (0.55 mol) .of hydroxylamine hydrochloride and the reaction medium was stirred until complete dissolution.

Stirring; was continued for 16 hours after the addition of 200 ml. of .methanol containing 92.6 g. (0.50 mol) of 2cthyl“3-iC5ranonethyihenzofuran end the solution was finally refluxed for 3 hours.

The solvent was evapor; !;ed off under reduced pressure and the residue obtained was taken up in ether. The ethereal solution was washed with water., dried over anhydrous sodium sulphate and made colourless wrfch active charcoal.

• By adding an ethereal solution of hydrochloric acid, 99.7 g. of 2~(2-ethyl-3-benzofuranyl)-acetamidoxine hydro20 chloride were obtained and recrystallized from a mixture of ethyl acetate and methanol.

Yield: . 78.3%; n.p. 158 - 161°0.

• By following the procedure described above and using .25 the appropriate starting products, the compounds listed hereunder were prepared: 'j ίο 2530 3- (2-cthyl-3-bensoi’nrnnyl.) methyl 4- (2-di-ii_-]>rop3pli!::iinc-ctby3 )-1 ^Vg'-cixaoj.aztil-J-onu hydrochloride 3- (2-ct}jyl-3-bcn;’.ofnranyl) r.etbyl4— [ ?_d:i.~p!_ bu ty 1 a;.· i no-e thyl )-1, · ,JI— Af— oxod’iaBol-5-onc monohydratcd oxalate 5_(2-ethyl-3-bc’vaofnranyl) mcthyl4-(2-pyrrolid:inrl-yl)-ethyl)-1,2,4-/^ oxaoiazol-5-one hydrochloride 3- (2-ethyl-3-benKof uranyl) -methyl4- ( J eyrrolidin-l-yl-n-propyl) 1 ,2,4-/y:'-oxadiaBol-3bone hydrochloride 3~ (2-ethyl-3-benzoi'uranyl) ncthyl4-( 2~piperi dino-ethyl )-1,2 ,4-A^oxadiazol-D-OBC hydrochloride 3- (2-ethyl-3-benzofuranyl) methyl4- ( 3~p j peri dir o-n-nr onyl )-1,2,4 -A 2oxadiazol-5-one hydrochloride ~(2-cthyl-3-benzoiuraayl)-r.ethyl4-(3-raorpboiino-n-propyl)~1,2,4/\2-oxadiagol-5-ore hydrochloride 3- (2-ethyl--3-bengofur&nylpmethyl4~(2-heptamethylerei.-.:ino-erhyl)1.2.4- 2^2_p3iadia2ol-3-one. 3~(2-ethyl-3-benzofuranyl) methyl4- (2-heptar»ethyleneir.ino-ethyl)1.2.4- /\^-o: 3- (2-otbyl-3-bengof urany1) methyl4~( 3-di -n-propyl ar.irio-n-pr opyl) 1^^l-A'—oxadiagol-^-one oxalate (2-ethyl-3-bcnzofuranyl) cethylt2- (4-n-propyl-piper azin-l-yl) ethyl)—1,2,4-Z\^-oxadiaaol-5-oae dihydrochloride 3~(2-ethyl-3-benzofurany]) methyl4- (2-(4 -methyl -piperasi. n-p-yl) - ethylj 1.2.4- /\2_OJ;aciiiiaoi_r,_ono dihyd.rochloride ΊΟΛ - 1GG (ethyl ac fcntc/sc c t on e ) 103 - 112 (ethyl acetate) *4*53 183 - 190 (wiih decomposition) (i sopropanol) 169 - 171 (methyl ethyl ketone) 177 - 180 (isopropanol) 172 - 175 (isopropanol/ ethyl ether) 119 - 122 (acetone/ethyl ether) (isoprop?/! ether) 199 - 201 (ethyl acetate/ methyl alcohol) 122 - 125 (ethyl acetate/ methyl alcohol) 228 - 252 (with decomposition) (isopropyl alcohol/methyl alcohol) 23Ο - 235 (with decomposition) (methyl alcohol). - 19 447 53 3-(2~othyl-5~chloro-3-be£),zofur;.myl) methyl. -4-( 2 -pyrrolidin- 1-yl-ethyl1.,2,4-2\‘--ox0diazol-5-one hydrochlox'ido 211 r 214- (with decomposition ) (isopropyl alcohol/methanbl) 5 3-(2-cihyl-5-chloro-3-bcnzofurany) methy] -4-(2-pipcridinoethyl)-1,2,4 -/\^‘-oxadiazol-5-one hydrochloride 205 - 208 (ethyl acet ate/noth ono3.) ip’ 3h(2-ethyl-5-ehloro-3-hcnKOiursnyl)· methyl -^-(2-norpholino-ethyl)1,2,4 -/\'-Oxndiaz ol-5-one hyd rochloride 225 - 220 (with decomposition) (ethyl acetatc/nethanol)15 3- (2-’r.ethy3.-3-henaoiura.nyl) met) 7)3. - 4- (2-moi'pbolino-ethyl)-1,2,4—f\‘~~ oxadiazol-5-one 130 - 132 (ethyl, ether) 3-(2-n-propyrl-3-henzoiuranyl) methyl -4-(2--morpholino-etbyl)1,2,4-A^-oxadiazol-S-one oxale te 145 - Ί48 (isopropyl alcohol) 20 3-(2“ihopropyl-5-'benzoiuseayl) methyl-4- (2-pyrrolidin-l-yl-ethy i) 1,2,4-A8-o?:aaiazol-5-one hydrochloride 220.- 223 (Isopropyl alcohol/ethauol) «5 . 3-(2-isopropyl-3-henzofuranyl) methyl -4-(2-piperidino-ethyl)1,2,4-A^~oxadi azol-5-one hydrochloride 217 - 221 (with decomposition) (methanol/ ethyl ether) 50 3-(?-isopropyl-3-honzofuriuiyl) methyl. -4—(2-morpholino-ethyl)-1,2,4-A,2-oxadiazol-5-one hydrochloride 211 - 214 (with decomposition) (methanol) 3-(2-ja-hutyl-3-henzofurany3) methyl -4-(2-piperidino-ethyl)1,2,4-A^-oradiazol-5-ons hydrochloride 174- - 17S (isopropanol/ ethyl ether) 35 3-(2-n-hutyl-3-honzofuraryl) methyl -4- (2-morpholino-ethyl)1,2,4—A^-oxadiazol-5-one hydrochloride 185 - 188 (isopropanol/ methnnol/ethyl ether) 40 3-(2-iaohhtyl-ρ-henzofuranyl) methyl -4-(2-morpholino~ethyl)1,2,4-/y-oxadiazol-5-one hydrochloride 185 - 189 (methanol/ ethyl ether) -20 10 J-( ?~p)ienyl“J-1 > ·:ι:'.ο£ηι·;iny 1) m,,- 1.}ν>-.ϊ 4-(Ρ-;.'·οιί.!<οΙ :inn- cthy.1.)-1,2,4~/\·’· oxadiazo.'l-5-one J-(2~nhotiyl-« nzofuruiiyl) me tb ..1· 4-( 3-C2-(2-1 ;,it /Ί )~J~bcn;'.o£uranylJ methyl -4-(?-:.orpholino-etbyl,)4,2,4~/^_ox,'idiaKol-5~one hydrochloride 'l4v - 142 (e i.n .oio l.) .8 - 211 (eth-anol) 211 - 215 (with deco:.:- , po.'-i tion) (i sopropanol/ methanol) ¢4) p.-poti ori r'F ?~(2-ethy.‘‘ -J-bongoftirnnyl)-It-(2-mornholinc»-eui.yj.)-· cpt·· --.idoxime.

To a solution of 7.9 g. (0.02 mol) of 5-(8-ethyl-5~ ρ benzofuronyi) me thyl -4-(2-iaoi’pho3.ino-ethyl)-1,2,4 ~/\ -oxe·15 diazol-5~one hydrochloride in 70 ml. of methanol was added, a solution of 5-2 g. (0.08 mol) of sodium hydroxide in J2 ml. of water.

The reaction medium was refluxed fox.· JO minutes end was evaporated under reduced pressure until three quarter’s of the volume were eliminated.

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

The .solution so formed was extracted witli other to give 5.89 β· of 2-(2-ethyl-3~bc-nzofuranyl)-N~(2-morpholi.Ho-ethyl)-acotamidoxime which represented a yield of 89%· The crude product was taken, up in a small quantity of methanol ana, while stirring, was acidified by means of a methanol solution containing J β. (O.JJ mol) of oxalic acid to give 8 g. of 2~(2-ethyl-2-benzoiuranyl)-li-(2--F.orpholino-ethyl)-acetamidox~ ime scsquioxalate. xicidi 85%; m.p. 1SJ ~ 164°0.

By following the procedure described above and using - 21 ·· the appropriate starting products, the compounds listed hereunder were prepared: Compound Hait i nr: 'I'orinl °C, 5 2- ( 2-ethyl ~3-ben zof u ranyl) -)1(2-dimethylauino-cthyl)acotamidoxime dihydrochloride 161 - 163 (methyl ethyl ' ketone/i nopropanol) 2-(2-ethyl-2-benzofuranyl)~Ii(2-diethylamino-ethyl)acetarjidoxime sesouioxalate 139 - 161 (with decomposition) (ethanol) 10 2- (2-ethyl-3-bensofur anyl)-IT- • (2-di-n-prcpylamiiiO--ctkyl)acetsmidoxime'dihydr0chloride 180 - 184 (with decomposition) (ethyl acetate/ methanol) 15. •2-(2-ethyl-3-honzofuranyl)-U- (2-di-n-butylamino-ethyl)aeetamidoxime dihydrochloride 165 - 168 (ethyl acetate/methanol) 2-(?-ethyi~3-benzo£uranyl)-K~ (2 -(pyrrolidin-l-yl-ethyl)-acetamidoximc dihydrocnloride 184 - 18? (with decomposition) (methyl ethyl };etone/i ccpropanol) 20 2- (2-ethyl- 3-benz of uranyl) -1T(.3- Cpyrrolidin-l-yl-n-propy) aeetamidoxime 79 - 62 (n-hexane/ petroleum ether 40/60¾.) 2-(2-ethyl-3~benzofuranyl)-li- (2-piperidino-ethyl)ncetamidoxime aihyerochloride 181 - 183 (with decomposition) (ethyl acetate/ isopropanol) 25 · 2-(2-ethyl-3-bonzofuranyl)-K(3-pipcridino-n-propyl)aeetamidoxime hydrochloride 1?1 - 173 (with decomposition J (isoprop and/ ethyl ether) 2- (2-etbyl-3-bcnzof uranyl) -TT( 3-morphalinq-n-pi'opyl) aeetamidoxime dihydrochloride 199 - 202 (isopropanol/ ethyl ether) 30 2- ( 2-ethyl-3-benzofuranyl )-I<- (P-heptamcthyleneimino-ethyl)- acetamidoxime 79 - 81 (n-hexane) 35 2- ( 2-etliyl - 2-b enz ofuranyl) -1Ϊ( 2-di-n-pi’opylaaino-n-propyl) aeetamidoxime dioxalate 123 - 126 (with decomposition) (ethyl acetate/ methanol) 2- (2-ethyl-3-benzofuranyl) -IT- [2-(4-inethyl-piperazin-l-yl)-ethyl3- aeetnniidoxiwe 121 - 122 (ethanol/water) - 2-(?~ethy3~3-hew',ofur;;nyl)~li- 161 - 165 [2-('4-n«propyl-pipt;rn%in-l-yl) *ethyl3-(ethanol/ethyl ether) acetami (ioxime, trihydrochloride 5 2-(2-ethyl-5-chloro-3-benzoiuranyl)-N-( 2-pyrrolidin-l-yl) -ethylacetomidoxime dihydrochloride 210 - 213 (with decosi position) (isopropanol) 2-‘(2-etliyl-5“chloro-3-bensofuranyl) -K- ( ?--}> ip cr id i no-ethyi) ucetamidoxime 118 - 120 (petroleum ether 40/80ϋ0.) 10 2-(2-othyl~5-chloro-3-henzof uranyl)-h- (2-piperidino~ctbyl)acetamidoxime dihydroehloride 157 - 160 (with decomposition) (ethyl acetate/ methanol) IS 2-(2-ct).yl“5-chioro-3~'bonzo£uranyl)~K-(2-morpholino-ethyl)ncetamidoximo' 110 - 112 (petroleum ether 60/80vC.) 2-(2-ethyl-5-chloro-3-benzofuranyl)-K-(2-morpholino-ethyl)acetsKidoxime dihydrochloride 122 - 126 (with decomposition) (ethyl acetate/ methanol) 20 2~(2-methyl~3~benzofuranyl)-N- (2-Eorpholino-ethyl)~acetamidoxine sesquioxalate 148 - 150 (with decomposition) methanol/ethyl ether) 2~(2-n-propyl-3-benzofuranyl)-N(2-morpholino-ethyl)acetai.iidoxi)ne ceaquioxalato 162 - 164 (with decomposition) (methanol) 25 2-(2-i souronyl-3-ben z ofuranyl) - N~ (3-pyrrolidin-l-yl)ethylaeetaEiidoxiiBe di hydrochloride 201 - 202 (with decomposition) (isopropanol) 30 2-(2-isopropyl“2—honzofuranyl)-I‘i~ (2-pi.peridino-ethyl )~ aeetanidoxime dihydrochloride 180 - 184 (ethyl acetate/ isopropanol.) ?- ( 2-i sopr onyl - J-ben zofuranyl) -1Ϊ(2-morpholino-ethyl)-acetaaidoxine dihydroehloride 196 - 199 (with decomposition) (acetone/ isopropanol) 35 2-(2~n-butyl~3-benzo£uranyl)-l!~ (2“piperidino-ethyl)-acetaaidoxime 72 - 74 (petroleum ether 40/80°C.) 2- (2-n-butyl-3-benzofuranyl) -i<- (2~morpholino-ethyl)-acetamidoxime sesquioxalate 115 (with decomposition) (methanol) 40 2-(2-icobutyl~3~benzofuranyl)“lI- (2-morpholino-ethyl)-acct:uaid.oxime dihydroehloride 172 - 174 (ethanol/ethyl ether) -23“ 2^2-(2-butyl )-3--benzofuronyl 3- 197 - 199 (with deccnlf-(2-Bei;pbQlino-etbyl>~aect{j«itioxi3so position) (xsopropanol) dihydrochloi-idc . 2»(?-j)henyX~3-hejiKOfuri«iiyl)-n- 157 - 159 ’ (P-morpJioljno-eUiyl )-ucetanido?. One (ethanol) sesquioxalate 2~(2-phenyi-3-benzofui'anyl)-l;- 162 - Ϊ64· (2-piperidino-ethyl)-aeetamidoxime (ether) Examp': e 2 ¢0 .2-(?-Ethy3.-5-benzofUranyl)-2,2-diaethyl-hT-(2-i;.orpholino-ethyl)acotariiaoxi me. (a) . Preparation of 2-(2-ethyl~3-bensofuranyi3-2-nethyl.propionitrile.

While stirring, a solution of 37 g. (0.2 laol) of 215 ethyl-J-cyariomethyl-benzofuran in 200 ml. of anhydrous ethyl ether v/as added, drop-by-drop, to a suspension of 17-2 g. (0.44- mol) - of sodium amide in 250 ml. of anhydrous ethyl ether.

Stirring was continued for 2 hours at room temperature end then a solution of 85.2 g. (0.6 mol) of methyl iodid.e in. 200 ml. of anhydrous ethyl ether was added drop-by-drop. Any excess of sodium amide was decomposed by adding a little water and the solution obtained was poured into water.

The resulting aqueous solution was extracted with ether and 22.45 g. of 2-(2~ethyl-3-benzofuranyi)~2-methyl25 ' propionitrile were obtained.

Yield: 52.7%J b.p. 95- 100°C. (0.0J mm Hg).' (b) Froparation of 2-(2-ethyl-3-benzofuranyl)-?,2-dimetbylflcctairiidoxime.

The aboye-named compound was prepared from 2-(230 by the procedure described . etbyl-3-benz9furanyl)-2-methyl-propionitrilc(/in Example 1(.a), • but using 1.5 mol of hydroxylamine hydrochloride and sodium - 24 ^4? S3 methylate for .each mole of 2-(2-cthyl-3-benzofuranyl)-2-mcthylpropxonitrile und continuing the reaction for 72 hours.

Yield. : 41% ; m.p. 118 - 120°C. after recrystallisation from a mixture of ethyl acetate and light petroleum ether, Melting point of the hydrochloride : 189 - 192 °C. after recrystallization from a mixture of ethyl acetate, isopropanoi and ethyl ether. (c) Preparation of 3-ri-(2-etli.yl-3~benzofur,-inyl)1-methyi-ethyl~|1,2,4-/S -oxadingol-5-onc The above-named compound war, prepared from 2-(2-ethyl«-3-henzo~ furanyl)-2,2-dimethyl-acetamxdoxime hydrochloride by the procedure described in Example 1 (b).

Melting point : 153 - 156°C. (d) Preparation of 5-r'I“(2-ethyl-3-benzofuranyl)-1-iacthyl-ethvn-» * 2 4-(2-morpholino-othyl)-1,2,4- Zh -oxadiazol-5-one The above-named compound was prepared from 3-(1~(2-ethyl-3benzofuranyl)-1-methyl-ethyl]-l,2,4-2^-oxadiazol-4-0ne by the procedure described in Example 1 (c).

Melting point of the hydrochloride : 215 ~ 219°C. after recrystallizatii 20 from a mixture of methyl ethyl ketone, isopropyl alcohol and ethyl ether.

By following the same procedure and using the appropriate starting-products, the compound cited hereunder was prepared : 3-(1“(2-ethyl-3bcnKofuranyl)-1-methyl''ethyl3-4- (2-piperidino-othyl) ?5 1,2,4-Δ' '-oxadi azol-5-one, Melting point of tho hydi’O chloride : 209 - 213°C, (decomposition) after recrystallisation from a mixture of acetone, isopropanoi and ethyl ether. (e) Preparation of 2-(2-ethyl-3-benzofuranyl)-2,2-dimethyl-N~(230 morphollno-ethylP-acetamidoxime The above-named compound was prepared from 3-(1-(2-ethy1-3benzofuranyl)-1-methyl -ethyl]-4-(2-morpholino-ethyl)-1,2, oxadiazol-5-one hydrochloride by the procedure described in Example 1 (t Melting point : 110 - 112°C. after recrystallization from n-hoxane, By following the same procedure and using the appropriate starting-products, the compound cited hereunder was prepared : 2~(2-cthyl.-3“bcnsofuranyl)-2,2-dimci.byl-N~(2~piperidino-othy3 )acetamidoximo. ’ 44753 -, Molting point : 94 - 97°C. after recrystallization from a mixture of ethyl other nnd petroleum ether boiling from 40 to 60°C, bkampu; 3 2-(2-othyl-3-bengofxiranyl)-2-othyl-H-(2-morphpl:ino-cthyl) aeetamidoxime a) Preparation of 2-(2-nthyl-3-bonzofuranyl)-butyronitrile J While stirring, 8.3ε (0.Ϊ06 mol) of a 50#- suspension of sodium ' amide in toluene, whicli was taken up in 50ml of ethyl ether, was added, drop-by-drop, to a solution of l8.52g (0.1 mol) of (2-ethyl-3benzofuranyl)-acetonitrile in 200ml of dry ether. The mixture was j 10 refluxed for one hour and was allowed to cool to room-temperature. -i Stirring was continued and a solution of 2Jg (0.1475. mol) of ethyl , iodide in 100ml of ethyl ether was added drop-by-drop. The reaction “ . medium was refluxed for 3 hours and was allowed to cool.

Any excess of sodium amide was carefully decomposed by adding a 15 little water and tho medium was poured into water. The nitrile was extracted with ether and isolated.

Field : 75#. Boiling point : 115 ~ 117°C. (0.5 mm.Hg) j b) Preparation of 2-(2-ethyl-3-benzofuranyl)-butyramidoximo The above-named compound was prepared from 2-(2~ethyl-33 20 benzofuranylj-butyronitrile by the procedure described in Example 1 (a), Melting point of the hydrochloride : 160 - 163°C. after recrystallizatiorj from ethyl acetate. c) Preparation of 3-C1-(2-ethyl-3~benzofuranyl) propyl]-1,2,4-Δ R’ oxadiazol-5-one · The above-named compound was prepared from 2-(2-ethyl-3-henzofuranyl)butyramidoxime by the procedure described in Example 1 (b).

Melting point : 130 - 132°C. after recrystallization from ethyl other and petroleum ether 40/60°. d) Preparation of 3“[1-(5-ethyl-3-benzofuranyl) propyl]-4-(2j 5θ morpholino-ethyl)-1,2,4- Δ -ox.-dlnzol-5-ono Tho above-named compound was prepnrod from 3-[1r(2-cthyl-3benzofuranyl) propyl3-1,2,4-ZS '-oxadiazol-5-one by the procedure described in Example 1 (c).

Melting point of the hydrochloride : -185 - 188°C. after rccrystal35 lization from icopropsnol, -26 o) Preparation of 2-(2-ctliyl-3-benzofni'.';nyl)-2-ethyl-T?-(2-niorp);olinoctliyl)-ocotariidoxi me The above-named compound was prepared from 3-C1-(2-cthyl-3benzofuranyl) propyl 3-4-(2-morpholino-ctJiyl)-1,2,4-/O>‘-oxadiazol5 5-one by the procedure described in Example 1 (d).

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

EXAMPLE 4 2-(2-ethyl-3-honhofnyonyl)-2-Bipthy3.-N-(2-moroholino-otI)yl)- acotaqic-oxime a) Preparation of methyl 2- (2-ethvl-3-benzofuranyl) -Propionate___ While stirring, ig of ferric nitrite was added to 500ml of liquid ammonia followed by 6,35s (0,276 at.g.) of sodium. Stirring was continued for 30 minutes and a solution of 54,5g (0.25 mol) of iwsthyl (2-ethyl-3-benzofuranyl) acetate in 50ml of dry ethyl ether was added drop-by-drop. Stirring was continued for 2 hours and a solution of 39c (0.275 mol) of methyl iodide in 50ml of dry ether were added drop-by-drop.

The reaction medium was allowed to cool to room-temperature whilebeing stirred for 2 hours. 100g of ammonium chloride were added to the brownish residue find the medium was extracted four or five times with ethyl ether.

The organic phases were collected, washed with water and dried over anhydrous sodium sulphate. The ether was evaporated off and 21.4g of methyl 2-(2-ethyl-3-benzofuranyl)- propionate were nM-ainod, Yield : 37%. Boiling point : 1OO°C (0,4 mm.Jig). b) Preparation of 2-(2-ethyl~3-benzofuranyl)-proplo)'ilc acid 4l,6g (0.179 mol) of methyl 2-(2-ethyl-3-benzofuranyl)-propionate were added to a solution of 12g (0.215 mol) of potassium hydroxide in a mixture of 240ml of water and 120ml of methanol, Tho reaction medium was heated for 3 hours over a water-bath and the methanol was evaporated off. The aqueous solution was acidified with hydrochloric acid and was extracted with other. The ethereal solution was dried over anhydrous sodium sulphate and tho solvent was evaporated off to give 39« of 2-(2-cthyl-3-benzofur£myl)-propionic acid.

Yield : 9θ%. Molting point : 62 - 64°C after recrystallization from petroleum ether 40 - 60° -27 4 4 7 5 3 σ) Preparation of ?-(?-eth?>1-3-be· •.•r>furnnyl)-propion.-iBixac A solution of 35.1g (0.161 mol) of 2-(2-cthyl-3-bcnaofuranyl)propionic acid in 100ml of thionyl chloride war. stirred for 12 hours at room-tcmpcraluro and then for one hour at the temperature of the water-bath, The excess of thionyl clilorid was evaporated off under· reduced pressure and the 2-(2-cthyl-3-hcn-.ofuranyl)-propionic acid chloride which formed was dissolved in 100ml of dry ether and the resulting solution was added, drop-by-drop, to 500ml of ethyl ether saturated with dry ammonia.

Tho reaction medium was stirred for 1 hour suid was allowed to stand for 12 hours. Tho ethereal solution was washed with water, dried over anhydrous sodium sulphate and tho solvent was evaporated off to give 35g of 2-(2-othyl-3i-1cnsofuraftyl)>-propionamido.

Yield : 100%. Melting point : 84 - 87°C after recrystallization from n-hoxane,' d) Preparation of 2~(2-othyl-3-bc·-.zofuranyll-propfonitrllc Λ solution of 35s (0.16 mol) of 2-(2-ethyl-3bensofuranyl)~ propionamide in 500r.il of toluene '..'as refuxed for 18 hours in the presence of I^0^· The organic phase was decanted off and the residue was carefully'decomposed with iced water and extracted with ether.

The organic phase was washed with water, dried over sodium sulphate and added, to (ihe -toluene phase.

The solvents were evaporated qff under reduced pressure and the residue was fractionated to give 23.8g of 2-(2-ethyl-3-benzofuranyl)propionitrile.

Yield : 74.4%. Boiling point : 105°C (0.2 mm.Hg). e) Preparation of 2-(2-ethyl-3-henBofuranyl)-prepionnmidoxime The above-named compound was prepared from 2-(2-cthyl-3benzofuranyD-propionitrile by the procedure described in Example 2 (b). Melting point of the hydrochloride : 152 - 155°C. after recryntallisatie from acotone-ethyl ether. f) Preparation of 3-ri-(2-othyl-3-henzofuranyl) ethylJ-1,2,4-Δ oxadiazol-5-onc 44?53 The above-named compound war; prepared from 2-(2-cthyl-3bcnzofurany.l)-propicnamidoxime by-the procedure described ir. Example 1 ( Molting point : 110 - 113C after recrystallization from ethyl ethei’petroleum ether 40 - 60°.

E) Preparation of 3-l~1(2-ethy1-5-~1icngofurnnyl) cthyl)-1,2,4-Δ ^-oaadjozol-5-onc otl) yl3-4- (2-no rnholl r.

The above-named compound was prepared from 3-C1-(2-othyl-3benzofuranyl) ethyl]-1,2,4-ZS2-oxadiazol-5-one by the procedure described in Example 1 (c).

Melting point : 132 - 135°0. after· recrystallization from isopx-opanolisopropyl ether. h) Prenaration of 2-(2-cthyl-3-bo)izofuranyi)-2-methyl-W-(2-mornholinoothyD-acotamidoxime The above-named compound was prepared from 3-C1-(2-cthy1-3bonzofuranyl) ethyl3-4-(2-morpholino-ethyl)-1,2, 4-/\,2-oxadiazol-5one by the procedure described in Example 1 (d).

Melting point : 112 - 115°0. ai'tex’ recrystallization from acctonepoti'oleum ether ho - 60°.

Melting point of the sesquioxnlate : 132 - 135°0. (decomposition) aftei’ recrystallization from methanol-ethyl other.

EXAMPLE 5 Hard-gelatine capsules were prepared in accordance with known pharmaceutical techniques : Ingredients mg per capsule 2 2 2-(2-ethyl-3~benzo furanyl)-N- (2-worpholino-ethyl)-acGiai?ULdoximQ sesquioxaTate 20 10 corn starch 194.3 204.3 colloidal silica 0.7 0.7 215.0 mg 215.0 mg - 29 447S3 ·

Claims (15)

1. c I. A l l-1 S

1. Compounds of the general formula : ΧΛ%__,-A-C^ -Oil sih-(ch 2 ) k -r 2 and the pharmaceutically acceptable acid addition salts thereof, wherein R^ represents a bi'anchod- or straight-chain alkyl group containing from 1 to 4 carbon ato is or a phenyl group, A represents one of the groups : CII, -cii 2 -C< and -C.c 2 h 5 K 2 represents a substituted amino group, X represents a hydrogen or chlorine atom or a methoxy group md n is the integer 2 or 3.

2. Compounds according to Claim 1 wherein Rg represents a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidin-l-yl, morpholino, piperidino or heptamethyleneimino group or a 1-piperazinyl group substituted in the 4-position by a sti aight-chain alkyl group containing from 1 to 4 carbon atoms.

3. 2-(2-Ethyl-3-henzefuranyl)-N-(. -morpholino-cthyl)-acetamidoxime and its pharmaceutically acceptable acid addition salts.

4. , Process for preparing a compound of formula I which comprises ring opening of a 3,4-disubstituted-1,<,4-z\ -oxadiazol-5-one represented by the general formula ϊ •N-0 ,-A-C‘ '11-0=0 O' J E 1 < CH 2V E 2 1Ϊ wherein R^, Rg, A, X and n have the name meanings as in formula I.

5. Process according to Claim 4 wherein the ring opening is accomplished by refluxingthe compound of formula II in an aqueous alcoholic medium, in the presence

6. Process according to Claim 5 wherein the bane is Godium hydroxide. 30 *4 7 $3

7. A pharmaceutical composition containing as essential active principle at least one compound or a pharmaceutically acceptable acid addition salt thereof as claimed in claim 1 in association with a pharmaceutical excipient therefor.

8. A pharmaceutical composition containing as essential active principle 2-(2-ethyl-3-benzofuranyl)-N-(2-morpholinoethyl) -acetamidoxime or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical excipient therefor.

9. A composition as claimed in claim 7 or 8 in a dosage unit form suitable for oral administration.

10. Method of treating pathological disorders or arterial pressure in a non-human subject in need of such treatment, said method consisting in administering to the said subject at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

11. A compound in accordance with Claim 1, as described in the foregoing Example 1 or 2.

12. A compound in accordance with Claim 1, as described in the foregoing Example 3 or 4.

13. A pharmaceutical composition substantially as described in the forgoing Example 5.

14. A process in accordance with Claim 4, substantially as described in the foregoing Example 1 or 2.

15. A process in accordance with Claim 4, substantially as