CH617688A5 - Process for the preparation of new acetamidoxime derivatives - Google Patents

Abstract

The compounds of formula I, the symbols of which have the meaning given in Claim 1, and which are novel, are obtained by hydrolytic opening with concomitant spontaneous decarboxylation of the external N,O-heterocyclic ring of a compound of formula II. The optical isomers, racemates and acid addition salts of the compounds I and II are also considered. The compounds of formula I are active for the treatment of pathological disorders of the arterial pressure. <IMAGE> <IMAGE>

Description

The invention also relates to the preparation of the pharmaceutically acceptable acid addition salts of the compounds of formula I.

The compounds of formula I are prepared by opening the ring of an A2-oxadiazol-1,2,4 one-5 disubstituted in positions 3 and 4 and represented by the general formula:

40

w

-A-C.

II-O

'K ~ C-0

II

45

(on2) n-n2

in which Ri, R2, A, X and n have the same values as in formula I, or an acid addition salt of this compound.

The opening of the cycle can be carried out in a known manner, for example by heating the compound in a hydroalcoholic medium in the presence of a base such as, for example, sodium hydroxide.

The compounds of formula II can be prepared by making

55 react, in an organic medium such as, for example, anhydrous acetone containing a small amount of methanol and in the presence of a base such as, for example, anhydrous potassium carbonate, an A2-oxadiazol-1, 2,4 one-5 substituted in position 3 and corresponding to the general formula:

60

X

65

The present invention relates to a process for the preparation of compounds corresponding to the following general formula:

vv

-A-C.

III-0

'I

"H-CsO

J.

ir m

3

617688

in which Ri, A and X have the same meanings as in formula I, with a chloroalkylamine, preferably in the form of the hydrochloride, corresponding to the general formula:

Cl- (CH2) n-R2

IV

in which R2 and n have the same meanings as in formula I.

The compounds of formula IV are already known.

The compounds of formula III can be prepared in a known manner, for example by reacting, in absolute etanol containing a base such as sodium ethylate, an amidoxime derivative represented by the general formula:

-CII2-C-I ^

VII

in which Ri, A and X have the same meanings as in formula I, or an acid addition salt of this derivative, with anhydrous diethyl carbonate.

The compounds of formula V can be prepared according to methods widely described in the literature. A particularly advantageous method consists in reacting, in an alcoholic medium containing a base, such as methylate or sodium ethoxide, a compound represented by the general formula:

X.

-AT,

Vs

■ <r

-R,

in which R1, R2 and X have the same meanings as in formula I, with hydroxylamine hydrochloride.

The compounds of formula VI in which A represents a methylene group are already known, having been described by Areschka et al. in Therapeutic Chemistry 7, 337 (1972), or can be prepared by the methods described in said publication.

The compounds of formula VI in which A represents the group

CH3

CH3

-VS-

can be prepared by reacting a compound of formula VI in which A represents the methylene group with a methyl halide such as, for example, methyl chloride, bromide or iodide.

The compounds of formula VI in which A represents one of the groups

H

CHs

H

-C2H5

-VS-

or

-VS-

can be prepared by alkylating, in liquid ammonia containing sodium amide prepared in situ, a compound of general formula:

in which Ri and X have the same meanings as in the 1 “formula I and R3 represents a methoxy or ethoxy group, by means of methyl or ethyl iodide and by reducing the ester function thus obtained in nitrile function, the reduction being done in a known manner.

The compounds of formula VII can be prepared, in known manner, from the compounds of formula VI in which A represents the methylene group.

It has been discovered that the compounds prepared according to the invention have useful pharmacological properties, capable of making them very advantageous for the treatment of affections of the cardiovascular system, characterized by high or low arterial pressures.

The main types of hypertension are essential hypertension and malignant hypertension and there is no universal therapy for these conditions, each patient may respond differently to the remedy used. There are therefore many antihypertensive agents which are used to combat the different types of hypertension.

Among these, ganglioplegic agents are known in that they interrupt the sympathicotonic impulses, thereby causing a relaxation of the vascular walls. This can be dangerous for patients who require increased tone of the vascular walls as a result of, for example, a change in position.

As indicated below, the compounds prepared according to the invention are devoid of any ganglioplegic activity. VI Other antihypertensive compounds, such as the alkaloids veratrum, are characterized by a narrow margin between their therapeutic and toxic doses. Overdoses can be dangerous and the practitioner must carefully determine the dosage and continuously adjust it according to the needs and response of the patient.

On the other hand, the compounds prepared according to the invention have toxic doses which are far greater than the quantities required to produce a pharmacological effect and are therefore very safe to use.

Other known agents exert an antihypertensive effect so sudden and powerful that their action is difficult to control. The compounds of the invention do not have these drawbacks. It has in fact been discovered that the hypertensive action of the compounds of the invention, while being appreciable, is easy to control.

A compound which must also be mentioned is the preferred compound from the series described in French patent No. 2,182,985, namely (ethyl) -2-benzofuranyl-3) hydrochloride -2 N, N-55 (n- propyl-3 aza-3 pentamethylene) -acetamidine.

This compound is chemically close to the compounds prepared according to the invention and it is also pharmacologically active for the treatment of experimentally induced hypertension.

60 However, the compounds prepared according to the invention are not only more active but also much less toxic than said compound.

In addition, the antihypertensive action of the compounds prepared according to the invention is exerted with little or no undesirable side effects 6s, while no sign of loss of activity due to addiction could be detected.

Finally, it is known that a diuretic component joined to an antihypertensive component is very useful for a

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4

posed intended for the treatment of hypertension, especially when the diuretic component does not cause the elimination of potassium ions but rather favors that of sodium ions.

It has been discovered that the compounds prepared according to the invention have a very favorable sodium excretion index, so that the compounds of the invention can be considered as valuable antihypertensive agents.

Pharmacological tests were carried out with the compounds prepared according to the invention, in order to demonstrate their antihypertensive effect on the various types of experimentally induced hypertension.

The first test was carried out on male rats weighing approximately 120 g and in which a state of chronic hypertension of renal origin was caused according to the method of Grollman [Proc. Soc. exp. Biol. Med., 57.102 (1944)].

According to this technique, the animals are anesthetized with ether and the adrenal gland is released from its attachments with the kidney while leaving it intact. The kidney is then exteriorized from its compartment without being detached from the body. A cord is then placed on the 8-shaped kidney and tightened slightly until the ellipsoidal shape of the kidney changes slightly. Ten days later, the other kidney is completely removed as well as the corresponding adrenal gland. About four weeks after the second intervention, most animals (60 to 70%) develop severe hypertension, the systolic pressure in most cases exceeding 180 mm Hg.

The rats thus treated are administered the compounds prepared according to the invention, at a rate of 25 mg / kg intragastrically. Blood pressure is measured immediately before administration and 1, 2, 3, 4, 5 and 6 hours after.

The following results were obtained:

Table I

Compound

Pressure drop

arterial

(mm.Hg)

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

(2-morpholino ethyl) acetamidoxime

36

(2-methyl-benzofuranyl-3) -2 N-

(2-morpholino ethyl) acetamidoxime

25

(2-Ethyl-5-chloro-benzofuranyl-3) -2N-

(morpholino-2-ethyl) acetamidoxime

21

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

(di-n-butylamino-2-ethyl) acetamidoxime

27

The same test, carried out with a well-known antihypertensive agent, namely α-methyl (3,5 dihydroxy phenyl) alanine, showed that an intragastric dose of 400 mg / kg of this product was required to cause a drop in blood pressure between 20 and 30 mm Hg.

Another agent recognized as having antihypertensive properties, namely hydrochlorothiazide, was found to be inactive for this test at the dose of 200 mg / kg administered intragastrically.

The same test was also carried out with the preferred product of French Patent No. 2,182,985, namely (2-ethyl-2-benzofuranyl-3) -2N, N- (n-propyl-3 aza-3-) dihydrochloride pentamé-thylène) acetamidine. At the dose of 50 mg / kg intragastrically, a drop of 14 mm Hg in blood pressure was obtained, as well as a drop of 24 mm Hg at the dose of 200 mg / kg by the same route.

Additional pharmacological tests were carried out in order to determine the antihypertensive activity of the preferred product prepared according to the invention, namely:

(2-Ethyl-benzofuranyl-3) -2 N- (2-morpholino ethyl) acetamidoxime (or L 9552).

These additional tests were all carried out on hypertensive rats. Each test was divided into two series. In the first series, a single dose of the compound to be studied is administered intragastrically to each animal and measures the blood pressure every hour for six hours after administration.

In the second series, the product to be studied is administered by the same route for eleven consecutive days and the blood pressure is measured daily during this period. In these two series of tests, the amount of product administered varies from animal to animal.

The results of the tests carried out are set out below:

1) Rats made hypertensive by the Grollman method.

By applying the technique described above, the following results were obtained:

Table II

Type of treatment

Maximum fall dose of

Time of fall

mg / kg maximum blood pressure pressure

(mm.Hg)

arterial

Single dose

10

14

4th hour

25

36

4th hour

50

55

3rd hour

Daily dose

10

18

6th day

(11 days)

25

32

5th day

50

47

4th day

2) Hypertension of endocrine origin

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

Rats weighing 90 ± 10 g are anesthetized with ether and a kidney is removed with the corresponding adrenal gland, after which they are administered subcutaneously 50 mg / kg of deoxycorticosterone acetate (DOCA) 5 days per week for 4 weeks. During this period, the rats receive as water drink containing 1% of Nacl, this being replaced by plain water as soon as the injection of DOCA ceases.

Under these circumstances, the blood pressure reached 200 mm Hg.

The following results were recorded:

Table III The following results were recorded:

Type of treatment

Dose

Maximum fall of

Time of fall

mg / kg

P.A. (mm.Hg)

maximum

Single dose

25

18

4th hour

50

26

4th hour

100

45

4th hour

Daily dose

25

15

5th day

(11 days)

50

30

4th day

100

49

4th day

3) Hypertension by excess of Nacl

This test was carried out according to the technique of Dahl, Knudsen, Heine and Leitl (Circuì. Res. 12,11-18,1968).

Male rats weighing 55 ± 5 g receive normal food for 6 weeks but containing 6% Nacl.

At the end of this period, the animals' blood pressure reached 180 mm Hg.

The following results were obtained:

5

10

is

20

25

30

35

40

45

50

55

60

65

5

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Table IV

Type of treatment

Dose

Maximum fall of

Time of fall

mg / kg

P.A. (mm.Hg)

maximum

Single dose

10

14

4th hour

25

27

4th hour

50

54

4th hour

Daily dose

10

13

7th day

(11 days)

25

26

4th day

50

53

3rd day

4) Neurogenic hypertension

This test was carried out according to the technique of Krieger and Imbs (Circuì. Res. 15, 511, 1964 and C.R. Soc. Biol. 162, 778, 1968).

Male rats weighing 200 to 250 g are anesthetized with ether and administered 0.5 mg of atropine sulfate intraperitoneally. The rat being fixed in dorsal decubitus, the anterior cervical region is incised on the midline. The vascular bundle including the sympathetic, the vague and the primitive carotid is exposed. The wave and the carotid are individualized while the sympathetic trunk is resected for one centimeter of its path. The upper laryngeal nerve is then cut. The carotid bifurcation is carefully dissected after reclining the sterno-cleido-mastoid and omohyoid muscles. The vessels thus released are brushed with a 10% solution of phenol in ethanol: the nerve fibers from the carotid sinus are thus destroyed.

The definitive rise in blood pressure occurs 5 to 8 days after the procedure.

The following results were obtained:

Table V

Type of treatment

Dose

Maximum fall of

Time of fall

mg / kg

P.A. (mm.Hg)

maximum

Single dose

10

18

3rd hour

25

37

4th hour

50

56

3rd hour

Daily dose

10

17

5th day

(11 days)

25

35

5th day

5) Genetic hypertension

This test was carried out according to the technique of Okamoto and Aoki (Jap. Circuì. J. 27, 282, 1963), on male rats belonging to a breed which has been specially bred to produce animals with high blood pressure. These animals used are about 10 weeks old and have a blood pressure of about 180 mm Hg.

The following results were obtained:

Table VI

Type of treatment

Dose

Maximum fall of

Time of fall

P.A. (mm.Hg)

maximum

Single dose

5

16

2nd hour

10

35

2nd hour

20

52

3rd hour

Daily dose

5

0

-

(11 days)

10

26

4th day

20

47

5th day

According to Plummer (Anti-hypertensive agents, P67, edited by Schütter, Académie Press NY and London, 1967) and, many other authors, any active substance on the different types of experimentally induced hypertension can be considered as potentially active on human hypertension.

In addition, it is now accepted that genetic hypertension represents the closest experimental hypertension model to essential human hypertension (which represents 80% of cases of pathological hypertension).

L 9552 is active on all five types of experimentally induced hypertension and particularly active on genetic hypertension.

From this, we can conclude that L 9552 is probably active on human hypertension.

Other pharmacological tests have been carried out to determine the diuretic properties of L 9552.

1> Volumetric urinary excretion

This test was carried out according to 1 ^, technique of Lipschitz et al (J. Phàntìacol. Exp. Therap. 79, 97,1943), using groufeâ of 20 male albino rats weighing 150 to 200 g and fasting since 18 hours.

The test substance is administered intragastrically immediately after intragastric administration of 50 ml / kg of a 9 ° / 00 solution of Nacl.

A control group of 20 rats receives only the Nacl solution.

The total amount of urine eliminated during 6 hours after administration is collected and measured.

The results are expressed as a percentage of the volume of solution administered and are given in the table below:

Table VII

Dose

Urinary excretion mg / kg

%

0

20 to 50

10

84

20

102

50

118

100

138

200

165

Maximum excretion for control animals is 50%, which means that results above this value can be considered representative of a diuretic effect.

2. Ionic balance of urinary excretion

This test was carried out according to the technique of Ambrosili et al (Minerva Nepol. 11, 56, 1964).

The test substance was administered intragastrically to batches of 20 male albino rats, weighing 140 ± 10 g and fasted for 18 hours, immediately after intragastric administration of 50 ml / kg of distilled water.

A control group of 20 rats received only distilled water.

The total amount of urine excreted for four hours after administration was collected and measured, and the excretion values of Na + and K + ions were determined.

These values were then converted into milliequivalents per liter (m Eq / 1) in order to obtain correct excretion values in Na + and K + ions independent of the increase in urine volume.

s

10

15

20

25

30

35

40

45

50

55

60

65

617 688 6

The ion balance was obtained according to the following formula:

[Na +] treated

. [K +] processed

Na = -—7 s

Balance [Na] witnesses

[K +] controls The following results were obtained:

10

Table VIII

Dose mg / kg

Urinary excretion

%

Na + (mEq / I)

K +

(mEq / 1)

Na + K +

Witnesses

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

25

These figures show that L 9552 has a very favorable sodium excretion index which is extremely important when it comes to treating hypertension.

Pharmacological tests have also been carried out to show that L 9552 is devoid of any ganglionic activity.

1) The blood pressure and the tone of the nictitating membrane of an anesthetized cat are recorded, after which the reaction of contracture of the membrane to the intravenous injection of adrenaline is tested as well as the electrical stimulation of the preganglionic fiber of the sympathetic cervical nerve.

It has been discovered that two doses of 5 mg / kg of L 9552 do not modify the height of the membrane contractions following the two chosen stimulation modes.

2) An intravenous dose of 5 mg / kg of L 9552 administered to 40 a dog, previously anesthetized with soda pentobarbital and atropine, does not modify the hypertension caused by the intravenous injection of 1 mg / kg of acetylcholine. In contrast, in the same animal, a ganglioplegic substance such as penthonium abolishes the hypertensive effect of acetylcholine.45 Finally, acute toxicity tests were performed on rats and mice kept under observation for 12 days after administration of a single dose.

The following results were obtained:

Table IX

Animals

Administration

LD (mg / kg)

LD0

LD50

LD95

Intraperitoneal mouse

30

70

110

intragastric

250

700

1.250

Intraperitoneal rat

80

200

350

intragastric

1,100

1,900

2,500

These figures compare very favorably with the active doses by intragastric route worth respectively 50 mg / kg and 100 mg / kg and the effects of which are described above, thus showing a very large margin of safety between the toxic and therapeutic doses.

For therapeutic use, the compounds prepared according to 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 one of its pharmaceutically acceptable acid addition salts, in combination with a pharmaceutical excipient.

For clinical use, the composition will preferably be presented in a form suitable for the chosen mode of administration, for example, a coated or uncoated tablet, a gel capsule or a capsule for oral administration.

The following examples illustrate the invention:

Example 1

Sesquioxalate of (2-ethyl-benzofurannyl-3) -2 N- (2-morpholino-ethyl) acetamidoxime a) Preparation of (2-ethyl benzofurannyl-3) -2 acetamidoxime

To a solution of 350 ml of methanol containing 37.4 g (0.55 mole) of sodium ethylate, 38.2 g (0.55 mole) of hydroxylamine hydrochloride are added and the reaction medium is stirred until with complete dissolution.

200 ml of methanol containing 92.6 g (0.50 mole) of 2-ethyl-cyanomethyl-3-benzofuran are added, the solution is stirred for 16 hours and finally refluxed for 3 hours.

The solvent is evaporated off under reduced pressure and the residue is taken up in ether. The ethereal solution is washed with water, dried over anhydrous sodium sulfate and discolored with active charcoal. By adding a hydrochloric acid solution in ether, 99.7 g of (ethyl-2-benzofuranyl-3) -2 acetamidoxime hydrochloride are obtained, which is recrystallized from a mixture of acetate. ethyl and methanol. Yield: 78.3%. Melting point: 158-161 ° C.

Following the process described above but using the appropriate starting materials, the following compounds were prepared:

Compound

Melting point ° C

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

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

(2-propyl-2 benzofurannyl-3) hydrochloride -2 acetamidoxime (2-isopropyl-benzofurannyl-3) hydrochloride -2 acetamidoxime (n-butyl-2 benzofurannyl-3) hydrochloride -2 acetamidoxime (isobutyl-2 benzofurannyl hydrochloride -3) -2 acetamidoxime (Butyl-2) hydrochloride -2 benzofurannyl-3) -2 acetamidoxime

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

(2-phenyl benzofurannyl-3) -2 acetamidoxime

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

131—133 (ethyl acetate-petroleum ether 30/40 ° C)

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

146-150 (methyl ethyl ketone-ethyl ether) 160-162

128-131 (methyl ethyl ketone-ethyl ether)

143-145 (ethyl acetate-ethanol)

182—185 (decomposition) (methyl ethyl ketone-ethanol-ether)

196—199 (decomposition) (isopropanol)

143-145

203—205 (decomposition) (isopropanol)

7

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b) Preparation of [(2-ethyl-3-benzofuranyl) methyl)] - 3 A2-oxadiazol-1,2,4 one-5 While stirring, 25.47 g (0.1 mol) of hydrochloride d are added. '(2-ethyl-3-benzofuranyl) -2 acetamidoxime to a solution of 13.6 g (0.2 mole) of sodium ethylate in s

250 ml of absolute ethanol. After the addition of 23.6 g (0.2 mole) of anhydrous diethyl carbonate, the mixture is heated at reflux for 24 hours.

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

Compound

[(2-methyl-benzofurannyl-3) methyl] -3A2-oxadiazol-1,2,4 one-5 [(n-propyl-2 benzofurannyl-3) methyl] -3 A2-oxadiazol-1,2,4 one- 5 [2-Isopropyl-benzofuranyl-3) methyl] -3A2-oxadiazol-1,2,4 one-5

[(n-Butyl-2 benzofurannyl-3) methyl] -3A2-oxadiazol-1,2,4 one-5 [(Isobutyl-2 benzofurannyl-3) methyl] -3 A2-oxadiazol-1,2,4 one- 5

[[(butyl-2) -2 benzofurannyl-3] methyl] -3 A2-oxadiazol-1,2,4 one-5

c) Preparation of [(2-ethyl-3-benzofuranyl) methyl] -3 2s

(2-morpholino-ethyl) -4 A2-oxadiazol-1,2,4 one-5 10.5 g (0.043 mole) d are introduced into a flask fitted with an agitator and a Soxhlet surmounted by a condenser '[(2-ethyl-3-benzofuranyl) methyl] -3 A2-oxadiazol-1,2,4 one-5 in solution in a mixture of 250 ml of acetone 3 "

anhydrous and 50 ml of methanol, then 7.1 g (0.051 mole) of anhydrous and finely ground potassium carbonate.

9.3 g (0.05 mole) of 1-chloro-2-morpholino ethane hydrochloride are introduced into the Soxhlet.

With stirring, the mixture is heated to reflux for 18 3s

The aqueous solution is exhausted with ether, then acidified with a dilute solution of hydrochloric acid.

A precipitate is obtained which is washed with water and dried under vacuum.

20 g of [(2-ethyl-3-benzofuranyl) methyl] -3A2-oxadiazo-1,2,4 one-5 are then collected and recrystallized from a mixture of ether and petroleum ether (40 / 60 ° C).

Yield: 81.9%. Melting point: 156-159 ° C.

Following the same process as described above but using the appropriate starting materials, the following compounds were prepared:

Melting point ° C

162-164 155-157

162-164 (ethyl ether petroleum ether 40/60 ° C)

157-159

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

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

169-172 (ethyl ether)

200-203 (Ethanol)

hours. After filtration of the salts, the solution is evaporated under reduced pressure. The residue is taken up in water and extracted with ether to give 15 g of [(2-ethyl-3-benzofuranyl) methyl] -3 (2-morpholino-ethyl) -4 A2-oxadiazol-1,2,4 one -5, melting at 105-106 ° C.

Yield: 97.6%.

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

Following the process described above but using the appropriate starting materials, the following compounds were prepared:

[(2-Ethyl-5 chloro-benzofurannyl-3) methyl] -3A2-oxadiazol-1,2,4 one-5 [(2-Phenyl benzofurannyl-3) methyl] -3A2-oxadiazol-l 2,4 2,4 one- 5

Compound

Melting point ° C

[(2-Ethyl-3-benzofuranyl) hydrochloride] -3 (2-dimethylamino-ethyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) hydrochloride] -3 (2-diethylamino-ethyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) hydrochloride] -3 (di-n-propyl-2-aminoamino) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofurannyl-3) methyl] -3 (di-n-butyl-amino-2-ethyl) -4A2-oxadiazol-1,2,4 one-5 oxalate monohydrate

[(2-Ethyl-3-benzofuranyl-3) methyl] -3 (2-pyrrolidino-ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(2-Ethyl-3-benzofuranyl) hydrochloride] -3 (3-pyrrolidino-propyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl-3) methyl hydrochloride-3 (2-piperidino-ethyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) hydrochloride-3 (3-piperidino-n-propyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) methyl] -3 (3-morpholino-n-propyl) -4 hydrochloride A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-benzofurannyl-3) methyl] -3 (heptametyleneimino-2 ethyl) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) hydrochloride] -3 (heptamethylene-2-ethylimino) -4A2-oxadiazol-1,2,4 one-5

[(2-Ethyl-3-benzofuranyl) methyl] -3 (di-n-propylamino-3 n-propyl) -4A2-oxadiazol-1,2,4 one-5 oxalate

[(2-Ethyl-3-benzofurannyl-3) methyl dihydrochloride-3 [(n-propyl-4-piperazino) -2 ethyl] -4A2-oxadiazol-1,2,4 one-5 [2-Ethyl benzofurannyl-3 dihydrochloride ) methyl] -3 [(4-methyl piperazino) -2 ethyl] -4A2-oxadiazol-1,2,4 one-5

[(2-ethyl-5 chloro-3-benzofuranyl-3) methyl] -3 (2-pyrrolidino-ethyl) -4 hydrochloride A2-oxadiazol-1,2,4 one-5

200—204 (methyl ethyl ketone-isopropanol)

166-169 (methyl ethyl ketone-isopropanol)

164—166 (ethyl acetate-acetone)

108-112 (ethyl acetate)

188-190 (decomposition) (isopropanol)

169-171 (methyl ethyl ketone)

177—180 (isopropanol)

172-175 (isopropanol-ethyl ether)

119-122 (ethyl acetone-ether)

74—75 (isopropyl ether)

199-201 (ethyl acetate-methyl alcohol)

122-125 (ethyl acetate-methyl alcohol)

228-232 (decomposition) (isopropanol-methanol)

230-233 (decomposition) (methanol)

211-214 (decomposition) (isopropanol-methanol)

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8

Compound

Melting point ° C

[(2-ethyl-5 chloro-3-benzofuranyl-3) methyl] -3 (2-piperidino-ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(2-ethyl-5 chloro-3-benzofuranyl-3-methyl] hydrochloride-3 (2-morpholino-ethyl) -4A2-oxadiazol-1,2,4 one-5

[(2-methyl-3-benzofurannyl) methyl] -3 (2-morpholino-ethyl) -4A2-oxadiazol-1,2,4 one-5

[(N-propyl-2-benzofurannyl-3) methyl] -3 (2-morpholino-ethyl) -4A2-oxadiazol-1,2,4 one-5 oxalate

Hydrochloride.de [(2-isopropyl-3-benzofuranyl) methyl] -3 (2-pyrrolidino-ethyl) -4Az-oxadiazol-1,2,4 one-5

[(2-isopropyl-3-benzofuranyl-3) methyl] -3 (2-piperidino-ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(2-isopropyl-3-benzofuranyl-3) methyl] -3 (2-morpholino ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(N-Butyl-2-benzofurannyl-3) methyl] -3 (2-piperidino-ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(N-Butyl-2-benzofurannyl-3) methyl] -3 (2-morpholino ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(2-isobutyl-3-benzofuranyl-3) methyl] -3 (2-morpholino ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(2-Phenyl-benzofurannyl-3) methyl] -3 2-morpholino ethyl-4A2-oxadiazol-1,2,4 one-5

[(Phenyl-2-benzofuranyl-3) methyl] -3 (2-piperidino-ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

[(N-2-butyl-2) -2 benzofurannyl-3) methyl] -3 (2-morpholino ethyl) -4A2-oxadiazol-1,2,4 one-5 hydrochloride

205-208 (ethyl acetate- methanol)

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

130-132 (ethyl ether)

145-148 (isopropanol)

220—223 (isopropanol-ethanol)

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

211-214 (decomposition) (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 (decomposition) (isopropanol-methanol)

d) Preparation of (2-ethyl-3-benzofurannyl) -2 N- (2-morpholino-ethyl) acetamidoxime To a solution of 7.9 g (0.02 mole) of hydrochloride of [(2-ethyl-benzofurannyl-3) is added ) methyl] -3 (2-morpholino ethyl) -4 A2-oxadiazol-1,2,4 one-5 in 70 ml of methanol a solution of 3.2 g (0.08 mole) of sodium hydroxide in 32 ml of water.

The reaction medium is heated at reflux for 30 minutes and is then evaporated to three quarters of its volume under reduced pressure. The residue is taken up in 200 ml of water and the pH of the solution is brought to 8.

The solution is extracted with ether and 5.89 g of (2-ethyl-benzofuranyl-3) -2 N- (2-morpholino-ethyl) acetamidoxime are obtained (yield 89%). The crude product is taken up in a small amount of methanol and acidified with stirring using a methanol solution containing 3 g (0.33 mole) 3s of oxalic acid.

8 g of (2-ethyl-3-benzofuranyl-3) -2 N- (2-morpholino-ethyl) acetamidoxime sesquioxalate are obtained.

Yield: 85%. Melting point: 163-164 ° C.

Following the process described above, but using the appropriate 40 starting materials, we also prepared:

Compound

Fusion point

(2-Ethyl-3-benzofuranyl) -2 hydrochloride (2-dimethylamino-ethyl) acetamidoxime

Sesquioxalate (2-ethyl-3-benzofuranyl) -2 N- (2-ethyl diethylamino) acetamidoxime

(2-Ethyl-benzofuranyl-3) -2 hydrochloride -2 N- (di-n-propylamino-2 ethyl) -acetamidoxime

(2-Ethyl-benzofuranyl-3) -2 hydrochloride -2 N- (di-n-butylamino-2 ethyl) -acetamidoxime

(2-Ethyl-3-benzofuranyl) -2 hydrochloride (2-pyrrolidino-ethyl) -acetamidoxime

(2-Ethyl-benzofurannyl-3) -2 N- (3-pyrrolidino-n-propyl acetamidoxime (2-ethyl-benzofurannyl-3) hydrochloride -2 N- (2-piperidino-ethyl) -acetamidoxime

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

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

(2-Ethyl-benzofurannyl-3) -2 N- (2-heptamethylenimino ethyl) acetamidoxime (2-Ethyl benzofuranyl-3) -2N- (di-n-propylamino-3 n-propyl) -acetamidoxime

(2-Ethyl-benzofurannyl-3) -2 N - [(4-methyl-piperazino) -2 ethyljacetamidoxime (2-ethyl-benzofurannyl-3) hydrochloride -2 N - [(n-propyl-4-piperazino) -2-ethyl] acetamidoxime

(2-Ethyl-5-chloro-benzofurannyl-3) -2 hydrochloride-2 (Pyrolidino-ethyl) acetamidoxime

161—163 (methyl ethyl ketane-isopropanol) 159-161 (decomposition) (ethanol)

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

165—168 (ethyl acetate-methanol)

184—187 (decomposition) methyl ethyl ketone-isopropanol

79—82 (n-hexane petroleum ether 40/60 ° C)

181—183 (decomposition) (ethyl acetate-isopropanol)

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

199-202 (isopropanol-ethyl ether) 79-81 (n-hexane)

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

121—123 (ethanol-water)

161—165 (ethanol-ethyl ether)

210-213 (decomposition) (isopropanol)

9

617,688

Compound

Melting point ° C

(2-Ethyl-5-chloro-benzofurannyl-3) -2 N- (2-piperidino-ethyl) -acetamidoxime (2-Ethyl-5-chloro-benzofurannyl-3) -2 N- (2-piperidino-ethyl) -acetomidoxime

(2-Ethyl-5-chloro-benzofurannyl-3) -2 N- (2-morpholino-ethyl) acetamidoxime (2-Ethyl-5-chloro-benzofurannyl-3) -2N- (2-morpholino-ethyl-acetamidoxime hydrochloride

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

(N-propyl-2-benzofurannyl-3) -2 N- (2-morpholino ethyl) -acetamidoxime sesquioxalate

(2-Isopropyl-benzofuranyl-3) -2 hydrochloride-2 N- (2-pyrrolidino-ethyl) -acetamidoxime

(2-isopropyl-benzofuranyl-3) -2 hydrochloride (2-piperidino-ethyl) -acetamidoxime

(2-Isopropyl-3-benzofuranyl-3) -2 hydrochloride (2-morpholino ethyl) -acetamidoxime

(n-Butyl-2 benzofurannyl-3) -2 N- (2-piperidino-ethyl) acetamidoxime Sesquioxalate of (n-butyl-2 benzofurannyl-3) -2 N- (2-morpholino ethyl) acetamidoxime

(IsobutyI-2 benzofurannyl-3) -2 N- (2-morpholino ethyl) acetamidoxime hydrochloride

[(N-butyl-2) -2 benzofurannyl-3] -2 hydrochloride -2 N- (2-morpholino ethyl) acetamidoxime

(2-Phenyl-benzofuranyl-3) -2 N- (2-morpholino ethyl) sesquioxalate acetamidoxime

(2-Phenyl benzofurannyl-3) -2 N- (2-piperidino-ethyl) acetamidoxime

118-120 (petroleum ether 40/80 ° C 157—160 (decomposition) (ethyl acetate-methanol)

110-112 (petroleum ether 60/80 ° C)

122-126 (decomposition)

(ethyl acetate-methanol)

148—150 (decomposition) (methanol-ether

ethyl)

162—164 (decomposition) (methanol) 201—202 (decomposition) (isopropanol) 180-184 (ethyl acetate - isopropanol)

196-199 (decomposition) (acetone-iso-propanol)

72—74 (petroleum ether 40/80 ° C) 115- (decomposition) (methanol)

172—174 (ethanol-ethyl ether)

197-199 (decomposition) (isopropanol) 157-159 (ethanol)

162-164 (ethyl ether)

Example 2

(2-Ethyl-benzofurannyl-3) -2 dimethyl-2,2 N- (2-morpholino ethyl) acetamidoxime)

a) Preparation of (2-ethyl benzofurannyI-3) -2

2-methyl-propionitrile While stirring, a solution of 37 g (0.2 mole) of 2-ethyl-3-cyanomethyl benzofuran in 200 ml of anhydrous ethyl ether is added dropwise to a suspension of 17.2 g (0.44 mol) of sodium amide in 250 ml of anhydrous ethyl ether.

Stirring is continued for 2 hours at room temperature and then a solution of 85.2 g (0.6 mole) of methyl iodide in 200 ml of anhydrous ethyl ether is added dropwise. Any excess sodium amide is broken down by adding a little water and the mixture is poured into water.

The aqueous solution obtained is extracted with ether and 22.45 g of (2-ethyl-benzofuranyl-3) -2-methyl-2-propionitrile are collected.

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

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

2,2-dimethyl acetamidoxime This compound is prepared according to the method of Example 1 (a) but starting from (2-ethyl benzofurannyI-3) -2 2-methyl-propionitrile and using 1.5 mole of hydrochloride of hydroxylamine and sodium methoxide for each mole of (2-ethyl-3-benzofuranyl) -2-methyl-2-propionitrile, the reaction lasting 72 hours.

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

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

c) Preparation of [(2-ethyl-3-benzofuranyl) -1 methyl-1 ethyl-1] -3 A2-oxadiazol 1,2,4 one-5 This compound was prepared from (2-ethyl benzofu-

Rannyl-3) -2 dimethyl-2,2 acetamidoxime following the method of preparation of Example 1 (b).

Melting point: 153-156 ° C.

d) Preparation of [(2-ethyl-3-benzofuranyl) -1 methyl-1 ethyl-1] -3 (2-morpholino ethyl) -4 to 2-oxadiazol 1,2,4 one-5 This compound was prepared for from [(2-ethyl benzofurannyl-3) -! methyl-1 ethyl-1] -3 A2-oxadiazo-1,2,4 one-5 following the procedure of Example 1 (c).

Melting point of the hydrochloride: 215-219 ° C after recrystallization in a mixture of methyl ethyl ketone, isopropanol and ethyl ether.

Following the same process but using the appropriate starting materials, the following compound was prepared:

[(2-ethyl-3-benzofuranyl) -1 methyl-1 ethyl-1] -3 (2-piperidino-ethyl) -4 A2-oxadiazoI 1,2,4 one-5.

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

40

45

n / a) Preparation of (2-ethyl-3-benzofuranyl) -2

2,2-dimethyl N- (2-morpholino-ethyl) acetamidoxime This compound was prepared from [(2-ethyl-benzofuranyl-3) -l methyl-1-ethyl-1] -3 (2-morpholino-ethyl) hydrochloride -4 A2-oxadiazol-1,2,4 one-5 following the operative mode 55 of Example 1 (d).

Melting point: 110-112 ° C after recrystallization from hexane.

By the same method but using the appropriate starting product, the (2-ethyl-benzofuranyl-60 3) -2 dimethyl-2,2 N- (2-piperidino-ethyl) acetamidoxime was also prepared. Melting point: 94-97 ° C after recrystallization from a mixture of ethyl ether and petroleum ether (40/60 ° C).

Example 3

65 (2-Ethyl-benzofurannyl-3) -2 ethyl-2

N- (2-morpholino ethyl) acetamidoxime a) Preparation of (2-ethyl-3-benzofuranyl) -2 butyronitrile While stirring, a solution is added dropwise

617688

10

18.52 g (0.1 mole) of (2-ethyl-3-benzofuranyl) acetonitrile in 200 ml of dry ether 8.3 g (0.106 mole) of a 50% suspension of sodium amide in toluene and taken up in 50 ml of ethyl ether.

The mixture is heated at reflux for one hour and then cooled to room temperature. Still with stirring, a solution of 23 g (0.1475 mol) of ethyl iodide in 100 ml of ethyl ether is added dropwise. The reaction medium is heated at reflux for 3 hours and then cooled.

Any excess sodium amide is carefully broken down by adding a little water and the medium is then poured into water. The nitrile is extracted with ether and then isolated. Yield: 75%. Boiling point: 115-117 ° C (0.5 mm Hg).

b) Preparation of (2-ethyl-2-benzofuranyl) -2 butyrami-

doxime

This compound was prepared from (2-ethyl-benzofu-rannyl-3) -2 butyronitrile according to the procedure of Example 1 (a).

Melting point of the hydrochloride: 160-163 ° C, after recrystallization from ethyl acetate.

c) Preparation of [(2-ethyl benzofurannyl-3) 1 propyl-1] -3 A2-oxadiazol-1,2,4 one-5 This compound was prepared from (2-ethyl benzofu-rannyl-3 ) -2 butyramidoxime following the procedure of Example 1 (b).

Melting point: 130-132 ° C, after recrystallization from a mixture of ethyl ether and petroleum ether 40/60 ° C.

d) Preparation of [(2-ethyl-3-benzofuranyl) -1 propyl-1] -3 (2-morpholino ethyl) -4 A2-oxadiazol-1,2,4 one-5 This compound was prepared from [(2-ethyl benzofurannyl-3) -! propyl-1] -3 A2-oxadiazol-1,2,4 one-5 following the procedure of Example 1 (c).

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

e) Preparation of (2-ethyl-3-benzofuranyl) -2 ethyl-2 N- (2-morpholino-ethyl) acetamidoxime This compound was prepared from [(2-ethyl benzofurannyl-3) -! propyl-1] -3 (2-morpholino ethyl) -4 A2-oxadiazol-1,2,4 one-5 following the procedure of Example 1 (d). Sesquioxalate melting point: 139-141 ° C (decomposition) after recrystallization from isopropanol.

Example 4 (2-Ethyl-benzofurannyl-3) -2 2-methyl-N- (2-morpholino-ethyl) acetamidoxime a) Preparation of (2-ethyl-benzo-furanyl-3) -2 methyl propionate

1 g of ferric nitrite is added with stirring to 500 ml of liquid ammonia and then 6.35 g (0.276 at. Gr.) Of sodium.

Stirring is continued for 30 minutes and then a solution of 54.5 g (0.25 mol) of (2-ethyl-3-benzofuranyl) -2 methyl acetate in 50 ml of dry ethyl ether is added dropwise. . Stirring is continued for 2 hours and a solution of 39 g (0.275 mole) of methyl iodide in 50 ml of dry ether is added dropwise.

It is allowed to cool to room temperature while continuing to stir the reaction medium for 2 hours.

100 g of ammonium chloride are added to the brownish residue and the medium is extracted 3 or 4 times with ethyl ether.

The organic phases are combined, washed with water and dried over anhydrous sodium sulfate. The ether is evaporated and 21.4 g of (2-ethyl-3-benzofuranyl) -2 methyl propionate are collected.

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

b) Preparation of (2-ethyl-3-benzofuranyl) -2 propionic acid 41.6 g (0.179 mole) of (2-ethyl-benzofuranyl-3) -2 methyl propionate is added to a solution of 12 g (0.215 mole) of potassium hydroxide in a mixture of 240 ml of water and 120 ml of methanol. The reaction medium is heated in a water bath for 3 hours and the methanol evaporates.

The aqueous solution is acidified with hydrochloric acid and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the solvent is evaporated. 39 g of (2-ethyl-benzofuranyl-3) -2-propionic acid are collected.

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

c) Preparation of (2-ethyl-3-benzofurannyl) -2 propionamide A solution of 35.1 g (0.161 mole) of (2-ethyl benzofu-rannyl-3) -2 propionic acid is stirred for twelve hours at room temperature. in 100 ml of thionyl chloride, then for one hour at the temperature of the water bath.

The excess thionyl chloride is evaporated under reduced pressure and the propionic acid chloride (2-ethyl-benzofu-rannyl-3) -2 formed is dissolved in 100 ml of dry ether. The solution obtained is added dropwise to 500 ml of ethyl ether saturated with dry ammonia.

The reaction medium is stirred for one hour and then left to stand for 12 hours. The ethereal solution is washed with water, dried over anhydrous sodium sulfate and the solvent is evaporated. 35 g of (2-ethyl benzofu-rannyl-3) -2 propionamide are collected.

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

d) Preparation of (2-ethyl-3-benzofuranyl) -2 propionitrile A solution of 35 g (0.16 mole) of (2-ethyl benzofuranyl-3) -2 propionamide in 500 ml of toluene is refluxed for 18 hours , in the presence of P2O5. The organic phase is decanted, the residue is carefully decomposed with ice water and extracted with ether.

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

The solvents are evaporated under reduced pressure and the residue is fractionated. 23.8 g of (2-ethyl-3-benzofuranyl) -2 propionitrile are collected.

Yield: 74.4%. Boiling point: 105 ° C (0.2 mm Hg).

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

doxime

This compound was prepared from (2-ethyl-benzofu-rannyl-3) -2 propionitrile by following the procedure of Example 2 (b).

Melting point of the hydrochloride: 152-155 ° C after recrystallization from a mixture of acetone and ethyl ether.

f) Preparation of [(2-ethyl-3-benzofuranyl) -1 ethyl-1] -3 A2-oxadiazol-1,2,4 one-5 This compound was prepared from (2-ethyl benzofurannyl- 3) -2 propionamidoxime following the procedure of Example 1 (b).

Melting point: 110-113 ° C after recrystallization from a mixture of ethyl ether and petroleum ether 40-60 ° C.

s

10

15

20

25

30

35

40

45

50

55

60

65

11

g) Preparation of [(2-ethyl-3-benzofuranyl) -1 ethyl-1] -3 (2-morpholino ethyl) -4 A2-oxadiazo-1,2,4 one-5 This compound was prepared from [(2-ethyl benzofu-rannyl-3) -1 ethyl-1] -3 A2 oxadiazol-1,2,4 one-5 following the procedure of Example 1 (c). s

Melting point: 132-135 ° C after recrystallization from a mixture of isopropanol and isopropyl ether.

h) Preparation of (2-ethyl-3-benzofuranyl) -2-methyl-2 N- (2-morpholino-ethyl) acetamidoxime 10

This compound was prepared from [(2-ethyl-3-benzofuranyl) -! ethyl-1] -3 (2-morpholino ethyl) -4 A2-oxadiazol-1,2,4 one-5 following the procedure of Example 1 (d). Melting point: 112-115 ° C after recrystallization from acetone and petroleum ether 40/60 ° C. îs Sesquioxalate melting point: 132-135 ° C (decomposition)

617688

after recrystallization from a mixture of methanol and ethyl ether.

Example 5

Capsules were prepared using the usual pharmaceutical techniques:

Ingredients mg per capsule

1. 2.

Sesquioxalate (2-ethyl-benzo-furannyl-3) -2 N- (2-morpholino-ethyl)

acetamidoxime 20 10

Corn starch 194.3 204.3

Colloidal silico 0.7 0.7

215.0 mg 215.0 mg

B

Claims (6)

617688 2 CLAIMS 1. Process for the preparation of new compounds of general formula: 27-011 mi- (C3ï2) n-R2 (I) in which Ri represents a linear or branched C1 to Ca alkyl chain or a phenyl radical, A represents one of the groups: CH3 : H3 H -CH2-, -VS- CH3 and H , C2H5 -VS- R2 represents a substituted amino group, X represents a hydrogen atom, a chlorine atom or a methoxy group and n represents 2 or 3, as well as pharmaceutically acceptable acid addition salts of these compounds, characterized in that '' it includes the opening of the cycle of an A2-oxadiazol-1,2,4 one-5 disubstituted in 3 and 4 and corresponding to the general formula: 25 GO)/ -A-C ^, wj Sv ^ N-CÎ = 0 (CIIa) a.R2 (II) 35 in which Ri, R2, A, X and n have the same meanings as in formula I, or an acid addition salt of this compound. 2. Method according to claim 1, characterized in that the opening of the cycle is carried out by heating the compound of formula II in a hydroalcoholic medium in the presence of a base. 3. Method according to claim 2, characterized in that the base is sodium hydroxide. 4. Method according to claim 1, characterized in that R2 represents a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino, heptamethyleneimino group or a pipera-zino-1 group substituted in position 4 by a linear C 1-6 alkyl chain. 5. Method according to claim 1 for the preparation of (2-ethyl-benzofurannyl-3) -2 N- (2-morpholino-ethyl) acetami-doxime and pharmaceutically acceptable acid addition salts. x- ^ A V II-OII 0 -A-C // "rni-Ccn2) n-i? 2 in which R 1 represents an alkyl group, linear or branched and containing from 1 to 4 carbon atoms or R 1 represents a phenyl group, A represents one of the following groups: 15 -CH2-, H CH3 CHS V *. -O- and C2H5 R2 represents an amino group such as, for example, a dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, pyrrolidino, morpholino, piperidino or hep-tamethyleneimino group or a piperazino-1 group substituted in position 4 with a linear alkyl chain containing from 1 to 4 carbon atoms, X represents a hydrogen or chlorine atom or a methoxy group, and n represents 2 or 3. It is understood that the compounds of formula I are considered in their racemic or optically active forms.