FI78903B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYTICAL PRODUCTS 3-ALKYLAMINO-1- (2-CHLORO-3,5-DIMETOXIFENOXY) - 2-PROPANOLER. - Google Patents

Abstract

1. Claims for the contracting states : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE : 3-amino-1-phenoxy-2-propanol derivative, characterized in that it is selected from the group constituted by (i) the 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2- propanols responding to the general formula see diagramm : EP0110746,P12,F1 in which R is CH(CH3 )2 or C(CH3 )3 ; and (ii) their addition salts. 1. Claims for the contracting state : AT Use of a 3-amino-1-phenoxy-2-propanol derivative, selected from the group constituted by (i) the 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)- 2-propanols responding to the general formula : see diagramm : EP0110746,P13,F1 in which R is CH(CH3 )2 or C(CH3 )3 ; and (ii) their non toxic addition salts for manufacturing a drug.

Description

1 78903

The present invention relates to a process for the preparation of novel therapeutically useful 3-alkylamino-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols. For the preparation of .5-dimethoxyphenoxy) -2-propanols of the general formula CH2OCl1NN / // \\ _O-CH2-CH-CH2-NH-R (I) yzJ oh CH., 0 where R is CH (CH3) 2 or CH (CH3) 3; and to prepare their addition salts.

FR Patents No. 3647M, No. 4061M; and No. 70 13806 20 and U.S. Patent No. 3 202 992, it is known that 3-amino-1-phenoxy-2-propanol derivatives generally have β-blocking properties. However, it is now the case that said derivatives have never been able to be prepared commercially due to certain disadvantages, in particular tolerability difficulties and / or too short β-blocker effects.

It has now surprisingly been found that the 3-alkylamino-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols according to the invention do not have the disadvantages described above and are therapeutically more effective than BSM publications 3647M and n (i) 1- (3,5-dimethoxyphenoxy) -3-isopropylamino-2-propanol of (4061M) and (ii) 1- (3,5-dimethoxyphenoxy) known from FR Patent No. 70 13806 -3-tert-butylamino-2-propanol and are at least as interesting as the known β-blocker Propranolol, which is structurally different from the new compounds.

From a practical point of view, the best compounds according to the invention are 1- (2-chloro-3,4-dimethoxyphenoxy) -3-tert-butylamino-2-propanol and its addition salts, in particular the hydrochloride. Experiments in animals and humans have shown that 3-tert-butylamino derivatives and their salts have a stronger effect than 3-isopropylamino derivatives and its salts.

Addition salts as used herein mean acid addition salts obtained by reacting the free base of formula (I) with an organic or inorganic acid, addition salts also meaning ammonium salts. Of the acids used for the preparation of the salts of the bases of formula (I), mention may be made in particular of hydrochloric acid, bro-15-hydrochloric acid, nitric acid, fumaric acid, malonic acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid, citric acid, citric acid, citric acid, maleic acid, maleic acid, methanesulfonic acid. Among the compounds which can be used to make ammonium salts, mention may be made in particular of ICH3 and C1CH3.

Therapeutically the best addition salts are acid addition salts, especially the hydrochlorides.

The new 3-amino-1-phenoxy-2-propanol derivatives can be prepared by: a) 2-chloro-3,5-dimethoxyphenol of the formula ch3o ci C y - oh di)

30 CH3O

is reacted with epichlorohydrin of the formula HOC-CH-CH-Cl (III) 35/0 3 78903 in the presence of pyridine to give 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane of the formula b) the epoxide IV thus obtained is reacted with an amine of the formula NH 2 R (V) wherein R is i-C3H7 or t-C4Hg, in C3-C3 alkanol.

The C 1 -C 3 alkanol used in step b) is preferably ethanol or methanol.

The preferred embodiment involves in step a) reacting 1 mole of compound II with 4-10 moles of compound III for 2-5 hours at 100-120 ° C, with epichlorohydrin III acting as a solvent and pyridine catalyst, and in step b) bringing 1 mole of epoxy IV to react with 8 to 12 moles of amine at the boiling point of the reaction mixture under reflux for at least 0.5 hours.

A number of compounds of the invention are described in Table I below

CH30 Cl

(j) -O-CH2-CHOH-C2-NHR

30 s- 'ch30 35 4 78903

Compound Code number R Melting point

Example 1 (b) CRL 41058 t-C4 H9 216 °

Example 2 (a) - t-C 4 H 9 85 °

Example 3 (b) CRL 41045 i-C3 H7 206 ° 5 Example 4 (a) - i-C3H7 97 °

Note. (a): free base (b): hydrochloride

The 3-alkylamino-1- (2-chloro-3,5-10 dimethoxyphenoxy) -2-propanols of the formula (I) and their addition salts are used as such as β-blocking drugs. According to the invention, there is provided a therapeutic preparation comprising at least one compound of the above formula (I) or a non-toxic addition salt thereof as a β-blocking agent in admixture with a physiologically acceptable excipient.

In addition, the compounds of the invention, and in particular the free bases, are obtained in the preparation of other substances as synthesis intermediates as shown in FR Patent Application No. 82-17935.

Other advantages and features of the present invention will become more apparent from the following text, which is given by way of illustration, after the preparation examples.

Preparation I

Preparation of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-tert-butylamino-2-propanol hydrochloride 1) 2-chloro-3,5-dimethoxyphenol

To a solution maintained at 35-40 ° C and containing 75 g (0.487 moles) of 3-5-dimethoxyphenol and 30,400 ml of CCl 4 is added in portions over 2.5 hours 70.5 g (0.528 moles) of N-chlorosuccinimide. It is then heated to about 70 ° C for 0.25 hours. The precipitate formed is filtered off and the filtrate is evaporated to dryness under reduced pressure. The evaporation residue thus obtained is purified by vacuum distillation and the distillate is washed with water. 56.5 g (61.65% yield) of 2-chloro-3,5-dimethoxyphenol are thus obtained, Ff. (Köfler) = 57 ° C.

2 78903 2) 1- (2-chloro-3,5-dimethoxyphenoxy-2,3-epoxypropane) Heat a solution of 40 g (0.212 moles) of 2-chloro-3 at about 115 ° C for 4 hours, 5-Dimethoxyphenol in 133 ml (1.697 moles) of epichlorohydrin with 0.25 ml of pyridine The reaction mixture is evaporated to dryness, the residue is dissolved in ethyl acetate and the ethyl acetate phase is washed successively with sodium hydroxide and water. This oil is purified by crystallization from isopropanol to give 36.5 g (yield 70.4%) of 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane which is chocolate brown powder Flnet (Köf-15 ler) = 96 ° C.

3) CRL 41 058

Heat a solution of 36 g (0.147 mol) of 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane and 107.5 g (1.472 mol-20 mol) of tert-butylamine under a condenser for 1 hour. In 150 ml of anhydrous ethanol. The reaction mixture is evaporated to dryness and the residue thus obtained is purified by crystallization from diisopropyl ether to give 37 g of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-tert-butylamino-2-propanol, which is a light brown powder. FInet (Köfler) = 85 ° C.

The free base thus obtained is treated under anhydrous condenser in anhydrous ethanol with hydrochloric acid ethanol. A precipitate forms which is separated to give 36.3 g (69.75% yield) of CRL 41 058 as a slightly light brown powder which is soluble in water at 12.5 g / l. Flnit (Köfler) = 216C.

Preparation II

Preparation of 1- (2-chloro-3,5-dimethoxyphenoxy) -3-isopropylamino-2-propanol hydrochloride 35 (Example 3; code number CRL 41 045) 6 78903

By doing as in preparation I, lie 3), but substituting isopropylamine for tert-butylamine, CRL 41 045 is obtained. Flnet (Köfler) = 206 ° C.

Below is a summary of the experiments performed with CRL 5 41 058 (compound of Example 1). In these experiments, unless otherwise stated, CRL 41 058 was suspended in an gum arabic solution at concentrations greater than or equal to 3 g / l and dissolved in distilled water at concentrations less than 3 g / l and given 10 intraperitoneally in a volume of 20 ml / kg in male mice and 5 ml / kg in male rats.

toxicity

In male mice, i.p. when administered, the LD-0 (maximum but non-lethal dose) is greater than 64 mg / kg, and the 15 LD-30 (dose at which 30% of the animals die) is of the order of 128 mg / kg. CRL 41,058 is less toxic than 1- (3,5-dimethoxyphenoxy) -3-tert-butylamino-2-propanol hydrochloride having an LD-50 given i.p. is of the order of 73 mg / kg in male mice.

20 Overall effect and reactivities

Groups of three mice are observed before, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours and 24 hours after ip administration of CRL 41 048. It is noted that 25 1) in mice - doses of 0.5 mg / kg, 2 mg / kg and 8 mg / kg do not cause general symptoms; - at a dose of 32 mg / kg it has an unstable sedative effect (2 out of 3 animals) which is transient (30 min), it causes shortness of breath (2 out of 3 animals) for 15-30 minutes; and 2) in rats, doses of 0.25 mg / kg, 1 mg / kg and 4 mg / kg do not cause general symptoms; 35 - 16 mg / kg has a transient (30 min) sedative effect on t 78903 and is difficult to breathe (2 of 3 animals in 3) for 30 minutes.

Examination of cardiovascular properties A - Anesthetized dog 5 Three dogs (mean weight 13.6 kg) anesthetized with nembutal are administered CRL 41 058 intraduodenally in successive doses of 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg and 10 mg / kg. Measure arterial pressure (recall that 1 mm Hg corresponds to about 1.333 10 x 102 Pa), heart rate, flow rate in the femoral artery, flow rate in the vertebrae, rectal temperature, and note skin color, bile color collected by catheterization of the bile duct.

15 CRL 41 058 reduces heart rate immediately after a dose of 0.5 mg / kg without any overall effect on arterial pressure. It does not lower vertebral artery pressure. The increase in flow rate in the femoral artery occurs in only one of three dogs with a low control flow rate of 20 (24 ml / min). In the other two dogs, the flow rate decreases. The temperature measured from the rectum and skin varies slightly. Skin color and not bile color change.

The effects of isoprenaline, measured after a cumulative dose of 19 mg / kg CRL 41 058, are strongly reduced: 3 pg / kg isoprenaline causes a diastolic arterial pressure of 119 mm Hg compared to a control of 48 mm Hg and a heart rate of 110 beats / min. compared to 245 bpm control. In two dogs whose isoprenaline dose was increased to 100 to 30 pg / kg, the tachycardia effect at this dose was lower than the control tachycardia effect at 0.3 pg / kg isoprena-line.

The antihypertensive effect of noradrenaline is also reduced: at a dose of 1 pg / kg noradrenaline, the systolic arterial pressure is 221 mm Hg compared to 280 mm Hg in the control.

B - Guinea pigs isolated from guinea pigs The 5 guinea pigs isolated from the right guinea pig are used to determine the pA2 of CRL 41 058 in relation to the heart rate induced by isoprenaline; After 15 minutes of contact, the mean pA2 is 8.21 ± 0.272.

These earplugs also determine the effect of CRL 41 058 on regulating muscle contraction and heart rate; no mean could be obtained, concentrations and dosage amounts of concentrations vary. The CRL has a positive contractile and pulse-regulating effect, which is greatest at the first concentration used, whatever it is (3 x 10'a to 10 "6M). In contrast, if, for example, a concentration of 10'6M is given for lower concentrations after having a stimulating effect, this 10'6M concentration has a negative effect on muscle contraction and heart rate (this phenomenon can be explained by the release of catecholamines).

C - Anesthetized rat

Rats with normal blood pressure are anesthetized with pentobarbital (75 mg / kg i.p.) and atropine (1 mg / kg i.p.). Measure their main arterial pressure, their heart rate, by integrating the arterial pressure. Catheterize the jugular vein for injections. If necessary, anesthesia is maintained with a subcutaneous pentobarbital syringe.

1) Determination of the effective dose of β-blocker 30 Three rats received CRL 41 058 intravenously in successive doses of 0.3 mg / kg, 1 mg / kg, 10 mg / kg and finally 30 mg / kg. Determine the dose that prevents tachycardia caused by i.v. of 0.03-0.3 pg / kg. with iso-prenaline (the dose needed to increase the heart rate from 30 to 50 beats / min). It is found that this dose is 1 mg / kg i.v.

2) Duration of β-blocker effect 5 rats receive 1 mg / kg CRL 41 058 i.v. It is noted that the 5-diastolic arterial pressure does not change, it remains at about 91 mm Hg; and - the heart rate decreases in 5 minutes from 345 to 290 beats / min (-16%), the maximum bradycardia is reached within 20 minutes: 280 beats / min 10 (-19%). After 90 minutes, the heart rate is 307 beats / min (11%).

In addition, 0.03 pg / kg isoprenaline i.v. causes - a decrease in arterial pressure from 91 to 65 mm Hg (-26 mm Hg); 1 mg / kg i.v. CRL 41 058 changes arterial pressure by 15 + 8 mm Hg (-69% relative to control change) in 5 minutes and 2 hours of observation; and - a change in heart rate from 345 to 384 beats / min (+39 beats / min); tachycardia, which is completely inhibited by CRL 41 058 within 5 minutes, returns to 50% of its initial value within 20 minutes; it returns to 92% of its initial value within 60 minutes.

Finally, 5 control rats receive physiological saline in place of the compound, it is observed that: - the arterial pressure remains constant; isoprenaline-induced hypotension is reduced by 40% during the experiment; and - the heart rate decreases to 28 beats / min after the nembutal injection required to maintain anesthesia, the isoprenaline-induced tachycardia remains constant over a 2-hour follow-up period.

30 D - Awake rat 6 genetically hypertensive rats with a catheter inserted into the femoral artery receive a dose of 20 mg / kg of CRL 41,058 in the cheek.

Arterial pressure decreases from 191 to 167 mm Hg within 6 hours 35 (-13%, statistically significant change). The heart rate decreases after 5 minutes, decreasing from 382 to 322 beats / min (-15%, statistically significant change); maximal bradycardia is reached after 2 hours (305 beats / min, -20%, statistically 5 significant change); then it decreases and is 322 beats / min after 7 hours, (-15%, statistically significant change).

24 hours after administration of CRL 41 058, it is observed that the arterial pressure has reached the same value as the control, the heart rate is still 330 beats / min (-13%, statistically significant change).

E - Conclusion

From the above experiments it can be concluded that CRL 41 058 is a very good β-blocker.

15 Clinical trials in humans have shown CRL

41 058 β-blocker effect at a daily dose of 40-50 mg (divided into 2-3 parts) for 2-6 weeks.

Therapeutic comparative experiments a) Subject 20 The therapeutic effect of the following four compounds was studied: - CRL 41 058 (according to the present invention) - Acebutolol (May and Baker. U.S.A.) - Atenolol (I.C.I.)

25 - Propranolol (I.C.I.) (FR patent 4061M

publication mentioned in Table 1)

The formulas of the compounds tested are shown below: CRL 41 058 30 CH30 Cl // \\ - O-CH2-CH-CH2-NH-C (CH3)

\ -ZZJ OH

35 CH3 ° 11 78903

Acebutol ^ COCH3 5 CH3-CH2-CH2-CONH -A \\-O-CH2-CH-CH2-NH-CH3 \ n / OH CH3

Atenolol 10 H2N-C-CH2 _y / \\ - 0-CH2-CH-CH2-NH-CH '^ "3 ö \ zi_ / OH ^ CH3 15

Propranolol & CH-.

0-CH2-CH2-NH-CH

OH ^ CH3 b) Study conditions The effect of compounds administered intravenously (I.D.) to an anesthetized dog on cardiovascular circulation and amines and reflexes was studied. In addition, the effect of compounds administered intravenously (IV) and cheek (VB) to an anesthetized dog on arterial blood pressure and heart rate with isoprena-line for tachycardia was studied, c) 27.4 kg) anesthetized with nembutal. Doses ranged from 0.1 to 10 mg / kg and compounds were administered every 30 minutes. Arterial blood pressure, heart rate, flow rate in the heart, and flow rate in the femoral artery were determined.

B. Modification of Amine Activity Test compounds were administered sequentially at 0.5; 1; 2.5; 5; At doses of 10 mg / kg every 30 minutes. The compound-induced modification of arterial blood pressure caused by noradrenaline, adrenaline, tyranine, dimethylphenylpiperazine, dopamine, angiotensin, acetylcholine, iso-prenaline, serotonin, histamine was studied.

Anesthetized dog 15 A. Labrador dogs were administered every 10 min by intravenous injection sequentially 3, 10, 30, and 100 pg / kg of test compound. Systolic blood pressure and heart rate from the tail artery were measured.

B. Test compounds were administered to the dog at 0, 1, 3 and 10 mg / kg buccal doses. Systolic blood pressure and heart rate from the tail artery were measured.

d) Results

The effect of the new compound CRL 41 058 on muscle contraction and pulse-sparing effect is negative starting at a dose of 0.15 mg / kg I.D .; this effect lowers the flow rate from the heart and left ventricular function, increases the total peripheral blood resistance, and lowers the flow rate in the femoral artery.

The new compound CRL 41 058 is starting at a dose of 0.25 mg / kg I.D. α ', β', DA ', antiserotonic. It has no antihistaminic or angiotensin activity, no ganglioplegia or atropine activity.

When CRL 41 058 is administered intravenously to 35 non-anesthetized dogs, i3 78903 - systolic blood pressure increases disproportionately with dose and heart rate decreases - isoprenaline-induced tachycardia decreases from 10 pg / kg; this effect occurs in less than 5 minutes and disappears in less than 5 hours at a dose of 30-100 pg / kg.

When CRL 41 058 is administered to the cheek, - the systolic blood pressure increases and the heart rate decreases; the intensity and duration of these effects are 10 proportional to the number of doses; - the tachycardic effect of isoprenaline is reduced. The maximum effect is after 1 hour and lasts for more than 24 hours at a dose of 3 mg / kg.

The dose of CRL 41 058 V.B., which reduces the tachycardia effect by 50 to 50% (+ 60-70 beats), is approximately 0.5 mg / kg.

The CRL β 'effect of the compound is competitive.

The antihypertensive effect of CRL in an anesthetized dog appears to be long after peak plasma concentrations are reached (2 dogs, 5 mg / kg VB, peak plasma concentrations at 1 h 30 min and 2 h 30 min, while the bradycardic effect occurs concomitantly with Hypertension may be due to the product itself or its metabolites.

e) Conclusion

In addition to the β-blocking effect, the compounds of the present invention have an α-blocking effect. In contrast, the known compounds are not α-blockers. This difference is of 30 fundamental qualities, as the combination of α-blocking and β-blocking produces an anti-serotonic effect, the great importance of which is known in therapy.

Known compounds increase heart rate, while the new compound CRL 41 058 decreases it.

Claims (4)

A process for the preparation of novel, therapeutically useful 3-alkylamino-1- (2-chloro-3,5-dimethoxypheno-5 xi) -2-propanols of the general formula CH ch 2 -ch-ch 2 -nh-r (i) 10 5 ° H ch 30 where R is CH (CH 3) 2 or CH (CH 3) 3; and their addition salts, characterized in that a) , 5-Dimethoxyphenol of the formula CH-10 Cl y-OH (II) CH 3 Cl is reacted with epichlorohydrin of the formula H₂C-CH-CHOCCl (III) The presence of pyridine to give 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane of the formula CH B) the epoxide IV thus obtained is reacted with an amine of the formula NH2R (V)