CS235985B2 - Method of 3-amino-1-fenoxy-2-propanol new derivatives production - 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

The invention relates to a process for the preparation of novel 3-amino-1-phenoxy-2-propanol derivatives, namely 3-8-alkyl-amino- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols of the formula I and their salts. These new derivatives are useful in medicine. ·

It is known, in particular, from French patents protecting medicines or medicaments. · 3467M-and -406Ι-1Γ, French Patent No. 2,042,390, and US Patent No. 3,203,992, i.e. derivatives belonging to the 3-amino-1-phenoxy-4-propanol group generally exhibit beta-3-amine. blocking properties. However, the derivatives of this group have never been marketed because they have some drawbacks, the most important being that they have a beta-blocking effect for a very short time.

Surprisingly, it has now been found that the 3-alkylamino-1- (2-chloro-3,5'-dimethyloxyphenyl) -2-propanols of the invention do not have the above drawbacks, being more therapeutically effective than 1- (3,5-dimethoxyphenoxy). -3-Ssopoopylamino-2-propanol from the French Patent Specification No. 364 * M and 4061M and nei 1- (3,5-Dimethylphosphino) zene-. tert-butyl amal-2-propanol from French Patent No. 2,042,390 et. they are at least as interesting as propannool, coi is a reference beta-bleaching product that is structurally different.

It is an object of the present invention to provide novel derivatives. 3-Amino-1-phenoxy-4-propanol from the group 3-alkylamino-1-phenoxy-2-propanol from the group 3-alkylamino-1- (2-chloro-3,5-dimethoxy / phenox-4-propanol)

CH3O

Cl

O-CH 2 -NH-CH 2 NH-R

OH (I) in which R is CHCl3 or CCCH3, and their editoral salts, characterized in that e) is reacted in the reaction with 2-chloro-3,5-diylthienyl of formula II

CH3O (II) with epichlorohydrin - formula III

C1-CH ₂ -CH-CH ₂ O

(III) in the presence of pyridine to give 1- (2-chloro-3,5-dimitholylphenols) -2,3-piperidepan of formula IV

(IV) read

b) reacting the obtained epoxide of formula IV with an amine of formula V

NHGRI ·> (V) ^'in kt ^m R ^e Re ^cording en ^and i ^^ CJ ^or C ^(ai Cj- ^{alk oh} ol, ^{whereupon the} ztoto ^u ^ ^p kt genus of formula I can optionally be reacted with or an organic acid.

Preferably, step (a) is reacted. MML compound of above formula II ^{are 4 and} 10 ^mm and Ly ^ ^ nu tohtorhyd výěe given by the formula H ^ ^I b ^{i 2 E} Game ⁵ Todt .When toptotě

100 DEG-120 DEG C. and in step b) reacting 1 mole of the epoxide of formula IV with 8-12 moles of amine of formula V in the presence of ethanol at reflux temperature for 0.5 to 1 hour.

Preferably, in step b), t-butylamine is used as the amine of the above formula (V). In this step, isopropylamine is also preferably used as the amine of the above formula (V).

In practice, the preferred compounds are i. According to the invention, 1- (2-cyclo-3,5-dimethyhosphenoxy) -3-tert-butylamine-2-propspanol and its editoral salts, in particular chlorohydrate. Tests with humans and animals have shown that the 3-tert-butylamino derivative and its salts are more effective than the 3-isopropylamine derivative and its salts.

As used herein, the term "acid addition salts" refers to the acid addition salts obtained by reaction of the free base of formula (I) with a minor or organic acid, and amide salts. Examples of acids which can be used to convert the free base of formula (I) into a salt include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, molar acid, acetic acid, propionic acid, acetic acid, acetic acid, acetic acid, hydrobromic acid. fumaric acid, mmaeinic acid, succinic acid, benzoic acid, cinnamic acid, mannitolic acid, malic acid, citric acid, tartaric acid, aspartic acid, glutamic acid, p-toluenesulfonic acid and methanesulfonic acid.

Examples of compounds which provide ammonium salts include, but are not limited to, CH-γ, CH ^C CC. Therapeutically preferred addition salts are acid addition salts, especially chlorohydrates.

λ

Some of the compounds of the present invention are listed in Table I without limitation.

Table I

CH3O

O-CH2-CHOH-CH2-NHR

i ... Product Code number R Melting point Example 1 (b) CRL 41058 t-C -Hg 216 [deg.] C .Example 2 Ca) - ' t-C-g 85 ° C .Example 3 (b) CRL 41045 ic ₃ H ₆ 206 ° C Example 4 (and) ic ₃ H ₆ 97 ° C Comment: (E) - free base (b) - chlorohydrate

3-alkylamino-1- (2-chloro-3 _I 5-dimethoxy-phenoxy) -2-propanol of formula I and their acid addition salts are pouHtelné as a beta-blocker drugs. OOdpovdající therapeutic composition contains ^at least one S ^ u ^ Nin formula I or ^ .mu.l net ick ^ox OH ^ou ^ i ^ 1 as active betj-blocking substance in admixture with lysiologicky přijateným excipient.

Otherwise, the compounds of the invention also serve as intermediates in the synthesis of other compounds. In this case, the compounds of the invention are in particular used in the form of the free bases.

V follows! In the following, the invention will be explained in more detail by way of examples, which are illustrative only and do not limit the scope of the invention.

Preparation

Obtaining chlorohydrate 1 - (2-chlorophenyl, 3,5-Lor di ^ ^ ^ m ^<th (3X ^ ^ ^ r ^ ff OOYYO 3-t ^ (^] ^ (^. Butylamino-2-propanol (Example 1; CRL code 41 058)

1) 2-chloro-3,5-dimethoxyphenol

To flowable u ^{d s} ržovan it at 'a temperature in the range ^35-40 ° C and consisting of 75 ^{g (0} 487 Love) 3,5-dimethyl-1 ^] ^ (^ ^ Dq yfen ^ lu and 400 ml tetracherreethanu is 70.5 g (0.528 mole) of N-chlorosuccinimide are introduced in portions over 2.5 hours and the reaction mixture is then heated for a period of 0.25 hours ^{at 70} DEG C. The precipitate formed is separated off. filtration and the filtrate was evaporated to dryness under reduced pressure.

The evaporation residue thus obtained is purified by distillation under vacuum, and then the dessilate is washed with water. There was thus obtained 56.5 g (yield: 61.65%, 2-chloro-3,5-diethoxyphenyl).

Melting point ^(Kofler Heat ^B Lo ^{K) 7} 5 ° C.

2) 1- (2-Chloro-3'-di-7-ethoxy) -oxy) -2, - epoyppropao

A solution of 40 g (0.212 mmlu) 2 ctleг-3,5-dieettoχrfeoolj in 133 ml (1.697 mole) of ^d epictlerhy Riou at present) of the 0.25 ml ^{of p} yri ^di nu heated by ^P to ^B in 4 ^h at Odin temperature of ¹¹ 5 ° ( »Reakčrní mixture is evaporated to dryness, the residue is taken up in ethyl acetate and the ethyl acetate phase is then graduate sodium carbonate solution and water.

After drying over sodium sulfate (anhydrous) and evaporation REU ^p oujtldla give a brown thick oil. This oil was purified by crystallization from isoprepylalketel to give 36.5 g (yield: 70.4%) of 1- (2-chloro-3,5-diethoxy) -phenyl] -2,3-ethoxypropane, which was in the form of chocolate brown powder.

Melting point ^{(Köfler s} in l ^{b ok):} 96 ° C.

3) CRL 41,058

A solution of 36 g (0.147 µl) of 1- (2-chloro-3,5-diethylphenyl) -2-ε-ε-ε-γ-epopane and 107.5 g (1.462 mmol) of tert-butyl lineate in 150 ml of anhydrous ethanol is heated to reflux. cooler for one hour. The reaction mixture is then evaporated to dryness and the residue was vyččstí kryytalizaci isopropyl ether to obtain 37 g 1 - ^ - chloro-5-dieetteχčfeoo χč} -3-tlrc · butyaaeine _2-propanolj> which has the form of a beige powder.

Temp ° t ^and tan (Kiiflfirův block): 85 ° C.

The free base thus obtained is heated to reflux with anhydrous ethianol and ethanol saturated with hydrochloric acid. A precipitate is formed which is isolated to give 36.3 g (yield: 69.75%) of CRL 41 058, which is in the form of a slightly beige, water-soluble powder up to 12.5 g / l.

Temperature ^and melting point (Kooil block): 216 ° C.

Preparation II

Obtaining 1- (2-chloro-3,5-dimethoxyphenoxy) -3-isoprapyl-amino-2-propenol chlorohydrate

• Proceed as in Step 3 of Preparation 1, substituting tert-butylamine for isopropylamine to give CRL 41 045.

Melting point (Kofler block): 206 ° C.

The following section describes the part of the tests that were performed with the product

CRL 41 058 (product of Example 1). In these tests, · CRL 41 058 is administered as a suspension in an aqueous gum arabic solution at concentrations greater than or equal to 3 g / l and ve. in the form of a solution in distilled water at concentrations of less than 3 g / l, unless otherwise specified, at a rate of 20 ml / kg body weight. of a male male and at a rate of 5 ml / kg body weight of a rat male.

Tooiicta

In male females, the DL-0 dose (the highest dose that is not yet lethal) is greater than 64 mg / kg and the dose of DL-30 (the dose at which 30% of the animals die) is about 128 mg / kg. The product CRL 41 058 is less toxic than dorphoryl-1- (3,5-dimethoxyphenoxy) -3-tert-butylamino-2-prlpanol, whose dose of DL-50 in ictraptritental administration in mice is males about 73 mg ^ kg.

General behavior and reactions

Groups of three animals were eaten 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 24 hours after administration of CRL 41 058 by the ictraptritral route. It was found that

1. in mice

doses of 0.5 mg / kg, 2 mg / kg and 8 mg / kg do not cause any significant symptoms;

doses of 32 mg / kg result in unconscious sedation (two animals out of three), which is transient (30 minutes) and dyspnea (two animals out of three) lasting 15 to 30 minutes; .

2. in rats

doses of 0.25 mg / kg, 1 mg / kg and 4 mg / kg do not cause any significant symptoms;

-dose of 16 mg / kg leads to transient sedation (30 min) ´ · and makes breathing difficult (in two animals out of three) for 30 minutes.

Study of cardiovascular properties

A) AnctSetized Dog · '<

T4 dogs (mean weight: 13.6 kg) anesthetized with nembutal received a dose of product • CRL 41 058 administered ictraduodenally in sequential doses of 0.5 mg / kg, 1 mg / cg, 2.5 m / kg, 5 mg / kg and 10 m ^ kg. Thereafter they were measured for? -Terial pressure, pulse, femoral artery flow, vertebral arterial flow, rectal temperature, and the skin color and bile color collected by catheterization were recorded. bile duct after cystecal ligation.

CRL 41 058 causes bradycardia starting at a dose of 0.5 mg / kg without any significant effect on arterial pressure. Said product is not a vertebral vasodilator. The increase in flow in the femoral artery occurs in only one dog out of three and is only small (24 ml / min). In the other two dogs, on the contrary, there is a reduction in flow. Skin and rectal, the temperature changes little. Skin and bile coloration does not occur.

The effects of isoprenaline detected after a cumulative dose of 19 mg / kg of CRL 41 058 are strongly reduced:

3 µg / kg of isoprenaline causes a diastolic arterial pressure change to 15,865 kPa instead of 6,399 kPa and a change in beats per minute instead of 245 beats per minute. In the two dogs in which the isoprenaline dose was increased up to 100 µg / kg, the tachycardic effect at this dose was lower than the tachycardic effect at the 0.3jug / kg isoprenaline dose.

Norepinephrine-induced hypertension is also reduced: at a dose of 1 µg / kg norepinephrine, the systolic arterial pressure changes to 29.464 kPa instead of 37,330 kPa at. comparative test.

B) Isolated atria of guinea pigs

The five true isolated ventricle atria were used to determine the pAg of CRL 41,058 against the chronotropic effect of isoprenaline; after 15 minutes of contact, the mean pAg is 8.21 ± 0.272.

The inotropic and intrinsic chronotropic effect of product CRL 41 058; no mean value could be effected, and the concentration and the order of application of these concentrations were variable. CRL 41 058 has the effect of ino ⁺ and chromo ⁺ , which is maximal at the first concentration used, whatever (3 x 10 ⁸ to 10 ^-6 M). Conversely, if, for example, a concentration of 10 @ -1 is administered at lower concentrations that have been stimulating, then the concentration of 10 @ -1 is ino a chrono (this phenomenon makes it possible to predict ketecholamine release).

C) Anesthetized rat

Rats are anesthetized with pentobarhital (75 mg / kg intraperitoneally) and atropinated (1 mg / kg intraperitoneally). They measure their carotid arterial pressure and their pulse by integrating the arterial pressure. The throat vein is catheterized for injection. If necessary, anesthesia is maintained by subcutaneous injections of pentobarbital.

1) Determination of the effective beta-blocking dose of the rat received CRL 41 058 intravenously at sequential doses of 0.3 mg / kg, 1 mg / kg, 3 mg / kg and 10 mg / kg and optionally 30 mg / kg. The dose that blocks tachycardia induced by intravenous application of 0.03 to 0.3µg / kg Isoprenaline (dose necessary to obtain a 30 to 50 beats per minute increase in heart rate) is determined. The dose was found to be 1 mg / kg intravenously.

2. The duration of the beta-blocking effect of the rats received intravenously 1 mg / kg of product CRL 41 058. It is observed that:

with

the diastolic arterial pressure did not change and remained at about 12.132 kPa and

-the temperature changes from 345 to 290 beats per minute in 5 minutes (ie 16% of the initial value); maximum bradycardia is reached after 20 minutes: 280 beats * <per minute (ie 19% of baseline). After 90 minutes, the heart rate reaches 307 beats per minute (reduced by 11%).

- change of arterial pressure from 12.132 to 8.666 kPa (i.e., about 3.466 kPa); after an intravenous dose of mg / kg of CRL 41 058, the change in arterial pressure is +1.067 kPa (-69% relative to the reference change) after five minutes and during a two-hour observation;

- the type changes from 346 to 384 beats per minute (i.e., 39 beats per minute), the tachycardia which was completely inhibited by CRL 41 058 at 5 minutes gains 50% of its value over time. 20 minutes; within 60 minutes it will regain 92% of its original value.

Finally, 5th reference rats received only physiological saline solution instead of said product, and it was observed that:

-arterial pressure remained constant; isoprenaline hypotension is reduced by 40% _{r a} during the test

- as a result of injections of nembutal required to keep animals in an anesthetic state, the heart rate is reduced by 28 beats per minute; isoprenaline tachycardia remains constant for a observation period of 2 hours.

D) A conscious rat of genetically hypertonic rats implanted with a catheter in the femoral artery received a product of 41,058 at a dose of 20 mg / kg Great Britain.

The arterial pressure changes from 25.464 to 22.264 kPa at 6 hours (13% reduction; statistically significant change); heart rate decreases from 382 to 322 beats per minute after 5 minutes (15% reduction statistically significant change); maximum bradycardia is reached after 2 hours (305 beats per minute, a 20% reduction statistically significant change); after 7 hours, it is 322 beats per minute (a reduction of 15 fy statistically noticeable change).

hours after delivery of CRL 41 058, it can be observed that the arterial pressure has reached its reference value with a pulse still 330 beats per minute (ie 13% reduction; statistically significant change).

E) Conclusion

The above tests show that ⁵ CRL 41 058 is a very good beta-blocking agent.

Human clinical trials have confirmed the beta-blocking effect of CRL 41 058 at a daily dose of 40 to 50 ing (divided into 2-3 smaller doses) for 2 to 6 weeks.

Claims (4)

SUBJECT OF THE INVENTION 1. A process for the preparation of the novel 3-amino-1-phenoxy-2-propanol derivatives of the group 3-alkylamino-1- (2-chloro-3,5-dimethoxyphenoxy) -2-propanols of the general formula I CH3O Cl (I) CH ₃ O in which R is CH ₂ CH 2 or CCCH 3), and their editoral salts, characterized in that a) is reacted in the reaction with 2-chloro-3,5-dimethoxyphenol of formula II CH ₃ O (II) with epichlorohydrin of formula III С1-СН _О -СН-СН _О 2 _in 2 (III) in the presence of pyridine to give 1- (2-chloro-3,5-dimethoxyphenoxy) -2,3-epoxypropane of formula IV (IV) then b) with the epoxide of formula IV is reacted with an amine of formula V, NH ₂ R (V) in which R represents them? or a tert-C ^H- in a C až-C ^-alcohol, whereupon the product of the formula I obtained is optionally reacted with a mineral or organic acid. 2. Process according to claim 1, characterized in that in step a) 1 mol of the compound of the above formula II is reacted with 4 to 10 moles of epichlorohydrin of the above formula II. 4 to 10. moles of epichlorohydrin of the above formula III over a period of 2 to 5 hours at a temperature of 100 to 120 ° C and in step b) react 1 mol of the epoxide of the above formula IV with 8 to 12 moles of amine of the above formula V in ethanol. of reaction medium for 0.5 to 1 hour. 3. A process according to claim 1, wherein tert-butylamine is used as the amine in step b) in step b). 4. A process according to claim 1, wherein isopropylamine is used as the amine of step (b) in step (b).