CS247575B1 - 1-Phenoxy-3-phenoxyethylamino-2-propanol derivatives and process for their preparation - Google Patents

Abstract

Derivatives of l-phenoxy-3-phenoxyethylamino-2-propanol, the described compounds of the general formula I Ar-0-CH.CHCH.NHCHnCH,-0 2 | 2 2 2 OH (I), in which Ar denotes 4-acetoxy-2,3,5-trimethylphenyl, 4-hydroxy-2,3,5-trimethylphenyl or 4-(2-methoxyethyl)phenyl and R denotes a methoxy group or methyl, and their addition salts with pharmaceutically suitable inorganic and organic acids show high alpha-1 and beta adrenolytic activity in animal experiments and have good prospects for use as drugs for hypertension in humans. The method of their preparation consists in the catalytic debenzylation of N-benzyl derivatives of compounds of general formula I, prepared by the reaction of l-Ar-2,3- -epoxypropanes with N-benzyl-2-(2-R-phenoxy)-ethylamines and, in the case of compounds of formula I in which Ar represents 4-hydroxy-2,3,5-trimethylphenyl, by hydrolytic cleavage of the O-acetyl group either at the stage of intermediate products or at the final stage of synthesis.

Description

The invention relates to 1-phenoxy-3-phenoxyethylamino-2-propanol derivatives of the general formula I

Ar-O-Cl 2 HCH 3 NHCl 4 CH 3 -O

OH

(X) wherein Ar represents 4-acetoxy-2,3,5-trimethylphenyl, 4-hydroxy-2,3,5-trimethylphenyl or 4- (2-methoxyethyl) phenyl and R represents methoxy or methyl, their addition salts with and pharmaceutically acceptable inorganic and organic acids and processes for their preparation.

The compounds of formula (I) are analogues of the known beta-adrenolytic metipraponolol, its desacetylderivative and the cardioselective beta-adrenolytic metroprolol, which have long been used clinically in the treatment of ischemic heart disease, some cardiac arrhythmias and hypertension. The main disadvantage of their use in the treatment of hypertension is the induction of reflex peripheral vasoconstriction and the slow onset of antihypertensive effect.

It has been found by pharmacological tests that the novel compounds of the formula I exhibit, in addition to the beta-adrenolytic activity, a high alpha-1 adrenolytic activity compared to metipranolol and matoprolol, which is a particularly advantageous property which prevents reflex vasoconstriction and significantly accelerates the onset antihypertensive effect.

The biological effects of the compounds of formula I were evaluated by a binding study on alpha-1 adrenergic receptors compared to 1 H-prazosin, a binding study on beta-1 and beta-2 adrenergic receptors compared to 1 H-dihydroalprenolol, by assessing the hypotensive and bradycardic effects of normotensive rats after intravenous and oral administration, antagonistic effect against the hypertensive effect of phenylephrine in despinalized rats, antagonism to the effect of isoprenaline on the heart rate in rabbits, hypotensive effect on DOCA hypertensive rats after oral administration, the effect on blood pressure and the pulse rate of normotensive ) and toxicity in mice.

In the following, the pharmacologically evaluated compounds of the formula I are designated with the numbers 1 to 5 i = I, Ar = 4-acetoxy-2,3,5-trimethylphenyl, R = OCH-j = I, Ar = 4-hydroxy-2,3 , 5-trimethylphenyl, R = OCH-j = I, Ar = 4-acetoxy-2,3,5-trimethylphenyl, R = CH3

4 = 1, Ar = 4-hydroxy-2,3,5-trimethylphenyl, R = CH ₃ = I, Ar = 4- (2-methoxyethyl) -phenyl, R ₃ = OCH

In in vitro binding studies, compounds 1 to 5 show a high affinity for alpha-1 adrenergic reoeptors and act more prominently than the known, clinically long-acting labetalol as an antihypertensive. Metipranolol, from whose structure compounds 1-4 are derived, shows virtually no affinity for alpha-1 reoeptors. They are also active in binding to beta-1 and beta-2 adrenergic receptors. Compounds 1 and 2 almost equal to that of metipranolol, and 5 to that of metroprolol. The results of the in vitro binding studies are consistent with the findings of antagonistic activity against the effects of phenylfrin and isoprenaline in vivo. Here too, a blocking effect on alpha-1 and beta-1 adrenergic receptors has been demonstrated. The alpha-1 adrenolytic effect of compounds 2 and 5 is comparable to that of labetalol.

The beta-1 adrenolytic effect of 1,2 and 4 is only slightly weaker than that of metipranolol.

At an intravenous dose of 2 mg / kg, the test substances cause more than 50% blockade of the pressure rise after phenylfrine application (5 µg (kg)) and virtually completely block the heart rate induced rise in isoprenaline (1 µg / kg). Both intravenous and oral administration of substances 1 to 5. Normotensive rats respond to administration of compounds 2 and 5 at an itravenous dose of 0.4 mg / kg by decreasing blood pressure and heart rate, and oral administration of these substances at 12 mg / kg to both normotensive and DOCA blood pressure drop lasts up to 60 minutes.

In monkeys (Macao Rhesus), after an intravenous dose of 1 mg / kg of these substances, a decrease in pressure to an 80% decrease in heart rate was also reported to an 80 = resting value. This persisted for 5 h. The administration of an intravenous dose of 6 mg / kg of compound 5 caused a sharp drop in blood pressure to virtually unmeasurable values accompanied by a 60% decrease in heart rate.

The intravenous toxicity of substances 1 to 5 determined in mice ranges from LD 50 values to 60 mg / kg. Also, oral toxicity is relatively low.

The results of the pharmacological tests performed so far indicate that the compounds of formula I are promising for use in the treatment of hypertension in humans. Compounds of formula I may be prepared by reaction of known epoxides of formula II

Ar-O-CH CH-CH ² \ / ² (II) in which Ar stands for 4-acetoxy-2,3,5-trimetylfeny or 4- (2-methoxyethyl) phenyl, are substituted, also phenoxyethylamine of the general formula III H ₂ NCH ₂ CH ₂ -O \ (III) wherein R is methoxy or methyl, and for the preparation of compounds of formula I in which Ar stands for 4-hydroxy-2,3,5-trimethylphenyl, cleaving 0- acetyl groups by acid hydrolysis. In the reaction, by heating the reaction components either without a solvent, or more preferably a solution thereof in a lower aliphatic alcohol to 20 ° C to the boiling point of the reaction mixture, at least two epoxide molecules of formula II with one 100% excess of primary amine of formula III.

This disadvantage is overcome by the process according to the invention, wherein the epoxide of the formula II is reacted with a secondary amine of the formula IV

wherein R is methoxy or methyl by heating a solution of their mixture in a lower C 1 -C 4 aliphatic alcohol, preferably in ethanol, to 20 ° C to the boiling point of the reaction mixture, and in the tertiary amine obtained,

wherein Ar is 4-acetoxy-2,3,5-trimethylphenyl or 4- (2-methoxyethyl) phenyl and R is methoxy or methyl, the N-benzyl group is then cleaved off by catalytic hydrogenation using palladium-on-carbon catalyst, carried out at a lower rate a C 1 -C 4 aliphatic alcohol, for example in methanol, in the presence of at least an equivalent of hydrochloric acid at a temperature of 20 to 40 ° C. Thus, in good yields, a compound of formula I in which Ar is 4-acetoxy-2,3,5-trimethylphenyl or 4- (2-methoxyethyl) phenyl and R is methyl or methyl, is obtained in the form of the hydrochloride. Compounds of formula I wherein Ar is 4-acetoxy-2,3,5-trimethylphenyl and R is methoxy or methyl, or dasacetylation of compounds of formula V wherein Ar is 4-acetoxy-2,3,5-trimethylphenyl and R is methoxy or methyl, and by removal of the N-benzyl group in the products by catalytic hydrogenation on palladium on activated carbon, again carried out, for example, in methanol in the presence of at least an equivalent of hydrogen chloride at 20 to 40 ° C. The desacetylation is carried out by boiling the hydrochloride solution of the appropriate base for several hours with the addition of conc. hydrochloric acid or a solution of hydrochloric acid in ethanol.

The hydrochlorides of the compounds of the formula I obtained by the process described above are purified by crystallization from lower aliphatic alcohols having from 1 to 4 carbon atoms or are converted by alkalization of aqueous solutions or suspensions, for example sodium hydroxide solution, which can be converted to neutralization by inorganic or organic acids. addition salts.

The secondary amines of formula XV are new. Prepared by reductive alkylation of primary amines of formula III with benzaldehyde, for example under catalytic hydrogenation conditions on a platinum catalyst in methanol. The details of the process for the preparation of the compounds of the formula I and of the intermediates of the formula V are given in the following non-limiting examples.

Example 1 1-Benzylamino-2- (2-methoxyphenoxy) ethane

To a solution of 20.5 g of 2- (2-methoxyphenoxy, ethylamine and 13.7 g of benzaldehyde in 100 ml of methanol) was added 0.2 g of platinum oxide and the mixture was hydrogenated under vigorous shaking under a hydrogen atmosphere (hydrogen overpressure of about 20 kPa). at about 20-25 ° C until the hydrogen uptake ceased (about 2 hours), the catalyst was filtered off with suction, washed with methanol and methanol was distilled off under reduced pressure, the residue (33 g) was taken up in 150 ml of ether and the basic product was shaken to dilute. The combined acidic aqueous solutions were shaken with 40 ml of ether and basified with 20% sodium hydroxide solution, and the precipitated base was shaken into ether.

The ether solution was washed with water and saturated sodium chloride solution and, after drying with anhydrous sodium sulfate, the ether was distilled off under reduced pressure. The obtained crude base (28.8 g) was purified by distillation under reduced pressure. 26.2 g (83%) of the product with a boiling point of 122 DEG-123 DEG C. at 2.66 Pa are obtained. The compound was analyzed as a crystalline hydrochloride having a melting point of 148-149 ° C after recrystallization from isopropyl alcohol.

Example 2 1-Benzylamino-2) 2-methylphenoxy) ethane

By analogy to Example 1, hydrogenation of a mixture of 18.9 g of 2- (2-methylphenoxy) ethylamine and 13.9 g of benzaldehyde in 100 ml of methanol was prepared in the presence of 0.2 g of platinum oxide 22.6 g of crude product base. Purified by distillation under reduced pressure. 21.5 g (71.3%) of product are obtained, b.p. 124-125 ° C at 13.3 Pa. The melting point of the hydrochloride crystallized from isopropyl alcohol is 176-177 ° C.

Example 3

1- (4-Acetoxy-2,3,5-trimethylphenoxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol

A mixture of 4.9 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane and 4.6 g of 1-benzylamino-2- (2-methoxyphenoxy) ethane in 31 ml of ethanol is heated to boiling. The ethanol was evaporated under reduced pressure, the residue was dissolved in ether and acidified with a solution of hydrogen chloride in ether to give a semi-solid hydrochloride. It is washed with ether and dissolved in 50 ml of methanol. To the solution was added a catalyst prepared by hadrogenation of a mixture of 2.7 g of activated carbon, 4.5 ml of a 10% palladium chloride solution and 30 ml of methanol. The mixture is hydrogenated by shaking under a hydrogen atmosphere until the consumption of hydrogen is complete (about 1.5 h). The catalyst is filtered off with suction, washed with methanol and the filtrate is evaporated under reduced pressure. The solid residue (7.8 g) was suction filtered after stirring with ether. 6.9 g (77.6%) of the title hydrochloride are obtained, m.p. 155-159 ° C. Recrystallization from 110 ml of isopropyl alcohol gave 6.0 g (67.5%) of pure hydrochloride, m.p. 162-163 ° C.

Example 4

1- (4-Hydroxy-2,3,5-trimethyl-phenoxy) -3 / 2- (2-methoxy-phenoxy) -ethylamino] -2-propanol

A solution of 11.0 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane and 10.3 g of 1-beirzylamino-2- (2-methoxyphenoxy) ethane in 70 ml of ethanol is heated to Boiling for 6 h. Ethanol is distilled off under reduced pressure. To a solution of the residue in 6 ml of ethanol was added 26 ml of a solution of hydrogen chloride in ethanol (0.116 g of HCl in ml of solution) and the mixture was heated to boiling for 5 h. The mixture was evaporated under reduced pressure. The crude 1- (4-hydroxy-2,3,5-trimethylphenoxy) -3- [N-benzyl-2- (2-methoxyphenoxy) ethylamino] -2-propanol hydrochloride residue is subjected to hydrogenation after dissolution in 25 ml of methanol. of a catalyst prepared by hydrogenating a mixture of 10 ml of a 10% solution of palladium chloride and 6 g of activated carbon in 60 ml of methanol. Hydrogenation is carried out under a slight overpressure of hydrogen (23 kPa) until the hydrogen consumption is complete (about 70 minutes). The catalyst is filtered off with suction, washed with methanol and the filtrate is evaporated under reduced pressure.

By dissolving the residue in 21 ml of isopropyl alcohol and adding 45 ml of ether to the cooled solution, the hydrochloride of the title compound crystallizes, which is filtered off with suction and washed with a mixture of isopropyl alcohol and ether (1: 3). There was obtained 15.2 g (92.2%) of the hydrochloride with a melting point of 97-102 ° C. The analytically pure material had a melting point of 101-103 ° C after recrystallization from isopropyl alcohol.

Example 5

1- (4-Acetpxy-2,3,5-trimethylphenoxy) -3- [N-benzyl-2- (2-methylphenoxy) ethylamino] -2-propanol

A mixture of 12.5 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane and 11.0 g of 1-benzylamino-2- (2-methylphenoxy) ethane in 80 ml of ethanol is heated to The ethanol is distilled off under reduced pressure, the oily residue (25.8 g) is dissolved in 50 ml of ether and the solution is acidified to pH about 5 by addition of a solution of hydrogen chloride in ether. The precipitated hydrochloride was crystallized by washing with ether and standing under ether for several hours. 21.0 g (87%) of the hydrochloride are obtained, m.p. 115-127 ° C. The analytically pure material had a melting point of 127-130 ° C after crystallization from isopropyl alcohol.

Example 6

1- (4-Acetoxy-2,3,5-trimethylphenoxy) -3- [2- (2-methylphenoxy) ethylamino] -2-propanol

To a solution of the hydrochloride of the product of Example 5 in 120 ml of methanol was added a catalyst prepared by hydrogenating a mixture of 6.8 g of activated carbon and 11.5 ml of a 10% palladium chloride solution in methanol and the mixture was switched under hydrogen. consumption of hydrogen (about 1.5 h). The catalyst is filtered off with suction, washed with methanol and the filtrate is evaporated under reduced pressure. The crystalline residue (24 g, m.p. 158 DEG-165 DEG C.) was recrystallized with 140 ml of ethanol. This gives 15.5 g (93.4%) of the hydrochloride of the title compound, m.p. 166-167 ° C. Analytically pure hydrochloride melts at 168-169 ° C after recrystallization from ethanol.

Example 7

1- (4-Hydroxy-2,3,5-trimethylphenoxy) -3- [2- (2-methylphenoxy) ethylamino] -2-propanol

A mixture of 7.0 g of 1- (4-acetoxy-2,3,5-trimethylphenoxy) -3- [2- (2-methylphenoxy) ethylamino] -2-propanol hydrochloride and 7 ml conc. of hydrochloric acid in 50 ml of ethanol is heated to boiling

h. After cooling and standing for several hours at about 5 ° C, 5.9 g (93.2%) of the hydrochloride product crystallized, m.p. 184-186 ° C. The analytically pure product had a melting point of 194-195 ° C after recrystallization.

Example

1- [4- (2-Methoxyethyl) phenoxy] -3- [N-benzyl-2- (2-methoxy) -ethylamino] -2-propanol

A solution of 9.2 g of 1- [4- (2-methoxyethyl) phenoxy] -2,3-epoxypropane and 10.3 g of 1-benzylamino-2- (2-methyloxyphenoxy) ethylamine in 70 ml of ethanol is heated to boiling for 7 h. Distilling off the ethanol under reduced pressure gave 19.8 g of an oily residue which crystallized on standing. Recrystallization from 60 mL of cyclohexane gave 17.4 g (92.9%) of the title compound, mp 60-62 ° C. The analytically pure material melts at 61-62 ° C.

Example9

1- [4- (2-Methoxyethyl) phenoxy] -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol

To a stirred suspension of 5.4 g of activated carbon in a mixture of 10 ml of a 10% palladium chloride solution and 50 ml of methanol is added a solution of 17.0 base, product of Example 8, in 50 ml of methanol acidified with conc. The mixture is heated to a temperature of about 40 ° C and hydrogenated at this temperature by shaking under a hydrogen atmosphere at a slight excess pressure of hydrogen (about 23 kPa) until the hydrogen consumption is stopped (about 10 minutes). The catalyst was filtered off and washed with methanol. Evaporation of the filtrate afforded the non-crystalline hydrochloride of the product, which was rendered alkaline with aqueous sodium hydroxide solution. The base is shaken into methyl ether. The methylene chloride solution is washed with water, saturated sodium chloride solution and, after drying with anhydrous sodium sulfate, the methylene chloride is distilled off under reduced pressure. The residue was recrystallized from ether to give 14.0 g of a crystalline base of the product which, upon determination of the melting point, changed the crystal form at 38-40 ° C and melted at 54-56 ° C. It is converted to crystalline hydrochloride by dissolving in 20 ml of isopropyl alcohol, acidifying the solution with a solution of hydrogen chloride in ether and adding 40 ml of ether. After standing for several hours at about 5 ° C, the hydrochloride is filtered off with suction and washed with a 1: 4 mixture of isopropyl alcohol and ether. 13.6 g (88.5%) of the hydrochloride are obtained, which according to elemental analysis crystallizes in the form of a hemihydrate. It has a melting point of 93.5 to 94.5 ° C.

Claims (5)

CLAIMS 1. 1-Phenoxy-3-phenoxyethylamino-2-propanol derivatives of the general formula I Ar-O-CH ₂ CHCH ₂ NHCH ₂ CH 2 -O OH R wherein Ar represents 4-acetoxy-2,3,5-trimethylphenyl, 4-hydroxy-2,3,5-trimethylphenyl, or 4- (2-) methoxyethyl) phenyl and R are methoxy or methyl, and addition salts thereof with pharmaceutically acceptable inorganic and organic acids. 2. A process for the preparation of 1-phenoxy-3-phenoxyethylamino-2-propanol derivatives of the general formula I according to claim 1, characterized by reacting the epoxides of the general formula II. Ar-O-CH ₂ CH 2 -PCH ₂ (II), in which Ar is 4-acetoxy-2,3,5-trimethyphenyl or 4- (2-methoxyethyl) phenyl, with secondary amines of formula IV wherein R is methoxy or methyl, prepares tertiary amines of formula V wherein Ar and R are the same as in formulas II and IV, and the N-benzyl group is removed by catalytic hydrogenation, wherein in the preparation of compounds of formula I wherein Ar is 4 -hydroxy-3,3,5-trimethylphenyl, the cleavage of the O-acetyl group is carried out either at the tertiary amine stage of formula V wherein Ar is 4-acetoxy-2,3,5-trimethylphenyl and R is methoxy, or methyl, and in the products obtained, the N-benzyl group is removed by catalytic hydrogenation, or at the stage of the compounds of formula I in which Ar is 4-acetoxy-2,3,5-trimethylphenyl R is methoxy or methyl. 3. Process according to claim 2, characterized in that the reaction of the epoxides of the formula II with the secondary amines of the formula IV is carried out in a lower aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol at the boiling point of the reaction mixture. 4. A process according to claim 2, wherein the catalytic hydrogenation of the N-benzyl group is carried out using palladium on activated carbon as a catalyst in a lower aliphatic alcohol having 1 to 4 carbon atoms, for example methanol, at a temperature of 20 to 50 °. C. 5. A process for the preparation of 1-phenoxy-3-phenoxyethylamino-2-propanol derivatives of the formula I in which Ar is 4-hydroxy-2,3,5-trimethylphenyl and R is methoxy or methyl according to claim 2, The method according to claim 1, wherein the cleavage of the O-acetyl group is effected by treatment with hydrogen chloride or hydrochloric acid in a lower C 1 -C 4 aliphatic alcohol, for example ethanol, at the boiling point of the reaction mixture.