CS199579B2 - Process for preparing new aryloxyaminobutanoles,stereoisomeres thereof and non-toxic additive salts with acids - Google Patents

Description

The present invention relates to a process for the preparation of novel aryloxyaminobutanols, their streoisomers and non-toxic acid addition salts.

The invention also provides medicaments containing these compounds.

Various β-symphatolytics have been used to treat cardiac rhythm disorders as well as to alleviate angina pectoris, the common feature being that they contain a residue of 1-aryloxy-3-alkylaminopropan-2-ol. For their use, asthma is a contraindication, since the compounds may cause asthma attacks by paralyzing the β-receptors in the bronchi. Because of their attenuating effect on the heart, these compounds cannot be administered during docompensation and heart attack.

The purpose of the investigations undertaken in the field of [beta] -receptor blocking has been to produce pharmaceutically active substances which do not, or only to a lesser extent, exhibit the above-mentioned undesirable side effects while maintaining or increasing the antiarrhythmic and other advantageous pharmaceutical effects.

It has been found that it is possible to obtain substances which meet the intended task by producing aryloxyaminobutanols instead of the aryloxyaminopropanes generally used.

Accordingly, the present invention provides a process for the preparation of the novel aryloxyaminobutanols of formula (I)

R-O-CH-CH-CH-CH2-NH-R ¹

C14 (I) wherein

R is naphthyl or phenyl optionally substituted with 1 to 3 carbon atoms or 1 to 2 halogen atoms, and

R ¹ is a C 1 -C 3 alkyl, C 5 -C 7 cycloalkyl, ring or phenylpropyl group, as well as their stereoisomers and non-toxic acid addition salts thereof.

The process according to the invention for the preparation of aryloxyaminobutanols of the formula I is characterized in that 1-aryloxy-2-hydroxy-4-aminobutane of the formula II

R - O - CH - CH - CH 2 - CH 2 - NH 2: I '

OH • (II).

and where

R is as defined above, reacted with a compound of formula III

X - R 1 (III) wherein

R1 is as defined above and

X is halogen, and the compound of formula (I) obtained is optionally converted into its non-toxic acid addition salt or liberated from its salt.

When R is a substituted naphthyl or phenyl group, preferably 1 to 2 halogen atoms or alkyl groups are suitable substituents. The alkyl group R 1 has 1 to 3 carbon atoms and can be, for example, a methyl, ethyl, propyl or isopropyl group. When R1 is a cycloalkyl group, this group has 5 to 7 carbon atoms, i.e. it may be, for example, a cyclohexyl, cyclopentyl or cycloheptyl group. X as a leaving group, which is preferably alkylated, means halogen, such as chlorine, bromine or iodine.

In the process according to the invention, the condensation reaction of the compounds of the formula II with the compounds of the formula III is carried out by boiling in an organic solvent, preferably an alkanol or dimethylformamide, preferably using a scavenger. For example, in the case of hydrohalic acids, this may be basic; preferably alkali metal carbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate are used.

The starting compounds of formula II are obtained by reduction of compounds of formula IV

R = O — CH2 — CH — CH2 — C = N (IV),

AND

OH

This reduction is carried out by catalytic hydrogenation or metal hydrides, working in a solvent environment. If the reduction is carried out catalytically, preferably alkanols such as platinum catalyst or preferably Rany nickel are used as solvents and reduced under a pressure of 0.5 to 0.8 MPa.

The non-toxic salts of the compounds of formula (I) are obtained in a manner known per se, using inorganic or organic salts. Mal maleates of the compounds of formula I are preferred.

The compounds of the invention are very good [beta] -sympatholytics suitable specifically for the heart. In pharmacological investigations, they are compared with three well-known and commonly used drugs having a β-receptor blocking effect. These three reference substances are 1-isopropylamino-3- (1-naphthyloxy) β-propan-2-ol hydrochloride (Propranolol) hydrochloride, Inderal), 1-isopropylamino-3- (2-allyloxyphenoxy) -propan-2-ol hydrochloride (Oxprenolol hydrochloride, Trasicor), and 4- (2-hydroxy-3-isopropylaminopropoxy) -acetanilide (Practolol, Dalzic).

Many of the compounds produced by the process of the invention exhibit excellent activity. Particular mention should be made of the maleate

1- (1-naphthyloxy) -4-cyclohexylaminobutan-2-ol - hereinafter referred to as Compound A - whose acute toxicity, measured intravenously in mice, is LD50 = 50 mg / kg, while this value for Propranolol is 37.5 mg / kg, for Oxprenolol 45.5 mg / kg and for Practolol

132.5 mg / kg.

Similar to the three reference substances, Compound A has a negative chronotropic and a negative inotropic effect on the frog heart isolated by Straub. The positive chronotropic and inotropic effect of Isoproterenium cannot be neutralized by Oxprenolol and Propranolol, whereas Compound A and Practolol can counteract this harmful effect.

In a Trendellenburg frog experiment, Compound A induces a widening of the blood vessels, which results in a 20-28% increase in the droplet number, whereas the reference substances have no effect on the droplet number.

In the Langendorff rat heart preparation, the use of Compound A similarly to the reference substances reduces the heart rate. Compound A and Propranolol have proven to be the most suitable for reducing the acceleration of the heart rate induced by Isoproterenol.

As demonstrated by gaping experiments, respiratory rate and inspiratory air volume are not affected by Compound A, as they are not affected by reference substances.

Regarding the effect that Compound A has on the coronary circulation of open-chested dogs with artificial respiration, Compound A is approximately equivalent to Inderal, Trasicor and Dalzic, i.e., in smaller amounts, it has no effect, whereas it induces in large doses slight decrease in coronary artery flow.

On the heart-lung preparations of cats prepared according to Starling, Compound A exhibits no cardiovascular activity. The arythmia induced in cats by Strophantine, with Compound A, turns away, reducing the toxicity of Strophantine. In this respect, Propranolol has the same effect, while the effect of Oxprenolol and Practolol is stronger. ·

It should be emphasized that, with regard to the reversal of Aconitin-induced arythmia in rats, the effect induced by Compound A outweighs the protective effect of all three reference substances used. The advantage of the compounds produced by the process of the invention is that they have a specific effect on the heart and thus can be used more generally than the known formulations due to the marked decrease in undesirable side effects. This specificity stems quite characteristically from the fact that - although Compound A has a better effect than the three reference substances in different induced arrhythmias or in many cases - it induces a significantly weaker response to induction of unwanted bronchial convulsions, such as as can be seen from the description below.

The guinea pig is inhaled with a 0.3% hystamine solution in the spray form. In the control group, this inhalation causes bronchial convulsions within 112 seconds. Pre-treated animals with Propranolol, Oxprenolol and Practoloi will experience bronchial convulsions as early as 20 to 25 seconds after inhalation of the histamine spray, whereas guinea pigs pretreated with Compound A will experience bronchial convulsions only after 75 to 80 seconds.

In experiments conducted also in guinea pigs to check these results, comparable results were obtained with respect to histamine-induced bronchial convulsions. While Inderal, Trasicor and Dalzic reduce the time to onset of bronchial convulsions by 25 to 45%, Compound A has virtually no effect on this time.

The invention also provides medicament preparations comprising substances produced by the method of the invention. The compounds of formula (I) may be formulated into pharmaceutical preparations with pharmaceutically acceptable, non-toxic, solid or liquid fillers or carriers. These preparations may be in the form of solids, in the form of tablets, coated tablets, enteric coated tablets, pills or capsules, but also liquid, for example in the form of suspensions, solutions or emulsions. These pharmaceutical preparations may optionally contain other pharmaceutically active substances.

The novel compounds prepared by the process according to the invention are characterized by advantageous effects, in particular:

1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate, 1- (1-naphthyloxy) -2-hydroxy-4- (4-phenyl-2-propyl) aminobutane maleate, maleate 1 - (2,3-dichlorophenoxy) -2-hydroxy-4-lsopropylaminobutane, 1-phenoxy-2-hydroxy-4- (1-phenyl-2-propyl) aminobutane maleate, 1-phenoxy-2-hydroxy-4 maleate -cyclohexyl-aminobutane.

The invention is further illustrated by the following examples, which are not to be construed as limiting.

He did. A mixture consisting of 1.56 g (0.0068 mol) of 1- (1-naphthyloxy) -2-hydroxy-4-aminobutane,

3.7 g (0.03 mol) of isopropyl bromide, 0.7 g (0.007 mol) of sodium carbonate, 200 ml of potassium iodide and 15 ml of ethanol are heated under stirring for 30 hours under reflux. After distilling off the solvent, the residue is taken up in dilute hydrochloric acid and shaken once with ether. The acidic phase is basified with 20% sodium hydroxide solution and then shaken with ether. The combined ether phases were washed and dried with magnesium sulfate. The residue obtained after distilling off the ether was treated with 0.0067 mol of maleic acid. There was thus obtained 1- (1-naphthyloxy) -2-hydroxy-4-isopropylaminobutane maleate, which, after recrystallization from isopropanol, melted at 147-149 ° C.

The following compounds can be prepared in a similar manner:

1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane, m.p. 163-165 ° C;

1- (1-naphthyloxy) -2-hydroxy-4- (1-phenylprop-2-yl) -aminobutane, m.p. maleate 152-155 ° C.

1-phenoxy-2-hydroxy-4-cyclohexylaminobutane, mp 110-112 ° C, 1-phenoxy-2-hydroxy-4- (1-phenylprop-2-yl) -aminobutane, mp 123-124 ° C C, a

1- (2,3-dichlorophenoxy) -2-hydroxy-4-isopropylaminobutane, m.p. 127 ° C.

EXAMPLE 2 A mixture consisting of 92.4 g (0.406 mol) of 3- (1-naphthyloxy) -3-hydroxybutyric acid nitrile, 500 ml of a 10% methanolic ammonia solution and 20 g of Raney nickel is hydrogenated in a shaking autoclave under pressure 0.6 to 0.7 MPa. After the hydrogen uptake is complete, the catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in 100 ml of ether. 8.46 g (90% of theory) of 1- (1-naphthyloxy) 2-hydroxy-4-aminobutane are obtained, melting at 73-75 ° C.

Example 3

88.6 g (0.5 mol) of 4-phenoxy-3-hydroxybutyric acid nitrile is hydrogenated in 500 ml of a 10% methanolic ammonia solution in the presence of 20 g of Raney nickel in a shaking autoclave at a pressure of 0.6 to 0.7

199879

MPa. Filtration of the catalyst and evaporation gave 85 g (94% of theory) of 1-phenoxy-2-hydroxy-4-aminobutane as a viscous oil. The product obtained solidifies slowly on standing and can be used immediately.

Example 4

42.7 g (0.174 mol) of 1- (2,3-dichlorophenoxy) -2-hydroxy-3-cyanopropane are hydrogenated at 0.5 MPa in the presence of Raney nickel in 200 ml of 10% methanolic ammonia solution. The residue obtained after filtration and concentration (almost quantitative yield], solidified. The obtained 1- (2,3-dichlorophenoxy J -2-hydroxy-4-aminobutane was recrystallized from ethyl acetate at a temperature ranging from 102 to 104 C. Other ^Ï processing, the product can be used in the raw state.

Example 5

Production, tablet 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate 40 g maize starch 164 g calcium phosphate 240 g magnesium stearate 1 g

445 g

The granules are thoroughly mixed together and first compressed into 100 pieces of tablets each weighing 445 milligrams. Each tablet contains 40 mg of the active substance.

Claims (3)

A process for the preparation of novel aryloxyaminobutanols of the general formula I R = O-CH2-CH-CH2-CH2-NH-R11 CPI (I) where R is naphthyl or phenyl, optionally substituted alkyl of 1 to 3 carbon atoms or 1 to 2 halogen atoms, and R ¹ represents an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms in the ring or a phenylpropyl group, as well as their stereoisomers and non-toxic acid addition salts of these compounds, characterized in that 1-aryloxy-2 hydroxy-4-aminobutane of formula II R = O-CH2-CH-CH2-CH2-NH2 AND OH (Π), I'll find where R is as defined above, reacted with a compound of formula III X - R ¹ (III), wherein R ¹ has the abovementioned meaning and X is a halogen atom, and the compound of formula I obtained is optionally converted into its non-toxic acid addition salt by reaction with or liberated from its salt. 2. Process according to claim 1, characterized in that the condensation reaction is carried out in an organic solvent, preferably an alkanol or dimethylformamide. Process according to Claim 1, characterized in that the condensation reaction is carried out in the presence of a base, preferably in the presence of sodium carbonate.