CS199578B2 - Process for preparing new aryloxyaminobutanoles,stereoisomers thereof and non-toxic additive salts with acids - Google Patents

Abstract

Novel aryloxyaminobutanols of the general formula (I) <IMAGE> in which R represents an optionally substituted aryl group and R<1> represents an alkyl, cycloalkyl or aralkyl group, it being possible for the aryl group to be substituted, and also the stereoisomers and the non-toxic acid addition salts of these compounds, are beta-receptor blockers and have antiarrhythmic action. The compounds are prepared by reacting compounds of the general formula (III) <IMAGE> and compounds of the general formula (IV> X-R<1> (IV> in which X represents a leaving group, or reacting compounds of the general formula (III) with compounds of the general formula (V) <IMAGE> and simultaneously or subsequently reducing, and if desired reacting the resulting compounds of the general formula (I) to give their non-toxic acid addition salts or liberating them from their salts. The stereoisomers of the formula III can be used as starting materials.

Description

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

The invention also provides medicaments containing these compounds.

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

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

It has been found that it is possible to obtain substances which satisfy the above stated task by producing aryloxyaminobutanols instead of the aryloxyaminopropanols generally used.

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

R = O-CH2-CH-CH2-CH2-NH-R1

OH (I), where

R is naphthyl or phenyl optionally substituted with 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 or a phenylpropyl group, as well as their stereoisomers and non-toxic acid addition salts thereof, characterized in that the compounds of the formula II

R = O-CH2-CH2-CH2-NH2. OH (Π) where

R is as defined above, reacted with compounds of formula III

O = R 1 (III), where

R 1 is as defined above, with simultaneous or subsequent reductions, and the compounds of formula (I) obtained are optionally converted into their non-toxic acid addition salts or released from their salts.

When R is a substituted naphthyl or phenyl group, the substituents are preferably halogen or alkyl groups. The alkyl group R 1 may have 1 to 3 carbon atoms and it is. for example methyl, ethyl, propyl or isopropyl. When R1 represents a cycloalkyl group, it may have 5 to 7 carbon atoms and is, for example, a cyclohexyl, cyclopentyl or cycloheptyl group.

In the process according to the invention, the reaction of the compounds of the formula II with the compounds of the formula III with simultaneous or subsequent reduction is carried out in an organic solvent, preferably in alkanols. The reduction is carried out by shaking in the presence of hydrogen and the catalyst at room temperature and atmospheric pressure. . The catalyst used is palladium on activated carbon, platinum or nickel.

The starting compounds of the formula II are obtained by reducing the compounds of the formula

R = O-CH2-CH-CH2-C = N

AND

OH (IV).

This one. the 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 Raney nickel are used as solvents and reduced at 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. Maleate compounds of the formula I are preferred.

The compounds of the invention are very good heart sympatholytics. In pharmacological research. are compared with three well-known and generally used substances having a blocking effect on β-receptors. The three reference substances are 1-isopropylamino-3- (1-naphthyloxy) -propan-2-ol hydrochloride (Propranolol hydrochloride, Indial), 1-isopropylamino-3- (2-allyloxyphenoxy) -propan-2- hydrochloride ol (Oxprenolol hydrochloride, Trasicor) and 4- (2-hydroxy-3-l- (opioxy) m -propoxy) -acetanilide (Practolol, Dajzic). ’

Many of the compounds produced by the process of the present invention are. characterized by excellent effect; particular mention should be made of 1- (1-naphthyloxy) -4-cyclohexylaminobutan-2-ol maleate, hereinafter referred to as "A" - whose. the acute toxicity measured i.v. in mice is LD 50 = 50 mg / kg, while this value is 37.5 mg / kg for Propranolol, 45.5 mg / kg for Oxprenol and 132.5 mg / kg for Practolol. ·

On Straub's isolated frog heart, compound “A” has a negative chronotropic like the three reference substances. and a negative inotropic effect. The positive chronotropic and inotropic effect of Isopreterenol cannot be neutralized by Oxprenolol and Propranolol, while 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 number of drops, while the reference substances have no effect on the number of drops.

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

As demonstrated by gaping experiments, respiratory rate and inhaled 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-breathing dogs with artificial respiration, Compound “A” is approximately equivalent to Inderal, Trasicor and Dalzic, i.e., in smaller amounts, has no effect whereas it induces a slight decrease in coronary vessel flow in large doses.

On cat-heart lungs,. prepared by Starling, the compound "A" is not characterized by any cardiac depressant effect. Arrhythmia induced in cats by Strophantin. with Compound “A”, the toxicity of Strophantine is reduced. In this regard, Propranolol has the same effect, while Oxprenolol and Practolol. is stronger.

It should be emphasized that, as regards the reversal of the Aconitin-induced arrhythmias in rats. Compound “A” overcomes the protective effect of all three reference substances used. The advantage of the compounds produced by the process according to the invention is that they have a specific heart action and thus are possible for these compounds. to use it more generally than the known preparations due to the significant decrease in adverse side effects. This specificity follows quite characteristically from. that although Compound “A” has arrhythmias induced in various ways. the same or in many cases better effect than the three reference substances,

В if, goes. o. development. unwanted bronchial. convulsions,. induces a substantially weaker reaction, such as. Yippee . - poor - from - below. 'try.

The guinea pig - is allowed to - - inhale a 0.3% · solution of histamine spray. In a group of control animals, this inhalation causes bronchial spasm during. 112 seconds Pre-administered Propranolol, Oxprenolol and Practolol animals will experience bronchial convulsions as early as 20 'to 25 seconds after inhalation. histamine spray, while in guinea pigs,. seized with compound “A”, se- rebrchial seizures - only occur after 75 to 80 seconds.

In experiments conducted also in guinea pigs - in order 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 seizures by 25 to 45%, Compound “A” has virtually no effect on this time.

The invention also relates to medicaments which - contain - substances produced by the process according to the invention. The compounds of formula (I) may be formulated into medicaments with pharmaceutically acceptable, non-toxic, solid - or liquid fillers or carriers. These preparations may be in the form of solids - and in the form of tablets, coated tablets; enteric coated dragees, 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.

Among the novel compounds prepared by the process according to the invention, the following advantages are particularly advantageous:

1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate, 1- (1-naphthyloxy) -2-hydroxy-4- (4-phenylprop-2-yl) aminobutane maleate, maleate-1 - (2,3-dichlorophenoxy) -2-hydroxy-4-isopropylaminobutane, 1-phenoxy-2-hydroxy-4- (1-phenylprop-2-yl) -aminobutane maleate, 1-phenoxy-2-hydroxy-4-cyclohexylaminobutane maleate.

The invention is illustrated in more detail by the following examples, but the scope of the invention is not limited thereto.

Example 1 ·

34.6 g (0.15 mol) of 3-hydroxy-4- (1-naphthyloxy) -butylamine, - 14.7 g (0.15 mol) of cyclohexanone, and 400 ml of anhydrous benzene are heated to boiling for 80 minutes. The benzene was then distilled off under reduced pressure and the Schiff base remaining as a residue was dissolved in 400 ml of methanol. - Shaking - and - - - cooling - with water (temperature not exceeding 40 ° C), add 5.8 g of sodium borohydride to the solution over 1 hour. The reaction mixture is allowed to stand for 3 hours, then 200 ml of water are added; - then - the mixture is extracted 4 times - always. 50 ml - chloroform. . After drying and evaporation of the solution, the residual base is dissolved in 100 ml of ethanol and treated with 16 g of maleic acid under gentle heating. - 52.4 g of 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate are obtained, m.p. 163 DEG-165 DEG C. (ethanol).

LD50 = 50 mg / kg. . .

Example 2

A mixture consisting of - 3.46 g - (0.015 mol) of 1- (1-naphthyloxy) -2-hydroxy-4-amino-butane, 1.47 g (0.015 mol) of cyclohexanone, 2 g. a catalyst consisting of 8% palladium on charcoal and 20 ml of ethanol are hydrogenated at room temperature at atmospheric pressure in a shaking apparatus. After the hydrogen uptake is complete, the catalyst is filtered off and 1.6 g of maleic acid is added to the filtrate with slight heating. Upon cooling, 1- (1'-dimethyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate is obtained in crystalline form, which melts at 163-165 ° C.

Example 1 a d 3

5.78 g (0.025 mol) -1- (1-naphthyloxy) -2-hydroxy-4-aminobutane and -4 g anhydrous acetone were heated for 1 hour to boiling in 60 ml benzene. The residue (theoretical amount) remaining after evaporation is dissolved in 60 ml of methanol and to this solution is added portionwise over 1 hour 1 g of sodium borohydride; shake the reaction mixture during hydrogenation. The reaction mixture is then allowed to stand for several hours and then diluted with water to twice its volume. Then, the mixture is extracted four times with -25 ml of chloroform, dried and the chloroform is distilled off. The residue is dissolved in - 20 ml of methanol - and - 2.27 - g of maleic acid is added to the solution. 7.2 g of 1- (1-naphthyloxy) -2-hydroxy-4 maleate are obtained. isopropylaminobutane, which melts at 147 DEG-149 DEG C. after recrystallization from isopropyl alcohol.

Example 4

A solution of 9.2 g (0.04 mol) of 1- (1- (4-phenyloxyl) -2-hydroxy-4-aminobutane) and 5.36 g (0.04 mol) of phenylacetone in 100 ml of benzene Heat to boiling for 1 hour. The residue obtained by evaporation is dissolved in 100 ml of methanol, followed by reduction according to Example 3 using 2 g of sodium borohydride. The base obtained is reacted with 4.3 g of maleic acid. 1- (1-Naphthyloxy) -2-hydroxy-4- (1-phenylpropyl-2-) - 199578 maleate is obtained.

-aminobutane, which melts at 152-155 ° C after recrystallization from ethanol.

Example 5

The mixture, consisting of 18.1 g (0.1 mol) of 1-phenoxy-2-hydroxy-4-aminobutane, 9.8 g (0.1 mol) of cyclohexanone and 180 ml of anhydrous benzene, is heated for 1.5 hours. hours to boil. After benzene was distilled off, the residue was dissolved in 170 ml of methanol and treated with 2.5 sodium borohydride with shaking and stirring. The mixture was allowed to stand for 1 day, diluted to twice the volume with water, extracted with ether, dried and evaporated. The residue obtained as a residue, m.p. 92 DEG C., is reacted with maleic acid in ethanol. This gives 1-phenoxy-2-hydroxy-4-cyclohexylaminobutane maleate, melting at 110 DEG-112 DEG C., which can be recrystallized from dioxane.

Example 6

9.05 g (0.05 mol) of 1-phenoxy-2-hydroxy-4-aminobutane and 6.7 g (0.05 mol) of phenylacetone, dissolved in 125 ml of benzene, are heated to. boiling for 1 hour. The Schiff base obtained as the benzene distillation residue is dissolved in 80 ml of methanol and reduced with 2.5 g of sodium borohydride which is added portionwise over 1 hour. The reaction mixture is left to stand for 1 day, diluted with 100 ml of water, extracted 3 times with 50 ml of ether, dried and evaporated. The residue was dissolved in 50 ml of ethanol and 4.45 g of maleic acid was added. There was thus obtained 1-phenoxy-2-hydroxy-4- (1-phenylpropyl-2-) aminobutane maleate, m.p. 123-124 ° C.

Example 7

The mixture, consisting of 5 g of 1- (2,3-dichlorophenoxy) -2-hydroxy-4-aminobutane, 4 g of anhydrous acetone and 50 ml of benzene, was heated to boiling for 1 hour. After benzene was distilled off and excess acetone was removed. as a residue, the Schiff base obtained was dissolved in 50 ml of methanol and reduced 0.76 g of sodium borohydride added portionwise. After addition of water, extraction with chloroform, drying and evaporation, the residue is dissolved in 10 ml of ethanol and 2.14 g of maleic acid is added. 5.9 g of 1- (2,3-dichlorophenoxy) -2-hydroxy-4-isopropylaminobutane maleate are obtained, which, after recrystallization, melts from ethyl acetate at 127 ° C. ,

Example 8

The mixture, consisting of 92.4 g (0.406 mol) of 3- (1-naphthyloxy) -3-hydroxybutyric acid nitrile, 500 ml of 10% methanolic ammonia solution and 20 g of Raney nickel, is hydrogenated in a shaking autoclave at a pressure of 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 9

88.6 g (0.5 mol) of 4-phenoxy-3-hydroxybutyric acid nitrile are 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 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.

He did

42.7 g (0.174 mol) of 1- (2,3-dichlorophenoxy) -2-hydroxy-3-cyanopropane were hydrogenated under 0.5 MPa in the presence of Raney nickel in 200 ml of 10% methanolic ammonia solution. The residue obtained after filtration and evaporation (almost quantitative yield) solidifies. The obtained 1- (2,3-dichlorophenoxy) -2-hydroxy-4-aminobutane melts after recrystallization from ethyl acetate at - 102 to 104 ° C. a crude product may also be used.

Prikladli '

Tablet production 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexytaminobutane maleate maize starch calcium phosphate magnesium stearate40 g 114 g 240 g g 445 g

First, granules are made from the thoroughly co-passed ingredients and 1000 tablets are each compressed, each weighing - 445 mg. Each tablet contains - 40 mg of the active substance.

Example 1 a d 12

A mixture of 21.1 g (0.1 mole) of 1- (2-methoxyphenoxy-4-hydroxy-4-aminobutane, 20 g of anhydrous acetone and 240 ml of benzene) was heated for 1 hour, the mixture was concentrated, dissolved in 240 ml of methanol. and reduced in one hour by the addition of 4 g of sodium borohydride added in small portions, then left to stand for 2 hours, diluted with water to twice the volume, extracted with chloroform, dried and evaporated. 9.8 g of maleic acid is added, after recrystallization from isopropanol, 22.8 g of 1- (2-methoxyphenoxy) -2-hydroxy-4199578 maleate are obtained.

isopropylaminobutane, m.p. 125-127 ° C.

Example - 1 and d - 13.

A mixture of 4.87 g (0.025 mole) of 1- (4-tolyloxy) -2-hydroxy-4-aminobutane, 2.45 g (0.025 mole) of cyclohexanone and 25 ml. of benzene was heated for 1 hour, after which the benzene was distilled off and the residue was dissolved in 40 ml of methanol. By adding 1 g of sodium borohydride, the reaction mixture is reduced and, after completion of the reaction, diluted to twice the volume with water. After dilution, the reaction mixture was extracted with chloroform. The chloroform extract was dried over sodium sulfate, filtered and distilled. The residue was dissolved in 20 ml of methanol. Addition of 2.27 grams of maleic acid - formed. salt. This is obtained after recrystallization from ethyl acetate

5.6 g of 1- (4-tolyloxy) -2-hydroxy-4-cyclohexylaminobutane maleate.

Claims (3)

OBJECT OF THE INVENTION Process for the novel aryloxyamino-butanols of the general formula I R-O-CH2-CH-CH2-CH2-NH-R ¹ AND OH (I), where R is naphthyl. or phenyl group. a pin optionally substituted with 1 to 3 carbon atoms or 1 to 2 halogen atoms; and R 1 represents a C 1 -C 3 alkyl group, cycloalkyl. a group having 5 to 7 carbon atoms or a phenylpropyl group, as well as - their stereoisomers and the non-toxic acid addition salts of these compounds, characterized in that the compounds of the formula II R = O-CH2-CH-CH3-CH2-NH2 OH (Π) where '. R is as defined above, - reacted with compounds of formula III O = R 1 (III), where R 1 is as defined above, with simultaneous or subsequent reductions, and the compounds of formula I obtained are optionally converted into their non-toxic acid addition salts or liberated from their salts. 2. A process according to claim 1 wherein said condensation reaction is carried out in an organic solvent environment under catalytic hydrogenation. 3. A process according to claim 1, wherein the solvent used is an alkanol and a palladium-on-carbon catalyst.