FI61304C - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA ARYLOXIAMINOBUTANOLER OCH DERAS GIFTFRIA SYRAADDITIONSSALTER - Google Patents

Description

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Budapest IV, Hungary-Hungary (HU) (72) Kalman Harsanyi, Budapest, Dezs $ Korbonits, Budapest, Erzsebet Molnär geb. Bakö, Szödliget, Jozsef Szegi, Debrecen, Hungary-Hungary (HU) (7U) Oy Kolster Ab (5U) Method for the preparation of new therapeutically useful aryloxyaminobutanols and their non-toxic acid addition derivatives - syraadditionssalter

The invention relates to a process for the preparation of new therapeutically useful aryloxyaminobutanols and their non-toxic acid addition salts.

Various β-sympatholytics, which have in common that they contain a 1-aryloxy-3-alkylaminopropan-2-ol group, are used to treat cardiac arrhythmias and to alleviate ailments in Angina pectoris disease. Asthma is a contraindication to their use, as said compounds can cause an asthma attack by blocking β-receptors in the keyholes. Due to their cardioprotective effects, the compounds also cannot be used in the case of decompensation or infarction.

The present invention is the result of studies on β-receptor blockers which sought to find pharmaceutically active substances which, while maintaining the antiarrhythmic effect and other advantageous pharmaceutical effects, have no or only minor side effects mentioned above.

2,613 0 4 These studies concluded that by using aryloxyaminobutanols instead of the commonly used aryloxyaminopropanols, side effects can be substantially reduced while maintaining the antiarrhythmic effect.

The invention relates to a process for the preparation of therapeutically useful compounds of general formula (I): R-O-CH 2 -CH-CH 2 NH-R 1 (I)

OH

for the preparation of aryloxyaminobutanols according to the formula, wherein R is an optionally halogen-substituted phenyl or naphthyl group, and R 1 is a C 1 -C 4 alkyl, C 1 -C 6 cycloalkyl or phenyl (C 1 -C 4) alkyl group, as well as for the preparation of non-toxic acid addition salts of these compounds.

The process according to the invention is characterized in that a) a compound of general formula III: R-O-CH 2 CH-CH 2 -NH 2 (III)

OH

wherein R is as defined above, compound 2 is reacted

with the general formula V: R

NSS'SsC = O (V) R3 ///. O 1 wherein R and R together with the carbonyl carbon form a C 1 -C 4 alkylidene, C 1 -C 6 cycloalkylidene or phenyl (O 0 -O 4) alkylidene group, and at the same time or subsequently reduced or b) a compound of general formula III, wherein R is as defined above is reacted with a compound of general formula IV: wherein R 1 is as defined above and X is as defined above and X is chlorine, bromine, iodine, sulphate, phosphate or alkylarylsulphonate group, and the resulting general the compound of formula I is, if desired, converted into a non-toxic acid addition salt or the base of formula I is liberated from its acid addition salt.

When R represents a substituted phenyl group, the substituent is preferably chlorine. The alkyl group R 1 is, for example, a methyl, ethyl, propyl or isopropyl group. When R 1 is a cycloalkyl group, it is a cyclohexyl or cyclopentyl group. When R 1 represents an aralkyl group, it may be, for example, a benzyl, phenethyl or phenylpropyl group.

3 61304

In carrying out the process according to the invention, according to process variant a), the reaction of the compound of the general formula (III) with the compound of the general formula (V) is carried out simultaneously or after reduction in an organic solvent medium, preferably an alkanol. The reduction is carried out by shaking in the presence of hydrogen and a catalyst at room temperature and normal pressure. Palladium carbon, platinum or nickel are used as catalysts.

In process variant b) according to the invention, a compound of general formula (III) is condensed with a compound of general formula (IV) by boiling in an organic solvent, preferably alkanol or dimethylformamide, preferably using a substance which binds the leaving molecule. In the case of hydrohalic acids, this substance may be, for example, a base, preferably an alkali metal carbonate such as potassium, sodium carbonate or sodium hydrogen carbonate. In process options a) and b), the compound of general formula (III) required as a starting material is obtained by reduction of the general formula (VI)

R-O-CH0-CH-CH0-C s N

'(VI)

OH

compound. This reduction is carried out catalytically by hydrogenation or by means of metal hydrides, the work taking place in a solvent medium. The solvent used in the catalytic reduction is preferably alkanols, the catalyst is platinum or, preferably, Raney nickel, and the reduction is carried out at a pressure of 5 to 8 atmospheres.

Non-toxic salts of the compounds of general formula (I) are prepared with inorganic or organic acids in a manner known per se. Preferred are the maleates of the compounds of general formula (I).

The compounds prepared according to the invention are very good cardiac-specific / ff sympatholytics. They were compared in pharmacological experiments with three β-receptor blockers well known and commonly used in pharmacy. The three reference compounds were 1-isopropylamino-3- (1-naphthyloxy) -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 of the invention have excellent potencies, in particular 1- (1-naphthyloxy) -4-cyclohexylaminobutan-2-ol maleinate - hereinafter "A" - which has an acute toxicity measured i.v. mice have an LD50 q = 50 mg / kg, while the corresponding values for 4 61304 are 37.5 mg / kg for propranolol, 45.5 mg / kg for oxprenol and 132.5 mg / kg for practical.

In a frog heart isolated according to Straub *, compound "A" as well as the three reference compounds show a negative chronotropic and a negative inorropic effect. The positive chronotropic effect of isoproterenol cannot be neutralized by oxprenolol and propranolol, while compound "A" and practolol are able to reverse this detrimental effect.

In a frog experiment, according to Trendellenburgh, compound "A" causes vasodilation, as evidenced by a droplet count increase of 20-28%, while the reference substances have no effect on the droplet count.

In the rat heart preparation, according to Langendorff, compound "A", like the reference substances, lowers the heart rate. Isoproterenol-induced increases in heart rate were demonstrated by Compound “A” and

As shown in the rabbit experiments, neither Compound "A" nor the reference substances affect respiratory rate and tidal volume.

The effect of compound "A" on cardiovascular circulation in artificially breathing dogs with an open chest is approximately equivalent to that of Inderal, Trasicar and Dalzic, i. lower amounts have no effect, while higher doses slightly reduce cardiac flow.

In cat heart-lung preparations prepared according to Starling, compound "A" did not show any cardioprotective effect. Compound "A" counteracts strophanthin-induced arrhythmia in cats, thus reducing the toxicity of strophanthin. In this respect, propranolol has the same effect, while oxprenolol and practrolol have a stronger effect.

It should be emphasized that in the control of arrhythmia induced by aconite in rats, the protective effect of compound "A" overcomes the protective effect of all three reference substances used. The compounds of the invention have the advantage of their cardiac specificity, and therefore, due to their much lower undesirable side effects, the compounds can be used much more commonly than known preparations. This specificity is particularly evident in the fact that although compound "A" has the same or in some cases better effect than the reference substances in various arrhythmia studies, this compound causes significantly less unwanted bronchospasm, as shown in the following experiment.

5 61 304

The guinea pigs were allowed to inhale a 0.3% histamine solution as a spray. In the control group, this treatment caused bronchospasm in 112 seconds. In animals treated with propranolol, oxprenol, and practol, bronchospasm appeared as early as 20–25 s after inhalation of the histamine spray, whereas in guinea pigs pretreated with Compound “A”, bronchospasm was not observed until 75–80 s.

Similarly, experiments in guinea pigs to control these results gave comparable results in histamine-induced bronchospasm. When Inderal, Trascor, and Dalzic shorten the time to onset of bronchospasm, Compound "A" has virtually no effect on this time.

Of the novel compounds prepared according to the invention, the following in particular have a particularly advantageous effect: 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleinate, 1- (1-naphthyloxy) -2-hydroxy-4- (phenylpropyl-2) - amino-butane maleinate, 1- (2,3-dichlorophenoxy) -2-hydroxy-4-isopropylaminobutane maleinate, 1-phenoxy-2-hydroxy-4- (1-phenylpropyl-2) -aminobutane maleinate, l-phenoxy-2-hydroxy-4-cyclohexylamino-butane-maleate.

The invention is further illustrated by the following examples.

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 boiled together for 80 minutes. The benzene is then evaporated off under reduced pressure and the residual Schiff's base is dissolved in 400 ml of methanol. With shaking and cooling with water (temperature up to 40 ° C), 5.8 g of sodium borohydride are added over one hour. After standing for 3 hours, 200 ml of water are added to the methanol solution, then the mixture is extracted 4 times with 50 ml of chloroform each time.

The solution is dried and evaporated, the residue obtained is dissolved in 100 ml of ethanol and 16 g of maleic acid are added to the solution with gentle heating. 52.4 g of 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleinate are obtained, melting at 163-165 ° C (ethanol). LDrn =

BU

50 mg / kg.

Example 2

A mixture of 3.46 g (0.015 mol) of 1- (1-naphthyloxy) -2-hydroxy-4-aminobutane, 1.47 g (0.015 mol) of cyclohexanone, 2 g of 8% palladium on carbon and 20 ml of ethanol, hydrogenated in a shaker at room temperature under normal pressure. After hydrogen uptake ceases, the catalyst is filtered off. 1.6 g of maleic acid are added to the filtrate with gentle heating. After cooling, crystalline 1- (1-naphthyloxy) -2-hydroxy-4-cyclohexylaminobutane maleinate is obtained, melting at 163-165 ° C.

Example 3 5.78 g (0.025 mol) of 1- (1-naphthyloxy) -2-hydroxy-4-aminobutane and 4 g of dry acetone are boiled for 1 hour in 60 ml of benzene. The residue obtained after evaporation (theoretical weight) is dissolved in 60 ml of methanol. To this solution is added 1 g of sodium borohydride in portions over an hour, and hydrogenated with shaking. The reaction mixture is allowed to stand for a few hours, then diluted with water to twice the volume. The mixture is then extracted 4 times with 25 ml of chloroform each time, the extract is dried and the chloroform is distilled off. The residue is dissolved in 20 ml of methanol, and 2.27 g of maleic acid are added to the solution. 7.2 g of 1- (1-naphthyloxy) -2-hydroxy-4-isopropylaminobutane maleinate are obtained, melting crystallized from isopropanol at 147-149 ° C.

Example 4

A solution of 9.2 g (0.04 mol) of 1- (1-naphthyloxy) -2-hydroxy-4-aminobutane and 5.36 g (0.04 mol) of phenylacetone in 100 ml of benzene is boiled for one hour. . The residue obtained after evaporation to dryness is dissolved in 100 ml of methanol, then reduced according to Example 3 with 2 g of sodium borohydride. The resulting base is reacted with maleic acid (4.3 g). 1- (1-Naphthyloxy) -4- (1-phenylpropyl-2) -aminobutane maleinate is obtained, which, recrystallized from ethanol, melts at 152-155 ° C.

Example 5

A mixture of 1.56 g (0.0068 moles) of 1- (1-naphthyloxy) -2-hydroxy-4-aminobutane, 3.7 g (0.03 moles) of isopropyl bromide, 0.7 g (0.007 moles) sodium carbonate, 200 ml of potassium iodide and 15 ml of ethanol, are heated under reflux and stirred for 30 hours. After distilling off the solvent, the residue obtained is dissolved in dilute hydrochloric acid and extracted once with ether. The acidic phase is made alkaline with 20% sodium hydroside and then shaken with ether. The ether phases are combined, washed and dried over magnesium sulfate. After distilling off the ether, 0.0067 mol of maleic acid are added to the residue obtained. 1- (1-Naphthyloxy) -2-hydroxy-4-isopropylaminobutane maleinate is obtained, melting, recrystallized from isopropanol at 147-149 ° C.

Example 6

A mixture of 18.1 g (0.1 mol) of 1-phenoxy-2-hydroxy-4-7 61304 aminobutane, 9.8 g (0.1 mol) of cyclohexanone and 180 ml of absolute benzene is boiled for 1.5 hours. . The residue obtained after distilling off the benzene is dissolved in 170 ml of methanol and reacted with sodium borohydride (2.5 g) with shaking and stirring. The mixture is allowed to stand for one day, diluted to twice its volume with water, extracted with ether, dried and evaporated to dryness. The residue obtained as a residue (m.p. 92 ° C) is reacted with maleic acid in ethanol. 1-Phenoxy-2-hydroxy-4-cyclohexylaminobutane maleate, melting at 110-112 ° C, is obtained, which can be recrystallized from dioxane.

Example 7 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 boiled for one hour. After distilling off the benzene, the Schiff base obtained as a residue is dissolved in 80 ml of methanol and reduced with 2.5 g of sodium borohydride, which is added portionwise over one hour. The mixture is allowed to stand for one day, then diluted with water, extracted 3 times with 50 ml of ether, dried and evaporated to dryness. The residue is dissolved in 50 ml of ethanol and reacted with maleic acid (4.45 g). 1-Phenoxy-2-hydroxy-4- (1-phenylpropyl-2-amino) -butane maleinate, melting at 123-124 ° C, is obtained.

Example 8 5 g of 1- (2,3-dichlorophenoxy) -2-hydroxy-4-aminobutane, 4 g of anhydrous acetone and 50 ml of benzene are boiled for one hour. After distilling off benzene and excess acetone, the residual Schiff's base is dissolved in 50 ml of methanol, and reduced by adding 0.76 g of sodium borohydride portionwise. The mixture is treated with water, extracted with chloroform, dried and evaporated, the residue is dissolved in 10 ml of ethanol and 2.14 g of maleic acid are added to the solution. 5.9 g of 1- (2,3-dichlorophenoxy) -2-hydroxy-4-isopropylaminobutane maleinate are obtained, melting after recrystallization from ethyl acetate at 127 ° C.

The starting materials were prepared as follows

Preparation 1

A mixture of 92.4 g (0.406 moles) of 3- (1-naphthyloxy) -3-hydroxybutyric acid nitrile, 500 ml of a 10% methanol solution of annonium and 20 g of Raney nickel is hydrogenated in a shaking autoclave at 6-7 at. After uptake of hydrogen, the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is digested in 100 ml of ether. 8.46 g (90%) of 1- (1-naphthyloxy) -2-hydroxy-4-amino-61304 butane are obtained, melting at 73-75 ° C.

Preparation 2 88.6 g (0.5 moles) of 4-phenoxy-4-hydroxybutyric acid nitrile in 500 ml of a 10% methanolic ammonia solution are hydrogenated in the presence of Raney nickel (20 g) at 6-7 ° C in a shaking autoclave. Filter and evaporate to dryness to give 85 g (94%) of 1-phenoxy-2-hydroxy-4-aminobutane as a viscous oil. The product solidifies slowly on standing and can be used immediately in the future.

Preparation 3 42.7 g (0.174 mol) of 1- (2,3-dichlorophenoxy) -2-hydroxy-3-cyanopropane in 200 ml of a 10% methanolic ammonia solution are hydrogenated in the presence of Raney nickel at 5 ° C. The mixture is filtered and evaporated to dryness, the residue obtained (almost quantitative yield) solidifies. 1- (2,3-dichlorophenoxy) -2-hydroxy-4-aminobutane recrystallized from ethyl acetate melts at 102-104 ° C. In the future, the raw product can also be used.

Claims (1)

A process for the preparation of aryloxyaminobutanols of the general formula (I): RO-CH 2 -CH-CH 2 -CH 2 -NH-R 11 (I) OH, in which R is an optionally halogen-substituted phenyl or naphthyl group , and R 1 is a C 1 -C 4 alkyl, C 1 -C 6 cycloalkyl or phenyl (C 1 -C 4) alkyl group, and for the preparation of non-toxic acid addition salts of these compounds, characterized in that a) a compound of general formula III : ROO 2 -CH-O 2 -CH 2 -N 2 (III) OH wherein R is as defined above is reacted with a compound of general formula V: R * - o (vl 2 3 wherein R and R together with carbonyl carbon) form a C 1 -C 4 alkylidene, C 1 -C 6 cycloalkylidene or phenyl (C 1 -C 4) alkylidene group, and simultaneously or subsequently reduced, or b) a compound of general formula III wherein R is as defined above is subjected to to react with a compound of general formula IV: wherein R 1 represents s and X is a chlorine, bromine, iodine, sulfate, phosphate or alkylarylsulfonate group, and the resulting compound of general formula I is converted, if desired, into a non-toxic acid addition salt or the base of formula I is liberated from its acid addition salt.