DE1948144C3 - 1 - (I -Keto-tetrahydronaphthyl-5-oxy) ^ -hydroxy-S-alkylaminopropanes, process for their preparation and pharmaceutical composition based on them - Google Patents

Description

in which R denotes an alkyl radical with up to 6 carbon atoms, as well as their pharmaceutically acceptable ones Acid addition salts.

2. 5- [3- (tert-Butylamino) -2-hydroxypropyloxy] -tetralone.

3. 5- [3- (Isopropylamino-2-hydroxy) propyloxy] tetralone.

4. The method for Hersieiiung the compounds according to claim 1, characterized in that one in a manner known per se, the tetralonol of the formula

(H)

with a compound of the general formula

25th

JO

X-CH ₂ -CHOH-CH ₂ X (III)

X-CH ₂ -CH - CH ₂ (IV)

40

in which X is a halogen atom, to compounds of the general formula V

or VI

OCH ₂ -CH - CH ₂ (VI) \ /

55

reacts and then the reaction products obtained with an amine of the general formula

R-NH ₂ ,

in which R has the meaning given above sits, implements.

5. Phi.rma / .eutic composition containing one or more compounds according to claim I in addition to customary carriers and auxiliaries.

The invention is based on the subject matter defined in the claims.

The compounds of the invention have a j3 adrenergic blocking effect and are therefore valuable in cases of angina pectoris, cardiac arrhythmias and related cardiovascular diseases.

It has been found that the compounds of the invention are effective in mammals, e.g. B. dogs, cats or Monkeys, both when administered orally and when injected, have a /? - adrenergic blocking effect. Generally, a dose of from about 0.1 to about 1 mg / kg of body weight when administered by the oral route will be or prescribed by injection. The /? - adrenergic The blocking action of the compounds of the present invention is achieved by administration of various Doses of isoproterenol after treatment of the test animal with the compounds according to the invention certainly. It was found that the responsiveness the Kerzkoritraktiönskrafl and the Heart rate compared to isoproterenol by the compounds according to the invention in various ways Extent, depending on the dose administered. As an example of the 0-blocking effect of the compounds according to the invention was the 5- [3- (tert-butylamino) -2-hydroxypropoxy] -tetraIon-hydro- chbrid administered intravenously to anesthetized dogs at a dose of 6.7 μg / kg. Then the dogs 03 μg / kg isoproterenol given. The connection was able to suppress 50% of the effects of isoproterenol on the dog's heart rate.

The dosage can vary according to age, gender. Body weight and species of the mammal to be treated can be varied.

The pharmaceutically acceptable acid addition salts also belong within the scope of the present invention of the compounds according to the invention, for example the hydrochlorides, hydrobromides, phosphates, Sulphates or the salts derived from organic acids, such as. B. the lactaie or salicylates.

The present invention also encompasses the d- or 1-enantiomers or the racemic mixture as well their salts described above.

Comparative data showing the superiority of the compounds according to the invention are given in ]. Med. Chem. 1970, 684 et seq.

The present invention also relates to dosage forms of the compounds according to the invention, which are suitable for oral or parenteral administration. Those for oral administration Suitable pharmaceutical preparations can be in the form of tablets, capsules, aqueous or oily Solutions and suspensions are present which are easily prepared by methods known to the person skilled in the art can. For example, tablets can be made by mixing the active ingredient with known ones Auxiliaries, such as B. calcium phosphate, lactose, mannitol mixed with z. B. Akazin or one Gelatin solution granulated and then compressed into tablets. The compounds can also be formulated that way that they result in a depot effect in the organism. Those suitable for parenteral administration Preparations can be made by putting the active ingredient in a parenterally acceptable Auxiliary material, such as IJ. sterile water, a sterile saline solution or oil. dissolves or suspends.

Another subject of the invention is a

drive to make these connections.

In the compounds of the formulas III and IV, X is, for example, Cl. The starting materials II and III or II and

IV are either refluxed together without solvent or at room temperature in an alcoholic solution containing a slight excess (1.1 mol) of a base, such as. B. Sodium Hydroxide, Potassium hydroxide or sodium methylate, to the corresponding intermediates of the formulas V and VI reacted The intermediates thus obtained

V and Vl are then, for example, by refluxing with the corresponding amine of the all-

10 common formula RNH ₂ treated. Suitable solvents for these reactions include, for example, lower aliphatic alcohols, such as. B. methanol or ethanol. The desired end products are obtained by known methods.

The tetralonol II is obtained by adding the corresponding Ether, which is commercially available, treated with hydrogen bromide in acetic acid.

The following examples are intended to illustrate the invention. Examples 1 and 2 relate to the preparation of Preliminary stages.

OH

Example '
5- (2,3-epoxypropyloxy) -l-tetralone

Q-CH ₂ -CH

-CH,

+ Cl-CHj-CH CH ₂

A solution of 83 g NaOH in 36.5 ml water is diluted with 292 ml of ethanol, and then 28.5 g of 5-hydroxy _": tetralone, and 98 g of epichlorohydrin were added. The mixture is stirred for 16 hours at room temperature and then left to stand for 2 to 3 days. The solution is then evaporated and the residue is partitioned between 180 ml of water and 250 ml of chloroform. The separated aqueous sliding »is with wide-

Ren 100 ml of chloroform extracted. The combined organic phases are washed twice with 100 ml of water, dried unii concentrated and give 41 g of residue. This is dissolved in 280 ml of ether, cooled, and 4.5 g of crystals are filtered off. The filtrate is evaporated to give 34 g of re-JO was standing; this is distilled at 136 to 144 ° C / 0.106 mbar and gives 26.1 g of product.

Example 2

3- (tetralone-5-oxy) -1,2-epoxy-propane
3- (Tetralone-5-oxy) -l-chloro-2-hydroxy-propane

+ CI-CH ₂ -CH CH,

13.8 g of 5-hydroxytetraIon are in 75 ml of epichlorohydrin dissolved, and the solution is refluxed for 44 hours. The excess epichlorohydrin is removed in vacuo by heating on a water bath and the residue in a short path microdistillation apparatus distilled. 5 fractions are obtained, boiling point 160 to 210 ° C./0.3 mbar. All have one strong ketone absorption, and the last two wise

CH

or - / - OCH ₂ CH-CH ₂ Cl I OH

also has a strong hydroxyl absorption. In earlier Experiments have shown that the low hydroxyl

absorption parallel to the low, value of the chlorine analysis and the high hydroxyl absorption parallel to high Chlorine values running; it is deduced from this that a mixture of the epoxy compound and chlorohydrin is obtained has been. These factions will be united

ω and used for reaction with amines.

Example 3

5- [3- (tert-Butylamino) -2-hydroxypropyloxy] -tetralone (or also 5-f. (3-tert-Butylamino) -2-hydroxypropyloxy] -

3,4-dihydro-l (2H) -naphthalenone)

OH

-CH-CH ₂ CI / or - / ¹ O-CH ₂ CH CH ₂ \ + H ₂ NC (CH,).,

O <

O —CH ₂ CH — CH, —NH UCH ₁ ), · HCl OH

6 ml of the mixture of epoxy and chlorohydrin compounds According to Example 2, 24 ml of t-biitylamine are added in 100 ml of 95% alcohol and the Mix on a steam bath under reflux for 2 hours cooked. Then the solvent is stripped off, the residue with a saturated sodium bicarbonate

5 6

sodium solution and ether triturated, and 9.2 g of nitrile are recrystallized; F. 170 to 171 ' ³ C.

Base filtered off. After two recrystallizations from acetonitrile: F. 226

acts, and the precipitated NaCl is filtered off. The up to 228 ° C.

Solution is stripped off and the residue from aceto-

Example 4

5- [2-Hydroxy-3- (isopropylamino) propyoxy] tetralone O

OCH, -CH CHJ or - / - OCH ₁ CH-CH ^ Cl \ + isopropylamine

"T" i _H )

OH

-OCH ₂ CH-CH ₂ NH-CH (CHj): · HCl

7 ml of the mixture of the epoxy and the chlorohydrin compound are dissolved in 10OmI 95% alcohol. 28 ml of isopropylamine are added and the solution Boiled under reflux for 2 hours. The solvent is stripped off and the residue with a saturated Triturated sodium bicarbonate solution, extracted with ether, which was washed with water, and the Solution dried. The calculated amount of alcoholic HCl is added in order to add the hydrochloride form, which is filtered off (4 g). The analytically pure one is obtained after two recrystallizations from alcohol Sample: F. 198.5 to 199.5 "C.

Example 5
5- [2-Hydroxy-3- (iscpropylamino) propyloxy] tetralone

O OH

OCH ₂ -CH

CH ₂ + isopropylamine + HCl

26.1 j (0.12 mol) of epoxide (see. Example 1) and 34.8 g (0.59 mol) of isopropylamine in 121 ml of 95% ethanol are refluxed for 40 minutes. The entire solution is evaporated and gives a residue that consists of 240 m! Cyclohexane is recrystallized with the formation of 29.5 g of product: F. 77 to 80 ⁰ C. This is dissolved in 135 ml of chloroform, ur; the HCl gas is

O =

OCH ₂ CH-CH ₂ NH-CH (Ch ₃ I ₂ ■ HCI

until the solution is acidic. Then 25 ml j ether added and stirred until solids precipitate. Another 240 ml of ether are added.

and stirring is continued for a time, filtered.

washed with ether and dried. 33 g are obtained

Product: m.p. 195 to 197.5 ° C. After recrystallization lier 4i from 320 ml of absolute ethanol: mp 196.5 to 198 ⁰ C.

Example 6
5 - [(3-tert-butylamino) -2-hydroxypropyloxy] tetralone

OCH ₂ -CH CH ₂ + HNC (CH,).,

O + HCI

20.1 g (0.918 mol) of epoxide and 33 g of tert-butylamine in 90 ml of 95% ethanol are refluxed for 40 minutes. The entire solution is evaporated and gives a residue which, from 90 ml of cyclohexane, gives 25.8 g of product: mp 84 to 86 ° C. crystallized. This is dissolved in 115 ml of chloroform and HCI gas is passed in until the solution is acidic, then

OH
O-CH; -CH-CH ₂ NH-C (CH,). · HCI

cooled and diluted with 17 ml of ether. After detaching a further 2.5 ml of ether are added to the crystals and stirring is continued for a while. the Crystals are filtered off. washed with ether and dried. and 28 g of product are obtained: F. 223 bis 225 "C. After recrystallization from absolute ethanol, a product with a melting point of 223.5 to 225.5 ° C. is obtained.

Claims (1)

Patent claims: 1. 1- (1-Keto-tetrahydronaphthyI-5-oxy) -2-hydroxy-3-alkyIamino-propane the general formula 0-CH ₂ -CHOH-CH ₂ -NH-R (I) IO