DE1618160C3 - 1- (2-Ethynylphenoxy) -2-hydroxy-3alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their preparation, and pharmaceuticals containing these compounds - Google Patents

Description

2. 1 - (2-Ethynylphenoxy) - 2 - hydroxy - 3 - tert-butylaminopropane as well as its physiologically compatible acid addition salts.

3. Process for the preparation of l- (2-ethynylphenoxy) - 2 - hydroxy - 3 - alkylaminopropanes general formula

OCH ₇ -CHOH-CH ₇ -NH-R

(I)

in which R denotes an alkyl radical having 1 to 4 carbon atoms, characterized in that one in an known way

a) a compound of the general formula
C = CH

C ^ ocH, -;

in the Z the group

-CHOH-CH ₂ HaI

35

40

(Hal = halogen atom) means with an amine of the general formula

45

H ₉ NO

(III)

in which R has the meaning given above, or that one

b) 1 - (2-Ethynylphenoxy) -2-hydroxy-3-aminopropane of the formula

R ₁ denotes a protective group which can be easily split off hydrogenolytically or hydrolytically, the group R _{1 is} replaced by hydrogen, or that one

d) an oxazolidinone of the general formula
C = CH

<ζ \ - OCH ₂ - CH

CH ₂ (VI)
Ν — R

in which R has the meaning given above, hydrolyzed, or that one

e) a urea derivative of the general formula C = CH

OCH ₂ - CHOH - CH ₂ -NC-NR ₂ R ₃

R O

(VII)

in which R has the meaning given above and R ₂ and R ₃ , which can be the same or different, denote hydrogen, alkyl radicals, aralkyl radicals or aryl radicals, preferably phenyl radicals, hydrolyzed by means of strong bases or acids and the compounds obtained in this way, if desired, in the customary manner converted into their physiologically compatible acid addition salts.

4. Medicinal products containing compounds of the general formula as active ingredients

C = CH

OCH ₇ -CHOH-CH, -NH-R

in which R denotes an alkyl radical with 1 to 4 carbon atoms, or their physiologically acceptable ones Acid addition salts in combination with customary auxiliaries and / or carriers.

OCH ₂ - CHOH-CH ₂ -NH ₂ (IV)

with a customary alkylating agent having 1 to 4 carbon atoms, or that one

c) a compound of the general formula C = CH

ζ \ - OCH ₂ -CH-CH ₂ -NH-R (V)

The invention relates to 1- (2-ethynylphenoxy) -2-hydroxy-3-alkylaminopropanes and their salts with interesting pharmacological properties in warm-blooded animals, Process for their preparation and medicaments containing these compounds. The new Compounds correspond to the general formula

60

C = CH

OCH ₇ -CHOH-CH ₇ -NH-R

OR ₁

in which R has the meaning given above and In this formula, R denotes an alkyl radical with up to 4 carbon atoms.

The new connections can be made in the following ways:

a) Implementation of a compound of the general e) Hydrolysis of a urea derivative of the general

Formal formula

(H)

in the Z the group

-CH

CH,

or

-CHOH-CH ₂ HaI

(Hal = halogen atom) means with an amine of the general formula

H ₇ NO

(III)

in which R has the meaning given above, in a manner customary for such reactions.

b) Introduction of the radical R into the primary amine of the formula

C = CH

-CHOH-CH ₂ -NH ₂

(IV)

for example by means of alkyl halides having 1 to 4 carbon atoms, which is more common for such reactions Wise.

c) Cleavage of an easily removable protective group from compounds of the general formula

C = CH

OCH ₂ -CH-CH ₂ -NH-R (V)
OR ₁

in which R has the meaning given above and R _{1 is} a protective group which can be easily split off hydrogenolytically or hydrolytically (for example an acyl or acetyl group), in a manner customary for such reactions.

d) hydrolysis of an oxazolidinone of the general formula

C = CH

OCH ₂ -CHOH-Ch ₂ -NC-NR ₂ R ₃

R O

(VII)

in which R has the meaning given above and R ₂ and R ₃ , which can be identical or different, denote hydrogen, alkyl radicals, aralkyl radicals or aryl radicals, preferably phenyl radicals, e.g. B. by means of strong bases or acids such as NaOH or HCl.

Some of the starting compounds for processes a) to e) are already known, and some can can be obtained by known processes, in which case compounds of the formula II or of the compounds of the formula

C = CH

OKt

(VIII)

in which Kt is hydrogen or a cation (for example an alkali metal ion), goes out. the Epoxides of the formula II can be prepared from compounds of the formula VIII by reaction with epichlorohydrin produce. The compounds of the formula VIII are, for example, according to the in Bull. Former Soc (Japan) 29, (1956), p. 471 (cited in CA. 51 (1957), col. 8705 b, described method can be produced.

With regard to the preparation of the starting compounds of processes a) to e), the following is additionally made References referenced:

in which R has the meaning given above, in the usual way, e.g. B. with KOH.

Journal of Pharm. Med. Chem. Vol. 5,

Pp. 69 to 76 (1952),
Journal Pharm. Pharmacol. Vol. 5,

Pp. 359 to 369 (1953),
Journal Pharm. Pharmacol. Vol. 9,

Pp. 10 to 19 (1957),
British Patent 984 189,
Belgian patent 641 133,
Chemical Abstracts Vol. 58, Sp. 3337e (1962)

such as
Houben-Weyl, Methods of the Organic

Chemistry, 1st and 2nd edition.

The compounds of the general formula I have an asymmetric group on the —CHOH group C atom and therefore occur in the form of racemates as well as optically active antipodes.

The optically active compounds can be obtained by either of the optically active ones Starting compounds or the racemates obtained in a conventional manner, for example by means of Dibenzoyltartaric acid or bromocamphorsulfonic acid, splits into their optical antipodes.

The compounds of the general formula obtained by processes a) to e) can, if desired be converted in the usual way into their physiologically acceptable acid addition salts.

Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, Methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorotheophylline.

The compounds of general formula I or their physiologically acceptable acid addition salts have valuable therapeutic, especially /? - adrenolytic Properties and can therefore be used, for example, for the treatment or prophylaxis of diseases coronary arteries and for the treatment of cardiac arrhythmias, especially tachycardias, used on people. The antihypertensive properties of the compounds are also therapeutic Interesting. Compounds of the general formula in particular have proven to be of value here I highlighted, in which R is the isopropyl or t-butyl radical, i.e. the compounds l- (2-ethynylphenoxy) - 2 - hydroxy - 3 - isopropylaminopropane and 1 - (2 rethynylphenoxy) - 2 - hydroxy - 3 - tert-butylaminopropane.

The single dose of the compounds according to the invention or their acid addition salts is 1 to 300 mg, (0.016 to 5 mg / kg) preferably at 15 to 100 mg (0.25 to 1.66 mg / kg) for oral use or at 0.1 to 25 mg (0.002 to 0.40 mg / kg) for parenteral use in humans.

The pharmaceutical processing of the compounds of general formula I into the customary application forms such as solutions, emulsions, tablets, coated tablets or depot forms can be used in a known manner using the usual galenic Auxiliary materials take place. The compounds according to the invention can also be used in combination with other active pharmaceutical ingredients, for example cardiac or circulatory sympathicomimetics or coronary dilators.

The following examples illustrate the invention:

A. Process examples

example 1

1- (2-Ethynylphenoxy) -2-hydroxy-3-isopropylaminopropane · HCl

12.8 g of 1- (2-ethynylphenoxy) -2,3-epoxypropane, by reacting 8.9 g (0.075 mol) of 2-ethynylphenol with 7.65 g (0.08 mol) of epichlorohydrin obtained in dilute NaOH are dissolved in 120 ml of methanol and 17.7 g (0.3 mol) of isopropylamine were added. After standing for several hours at room temperature, 2.5 hours heated to 60 to 70 ° C, then the volatile components are distilled off under reduced pressure. The remaining residue is recrystallized from ethyl acetate with the addition of petroleum ether. The base is dissolved in dilute HCl, filtered through charcoal and after addition of NaOH the precipitated solid Base sucked off. It is recrystallized again from ethyl acetate / petroleum ether. Yield 9.6 g, m.p .: 93 up to 95 ° C.

The crystalline hydrochloride is obtained by dissolving the base in acetonitrile and adding ethereal HCl obtained, the melting point of which is 143 to 145 ° C.

Example 2

1- (2-Ethynylphenoxy) -2-hydroxy-3-tert-butylaminopropane · HCl

12 g (0.07 mol) 1- (2-ethynylphenoxy) -2-hydroxy-3-tert-butylaminopropane are dissolved in 100 ml methanol and 18 g (0.025 mol) tert-butylamine are added, the mixture is left to stand overnight at room temperature, then Heated to about 60 ° C for 2 hours. After the solvent has been distilled off under reduced pressure, the residue that remains is dissolved in dilute HCl and filtered through activated charcoal. The clear aqueous solution is then made alkyl with NaOH. The precipitating basic components are taken up in ether, the ethereal phase is _{dried over MgSO 4} and the ether is distilled off. The remaining oily residue is dissolved in ethanol and the hydrochloride is precipitated by adding ethereal HCl. After the crystals have been isolated, the mixture is recrystallized twice more from ethanol with the addition of ether, melting point: 172 to 174 ° C.

Example 3

1- (2-Ethynylphenoxy) -2-hydroxy-3-sec-butylaminopropane · HCl

The crude l- (2-ethynylphenoxy) -2,3-epoxypropane (13.8 g) obtained from 10.4 g (0.088 mol) of 2-ethynylphenol and 8.8 g (0.095 mol) of epichlorohydrin is dissolved in 120 ml of ethanol with 22 g (0.3 mol) of sec-butylamine reacted by heating for two hours. After the solvents have been distilled off in vacuo, the residue is stirred with dilute HCl, extracted with ether and the aqueous phase is made alkaline with NaOH. The precipitated oily base is taken up in ether, _{washed with H 2} O, _{dried over MgSO 4} and the ether is distilled off. The solid residue is recrystallized from ethyl acetate and petroleum ether. The base is then dissolved in ethanol, acidified with ethereal HCl and the precipitating hydrochloride is isolated. Yield 7.4 g, m.p .: 149 to 15 ° C.

B. Formulation Examples

1. Depot dragees
core

l- (2-ethynylphenoxy) -2-hydroxy-

3-isopropylaminopropane · HCl .. 40.0 g

Carboxymethyl cellulose (CMC) ... 300.0 g

Stearic acid 20.0 g

Cellulose acetate phthalate (CAP) 40.0 g

400.0 g

Production of the coated tablets

The active ingredient, the CMC and the stearic acid are mixed intensively and the mixture in the usual way Granulated way, a solution of the CAP in 200 ml of a mixture of ethanol / ethyl acetate used. The granules are then compressed into 380 mg cores, which are then mixed with a sugary one in the usual way 5% solution of polyvinylpyrrolidone in water. Each coated tablet contains 25 mg of active ingredient.

2. Solution for injection

The solution is made from the following components:

l- (2-ethynylphenoxy) -2-hydroxy-

3-tert-butylaminopropane

HCl 2.5 parts

EDTA sodium salt

(Ethylenediamine tetra-

acetic acid). _; ,. 0.2 parts

Distilled water 100.0 parts

Manufacturing

The active ingredient and the EDTA salt are dissolved in enough water and mixed with water to the desired level Volume filled up. The solution is filtered free of suspended particles and placed in 1 cc ampoules filled under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 25 mg of active ingredient.

Comparative experiment

The valuable properties of the substances according to the invention were determined by measuring the heart rate determined on live guinea pigs under urethane anesthesia. The dose tested in each case was injected intravenously. Then 1 y / kgdes became tachycardia causative sympathicomimetic isoproterenol injected and the maximum change in Heart rates observed. (Determination of the so-called isoproterenol-antagonistic effect). The substance according to the invention was tested, starting at 0.1 g / kg, in 5 increasing steps one after the other Cans on the same animal. Each substance was tested in this way on four different animals. When The standard substance was the well-known /> '- Adrenolyticum 3,4-dichloroisoproterenol (DCI), the effect of which was set equal to 1.

substance Isoproterenol ¹⁰ (as HCl salt) antagonistic
effect A. State of the art 1 - (1-naphthoxy) -2-hydroxy- 15 3-isopropylaminopropane 15-DCI B. Invention l- (2-ethynylphenoxy) -2-hydroxy- 3-isopropylaminopropane 39 · DCI 20 1 - (2-ethynylphenoxy) -2-hydroxy- 3-tert-butylaminopropane 89 · DCI

409 617/254

Claims (1)

Patent claims: 1. 1 - (2-Ethynylphenoxy) -2-hydroxy-3-alkylaminopropanes of the general formula (I) / "^ OCH ₂ -CHOH-Ch ₂ -NH-R in which R denotes an alkyl radical with 1 to 4 carbon atoms, as well as their physiologically tolerable ones Acid addition salts.