DE1643266C3 - 1 phenoxy 2 hydroxy 3 sec alkylamino propane, a process for their production and preparations containing them - Google Patents

Description

CN

in which R ₁ denotes an alkyl radical with 1 to 5 carbon atoms and R ₂ denotes an alkyl radical with 2 to 6 carbon _{atoms and 5} material atoms, and also their acid addition salts.

2. A method for the preparation of compounds according to claim 1, characterized in that a compound of the general formula is used in a manner known per se

OCH, - Z

(H)

or the group - CH (OH) - CH ₂ - Hai and Hai denotes a halogen atom, with an alkylamine of the formula

H, N -CH

(IH)

40

in which R ₁ and R _{2 have} the abovementioned meaning, and, if desired, the compound obtained is converted into an acid addition salt. 3. Pharmaceutical preparations containing a compound according to claim 1 as active ingredient.

The invention relates to 1-phenoxy-2-hydroxy-3-sec-alkylamino-propane the general formula

OCH ₂ -CHOh-CH ₂ -NH-CH

55

60

CN

and their acid addition salts, processes for their preparation and medicaments containing them.

In this formula, R ₁ denotes an alkyl group with up to 5 carbon atoms, R ₂ denotes an alkyl group with 2 to 6 carbon atoms.

OCH ₂ - Z

(H)

CN

in the Z the group

- CH CH,

or - CH (OH) - CH ₂ - Hai and Hai mean a halogen atom with an alkylamine of the general formula

NH, -CH

(ΙΠ)

R,

in which R ₁ and R _{2 have} the abovementioned meaning. ..

That is necessary to carry out the procedure The starting material is already known. Thus, the epoxides of the formula II can easily be converted of epichlorohydrin with a phenol or phenolate of the general formula

OKt

(IV)

CN

in which Kt is hydrogen or a cation (e.g. an alkali metal ion). The epoxies can in turn be used to produce other starting materials. For example let the halohydrins of the formula II by reacting the epoxides with the corresponding hydrohalic acid represent.

The compounds according to the invention have an asymmetric carbon atom and therefore come as Racemate as well as in the form of the optical antipodes. The latter can except by resolution with the help of customary auxiliary acids such as dibenzoyl-D-tartaric acid or D-S-bromocarapher-S-sulfonic acid too can be obtained by employing optically active starting material. The 1-phenoxy-3-aminopropanols according to the invention of the general formula I can be physiologically tolerated in the customary manner Acid addition salts are converted. Suitable acids 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 compound of the general formula I or its physiologically acceptable acid addition salts have valuable therapeutic, especially / J-adrenolytic properties in animal experiments on guinea pigs shown and can therefore, for example, for the treatment or prophylaxis of diseases of the Coronary arteries and for the treatment of cardiac arrhythmias, in particular tachycardias, in the Can be used in human medicine. Also the antihypertensive properties of the compounds are therapeutically interesting.

Comparative experiments

Testing for isoproterenol-antagonistic effect took place on live guinea pigs. 3,4-dichloroisoproterenol was used as the standard substance (DCI), the effect of which was set equal to 1.

Compound (as HCl salt)

A. State of the art (Belgian
Patents 641,133 and
652 336)

1 -m-Tolyloxy ^ -hydroxy ^ -isopropylaminopropane (Active ingredient of Doberol «)

B. Invention

1- (2-Cyanophenoxy) -2-hydroxy-3- (1-methylpropyl) aminopropane

1- {2-cyanophenoxy) -2-hydroxy-3- ( 1-methylbutyl) aminopropane

1- (2-Cyanophenoxy) -2-hydroxy 3- (1-ethylpropyl) aminopropane

soproterenol-antagon. effect

5 χ DCI

29 DCI 37.5 DCI 14.8 DCI Yield: 7.6 g, m.p. 124 to 126 ° C.

Calculated ... C 59.04, H 7.43, N 9.84%; found .... C 58.95, H 7.62, N 9.90%.

Example 2

1 - (2-Cyanophenoxy) -2-hydroxy-3- (1,3-dimethylbutylamino) propane - HCl

8.75 g (0.05 mol) of 1- (2-cyanophenoxy) -2,3-epoxypropane are dissolved in 100 ml of ethanol and, after the addition of 7.5 g (0.075 mol) of 1,3-dimethylbutylamine, refluxed for 2 hours. After the solvent has been distilled off, the residue is digested with dilute HCl and freed from insoluble constituents by filtration. The acidic solution is extracted with ether and, after the organic phase has been separated off, made alkaline with NaOH. The precipitated base is taken up in ether, washed with water, _{dried over MgSO 4} and evaporated to dryness. The remaining base is dissolved in a little ethanol, acidified with ethereal HCl and the precipitated hydrochloride is filtered off with suction. It is recrystallized from alkynol with the addition of ether.

The single dose of the substances according to the invention is 1 to 300 mg; preferably ^: ε 5 to 100 mg (oral) or 1 to 20 mg (parenteral).

The pharmaceutical processing of the compounds according to the invention in the usual application forms, such as solutions, emulsions, tablets, coated tablets or depot forms, can be carried out in a known manner using the pharmaceutical auxiliary disintegrants, binders, coatings or lubricants, flavorings, Sweeteners, means to achieve a depot effect or solubilizers happen. The compounds according to the invention are also suitable for combination with other pharmacodynamically active substances, such as coronary dilators or sympathomimetics.

The following examples illustrate the invention.

A. Preparation Examples Example 1

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

8.75 g (0.05 mol) of 1- (2-cyanophenoxy) -2,3-epoxypropane are dissolved in 100 ml of ethanol, 14.6 g (0.2 mol) of sec-butylamine are added and after standing for 12 hours they are added 2O ⁰ C heated to boiling under reflux for 1.5 hours. After concentration in vacuo, the residue is dissolved in dilute hydrochloric acid, extracted with ether and, after the aqueous phase has been separated off, NaOH is added to it. The base which precipitates is taken up in ether, the organic phase is separated off, _{dried over MgSO 4} and concentrated in vacuo. The residue is dissolved in a little ethanol and acidified with ethereal HCl. The precipitated hydrochloride is filtered off and recrystallized from ethanol / ether.

Yield: 3.9 g, melting point 140 to 142 ° C.

Calculated
found .

C 61.43, H 8.06, N 8.95%; C 61.20, H 7.99, N 8.92%.

Example 3

1- (2-Cyanophenoxy) -2-hydroxy-3-sec-pentylaminopropane -.HCl

8.75 g (0.05 mol) of 1- (2-cyanopbenoxy) -2,3-epoxypropane are refluxed for 3 hours together with 6.5 g (0.075 mol) of sec-phenylamine. The residue remaining after the ethanol has been distilled off is digested with dilute HCl, the insolubles are filtered off and the aqueous phase is extracted with ether. After the aqueous solution has been rendered alkaline, the precipitated base is taken up in ether, _{washed with H 2} O and dried _{over MgSO 4.} The ether is distilled off, the basic residue is dissolved in ethanol and acidified with ethereal HCl. The precipitating crystals are recrystallized from ethanol with the addition of ether.

Yield: 5.8 g, m.p. 109-112 ° C.

Calculated ... C 60.29, H 7.76, N 9.38%; found .... C 60.80, H 7.68, N 9.15%.

Example 4

l- (2-cyanophenoxy) -2-hydroxy-3- (l-ethylpropylamino) propane ■ HCl

8.75 g (0.05 mol) of 1- (2-cyanophenoxy) -2,3-epoxypropane are reacted in 100 ml of ethanol with 6.5 g (0.075 mol) of 1-ethylpropylamine by refluxing for 2 hours. After the ethanol has been distilled off, the residue is digested with dilute HCl and insoluble components are filtered off. NaOH is added to the aqueous solution and the precipitating base is taken up in ether. After washing with H ₂ O, the organic

see phase _{dried with MgSO 4} , the ether is distilled off. The residue is recrystallized from ethanol with the addition of ether.

Yield: 5.8 g mp 137-138 ° C.

Calculated ... C 60.29, H 7.76, N 9.38%;
found .... C 60.30, H 7.98, N 9.52%.

Example 5

1- (2-Cyanophenoxy) -2-hydroxy-3- (3,3-dimethyl-butyl- (2) -amino) -propane · HCl

12.35 grams (0.07 moles) of 1- (2-cyanophenoxy) -2,3-epoxypropane and 6.5 grams (0.06 moles) of 2-amino-3,3-dimethylbutane are dissolved in 50 ml of methanol and heated to boiling for 5 hours. After distilling off the solvent dilute hydrochloric acid is added and extracted twice with ether. The aqueous phase is then made alkaline with sodium hydroxide solution and the base which separates out is taken up in ether. When ethereal hydrochloric acid is added, 1- (2-cyanophenoxy) - 2 - hydroxy - 3 - (3,3 - dimethylbutyl - (2) amino) propane is precipitated · HCl as a white crystalline powder. It is recrystallized three times from isopropanol and then melts at 172 ° C.

The yield is 3.6 g, which is 19% of theory.

Calculated ... C 61.37, H 8.06, N 8.96%;
found .... C 61.81, H 7.58, N 8.88%.

Example 6

1- (2-Cyanophenoxy) -2-hydroxy-3- (octyl- (2) -amino) propane · HCl

12 g (0.068 mol) 1- (2-cyanophenoxy) -2,3-epoxypropane and 9 g (0.07 mol) 2-octylamine are in 50 ml Dissolved methanol and heated to boiling for 5 hours. After the solvent has been distilled off, it is diluted Hydrochloric acid was added and extracted twice with ether. The aqueous phase then becomes alkaline soda placed and the base which separated out was taken up in ether. When adding more essential Hydrochloric acid crystallizes 1- (2-cyanophenoxy) -2-hydroxy-3- (octyl- (2) -amino) -propane · HCl from. It is recrystallized twice from isopropanol and then melts at 120 ° C.

The yield is 2 g, that is 8.6% of theory.

Calculated ... C 63.42, H 8.58, N 8.22%;
found .... C 65.30, H 8.66, N 8.23%.

Example 7

1- (2-Cyanophenoxy) -2-hydroxy-3- (heptyl- (3) -amino) -propane · HCl

The representation is analogous to the above example from 1- <2-cyanophenoxy) -2,3-epoxypropane and 3-heptylamine in methanol.

Mp. 97 ° C., yield 16.3% of theory.

, o Calculated ... C 62.46, H 8.32, N 8.57%; found .... C 61.81, H 8.26, N 8 _: 58%.

Example 8

1 - (2-Cyanophenoxy) -2-hydroxy-3- (1,3,3-trimethyl-1-butylamino) propane · HCl

From 1 - (2 - cyanophenoxy) - 2,3 - epoxypropane and 1,3,3-trimethylbutylamine an analogue was made in ethanol Example 2 the title substance d?

Mp 125-127 ° C (Hydrochlo: id).

Calculated ... C 62.47, H 8.33, N 8.57%; found C 63.63, H 8.36, N 8.6O%.

B. Formulation Examples

1. Tablets

1 - {2-cyanophenoxy) -2-hydroxy-

3-sec-butylaminopropane · HCl 40.0 mg

Corn starch 164.0 mg

sec-calcium phosphate 240.0 mg

Magnesium stearate 1.0 mg

445.0 mg production

The individual components are intensively mixed with one another and the mixture is mixed in the usual way granulated The granules are compressed into tablets weighing 445 mg, each of which is 40 mg (8.9%) Contains active ingredient.

2. Gelatin capsules The contents of the capsules are made up as follows:

1 - {2-cyanophenoxy) -2-hydroxy-

3-sec-butylaminopropane · HCl 25.0 mg corn starch 175.0 mg

200.0 mg production

The components of the capsule contents are mixed intensively, and 200 mg servings of the mixture are made filled in geiptine capsules of suitable size. Each capsule contains 25 mg (12.5%) of the active ingredient.

Claims (1)

Patent claims: 1. 1 -Phenoxy ^ -hydroxy-S-sec-alkylaminopropanes of the general formula The new compounds can be prepared by reacting a compound of the general formula ^ X-OCH ₂ -CHOH-CH ₂ -Nh-CH (I)