NO136094B - - Google Patents

Description

US patent 3,536,712 describes, among other things, the racemic mixtures of the compounds with the general formula I,

and their physiologically compatible salts with inorganic or organic acids, which possess valuable pharmacological properties, in particular a broncholytic action.

In the above general formula I means

Hal a chlorine or bromine atom,

R^ a hydrogen, chlorine or bromine atom and

R is a linear or branched alkyl radical of 2 to 5 carbon atoms or a cycloalkyl radical of 3 to 6 carbon atoms.

It has surprisingly been found that an optically active antipode of the compounds of the above general formula has a selective effect on the adrenergic -3-receptors, the d (+)-compounds of the general formula I having a selective effect on (3^- the receptors.

The new optically active antipodes are produced by the following procedure

Separation of a racemic mixture of the compounds of the general formula I, wherein R, R, and Hal are as indicated above, in the optically active antipodes, to recover the d-compound.

The racemate resolution of the d,l form of a compound of the above general formula I is carried out by fractional crystallization of a mixture of its diastereomeric salts with an optically active acid, e.g. d-tartaric acid, 1-tartaric acid, d-dibenzoyl-tartaric acid, 1-dibenzoyltartaric acid, d-camphorsulfonic acid, 1-malic acid, 1-mandelic acid, d-a-bromocamphor-ir-sulfonic acid or l-quinic acid.

The new, optically active compounds with the general formula

I can be transferred to its physiologically compatible salts with inorganic or organic acids. As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid and maleic acid are used.

As mentioned at the outset, they exhibit new d-connections

with the general formula I a selective blocking effect on the 3-^-receptors.

For example, the connections were

A = d-1-(4-amino-3,5-dichlorophenyl)-2-cyclopropylaminoethanol hydrochloride, and

B = d-1-(4-amino-3,5-dichloro-phenyl)-2-tert-butylamino-ethanol hydrochloride

examined with regard to effects on the 3-receptors:

The γ-blocking effect was examined as antagonism to tachycardia induced by a standard dose of 1.0 µg/kg i.v. N-isopropyl norepinephrine sulfate in anesthetized cats. On the basis of the percentage mean reduction of the increase in heart rate produced by the N-isopropyl norepinephrine sulfate obtained with the different doses, an ED^^ was determined by graphical extrapolation (see Tables I and II).

The floristic effect was investigated as antagonism to the bronchospasm which was triggered by the intravenous administration of 20 Y/kg acetylcholine, on anesthetized guinea pigs in the experimental device according to Konzett-Rossler after i.v. administration. On the basis of the percentage reduction of bronchospasm obtained with the various doses, an ED^Q was determined by graphical extrapolation (see Table I).

The 3^-blocking effect was investigated as antagonism to the broncholytic effect, which was observed with .5 Y/kg i.v. N-isopropyl norepinephrine sulfate in the experimental device according to Konzett-Rossler on anesthetized guinea pigs, when the bronchospasm is triggered with a standard amount of 20 U/kg i.v. acetylcholine (see Table II).

The acute toxicity of the compounds was determined on groups of 10 mice each. LD^Q was determined as the dose which caused 50% of the animals to die within 7 days of intravenous administration, by the method according to Litchfield and Wilcoxon.

The following tables contain the values found:

Known 3-blocking agents do not distinguish between the different types of 3-receptors, but lead to a general blocking of the Ø-receptors. The known 3-blocking agents can therefore, due to their non-selective effect on the 3^-receptors, induce, not only in asthmatics (Mc Neill in Lancet II, 1101

(1964), Zaid A. Beall in New England J. Med. 275, 580 (1966) and Meier et al. in Dtsch. With. Wschr. 91, 145 (1966)), but also in lung-healthy subjects (Mc Neill a. Ingram in Am. J. Cardiol. 18, 473 (1966)) an increase in respiratory distress due to blocking of the 32 receptors. Their therapeutic applicability is therefore significantly limited.

The new d-(+)-compounds with the general formula I thus differ from the known 3-blocking agents mainly by a selective blocking effect on 3-j. - the receptors. In that the risk of triggering an asthma attack as a side effect disappears, they thus exhibit significant advantages in relation to the known 3-blocking agents with regard to therapeutic use.

The new compounds with the general formula I can optionally be used in combination with other active substances in usual pharmaceutical preparation forms. The single dose amounts to 10-100y, preferably 20-50y.

The following examples shall serve to further illustrate the invention.

Example 1

d- 1-( 4- amino- 3, 5- dichloro- phenyl)- 2- cyclopropylamino- ethanol- hydrochloride

177 g (0.678 mol) of d,1-1-(4-amino-3,5-dichlorophenyl)-2-cyclopropylamino-ethanol and 122 g (0.340 mol) of d-dibenzoyl-tartaric acid are dissolved in 2 1 of hot, absolute ethanol, filtered and allowed to stand for 1 day at room temperature for crystallization. The product obtained is recrystallized 6 times from methanol-ether, whereby the pure d-[1-(4-amino-3,5-dichloro-phenyl)-2-cyclopropylamino-ethanol]-d-dibenzoyl tartrate with melting point 164 .5-167°C (dec.).

[α]^g^ = +211.7° (c = 2.082 in'dimethylformamide.

The salt is dissolved in methanol and concentrated ammonia under heating, and the base is brought to crystallisation by the addition of water. Melting point: 138-.14 2 , 5°C,

ta]364 = +158'6° (c = 2.050 in chloroform).

The base is dissolved in absolute ethanol, neutralized with absolute ethanolic hydrochloric acid and the crystallization of the d-1-(4-amino-3,5-dichlorophenyl)-2-cyclopropylaminoethanol hydrochloride is completed by adding ether. Melting point: 180.5-181.5°C (dec.),

[a]^° = +103.2° (c = 2.016 in water). Yield 1.6% of the theoretical.

Oak sample 2

d- 1-( 4- amino- 3, 5- dichloro- phenyl)- 2- isopropylamino- ethanol Melting point for the hydrochloride: 176-179°C (dec.);

[a]^g4 = +134.3° (c = 2.018 in water).

Prepared from d,1-1-(4-amino-3,5-dichloro-phenyl)-2-isopropylamino-ethanol by fractional crystallization of the d-dibenzoyl tartrate analogously to example 1. Yield 7.2%.

Example 3 d-1-(4-amino-3,5-dibromo-phenyl)-2-tert.-butylamino-ethanol Melting point for the hydrochloride: 182-185°C (dec.);

[a]364 = +106'2° <c = 2.004 in water).

Prepared from d,1-1-(4-amino-3,5-dibromo-phenyl)-2-tert-butyl-amino-ethanol by fractional crystallization of the 1-dibenzoyl tartrate analogously to example 1. Yield,4, 3%.

Example 4 d-1-(4-amino-3,5-dibromo-phenyl)-2-tert.-pentylamino-ethanol Melting point for the hydrochloride: 188-189.5°C (dec.);

[a]^g4 = +103.4° (c = 2.030 in water).

Prepared from d,1-1-(4-amino-3,5-dibromo-phenyl)-2-tert.-pentylamino-ethanol by fractional crystallization of the 1-dibenzoyl tartrate analogously to example 1. Yield 6.4%.

Example 5

d- 2- ethylamino- 1-(4- amino- 3, 5- dichloro- phenyl)- ethanol Melting point for the hydrochloride: 175-177°C (dec.);

[a]364 = +139'2° <c = 2.018 in water).

Prepared from d,1-2-ethylamino-1-(4-amino-3,5-dichloro-phenyl)-ethanol by fractional crystallization of the d-dibenzoyl tartrate analogously to example 1. Yield 12.5%.

Example 6

d- 1-(4-amino-3,5-dichloro-phenyl)-2-butylamino- ethanol Melting point for the hydrochloride: 174-176°C;

[a]2-0,. = +105.7° (c = 2.008 in water).

364

Prepared from d,1-1-(4-amino-3,5-dichloro-phenyl)-2-butylamino-ethanol by fractional crystallization of the d-dibenzoyl tartrate analogously to example 1. Yield 9.9%.

Example 7 d-1-(4-amino-3-bromo-5-chloro-phenyl)-2-isopropylamino-ethanol Melting point: 126-128°C;

[ct]436 = +35'2° (c = 2'° 1 methanol).

Prepared from d,l-l-(4-amino-3-bromo-5-chloro-phenyl)-2-isopropylamino-ethanol by fractional crystallization of the d-dibenzoyl tartrate analogously to example 1. Yield 8.0%.

Example 8

d- 1-(4- amino- 3- bromo-phenyl)- 2- tert.-butylamino- ethanol Melting point: 150°C;

[a]^gg = +15.1° (c = 2.0 in methanol).

Prepared from d,1-1-(4-amino-3-bromo-phenyl)-2-tert-butylamino-ethanol by fractional crystallization of the 1-dibenzoyl tartrate analogous to example 1. Yield 4.5%.

Example 9 t d-1-(4-amino-3,5-dichloro-phenyl)-2-cyclopentylamino-ethanol Melting point for the hydrochloride: 131.5-133°C;

ta]364 = +115'2° <c = 1/996 in water).

Prepared from d,1-1-(4-amino-3,5-dichloro-phenyl)-2-cyclo-pentyl-amino-ethanol by fractional crystallization of the 1-dibenzoyl tartrate analogous to example 1. Yield 3.0% .

Example 10 d-1-(4-amine o-3,5-dichloro-phenyl)-2-cyclobutylamino-ethanol Melting point for the hydrochloride: 183-183.5°C (dec.);

lal364 = +108'4° <c = 2.118 in water).

Prepared from cL, 1-1-(4-amino-3, 5-dichloro-phenyl)-2-cyclo-butyl-amino-ethanol by fractional crystallization of the d-dibenzoyl tartrate analogously to example 1. Yield 7.3 %.

Example II

d- 1-(4- amino- 3, 5- dichloro- phenyl)- 2- tert.- butylamlno- ethanol- hydrochloride

128.5 g (0.464 mol) d,1-1-(4-amino-3,5-dichloro-phenyl)-2-tert-butylamino-ethanol and 88 g (0.234 mol) 1-dibenzoyl-tartaric acid hydrate heated to boiling in 2 1 ethanol. After a short dissolution, a precipitate begins to separate, and after a delay of several hours it is suctioned off. The compound is recrystallized twice from methanol, whereby the pure d-[1-(4-amino-3,5-dichloro-phenyl)-2-tert.-butylamino-ethanol)]-1-dibenzoyl tartrate with melting point 201 .5-202°C (dec.).

[a]^g4 = -192° (c = 2.42 in dimethylformamide).

The salt is dissolved in dimethylformamide, the solution is made alkaline with 2N ammonia, and d-1-(4-amino-3,5-dichloro-phenyl)-2-tert-butylamino-ethanol is brought to crystallization by adding water. Melting point: 127-128.5°C;

[a]^. = +244° (c = 2.28 in chloroform).

The base is dissolved in a little absolute ethanol and some ether, neutralized with absolute, ethanolic hydrochloric acid and d-1-(4-amino-3,5-dichloro-phenyl)-2-tert-butylamino-ethanol hydrochloride is brought to crystallization by further addition of ether. Melting point: 197.5-198°C (dec.). Dividend 13.3%.

[a]= +126° 2.15 in

Claims (1)

Analogy method for the preparation of therapeutic active d compounds of the general formula I, where Hal is a chlorine or bromine atom, R^ is a hydrogen, chlorine or bromine atom, and R is a linear or branched alkyl residue with 2 to 5 carbon atoms or a cycloalkyl residue with 3-6 carbon atoms, and physiologically compatible salts thereof with inorganic or organic acids, characterized in that a racemic mixture of a compound of the general formula I is split into its optical active antipodes, by fractional crystallization of a diastereomeric salt of this compound with an optically active acid, to recover the d-compound, and optionally the obtained d-compound is transferred to its physiologically compatible salts with inorganic or organic acids.