CS199571B2 - Method of preparing l-1-/4'-hydroxyphenoxy/-2-hydroxy-3-isopropyl aminopropane - Google Patents

Abstract

1470039 Alkanolamines CIBA-GEIGY AG 6 Feb 1975 [8 Feb 1974] 5080/75 Heading C2C (L) - 1 - (4 - Hydroayphenoxy) - 2 - hydroxy- 3-isopropylaminopropane and its salts are prepared by standard methods, e.g. resolution or removal of O and/or N protecting group(s), optionally followed by salt formation. The preparation of 4-(2,3-epoxypropoxy)- phenyl - # - D - glucopyranoside, 1 - [p - (#- D - glucopyranosidyloxy)phenoxy] - 3 - isopropylamino - 2 - propanol, 1,2 - O - isopropylidene- 6 - O - (4 - benzyloxyphenyl) - α - D - glucofuranose, 6 - O - (4 - benzyloxyphenyl) - D - glucose, 1 - (4 - benzyloxyphenoxy) - 2S,3 - dihydroxypropane, 1 - (4 - benzyloxyphenoxy) - 2R - hydroxy - 3 - p - tosyloxypropane and 1 - isopropylamino - 2S - hydroxy - 3 - (4 - benzyloxyphenoxy)- propane and its hydrochloride is described. The above compounds may be used for the treatment of myocardial insufficiency, in the form of pharmaceutical preparations containing them in association with a carrier.

Description

The invention relates to a process for the preparation of the novel L-1- (4 ' -hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of the formula I

HIM

O-CH 2 CH 3 OH-CH 3 NH-CHICH 1

The Fischer projection of the compound of formula is:

μο-с-н

CHjrNH-CHICHPz (L) and corresponds to the S-form in the Cahn-Ingold-Prelog nomenclature:

ν (CH ₃ ) ₃ CH-NH-Cn / _sj ^m

I In MS. No. 131,156 discloses 1- (4-hydroxyphenoxy) -2-hydroxy-3-aminopropanes of the formula I wherein X is hydrogen or benzyl and R is hydrogen, alkyl except isopropyl or arylalkyl. According to the data of column 1 of the above-cited patent, the compounds of the formula I show a blocking effect on adrenenergic receptors.

Dutch Patent Application 6,409,883 discloses 1- (p-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane, which is prepared according to Method A by reaction of p-hydroxyphenoxypropylene oxide with isopropylamine, and is characterized as the hydrochloride, m.p. 166-169 ° C. C. This compound as well as other compounds mentioned therein are prepared in the form of racemates. According to the literature cited, and particularly in the context of the present invention, the interesting 1- (p-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane causes bradycardia and also has an antagonistic effect against N-isopropylnoradrenaline.

It has now been found that the novel compound of the invention has valuable pharmacological properties, in particular an effect on adrenergic γ-receptors, which could not be expected from the prior art. Thus, the L-antipod specifically stimulates cardiac β-receptors. In particular, it acts positively inotropically and chronotropically on the isolated guinea pig chamber at a concentration of 0.005 to 0.5 µg / ml and intravenously in anesthetized cats at a dose of 0.001 to 0.1 mg / kg. As can be seen from experiments on narcotized cats, the novel compound does not act at the indicated doses, which are clearly positively inotropic and chronotropic, at all, or at least only at a decrease in arterial blood pressure, stimulating them specifically cardiac β-receptors compared to β-receptors. and is thus qualitatively distinguished from isoproterenol, which equally strongly stimulates heart and blood vessel receptors. Since pressure drop leads to tachycardia, tachycardia can be expected to be substantially lower than that of isoproterenol when used in humans at doses that are equally potent inotropic.

It is also particularly advantageous that the novel compound is significantly more potent than isoproterenol in narcotized cats and that a clear effect is also obtained after an intraduodenal administration of 0.05 mg / kg.

Thus, the novel compound can be used as a positively inotropic active agent, particularly for treating cardiac muscle disorders either alone or in combination with other preparations such as cardiac glycosides. Administration can be carried out in the form of suitable pharmacological preparations in an oral dose of 1 to 25 mg per dose or intravenously in an amount of 1 to 20 µg / kg per dose or by infusion, in an amount of 0.2 to 2.0 µg. kg / minute.

The present invention provides a process for preparing L-1- (4'-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of formula I

HO Х ~~ 0гО-СН C4 C4 (OH) -Ch NH NH-CH (CH ₃ 4 ~ (L), (Π and its salts with acids, characterized in that the DL-acemic base is converted by reaction with (+) - di-O, O'-p-toluoyl-D-tartaric acid to a mixture of diastereomeric salts, from which the L-salt is separated by fractional crystallization from a suitable solvent and the L-base is liberated therefrom, optionally converted to the salt with acid.

Preferably, a mixture of methanol and water is used as the solvent.

Depending on the reaction conditions and the starting materials, the end product is obtained either in free form or in acid salt form, which are also within the scope of the invention. Thus, for example, basic, neutral or mixed salts as well as their hemi-, mono-, sesqui- or polyhydrates can be obtained. Acid salts The novel compounds can be converted into the free compound in a known manner, for example with basic agents such as alkali or ion exchangers. On the other hand, the free base obtained can form salts with inorganic or organic acids. In particular, those acids which are suitable for the formation of therapeutic salts can be used to prepare acid salts. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic acid, acid succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid or pyruvic acid, benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or emonic acid, methanesulfonic acid, ethanesulfonic acid , hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid or sulfanilic acid.

These and other salts of the novel compound, such as picrate, can also be used to purify the free base by converting the free base into a salt, separating it and liberating the base again from the salt. Due to the close relationship between the new compound in free form and in the form of its salts, in the above and the following description, the free compound is analogously understood to mean corresponding salts, if appropriate.

The starting material can be prepared by known methods.

The inotropic and chronotropic effect and efficacy of the isolated guinea pig heart chamber were determined for the following compounds:

I. L-1- (4-hydroxyphenoxy) -3-isopropylamino-2-propanol hydrochloride (prepared according to the present invention),

II. D-1- (4-hydroxyphenoxy) -3-isopropylamino-2-propanol hydrochloride,

III. DL-1- (4-hydroxyphenoxy) -3-isopropylamino-2-propanol hydrochloride (known from Dutch Patent Application No. 6,409,883).

A. Methodology

Frequency (right ventricle) and contractile amplitude (left ventricle) (isometric contraction below 0.5 g diastolic bias) are continuously recorded on the right, spontaneously beating, and left, constant 2.5 Hz excited guinea pig chamber. The organ bath contains 50 ml Krebs-Henseleit solution 32 ° C. The addition of the compound is carried out cumulatively. and an effective dose curve was determined.

B. Results

The maximum positive inotropic and chronotropic effect (E) of the test compounds is very close. The contraction amplitude increases by an average of 10 to 13 mm (= 500 to 650 mg) and a frequency of 59 to 73 beats per minute.

However, potency varies considerably between the three compounds. Compound I is about 2 times more potent than compound III and 60 to 70 times more potent than compound II.

The results of the experiments are summarized in Table 1 below.

Table 1

Comparison of effect of compounds I, II and III on isolated guinea pig chamber. Compound count parameter ⁿ default EAabs.

potency EC 50 (molar)

AND 8 F 149 + 5 + 73 + 6 3.2.10-8 C 51 + 3 + 13 + 1 3.5.10- ⁸ II 8 F 147 + 2 + 59 + 6 1,9.10- ⁶ C 48- + 4 + 11 + 1 2,5.10-θ III 11 F 149 + 4 + 65 + 3 4,6.10-8 C 45 + 4 + 10 + 1 6,0.10-8

Values: x + s _x

X) F = right ventricular frequency (beat / minute).

C = left ventricular contraction amplitude (mm; 1 mm - 50 mg)

C. Toxicity

Compounds I, II and III were tested in Tif MAG f mice and Tif RAI f rats

The average weight of the mice was 19.8 g and the rats were 100 g. Prior to the start of the experiment, the mice and rats were kept for at least 5 to 8 days in the laboratory at + 22.1 ° C and 55 + 5% RH and 14 days exposure. Groups of 5 animals were housed in Macro Cages and had free access to standard diet and drinking water.

LD 50 values were calculated by Probitanalysis (A. Goulden: Methods of Statistical Analysis, John Will and Sons 1960, 3rd edition, pp. 404-408).

The results are summarized in Table 2.

Table 2

Compound species sex application solution v LD50 mg / kg II mouse 9 intravenously H2O dest. 74 (71 to 77) <2 per os H2O dest. 780 (610 to 1010) rat <3 9 intravenously H2O dest. 190 (177 to 204) 6 9 per os H2O dest. > 3000 AND mouse ó 2 intravenously H2O dest. 162 (144 to 182) Г 9 per os H2O dest. 950 (800 to 1140) rat <9 intravenously H2O dest. 257 (248 to 265) rf 9 per os H2O dest. 4930 (4290-5670) III mouse d 9 intravenously H2O dest. 132 (123 to 141) rf 9 per os H2O dest. 910 (740 to 1110) rat 3 9 intravenously H2O dest. 250 (230-271) ύ 9 per os H2O dest. 5960 (4800-7390)

The novel compound can be used as a medicament, for example in the form of pharmaceutical preparations, which comprise the new compound or the corresponding salt in admixture with, for example, solid or liquid pharmaceutically acceptable organic carriers for enteral, for example oral or parenteral administration. Suitable materials are those which do not react with the novel compound, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycol, petrolatum, cholesterol or other known carriers. Suitable pharmaceutical preparations are, for example, tablets, dragees, capsules, suppositories, ointments, creams or liquid forms, such as solutions (for example, infusion or syrups, suspensions or emulsions). , wetting or emulsifying agents, salts for varying the osmotic pressure, or buffers, as well as other therapeutically useful substances The preparations which are also useful in veterinary medicine are prepared in a conventional manner. 100 mg per os, preferably about 20 to 40 mg per os.

The following example illustrates the invention in more detail without restricting it in any way. Temperatures are given in degrees Celsius.

Example

4.5 g of (+) - 1- (4'-hydroxyphenoxy) -2-hydroxy-3-sopropylaminopropane are dissolved in 30 ml of methanol and mixed with a solution of - 8.1 grams of (+) - di-O, O ' -p-toluoyl-D-tartaric acid in 25 ml. methanol and 25 ml of water. The solution is then concentrated to a slight turbidity at room temperature and in a water pump vacuum and then allowed to stand for 15 hours at 0 ° C. The precipitated crystals were filtered off and recrystallized twice from 1: 1 methanol: water to give 3.7 g of (-) - 1- (4'-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane (+) - di- O, O'-ptoluoyl-D-η 5 - (η 5 - (η 5 -) - η (η 4 -) - filtrate mp 134-137 degrees Celsius.

To isolate the free enantiomeric base, the salt is partitioned between a 2 N hydrochloric acid solution and ethyl acetate. (+ J-di-O, O'-p-toluoyl-D-tartaric acid can be recovered from this extract. The hydrochloric acid solution is basified with concentrated ammonia, saturated with sodium chloride and shaken with ethyl acetate. The organic phase is washed with brine, The residue was recrystallized from ethyl acetate to give 1.0 g of pure (--- 1- (4'-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane, mp 129-130 ° C). [.alpha.] D @ 20 = 0.9 + 0.5 DEG (1% methanol solution) Reaction with fumaric acid gives a neutral fumarate, having a crystallization from methanol and ether of 11. 210 DEG -211 DEG C. [a] _D 20 = -21.5 ± 0.5 ° (1% solution in methanol). hydrochloride mp 125-126 ° C, 129-130 ° C, [aa! ^ ⁰ = -26 ° ± 1 (1% solution in methanol).

Claims (3)

Process for the preparation of L- (4'-hydroxyphenoxy) -2-hydroxy-3-sopropylaminopropane of the formula I and its acid salts, characterized in that the DL-acemic base is converted by reaction with (+) - di-O, O'-p-toluoyl-D-tartaric acid to form a mixture of diastereomeric salts, the L-salt is separated by fractional crystallization from a suitable solvent, and the L-base is liberated therefrom, optionally converted to the acid salt. 2. The process of claim 1 wherein the solvent is a mixture of methanol and water. 3. The process of claim 1 wherein the L-base is converted to a therapeutically acceptable salt.