CS199573B2 - Method of preparing l-1-/4'-hydroxyphenoxy/-2-hydroxy-3-isopropyl aminopropane - Google Patents

Description

The invention relates to a process for the preparation of a new one. L-1- (4‘-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of formula I

HIM

O-CH 2 CH (OH) -CH 2 NH-CH (CH 3, (L) (I)

The Fischer projection of the compound of formula I is:

CPrO I ^A

HO-C- H

CH 2 NH-CH 2 CH 2 (L) and corresponds to the S form in the Cahn-Ingold-Prelog nomenclature:

(CH 1 - CH - NH - CH 2 OH (S)

The novel compound has valuable pharmacological properties, in particular an effect on adrenergic β-receptors. Thus, it specifically stimulates cardinal β-receptors. In particular, it acts positively inotropically and chronotropically on an 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 evidenced by experiments on narco-fused cats, the novel compound at the indicated doses, which are clearly positively inotropic and chronotrotpine, has no or minimal effect on blood pressure drop in the arteries, it stimulates them specifically by the cardinal? reoeptors in blood vessels and thus distinguishes it qualitatively from isoproterenol, which equally strongly stimulates the β-receptors of the heart and blood vessels. Since pressure drop leads to tachycardia, it can be expected that when used in humans at doses that are equally potent inotropic, tachycardia will be significantly lower than that of isqproterenol.

In particular, it is particularly advantageous that the novel compound is substantially more effective than narcotenol in anesthetized 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 inotropically active agent, particularly for the treatment of 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 infusion in an amount of 0.2 to 2.0 µg. / kg / niinut.

According to the invention, L-1- (4‘-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane is prepared by reducing the hydroquinone derivative of the general formula II with hydrogen in the presence of palladium on carbon catalyst.

OH

O-CH 2 CH-CH 2 N-CH (CH 2 (L) (ID wherein at least one of Z 1 and Z 2 is n-arylalkyl and the remainder is hydrogen or a corresponding salt thereof and optionally recovered from L the salt is liberated or the L-base obtained is converted into an acid salt.

The reductable residues Z 1 and / or Z 2 are, for example, N-arylalkyl, such as benzyl, α-arylalkoxycarbonyl, such as benzyloxycarbonyl, which can be cleaved in a conventional manner, for example by hydrogenolysis, in particular hydrogen in the presence of a hydrogenation catalyst,

The reduction must be carried out in such a way that other reducible groups are not attacked. In particular, the described reduction with catalytic hydrogen using an unsulfidated hydrogenation catalyst is carried out at a low temperature, for example between -50 and +50 ° C, preferably at 0 to 25 ° C.

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 can be obtained, as well as their gaming, mono-, sesqui- or polyhydrates. The acid salts of the novel compound 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 therapeutically useful salts may 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, ipropionic 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, acid hydroxyethane sulfoic acid, ethylenesulfonic acid, halobenzene disulfonic 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 compounds are known or, if new, can be prepared by known methods.

Compounds of formula II wherein Z 1 is an α-aralkyl radical and Z 2 is a hydrogen atom or an α-aralkyl radical can be prepared, for example, by preparing a compound of the formula III

OH _ZrO - (γ-CH 2 CH-CH / I, (D, L) (III) wherein Z 1 is as defined above and Y 1 is a reactive esterified hydroxy group, reacted in a conventional manner with a compound of formula IV

Z2

NH-CH (CH 3) 2 (IV), wherein Z 2 is as defined above, whereupon the L-form is separated from the racemate, for example by fractional crystallization.

Compounds of formula II wherein Z 1 is an α-aralkyl radical and Z 2 is a hydrogen atom or a ·-aralkyl radical can be prepared by reacting a compound of formula V ζ ₇ ο-ζ 4 -ομ (V) with a compound of formula VI

Xi Z ₂ ! and

A - CH 2 - CH - CH 2 - N - CH [CH 3] 2 (VI), (I 1 wherein A is a reactive esterified hydroxyl group, for example a halogen atom such as chlorine or bromine atom and X 1 is hydroxyl or A and X 1 together form an epoxy group or when Z 2 is a hydrogen atom, A forms a direct bond with the amino group of the amino group.

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 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, vaseline, 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 syrup), suspensions or emulsions, optionally sterilized or containing auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers, as well as other therapeutically useful substances Preparations which are also useful in veterinary medicine are prepared in the conventional manner The daily dose in warm-blooded animals weighing about 75 kg is about 10 to 100 mg per os, preferably about 20 to 40 mg per os.

The following examples illustrate the invention without limiting it in any way. Temperatures are given in degrees Celsius.

Example 1 aj A solution of 1.6 g of 1-isopropylamino-2S-hydroxy-3- (4-benzyloxyphenoxy) -propane hydrochloride in 160 ml of ethanol is hydrogenated at normal pressure to 0.2 g of 5% palladium on carbon. amount

B of hydrogen, the catalyst was filtered off and the solution was evaporated to dryness. The residue was dissolved in 45.6 ml of 0.1 N sodium hydroxide solution and extracted with ethyl acetate. After drying over magnesium sulfate, the organic phase was evaporated to dryness and the residue was recrystallized from ethyl acetate to give 1-isopropylamino-2S-hydroxy-3- (4'-hydroxyphenoxy) -propane, mp 127-128 ° C, [α] ] _D ²⁰ = -1 ° ± 1 °, [α] ²⁰ = + 2 ° + 1 ° (methanol, c - 0.940j.

A solution of 0.7 g of the obtained 1-isopropylamino-2S-hydroxy-3- (4'-hydroxyphenoxy) propane in 5 ml of methanol is treated with 9.1 ml of a 4% solution of fumaric acid in methanol. Ether was then added until the solution became cloudy and the solution was cooled. The obtained crystals are filtered off, dried and 1-isopropylamino-2S-hydroxy-3- (4'-hydroxyphenoxy) -propane is recovered: 1/2 fumarate mp 209 DEG -211 DEG C., [ _.alpha. ] _D @ ²⁰ = -23 DEG + 1 °, [°] h1, ²⁰ = -68 ° + 1 ° (methanol c = 1.061), hydrochloride mp 125-126 ° C, 129-130 degrees C, [α] _D ²⁰ -26 ° + 1 ° (methanol c = 1.

The starting material can be prepared as follows:

bj To a melt of 100 g of 5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose and 100 g of hydroquinone monobenzyl ether heated to 120 ° C was added a few drops of pyridine while maintaining the internal temperature below 140 ° by external cooling with lukewarm water. C. After the exothermic reaction had ceased, the reaction mixture was stirred for 30 minutes at 140 ° C and then cooled to 80 ° C, diluted with 500 ml of methanol and then with water until turbidity occurred. After standing at 0 ° C for several hours, the precipitated crystals are filtered off, recrystallized from methanol to give 1,2-O-isopropylidene-6-O- (4'-benzyloxyphenyl) -α-D-glucofuranose, m.p. 99 DEG-102 DEG C., Rf = 0.25 on a thin layer of silica gel in methylene chloride: methanol 15: 1.

c) A solution of 127.3 g of 2-O-isopropylidene-6-O- (4'-benzyloxyphenyl) -α-D-glucofuranose in 800 ml of glacial acetic acid heated to 70 degrees Celsius is mixed dropwise with 500 ml of stirring. ml of water, stirred for 14 hours at 70 ° C and then evaporated to dryness under a water pump vacuum. The crystalline residue is recrystallized from 1 liter of glacial acetic acid to give 6-O- (4'-benzyloxyphenyl) -D-glucose,

1.1. 164-168 ° C, Rf = 0.61 on a thin layer of silica gel in methanol [.alpha.] _D @ ²⁰ = -62 DEG + 1 DEG (methanol c = 0.985.

(d) A suspension of 36.2 g of 6-O- (4'-benzyloxyphenyl) -D-glucose in a mixture of 600 ml of methanol, 10 ml of glacial acetic acid and 60 ml of water is mixed portionwise with 64 g of periodate over 15 minutes. The reaction mixture is stirred for 20 hours at about 25 DEG C. The insoluble material is then filtered off, the filtrate is evaporated to dryness, the residue is dissolved in chloroform, the solution is washed with water, dried over magnesium sulphate and the solvent is evaporated under water pump vacuum. 150 ml of methanol and added dropwise over 45 minutes to a solution of 3.8 g of sodium borohydride in 150 ml of methanol and 40 ml of water cooled to -5 DEG C. After a further 15 hours at 25 DEG C., the reaction mixture is evaporated to dryness. Dissolve in chloroform, wash with ice-cold 2 N hydrochloric acid and water and, after drying over magnesium sulphate, evaporate the solvent in a water pump vacuum. m.p. 134-138 [deg.] C., Rf = 0.32 on a thin layer of silica gel in methylene chloride: methanol 15: 1, yields 1- (4 ' -benzyloxyphenoxy) -2S-3-dihydroxypropane.

e) A solution of 8.2 g of the obtained 1- (4'-benzyloxyphenoxy) -2S-3-dihydroxypropane in 20 ml of pyridine, cooled to -10 ° C, is added dropwise with stirring to a solution of 5.7 with stirring and exclusion of air humidity. g of p-tosyl chloride in 30 ml of pyridine and the reaction mixture was allowed to stand for 16 hours at 25 DEG C. The reaction mixture was diluted with chloroform and water, the separated organic phase was washed with glacial 2N hydrochloric acid, water, saturated sodium bicarbonate solution and then again The residue is chromatographed on a 250 g silica gel column with methylene chloride / ethyl acetate 19: 1, and the product is crystallized from ethyl acetate / petroleum ether to give 1- (4'-benzyloxyphenoxy) -2R. -hydroxy-3-p-tosyloxypropane mp 70-74 ° C, Rf = 0.36 on a thin layer of silica gel in methylene chloride-ethyl acetate 19: 1, [α] _π ²⁰ = 11 + Γ (chloroform c = 1,631 ).

A solution of 3.8 g of 1- (4-benzyloxyphenoxy) -2-R-hydroxy-3-p-tosyloxypropane in 40 ml of ethanol and 4 ml of isopropylamine was kept at 50 ° C for 30 hours and then evaporated to dryness. dissolved in methylene chloride and the solution was washed with 2N sodium hydroxide solution, then with water, dried over magnesium sulfate and the solvent was distilled off to give 1-isopropylamino-2S-hydroxy-3- (4-benzyloxyphenoxy) -propane which was recrystallized from the mixture methylene chloride and petroleum ether, mp 91-93 ° C.

This compound was dissolved in a small amount of ethanol and adjusted to pH 4 by addition of an alcoholic hydrochloric acid solution, then ether was added until turbidity was observed. After cooling, 1-isopropylamino-2S-hydroxy-3- (4-benzyloxyphenoxy) propane hydrochloride crystallizes which is filtered off and dried, m.p. 161-163 ° C, (?% ^2θ = -19 ° ± 1 °, [? [.Alpha.] _{D @} ²⁰ = - 57 + 1 DEG (methanol c = 4.903).

Example 2

Using the procedure of Example 1, 2.06 g of 1-isopropylbenzylamino-2S-hydroxy-3- (4-benzyloxyphenoxy) propane hydrochloride was used as a crude product for hydrogenolysis to give 1-isopropylamino-2S-hydroxy-3- (4). -hydroxyphenoxy] propane mp 127-128 ° C, [α] π ²⁰ = -Γ ± 1 °; [α] H ²⁰ = + 2 ° + 1 ° (methanol c = 0.940); hydrochloride mp 125-126 ° C; 130 DEG C. [.alpha.] D @ ²⁰ = -26 DEG + 1 DEG (methanol c = 1).

The starting material was prepared by reacting 1- (4-benzyloxyphenoxy) 2R-hydroxy-3-p-tosyloxypropane, prepared as described in Example 1f, with N-benzyllsopropylamine. The crude product 1-isopropylbenzylamino-2S-hydroxy-3- (4-benzyloxyphenoxy) propane hydrochloride obtained as such is used as such for further processing.

Claims (2)

1. A process for the preparation of L-1- (4 ' -hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropanone of the formula I HIM O-CH = CH (OH) -CH-NH-CH (CH ^ (L) (I) and its salts with acids, characterized in that hydrogen in the presence of palladium on carbon catalyst is reduced hydroquinone derivatives of general formula _II-ZFO 0 ° - ^c P _A OH II CH-CH 2 N-CH (L) (ID wherein at least one of Z 1 and Z 2 is an α-aralkyl radical and the remainder is a hydrogen atom or a corresponding salt thereof and optionally liberates the base or recovered from the L-salt obtained The L-base is converted to the acid salt. 2. The method of claim 1 wherein the free compound of formula I is converted to a therapeutically useful acid salt. severografía, n. p., xivoM 7, Most