CS199572B2 - 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 L-1- (4‘-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane of the formula I

HO CH (OH) -CH _from NH-CH (CH ₃ ) ₁ (LJ (I))

Fischer projection of the compound of formula I

BOY

AND

CH _Z NH-CH (CH ₃ ) _Z (L) and corresponds to the S form in the Cahn-Ingold-Prelog nomenclature:

(CH ₃ ) _Z CH-NH-CH ₂

CP £ O ι, Ή

OH

(WITH)

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 it follows from experiments on narcotized cats, the novel compound does not act at all at the indicated doses, which are clearly positively inotropic and chronotropic at all or at least at a decrease in arterial blood pressure; in blood vessels, and is distinguished 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 calculated that when used in humans at doses that are equally potent positive inotropic, tachycardia will result in substantially lower tachycardia than isoproterenol.

It is also particularly advantageous that the novel compound is significantly longer active in narcotized cats than isoproterenol and further that a clear effect is also obtained after intraduodenal administration in an amount 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 / minute.

L1- (4'-Hydroxy-phenoxy) -2-hydroxy-3-isopropylamino-propane may be prepared according to the invention in a known manner by hydrolyzing (-I- [p- (, β-D-glucopyranosidyloxy) in a slightly acidic environment. Phenoxy] -3-isopropylamino-2-propanol for II

OH ^from 7 O ° - ^C, --CH - CH _£ NH CHICHz (D (ID or a salt thereof, wherein Z is / 3-D-glukopyranosidylový radical or a. Salt, and from the obtained salt base was released and optionally converting the base into an acid salt.

The hydrolysis is carried out in a conventional manner, for example in the presence of a hydrolytic agent, for example in the presence of acidic agents such as aqueous mineral acids such as sulfuric acid or hydrohalic acids such as hydrochloric or hydrobromic acid or organic acids such as suitable carboxylic acids such as is α-haloalkanoic acid, for example trifluoroacetic acid or chloroacetic acid, organic sulfonic acids such as benzenesulfonic acid or toluenesulfonic acid or in the presence of ion exchangers or in the presence of basic agents such as alkali metal hydroxides such as sodium hydroxide. The oxycarbonyl, arylsulfonyl and cyano groups may preferably be cleaved by acidic agents such as hydrohalic acid. Particularly suitable are, for example, cleavage with aqueous hydrochloric acid, optionally in admixture with acetic acid.

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 gaming, mono-, sesqui- or polyhydrates can be obtained. 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 can be used for the preparation of acid salts. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, aliphatic, alicyclic, and -; mild or heterocyclic carboxylic or sulfonic acids such as formic acid, acetic acid, propionic 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 embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, (p-toluenesulfonic acid, cyclohexylaminosulfonic acid or sulfanic 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 releasing the base from the salt. Due to the close relationship between the novel compound in the free 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.

For example, compounds of formula II wherein Z 1 is a hydrolytically cleavable group can be prepared by treating a compound of formula III

OH ^{ζ ι-} ° ~ ζ ^ - O-CH = CH-CH-Y (D, L) (ID) • Γ:;

wherein Z 1 is as defined above and Y 1 is a reactive esterified hydroxy group, reacts with an amine of formula III

HaN-CH (CH3) 2 (ΠΙ), wherein Z3 is as defined above or a hydrogen atom, whereupon the L-form is separated from the racemate, for example by fractional crystallization.

The compounds of formula II can also be prepared by treating a compound of formula IV

(IV) is reacted with a compound of formula V 'X 1

A — CHa — CH — CHa — NH — CH (CH3) 2 (L) (V), wherein A is a reactive esterified hydroxyl group, for example a halogen atom such as a chlorine or bromine atom, and X1 is hydroxyl or A and X1 together form an epoxy 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, e.g. 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. Possible pharmaceutical preparations are tablets, dragees, capsules, suppositories, ointments, creams or liquid forms, such as solutions (for example infusion or syrup), suspensions or emulsions. Optionally, these preparations are sterilized or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically suitable substances. Preparations which are also useful in veterinary medicine are prepared in 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 6.0 g of diastereoisomers of 1- [β- (β-D-glucopyranoisidyloxy) phenoxy] -3-isopropylamino-2-propanol mp 157-160 ° C / 186-187 ° C are dissolved in 20 ml of 2 N of sulfuric acid and heated at 80 ° C for three hours. The reaction mixture was cooled, basified with concentrated ammonia, saturated with sodium chloride and shaken with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and evaporated in a water pump vacuum. 2.0 g of (-) - 1- (4-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane [α] _D ²⁰ - 0.9 + 0.5 ° are obtained (c = 1.0% by weight). The neutral fumarate prepared by treatment with fumaric acid crystallizes from a mixture of methanol and ether and has a melting point of 210 DEG-211 DEG C., [ _.alpha. ] _D @ ²⁰ = = -21.5 DEG. + -. 0.5 (c = 1.01% w. in methanol). hydrochloride mp 125-126 degrees Celsius 129.až 130 DEG C. [QS] d ^z0 = -26 ° ± 1 (1% solution in methanol) The starting material for this reaction can be prepared as follows: 27.2 g (0.1 mol) of hydroquinone-β-glucopyranoside and 250 ml of epichlorohydrin are dissolved in 1.0 liter of ethanol, 6.9 g (0.05) are added. The reaction mixture was heated to boiling for 6 hours, the precipitate was filtered off, the filtrate was evaporated in a water pump vacuum, the residue was dissolved in ethanol and filtered, and the filtrate was cooled and ether was added until turbidity occurred. the reaction product is filtered off and 442,3-epoxypropoxy) -phinyl- [beta] -D-glucopyranoside is obtained as a mixture of the two possible diastereoisomers.

g of this mixture of diastereoisomers was dissolved in 300 ml of methanol and the reaction mixture was heated to boiling with 18.5 g of isopropylamine for 6 hours. The reaction mixture was then evaporated to dryness. The residue is dissolved in 35 ml of water and treated with 11.6 g of cyclohexylsulfamic acid in acetone. To this solution was added acetone until turbidity occurred. In this process ¹ , a crystalline reaction product starts to precipitate. For complete crystallization, the reaction mixture is left to stand 15; hours at 0 ° C. The precipitated crystals are filtered off and recrystallized from a mixture of acetone and water. This eliminates the undesired diastereoisomer for further operation.

The mother liquors resulting from the crystallization process were combined and evaporated in a water pump vacuum to a syrup which was dissolved in 50 ml of water. This solution was filtered on a 200 ml Amberlite IRA-400 column (strongly basic trimethylammonium ion exchanger (0.38-0.045 mm grain size)). The column was washed with water and eluted until the liberated base was completely rinsed. The combined aqueous eluates were evaporated to dryness in a water pump vacuum and recrystallized three times from a mixture of methanol and isopropanol. There was thus obtained the second diastereomer of 1- [β- (β-D-glucopyranosidyloxy) -phenoxy] -3-isopropylamino-2-propanol, mp 157-190 ° C (188-189 ° C).

Claims (3)

the subject of the invention Process for the preparation of L-1- (4‘-hydroxyphenoxy) -2-hydroxy-3-isoprapylaminopro (Formula I) OH (L) NO - ^^ - O-CH = CH-CH = NH-CHlCH ^^ and its salts with acids, characterized in that the mild acid hydrolysis of (L) Zf0--30-CH _Z where Z is a β-D-gluicopyranosidyl residue or an acid salt thereof, and the base is liberated from the salt obtained and optionally converted into an acid salt. 2. A process according to claim 1, wherein (I) (-) - 1- [β- (β-D-gluicopyranosidyloxyphenoxy) -3-isopropylamino-2-propanol of formula II OH (CH-CH3 (NW-CH3CH3)) that the hydrolysis is carried out in 2 N sulfuric acid. 3. The process of claim 1 wherein the base is converted into a therapeutically acceptable salt.