DE1143822B - Process for the production of reserve acid derivatives - Google Patents

Description

Process for the Production of Reserp Acid Derivatives The invention relates to a process for the production of reserp acid derivatives of the general formula I. wherein R1 is an alkyl radical having 1 to 6 carbon atoms, e.g. B. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl or n-hexyl radical, and Ra an alkyl radical with 1 to 7 carbon atoms or an aryl radical, For example, a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-, sec- or tert-butyl, n-pentyl, isopentyl, 2,2-dimethylpropyl (1) - , n-hexyl, isohexyl, n-heptyl or phenyl radical, and of their N-oxides and salts.

The new compounds show both antihypertensive and conditional by influencing the central nervous system, sedative effect or tranquillizer properties. There are also some qualitative differences that affect the group of new compounds can be observed.

For example, comparing their hypotensive and sedative results Effect with that of the natural Rauwolfia alkaloids such as reserpine and deserpidine or rescinnamine that some of the new compounds are primarily sedative and show only insignificant hypotensive effects, whereas others show this relationship just the other way around.

The compounds obtainable according to the invention can therefore be used as medicaments used in human and veterinary medicine, e.g. B. as antihypertensive drugs to treat high blood pressure, e.g. B. benign or malignant hypertension, renal hypertension or pregnancy hypertension, e.g. B. Pregnancy toxemia and / or as sedatives for the treatment of hyperactivity, states of tension and excitement, z. B. in cases of mental confusion. The new compounds can also be used as intermediates for the production of other valuable substances or as feed additives for Animals are used.

From the process products caused z. B. the O- (O ', O'-diethyl-phosphoryl) -reserpsäuremethylester when administered orally to dogs in Doses of 3.0 mg / kg represent a decrease in the average arterial blood pressure of 60 mm.

Under the same conditions, the well-known 0- (0 '-carbethoxy- syringoyl) -reserpsäuremethylester achieved a blood pressure decrease of only 38 mm.

In the case of oral administration, the process product mentioned is therefore approximate twice as strong hypotensively effective as the comparison substance.

With subcutaneous administration of 50.0 mg / kg des o - (0 ', 0' - diethyl - phosphoryl) - reserps acid methyl ester in the mouse becomes a distinct 5 hours sustained sedation achieved. A subcutaneous dose of 100 mg / kg of the known O- (4n-acetylaminobenzoyl) -reserp acid methyl ester however, does not induce sedation in the mouse.

The new compounds are obtained by using a reserp acid ester of the general formula II in a manner known per se or its N-oxide with a phosphorus halide of the general formula III where Hal stands for a halogen atom, preferably a chlorine atom, but also a fluorine or bromine atom, and optionally then converts the free compound obtained or its salts into an N-oxide or converts the bases obtained into their salts or the salts obtained into the bases.

The esterification takes place z. B. in the presence of an acid-binding agent By means of, preferably an organic base containing a tertiary nitrogen atom, z. B. a monocyclic base such as pyridine, picoline, lutidine or collidine, one Tri-lower alkylamine, such as trimethylamine, dimethylethylamine, diethylmethylamine, Triethylamine or tri-n-propylamine, a di-lower alkyl-arylamine, such as dimethylaniline or diethylaniline, or an inorganic acid-binding salt, e.g. B. one Alkali metal carbonate, such as sodium or potassium carbonate or hydrogen carbonate.

The above-mentioned liquid bases can be used at the same time as a solution or diluents are used.

Other solvents or diluents which can be used for the esterification are for example halogenated hydrocarbons, such as methylene or ethylene chloride, Chloroform or tetrachloroethane, or formamides such as dimethylformamide.

The new compounds are obtained depending on the process conditions as bases or as salts.

The salts can be converted into the bases in a manner known per se be e.g. B. by reaction with basic agents such as silver carbonate or aqueous Ammonia. The bases on the other hand can be, for. B. by reacting with a therapeutic applicable acid, converted into salts, if necessary in the presence of a solvent or diluents, e.g. B. a lower alkanol such as methanol, ethanol, n-propanol or isopropanol. Acids that can be used therapeutically are, for example, inorganic ones or organic acids, such as hydrohalic acids, sulfuric or phosphoric acids, Nitric acid or perchloric acid, or aliphatic or alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, oxalic, amber, Glycol, milk, apple, wine, lemon, ascorbic, hydroxymalein, dihydroxymalein or pyruvic acid, phenylacetic, benzoic, p-amino-benzoic, anthranil, p-hydroxybenzoic, Salicylic or p-aminosalicylic acid; Methanesulfone, ethanesulfone, hydroxyethanesulfone, Ethylene sulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, methionine, Tryptophan, lysine, or arginine.

If necessary, N-oxides of the new compounds are per se known methods, e.g. B. by the action of an N-oxidizing agent on the phosphoric acid esters mainly dissolved in an inert solvent. Examples of N-oxidizing agents are hydrogen peroxide, ozone, persulfuric acid or particularly organic peracids, e.g. B. percarboxylic acids, such as peracetic-perbenzoe- or monoperphthalic acid, or per- sulfonic acids, such as p-toluene-persulfonic acid, called.

Inert liquids are e.g. B. aromatic hydrocarbons, such as Benzene or toluene, halogenated hydrocarbons such as chloroform or ethylene chloride, or lower alkanols such as methanol or ethanol. For the N-oxidation is appropriate both any excess of oxidizing agent and increased temperature are avoided, in order to exclude other types of oxidative changes.

The reserp acid esters used as the starting product, their N-oxides or salts are known or are prepared in a manner analogous to the known compounds won. For example, you can either use reserpic acid with a diazo-lower alkane esterify or reserp acid lactone with lower alkanols in the presence of the appropriate Subjecting catalysts to alcoholysis and, if appropriate, the esters obtained convert into N-oxides through the action of peracids, hydrogen peroxide or ozone.

The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.

Example 1 A mixture of 2.07 g of methyl reserpate, 1.05 g of diethylphosphoryl chloride and 25 cm3 of pyridine are left in a closed vessel Stand at room temperature for 16 hours. The reaction mixture is then poured into 400 cm3 ice-cold, 100% aqueous soda solution, filtered after 2 to 5 hours If the granulated precipitate stands, wash it with water and dissolve it in methylene chloride on. The solution obtained is now through a short, filled with magnesium silica gel The column was filtered, the filtrate was concentrated under reduced pressure and the residue crystallized from ethyl acetate. The O- (O ', O'-diethylphosphoryl) -reserp acid methyl ester is obtained in this way from melting point 167 to 169 °; Yield 2.0g.

Example 2 The mixture of 3.3 g of methyl reserpate, 2.5 g of diphenylphosphoryl chloride and 40 cm3 of pyridine are left to stand for 16 hours at room temperature and are poured onto them into a cold, 100%, aqueous soda solution. The precipitated, granulated precipitate is filtered off after standing for 2 to 5 hours, washed with water and dissolved in methylene chloride solved.

The resulting solution is filtered through a short, magnesium-silica gel filled column, the filtrate is evaporated to dryness and the residue crystallizes from ethyl acetate with a low content of diethyl ether. The thus obtained O- (O ', O'-Diphenyl-phosphoryl) -reserpsäuremethylester melts at 192 to 193 °; Yield 4.0g.

Example 3 3.0 g of reserp acid methyl ester, which takes 3 hours at 90 " had been dried under reduced pressure, and 1.25 g of dimethylphosphoryl chloride added to 30 cm3 of dry pyridine and shake the mixture for 5 minutes, with Tap water is cooled.

After standing overnight, the reaction mixture is poured into 400 cm3 of cold, 50% aqueous soda solution, with an initially oily precipitate fails, which solidifies into granules after standing for 2 to 5 hours. This is filtered off, washed with water, air dried, dissolved in methylene chloride and the Solution filtered through a column filled with kieselguhr. The filtrate becomes dry concentrated and the residue crystallized twice from ethyl acetate. Man thus obtains the O- (O ', 0'-dimethyl-phosphoryl) -reserpsäuremethylester from the melting point 249 to 252 °; Yield 0.8g.

Claims (1)

PATENT CLAIM: Process for the production of reserp acid derivatives of the general formula wherein R1 is an alkyl radical with 1 to 6 carbon atoms and R2 is an alkyl radical with 1 to 7 carbon atoms or an aryl radical, and of their N-oxides and salts, characterized in that a reserp acid ester of the general formula or its N-oxide with a phosphoryl halide of the general formula in which Hal stands for a halogen atom and, if appropriate, then converts the free compound obtained or its salts into an N-oxide or converts the bases obtained into their salts or the salts obtained into the bases. Publications considered: Austrian patent specification No. 204703; published documents of Belgian patent No. 568 285.