NO843906L - NEW 1- (ALKYL-HYDROXY-PHENYL) -1-HYDROXY-2- (ALKYLAMINO) PROPANES - Google Patents

Description

It is known that hydroxyphenalaralkylaminoalcohols of the general formula

in which R means an alkylene residue with 2 to 5 carbon atoms, has a strong vasodilating effect by simultaneously increasing the heart's stroke volume and frequency. Moreover, these compounds have a uterospasmolytic action (see German patent 11 82 245).

The invention relates to the items specified in the patent claims.

The compounds according to the invention are pharmacologically active

some In particular, the beneficial circulatory effects have a particularly high positive inotropic effect. With some compounds, there is only a small effect on heart rate and blood pressure. After experiments on large animals, the compound according to the invention is approximately pure 3-mimetic, while the compounds known from German patent 11 82 245 (for example the known active substance bufenin) act as 3 2-mimetic. The compound according to the invention therefore differs in effect in principle from the previously known compounds.

In the following, some explanations are given which are essential for the invention.

The alkyl and alkoxy groups occurring in formula I can be linear or branched. R, is in particular a methyl or ethyl group, which is preferably in the 4-position, if the hydroxy group is in the 3-position. In the case of the alkyl groups and the alkoxy groups of the residue R2, it is also about spe-

specifically about alkyl and alkoxy groups, each with one or two carbon

atoms, especially of methyl and methoxy groups. Preferably, R 2 is an unsubstituted phenyl radical. Halogen atoms include, for example: Chlorine, fluorine and bromine, especially fluorine and chlorine.

If R 2 is a phenyl residue, this may contain one, two or three of the aforementioned substituents, as these may be the same or different. If R 2 is a cycloalkyl radical, it turns out to be the cyclopentyl or cyclohexyl radical, each of which may contain one or two of the aforementioned substituents (same or different).

The group Alk can be linear or branched.

Examples for the latter are: -(CH^^-, -(CH2)4~,

The hydroxy group of the left phenyl residue of formula I is in particular in the meta or para position. The residue R, is preferably located in a position adjacent to this hydroxy group, the para position being particularly relevant, if the hydroxy group. is in meta position. When the hydroxy group is in the para position, R1 is preferably in the meta position.

The compounds according to example 1 have particularly favorable properties.

The compound according to the invention usually contains two or three asymmetric carbon atoms. Mixtures of diastereoisomers can therefore occur during the synthesis. These mixtures can be separated in the usual way, for example by recrystallization. Enantiostereoisomers can be resolved from the pure racemates using optically active auxiliary substances (e.g. optically active acids) in a manner known per se. However, it is also possible in the synthesis to use optically active resp. diastereomeric starting substances in that the corresponding enantiostereomers are obtained, resp. diastereomeric end products. For the practical pharmaceutical application,

when it comes to pure isomers or mixtures of isomers.

Formula I includes all possible enantiomers and diastereomers.

Depending on the process conditions and starting materials, the end products with formula I are obtained in free form or in the form of their salts. The salts of the final substances can in a manner known per se, for example with alkali or ion exchangers

taken to the base. Salts can be prepared from the latter by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically useful salts. Examples of such acids should be mentioned: Hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids

from the aliphatic, alicyclic, aromatic or heterocyclic series, as well as sulphonic acid.

Examples of this are: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid,

or pyruvic acid, phenylacetic acid, benzoic acid, p-amino-benzoic acid, anthranilic acid, p-hydroxy-benzoic acid, salicylic acid, or p-amino-salicylic acid. Embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, or sulfanilic acid, or also 8-chloro-theophylline.

In the specified methods for preparing the compounds according to the invention, the amino groups which react can contain known and common protective groups. These are residues that are easily split off by hydrolysis or hydrogenolysis, and are often split off already during the reaction. If such protective groups are not removed during the process reaction, removal takes place after the reaction. Often the starting compounds, due to their preparation, already contain such protecting groups.

These protection groups concern, for example,

about easily solvolytically cleavable acyl groups or hvdrogenating cleavable groups. The solvolytically removable protective groups are removed, for example, by saponification with dilute acids, or with the help of basic substances (pot ash, soda ash, aqueous alkali solutions, alcoholic alkali solutions, NH3), at temperatures between 10 and 150°C, especially 20-100°C. Hydrogenating cleavable groups such as arylalkyl residues (benzyl residue) or hydroxycarbonyl residues (carbobenzoxy residue) are conveniently removed by catalytic hydrogenation in the presence of aqueous hydrogenation catalysts (noble metal catalysts), especially palladium catalysts, or also platinum catalysts (platinum oxide) Raney nickel,

in a solvent or suspension agent, optionally under elevated pressure (for example 1-50 bar), at temperatures between 20 and 150°C, especially 30-100°C, preferably 40-80°C. As resolution or suspending agent, for example: Water, lower aliphatic alcohols, cyclic ethers, such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide, etc. as well as mixtures of these agents.

Examples of protective groups that can be removed by hydrogenolysis include: benzyl residue, α-phenylethyl residue, benzyl residues substituted in the benzene nucleus, (p-bromo- or p-nitrobenzyl residue) carbobenzoxy residue, carbo-benzthio residue, tert-butylhydroxycarbonyl residue. Examples of hydrolytically cleavable residues are: Trifluoroacetyl residue, phtatyl residue, trityl residue, p-toluenesulfonyl residue, etc., as well as lower alkanoyl residues such as acetyl residue, formyl residue, tert-butylcarboxy residue, etc.

In particular, the protective groups common in peptide synthesis, and the usual cleavage procedures are mentioned. Among other things, reference is also made here to the book by J§sse P. Greenstein and Milton Winitz "Chemistry of Amino Acids", New York 1961, John Weley ond Sons. Inc. Volume 2, eg 883 et seq. The carbaloxy group (for example, low molecular weight) is also mentioned.

If the starting materials also contain phenolic or alcoholic hydroxy groups, these can likewise be protected by the above-mentioned protective groups, as the cleavage takes place in the same way.

For procedure a):

Method a) is carried out in a solvent or suspension agent at temperatures which are, for example, between 20 to 150°C, preferably 40 to 150°C. For example, you work in a neutral to alkaline pH range. Optionally, work can also be done under elevated pressure (up to 150 bar). Examples of solvents or suspending agents include: Water, lower aliphatic alcohols with 1-6 C atoms, saturated alicyclic and cyclic ethers with 2-6 C atoms, lower alkylamido resp. dialkylamides of aliphatic C^-C^-carboxylic acids, cyclic aliphatic acid amides (5 or 6 ring) such as N-methyl-pyrrolidone as well as mixtures of these agents.

Examples of reducing agents include: Catalytically activated hydrogen using common metal catalysts (with and without carrier), such as noble metal catalysts (palladium, palladium charcoal, palladium on barium sulphate, platinum, platinum oxide, or also Raney hiccup). Solvents are preferably polar agents, such as alcohols or alcohol-water mixtures. However, the reduction is also possible with light metal hydrides, especially complex light metal hydrides (sodium borohydride, cyanoborohydride, lithium aluminum hydride, lithium hydride, sodium triethoxy aluminum hydride, sodium bis-2-methoxyethoxy aluminum dihydride, lithium tri-tert.-butoxy aluminum hydride and the like) with alicyclic or cyclic ethers preferably being used as solvents at temperatures of preferably 20-100°C.

Furthermore, the reduction can take place with aluminum amalgam or aluminum alcoholates (for example aluminum isopropylate/isopropanol) and similar agents, or by electrolytic reduction or possibly also by nascent hydrogen such as zinc/acid (zinc glacial acetic acid, zinc hydrochloric acid).

In addition to the already mentioned solvent, aromatic hydrocarbons (benzene, toluene) can also be used.

Hydrogenolytically cleavable protecting groups present (for example benzyl groups) are usually cleaved by reduction, if this reduction takes place with the aid of hydrogen in the presence of hydrogenation catalysts, especially palladium catalysts. If the protective groups present are not cleaved off during the reaction, these are removed in the manner already indicated after completion of the reaction.

The production of the starting compounds of formula II used in method a) can, for example, take place by a compound of formula

is condensed with a compound of formula

In formula VIII, Alk' means a linear or branched alkylene group with 2 or 3 carbon atoms, and M means either the group C(R)=0 or -CHR-NH 2 , where R means hydrogen or a methyl group. In formula IX, S means the group -C(CH3)=0 or the group -CH(CH3NH2. R1 and" W have the already stated meanings. M and S are thereby respectively different. Primary amino groups in the groups -CHR-NH2 or - CH(CH3)-NH2 is preferably protected with one of the above-mentioned protecting groups, especially a hydrogenolytically cleavable protecting group such as the benzyl group.The condensation of the compounds of formula VIII and IX is usually carried out at temperatures between 20 and 150°C, especially 40 to 100°C, in a solvent or dispersant, such as lower aliphatic alcohols, water-alcohol mixtures, dimethylformamide or dimethylformamide-containing solvent mixtures.

Not first isolating the reaction product formed by reacting the compound of formula VIII with the compounds of formula IX; for the reaction corresponding to method a), but at the same time treating the same reaction medium with a reducing agent. This applies in particular when catalytically activated hydrogen is used as the reducing agent. Thereby, it is also quite possible that the reducing agent, in particular catalytically activated hydrogen, is already present from the beginning during the reaction of the compound of formula VIII with the compound of formula IX. Consequently, in method a), a mixture of starting components of formula VIII can also be used as starting compounds of formula II

among others IX.

Furthermore, the starting compound of formula II can be obtained by a compound of formula R2~Alk-Hal or R2-Alk-O-tosyl (p-toluenesulfonyl residue), in which R^ has the indicated meaning, Alk means a linear or branched alkylene group with

3 or 4 C atoms, and Hal means a halogen atom (preferably chlorine or bromine), react with a compound

wherein R-j^ and W have the indicated meanings, and the primary amino group may also be protected with a conventional protecting group. In an analogous way, a compound with the formula R2~Alk-NH2 in which R2 and Alk have the indicated meaning, and

the amino group can likewise contain a conventional protecting group, reacted with a compound of formula

wherein R 1 and W have the indicated meaning, and Hal means a halogen atom (preferably bromine). Hydroxy groups present are thereby preferably likewise protected with ordinary protective groups. The latter reactions are carried out, for example, with or without solvents at temperatures between 20 and 200°C, preferably 50-180°C, possibly in the presence of acid-binding agents. Solvents include, for example: Aromatic hydrocarbons, aliphatic ketones, ethers, halogenated hydrocarbons, acid amides, alcohols, sulphoxides.

For method b):

Method b) can be carried out without additional solvent or in a suitable solvent or dispersant. Examples of solvents or dispersants include: Aromatic hydrocarbons, such as benzene, mesitylene, toluene, xylene, lower aliphatic ketones, such as e.g. acetone, methyl ethyl ketone, halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride, ethers such as tetrahydrofuran and dioxane, sulfoxides such as dimethyl sulfoxide, tertiary acid amides such as dimethylformamide and N-methylpyrrolidone, lower alcohols, such as methanol, ethanol, isopropanol, amyl alcohol, butanol, tert.-butanol, etc. The reaction is carried out, for example, at temperatures from 20° to 200°C, preferably 50-180°C, or also 80-120°C. If a resolution or dispersion agent, one often works at the reflux temperature of this agent. The reaction often proceeds already at normal temperature, resp. at a temperature between 20 and 50°C.

It may be appropriate to use one of the starting compounds in excess and/or to put the reaction components with the general formula III in dissolved or suspended form, until the dissolved resp. suspended reaction components of the general formula IV. The molar ratio between the compounds with the general formulas III and IV can amount to 1:1 to 1:10 and possibly even more.

When carrying out the reaction, as ethylene oxide starting compounds instead of the ethylene oxide compound,

(if in formula III X in the form of a hydroxy group with the neighboring hydroxy group forms the ethylene oxide ring), the corresponding halohydrin is also used, or a mixture of these two compounds (synthesis raw product).

Optionally, the reaction can also be carried out in the presence of acid-binding agents, such as alkali carbonates, pot ash, soda ash, alkali hydroxides or tertiary bases.

If Z or X means an esterified hydroxy group, then these are reactive esters. A reactive ester is thereby, for example, that of a strong organic or inorganic acid, above all a hydrohalic acid, for example chloro, bromic or hydroiodic acid, or a sulphonic acid, such as an aryl- or C^-Cg-alkylsulphonic acid, for example of lower alkylbenzenesulphonic acid ( p-toluenesulfonic acid). The reaction is carried out using a reactive ester, preferably in the presence of a basic condensing agent, or an excess of amine. Solvents include agents such as dioxane/water, dimethylformamide/water or lower saturated aliphatic alcohols.

If Z or X means an amino group or if hydroxy groups, especially phenolic hydroxy groups, are present, these may contain one of the protective groups already indicated, for example a benzyl group. If these protecting groups are not already split off during the reaction, they can be removed in the manner already indicated after the reaction has finished.

Starting substances of formula III are known, or prepared

by corresponding keto compounds according to such methods as, for example, are described in the following literature: W.H.

Hartung. J. C. Munch, E. Miller and F. Crossly, J. Am. Chem. Soc. 53, 1931, pages 4149-4160 (starting substances III with X = NH 2 ), Houben-Weyl*Methoden der OrganischenChemie volume IV)ld (1981), pages 308-310 (starting substances III with X = halogen, or another esterified hydroxy group) . The latter compound can also be prepared analogously Houben-Weyl 7 Methoden der Organischen Chemie, volume V/3 (1962), page 503 ff, volume 6/2 ;(1963) page 475 ff or volume IX (1955) page 426. ;The starting substances with formula IV is known.;The compounds of formula III containing an ethylene oxide ring are known, resp. can be prepared in the usual way from halogen hydrides, with formula III, in which X means halogen (see here Houben-Weyl, Methoden der Organischen Chemie, volume 6/3; (1965), page 374 et seq.): Treatment of the halohydrin with alkaline agents, for example alcoholic KOH at low temperatures. The phenolic hydroxy group is preferably protected and the protective groups are optionally removed again afterwards. ;To method c);Removal of protective groups according to this method takes place under the conditions already specified here. Starting substances with formula V can, for example, be obtained according to method a) and b). The compounds produced according to the invention are suitable for the production of pharmaceutical compositions and preparations. In pharmaceutical compositions or medicinal products contain as active substance in one or more of the compounds according to the invention possibly in a mixture with other pharmacologically or pharmaceutical active substances. The preparation of the medicines takes place in a known manner, as the known and usual pharmaceutical excipients can be used, such as usual carriers and diluents. Such carriers and auxiliaries include, for example, such substances as in the following literature are indicated as excipients for pharmacy, cosmetics and related areas, resp. recommended: Ullmann's Encyklopadie der technischen Chemie, volume 4, (1953), pages 1 to 39, J. of Pharmaceutical Sciences, volume 52, 1963), page 918 et seq. H. v. Czetsch-Lindenwald, Hilfstoffe flir Pharmazie und angrenzende Gebiete, Pharm. Ind. Volume 2. 1961, page 62 et seq., Dr. H.P. Fiedler, Lexikon der Hilf stoffe flir Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in Wiirtemberg 1971. ;Addition of other medicinally active substances is possible. ;The compound according to the invention shows in anesthetized dogs (circulation test) a good positive inotropic effect as well as an increase in heart rate volume, for example a 100% increase in heart muscle force is achieved by the above-mentioned test method at a dosage of 0.1 mg/body weight kg (dog). The lowest, already inotropically effective dose in the above-mentioned animal experiments is, for example; 0.1 mg/kg orally; 0.01 mg/kg intravenously.; As a general dose range, for the inotropic effect (animal experiments as above) there is for example in speech: ;0.1 to 1.0 mg/kg orally, especially 0.3;0.01 to 0.1 mg/kg intravenously, especially 0.03. The compounds according to the invention are therefore suitable, for example, for the treatment of Myocardial insufficiency. The pharmaceutical preparations usually contain between 0.01 mg to 100 mg, preferably 0.1 to 50 mg, of the active components produced according to the invention. Administration can, for example, take place in the form of tablets, capsules, pills, dragees or in liquid form. As liquid forms of application, for example: 01 je-like or alcoholic resp. aqueous solutions as well as suspensions and emulsions. Preferred application forms are tablets containing between 5 mg and 50 mg, or solutions containing between 0.1% to 5% of the active substance. ;The individual doses of the active components produced according to the invention can, for example, be a) for oral drug forms between 5 mg and 50 mg, preferably 10 to 40 mg, and b) for parenteral drug forms (for example intravenous, intramuscular) between 0.5 mg and 5 mg, preferably between ;2 mg and 4 mg.; (The doses are respectively referred to the free base); For example, 1 to 3 tablets with a content of 10 to 30 mg of active substance can be used 3 times a day, or for example by intravenous injection 1 to 5 times a day in an ampoule of 1 to 5 mg content with 0.5 to 5 mg substance. For oral administration, the minimum daily dose is, for example, 10 mg, the maximum daily dose for oral administration should not exceed 100 mg. For the treatment of dogs and cats, the single oral dose is usually between approximately 0.1 and 1.0 mg/kg body weight, the parenteral dose approximately between 0.01 and 0.1 mg/kg body weight. The acute toxicity of the compounds produced according to the invention on mice (expressed by the LD 50 mg/kg method according to Miller and Tainter: Proe. Soc. Exper. Biol. a. Med. 57, (1944) 261) lies, for example, at oral application between ;4 00 and 6 00 mg/kg.;The drugs can be used in human medicine, veterinary medicine, as well as in agriculture alone or in a mixture with other pharmacologically active substances. Example 1 d, -1-(3-hydroxy-4-methyl-phenyl)-1-hydroxy-2-(3-phenyl-propylamino)-propane; ; 4.2 g of 1-(3-benzyloxy-4-methyl-phenyl)-1-oxo-2-(3-phenylpropyl-amino)-propane hydrochloride is hydrogenated in 80 ml of 90% ethanol while adding 0.7 g 10% palladium-charcoal catalyst at 50°C. Filter, evaporate, dissolve the residue in vinegar. The crystallized salt is suctioned off and dried. Yield 3.2 g. Melting point of the hydrochloride 160-161°C. Preparation of the starting compound: 8.2 g of 1-(3-hydroxy-4-methyl-phenyl)-propanone (1) is reacted together with 7.6 g of benzyl chloride, 8.4 g of potassium carbonate. 0.28 g sodium jpdid in 35 ml 95% ethanol, at reflux temperature. After 6 hours of boiling, it is allowed to cool, mixed with water, sucked off and recrystallized from isopropanol. ;You get 12.5 g of the corresponding 3-benzyloxyketone (m.p. 55-56°C). ;11.5 g of this compound are mixed under nitrogen in 80 ml of anhydrous chloroform at 50°C with stirring during ;2 hours, with a solution of 7.2 g of bromine in 17 ml of chloroform.;It is allowed to cool in nitrogen stream, evaporates on a rotary evaporator and recrystallizes from isopropanol. One thus obtains 11.2 g of 2-bromo-1-(3-benzyloxy-4-methyl-phenyl)-propanone-(1), which melts at 62-63°C. ;A mixture consisting of 10.0 g of 2-bromo-1-(3-benzyloxy-4-methyl-phenyl)-propanonefl), 4.5 g of 3-phenylpropylamine, 40 ml of ethanol and 3.65 g of triethylamine is boiled 7 hours under reflux and then evaporated on a rotary evaporator. The residue is taken up in water and chloroform, the chloroform phase is separated and this is treated twice with diluted ammonia solution, and twice with water. The extract dried over potassium carbonate is evaporated, the residue is dissolved in acetic acid ethyl ester, and acidified with alcoholic hydrochloric acid. The precipitated hydrochloride is suctioned off the next day, and recrystallized from isopropanol. The thus formed 1-(3-benzyloxy-4-methyl-phenyl)-1-oxo-2-(3-phenyl-propylamino)-propane hydrochloride melts at 175-176°C. ;Yield 5.4 g.;Analogous to example 1, the d, ~ £ -compounds listed in table 1 are obtained with formula ; by catalytic hydrogenation of the correspondingly protected d.^-ketones of formula ; in the presence of a 10% palladium charcoal catalyst. The residue formed after removal of the solvent is recrystallized from isopropanol each time. The preparation of the starting compounds for examples 2 and 3 takes place analogously to example 1, with the following change being made: The condensation product of 2-bromo-1-(3-methyl-4-benzyl-oxy-phenyl)-propanone-(1) with 3-phenyl-propylamine or 1-methyl-..... 3-phenyl-propylamine is not taken up in chloroform, but in a methylene chloride-water mixture and the residue formed after evaporation of the methylene chloride is dissolved in acetone and acidified with hydrochloric acid. ; Example 4 d, ~ C -1-(3-hydroxy-4-methyl-phenyl)-1-hydroxy-2-(3-p-fluoro-phenyl-propylamino)-propane; 23.4 g 1-(3-benzyloxy-4-methyl-phenyl)-1-oxo-2-(3-p-fluoro-phenyl-propyl-benzylamino)-propane-p-toluenesulfonate (crude product, m.p. 140-142°C) is taken up in water and excess caustic soda, and shaken 4 times with methylene chloride to extract the base. The solvent is distilled off, the residue is dissolved in 130 ml of ethanol, acidified with 1-N hydrochloric acid, hydrogenated at 60°C with the addition of 2 g of 10% palladium-charcoal catalyst, with hydrogen while shaking. After completion of the hydrogen uptake, the residue is distilled off and recrystallized from acetone. You get 5.8 g of the hydrochloride of m.p. 147-149°C. ;The starting material is obtained as follows: 30 g of p-fluorophenylpropyl-benzylamine hydrochloride is stirred with 200 ml of water and excess conc. ammonia solution. The mixture is shaken four times with methylene chloride, and the methylene chloride is distilled off. The residue is dissolved in 240 ml of toluene, and 17.9 g of 2-bromo-1-(3-benzyloxy-4-methyl-phenyl)-propanone-(1) are added and the resulting solution is boiled for 18 hours under reflux. It is put overnight in a refrigerator, and the HBr salt is sucked off from the excess starting product. (14.9 g, m.p. 176-178°C). The toluene filtrate is distilled off in a vacuum, the residue is made alkaline with a 10% ammonia solution, and shaken four times with methylene chloride. The dried methylene chloride solution is evaporated and the residue is dissolved in acetone. It is acidified with p-toluenesulfonic acid and the formed p-toluenesulfonate is precipitated with petroleum ether (m.p. 140-142°C). ;Example 5;d, * C-1-(3-methyl-4-hydroxy-phenyl)-1-hydroxy-2-[3-(3,4-dimethoxy-phenyl)-propylamino-7-propane

10.5 g of 3-(3,4-dimethoxyphenyl)-propanol tosylate are now reacted together with 7.7 g of d,£-3-methyl-4-benzyloxy-norephedrine and 3.65 g of triethylamine in 60 ml of n-butanol . One cooks 15

hours under reflux, evaporates in rotary evaporators,

and takes up the residue in a chloroform-water mixture. The phases are separated and the chloroform phase is shaken twice with diluted caustic soda and twice with water. After drying with potassium carbonate, filter and evaporate, dissolve in acetic acid, and acidify with alcoholic hydrochloric acid. Next, aspirate and recrystallize from ethanol. 6.6 g of 1-(3-methyl-4-benzyloxy-phenyl)-1-hydroxy-2-/3-(3,4-dimethoxy-phenyl)-propylamino/-propane hydrochloride are obtained, which melts at 198 -200°C. To remove the benzyl protecting group, 5.2 g of the formed benzyl compound is hydrogenated with the addition of 0.5 g of 10% palladium-charcoal catalyst in 55 ml of 90% ethanol at 50°C. The residue is filtered, evaporated and recrystallized from isopropanol. The m.p. of the hydrochloride 188-189°C. Yield 3.3 g.

d, i^-3-methyl-4-benzyloxy-norephedrine can be obtained as follows:

36.2 g of d, £-3-methyl-4-hydroxy-norephedrine (compare ex. 11) is taken up in one of 13.1 g of 85%-igKOH and 100 ml of ethanol produced alcoholic calyx. It is evaporated in vacuo, mixed with 22.8 g of benzyl chloride in 220 ml of dimethylformamide, and stirred for 100 hours at 20°C. It is evaporated in a rotary evaporator under vacuum, taken up in 130 ml of water and acidified with hydrochloric acid. (pH 3). The filtered solution is made alkaline with caustic soda and shaken out with chloroform. The chloroform phase is dried with potassium carbonate, filtered and evaporated. After thorough drying of the residue in a vacuum and drying cabinet, 35.2 g of d, -£-3-methyl-4-benzyloxy-norephedrine is obtained (m.p. 95-96°C, yield 65% of the theoretical). Analogous to example 5, the partial compounds of formula listed in Table II are obtained

by reacting d",£,-3-methyl-4-benzyloxy-norephedrine and the corresponding tosylate of propanol R-(Cr^)-j-Orl and subsequent removal of the protecting group by hydrogenation, in respectively 55 ml 90 % ethanol at 50°C in the presence of 0.5 g of 10% palladium-charcoal catalyst. In examples 7 and 8, in the starting tosylate, the phenolic hydroxy group is likewise protected with a benzyl group. In example 9, it is used for the hydrogenation of 15 g starting compounds, 3 g palladium catalyst (solvent 15 ml water, and 300 ml ethanol, temperature 58°C). Preparation of the starting material here the norephedrine compound is heated with 3-cyclohexyl-proanol-tosylate for 45 hours in 32 0 ml butanol and 27 ml triethylamine during to-back race.

In Example 10, 1.5 g of catalyst (120 ml of 90% ethanol, temperature 55°C) is used for the hydrogenation of 17.8 g of starting compounds. To prepare the starting material, the norephedrine compound is heated with the corresponding tosylate and 12.5 ml of triethylamine in 150 ml of ethanol for 32 hours with stirring and reflux.

Example 11 "f -1-(3-methyl-4-hydroxy-phenyl)-1-hydroxy-2-(3-phenyl-propyl-amino)-propane

9.1 g, C-3-methyl-4-hydroxy-norephedrine, 10.0 g 3-phenylpropyl bromide, 6.1 g triethylamine and 50 ml butanol are boiled for 8 hours under reflux. The solvent is distilled off on a rotary evaporator, and the residue is taken up in a methylene chloride-water mixture. The separated methylene chloride phase is washed twice with dilute ammonia solution and once with water, dried over sodium sulfate, filtered and evaporated. The remaining base is dissolved with acetone and acidified with alcoholic hydrochloric acid. The next day, vacuum and dry.

The m.p. of the hydrochloride 181-182°C, yield 5.2 g.

The levorotatory starting norephedrine compound is obtained as follows

33.3 g of 2-bromo-1-(3-methyl-4-benzyloxy-phenyl)-propanone-(1) are boiled together with 21.8 g of ditoenzylamine, 10.4 g of triethylamine and 200 ml of toluene for 12 hours with stirring and backflow. Mix with 100 ml of water, separate and shake the toluene vessels three more times with water. After drying with potassium carbonate, it is evaporated, and the residue is recrystallized from 50 ml of ethanol. The dibenzyl compound thus formed (m.p. 77-80°C, yield 32.7 g) is hydrogenated in an alcoholic solution (200 ml of ethanol and 8 ml of water) at 55°C with the addition of 2.0 g of 10% palladium-charcoal catalyst. It is filtered, evaporated and dried in a vacuum. The yield of d,tS-3-methyl-4-hydroxy-norephedrine is 13.5 g.

200 g of this d,f-norephedrine base are dissolved in 2 liters of ethanol and mixed with stirring with 276.4 g of (-)-N-(1-methyl-2-phenyl-2-hydroxyethyl)-maleic acid monoamide. You leave it overnight in a refrigerator and suck out the crystallized salt. It is then recrystallized two more times from ethanol. The thus formed 123.6 g of the pure salt /~a7p°<+><1>0.5° is stirred with 185 ml of water and 141.5 ml of 2-N HaOH. After approx. After 5 hours, suction is applied and recrystallized from ethanol. 39 g of <C-3-methyl-4-hydroxy-norephedrine is obtained, which melts at 171-173°C.

1~ 27q0 d9/10° ml methanol): -15.9°.

Claims (6)

1. Compounds with formula in which R^ means a C^-C^ -alkyl group, R2 means a phenyl radical optionally substituted with halogen atoms, hydroxy groups, C^-Cg-alkyl groups or C^-Cg-alkyl groups, or a optionally with C^-Cg-alkyl groups or C -^ -C 8 -Alkoxy groups substituted cycloalkyl radical with 5 or 6 ring carbon atoms and Alk means an alkyl group of 3 or 4 carbon atoms, and their acid addition alters. 2. Process for the preparation of compounds of formula in which R^ means a C^-C^ -alkyl group, R2 means a phenyl radical optionally substituted with halogen atoms, C-,-C,-alkyl groups or C-j^-Cg-alkyl groups, or an optionally with C-^-Cg-alkyl groups or C 1 -C 8 -Alkoxy groups substituted cycloalkyl radical with 5 or 6 ring carbon atoms, and Alk means an alkylene group of 3 or 4 carbon atoms and their acid addition salts, characterized by ata) a compound of the general formula II in which R^ , R 2 and Alk have the indicated meaning, W means oxygen, or a hydroxy group + a hydrogen atom, the secondary nitrogen atom and/or the phenolic hydroxy group <p> pe can also be protected and that between the secondary nitrogen atom and the group Alk or the grouping -CH(CH3 ) can also have a double bond, the CO group and/or a double bond is reduced and any protective groups present are removed, or b) a compound of formula is reacted with a compound of formula in that in formulas III and IV R and Alk have the indicated meaning, phenolic hydroxy groups can also be protected, and Z and X are each different, and mean an amino group, resp. a protected amino group, or a hydroxy group esterified with a strong inorganic or organic acid, since such a hydroxy group in formula III in unesterified form together with a neighboring hydroxy group can also form an ethylene oxide ring, and any protective groups present in the compounds formed are split off orc) in a compound of formula in which R , R 2 and Alk have the indicated meaning, and the secondary nitro atom and/or phenolic hydroxy groups are protected, the protective groups present are removed by catalytic hydrogenation or by alkaline or acid saponification, and optionally the compounds formed according to method a) are transferred to acid addition salts. 3. Method according to claim 2, for the production of compounds with formula in which Alk means the group (CH^^, R2 is unsubstituted phenyl residue, and means methyl in the 4-position, if the hydroxy group of the associated phenyl residue occurs in the 3-position, or R^ means methyl in the 3-position, while the hydroxy group in the corresponding phenyl ring is in the 4-position, characterized in that a method according to claim 2a)-c) is used. 4. Medicinal product containing a compound of the general formula I in addition to usual carrier and/or dilution resp. excipients. 5. Process for the preparation of a medicinal product, characterized in that a compound of the general formula I is processed resp. brought into a therapeutically usable form with usual pharmaceutical carriers or diluents or other excipients. 6. Use of a compound of the general formula I for the manufacture of pharmaceuticals.