DE3434199A1 - Novel 1-alkylhydroxyphenyl-1-hydroxy-2-alkylamino propanes - Google Patents

Abstract

Novel compounds of the formula <IMAGE> in which R1 is a C1-C4-alkyl group, R2 represents a phenyl radical optionally substituted by halogen, hydroxy groups, C1-C6-alkyl groups or C1-C6-alkoxy groups or a cycloalkyl radical having 5 or 6 ring carbon atoms and optionally substituted by C1-C6-alkyl or C1-C6-alkoxy, and Alk denotes an alkylene group comprising 3 or 4 carbon atoms, and their acid addition salts have positively inotropic action.

Description

New 1- (alkyl-hydroxy-phenYl) -1-hydroxy-2- (alkylamino) -

propane It is known that hydroxyphenalaralkylamino alcohols of the general formula in which R is an alkylene radical with 2 to 5 carbon atoms, have a powerful vasodilator effect while at the same time increasing the stroke volume and the frequency of the heart. In addition, these compounds have a uterospasmolytic effect (see German patent specification 11 82 245).

The invention relates to the subject matter defined by the claims.

The compounds according to the invention are pharmacologically active. In particular they have favorable circulatory effects, in particular a high positive inotropic Effect. With some connections there is only a slight influence on the Heart rate and des Blood pressure. After experiments on the whole animal the compounds according to the invention represent almost pure β1 mimetics, while the compounds known from German patent specification 11 82 245 (for example the well-known active ingredient buphenine) has a B2-mimetic effect. The compounds according to the invention therefore differ in their action in principle from the previously known compounds.

The following information is essential to the invention Explanations.

The occurring in the formula I alkyl and alkoxy groups can or be branched. R1 is especially a methyl or ethyl group, which is preferred is in the 4-position if the hydroxyl group is in the 3-position. at the alkyl groups and alkoxy groups of the radical R2 are also in particular around alkyl and alkoxy groups each having one or two carbon atoms, in particular around methyl and methoxy groups. R2 is preferably an unsubstituted phenyl radical. Possible halogen atoms are, for example: chlorine, fluorine and bromine, in particular Fluorine and chlorine.

If R2 is a phenyl radical, this can be one, two or three of the contain said substituents, which may be the same or different. If R2 is a cycloalkyl radical, it is the cyclopentyl or cyclohexyl radical, each one or two of the named substituents (same or different) may contain.

The group Alk can be straight or branched.

Examples of the latter are: - (CH2) 3-, - (cH2) 4-, The hydroxyl group of the left phenyl radical of the formula I is in particular in the meta or para position.

The remainder R1 is preferably in the neighboring position to this Hydroxy group, the para position in particular coming into question if the hydroxy group stands in meta position. If the hydroxyl group is in the para position, is R1 preferably in the meta position.

The connection according to the example has particularly favorable properties 1.

The compounds according to the invention generally contain two or also three asymmetric carbon atoms.

Mixtures of diastereoisomers can therefore occur in the synthesis. You can use these mixtures on usual Way, for example through Recrystallize, separate.

The enantiostereoisomers can be derived from the pure racemates with Help optically active auxiliary substances (for example optically active acids) in an split up in a known way. But it is also possible during the synthesis optically to use active or diastereomeric starting materials, the corresponding enantiostereomeric or the diastereomeric end products are obtained. Pure isomers or isomer mixtures are used for practical pharmaceutical use in question.

The formula I encompasses all possible enantiomers and diastereomers.

Depending on the process conditions and starting materials, the End products of the formula I in free form or in the form of their salts. The salts of the end products can in a manner known per se, for example with alkali or ion exchangers be transferred back to the bases. The latter can be broken down by implementation with organic or inorganic acids, especially those that lead to formation of therapeutically usable salts are suitable to obtain salts. As such Examples of acids are: hydrohalic acids, sulfuric acid, organic Mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and sulfonic acids.

Examples are: ant, vinegar, propion, amber, glycol, Milk, apple, wine, lemon, ascorbic, maleic, fumaric, hydroxymalein, or Pyruvic acid; Phenyl acetic acid, benzoin, p-amino-benzoin, anthranil, p-hydroxy-benzoin, Salicylic or p-aminosalicylic acid, emboxylic acid, methanesulfonic, athanesulfonic, hydroxyethanesulfonic, Ethylene sulfonic acid; Halobenzene sulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid or 8-chloro-theophylline.

In the specified process for the preparation of the invention Compounds can include the reacting amino groups, known and customary Contain protecting groups. These are residues that are produced by hydrolysis or Hydrogenolysis are easily split off and are often split off during the reaction will. If such protective groups are not split off during the process reaction are then split off after the reaction. Often the starting compounds contain already such protective groups due to their production.

These protecting groups are light, for example acyl groups which can be split off by solvolysis or groups which can be split off by hydrogenation. The solvolytic Removable protective groups are diluted, for example, by saponification with Acids or by means of basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, NH3) at temperatures between 10 and 1500 C, in particular 20 - 1000 C, split off. Groups that can be split off by hydrogenation, such as arylalkyl radicals (benzyl radical) or hydroxycarbonyl radicals (carbobenzoxy radical) are expedient by catalytic Hydrogenation in the presence of conventional hydrogenation catalysts (noble metal catalysts), in particular palladium catalysts or platinum catalysts (platinum oxide), Raney nickel, in a solvent or suspending medium, optionally under increased Pressure, (for example 1 - 50 bar) at temperatures between 20 - 1500 C, in particular 30-1000 ° C., preferably 40-800 ° C., are split off. As a solvent or suspending agent come work. rht! into consideration: water. lower aliphatic as Protective groups that can be split off by hydrogenolysis come, for example, in Question: Benzyl radical, d-phenylethyl radical, benzyl radicals substituted in the benzene nucleus (p-bromine or p-nitrobenzyl radical), carbobenzoxy radical, carbobenzthio radical, tert. -Butylhydroxycarbonyl radical.

Examples of hydrolytic removable radicals are: trifluoroacetyl radical, Phthalyl radical, trityl radical, p-toluenesulfonyl radical and similar and lower alkanyl radicals such as acetyl radical, formyl radical, tert. -Butylcarboxyrest and the like.

In particular, the protective groups customary in peptide synthesis come into play and the spin-off procedures customary there in question. Among other things, this is also to the book by Jesse P. Greenstein and Milton Winitz "Chemistry of Amino Acids", New York 1961, John Wiley and Sons, Inc. Volume 2, e.g. page 883 and the following, referenced. Also the carbalkoxy group (for example low molecular weight) it is an option.

If there are also phenolic and / or alcoholic substances in the starting materials Hydroxy groups can also be present through the protective groups mentioned above be protected, the cleavage taking place in the same way.

Re d ('In process a) Process a) is carried out in a solution or Suspending agent carried out at temperatures, for example between 20 to 1500 ° C, preferably 40 to 1500 ° C. For example, one works in neutral to alkaline pH range. If necessary, it can also be used under increased pressure (up to 150 bar). Examples of solvents or suspending agents are used Consideration: water, lower aliphatic alcohols with 1 - 6 carbon atoms, saturated alicyclic and cyclic ethers with 2 - 6 carbon atoms, lower alkylamides respectively Dialkyl amides of aliphatic C1-C2 carboxylic acids, cyclic aliphatic acid amides (5- or 6-membered ring) such as N-methyl-pyrrolidone and mixtures of these agents.

Possible reducing agents are: Catalytically activated hydrogen using common metal catalysts (supported and unsupported) such as noble metal catalysts (Palladium, palladium carbon, palladium on barium sulfate, platinum, platinum oxide or also Raney Nickel).

The solvents used here 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 hydride, Lithium hydride, sodium triethoxy aluminum hydride, sodium bis-2-methoxy ethoxy aluminum dihydride, Lithium tri-tert. -butoxy-aluminum hydride and similar), whereby as a solvent preferably alicyclic or cyclic ethers are used at temperatures from preferably 20 - 1000 C.

Furthermore, the reduction with aluminum amalgam or aluminum alcoholates can be used (for example aluminum isopropylate / isopropanol) and similarly acting agents or by electrolytic reduction or, if necessary, with nascent hydrogen such as zinc / acid (zinc / glacial acetic acid, zinc-hydrochloric acid).

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

Protective groups that can be split off hydrogenolytically (for example Benzyl groups) are generally split off during the reduction, if these Reduction by means of hydrogen in the presence of hydrogenation catalysts, in particular Palladium catalysts. If protective groups are not present during the Reaction are split off, then these are in the manner already indicated removed after completion of the reaction.

The starting compounds of the formula II used in process a) can be prepared, for example, by combining a compound of the formula R2 - Alk '- M VIII with a compound of the formula is condensed. In formula VIII, Alk 'denotes a straight or branched alkylene group having 2 or 3 carbon atoms, and M denotes either the group C (R) = O or -CHR-NH2, where R is hydrogen or a methyl group. In formula IX, S denotes the group -C (CH3) = O or the group -CH (CH3) NH2.R1 and W have the meanings already given. M and S are each different. The primary amino group in the -CHR-NH2 or -CH (CH3) -NH2 groups is preferably protected by one of the above-mentioned protective groups, in particular a hydrogenolytically cleavable protective group such as the benzyl group. The condensation of the compounds of the formulas VIII and IX is generally carried out at temperatures between 20 and 1500 ° C., in particular 40 to 1000 ° C., in a solvent or dispersant such as lower aliphatic alcohols, water-alcohol mixtures, dimethylformamide or solvent mixtures containing dimethylformamide.

It is possible that by reacting the compounds of the formula VIII with compounds of the formula IX obtained reaction product for the reaction accordingly the process a) not to be isolated first, but immediately in the same reaction medium with the reducing agent to treat. This applies in particular, if catalytically activated hydrogen is used as the reducing agent. Included it is just as well possible that the reducing agent, in particular catalytically activated Hydrogen, right from the start in the implementation of the compounds of the formula VIII is present with compounds of Formula IX. Accordingly, the Process a) as the starting compound of the formula II also includes a mixture of the starting components of formula VIII and IX can be used.

In addition, starting compounds of the formula II can be obtained by using a compound of the formula R2-Alk-Hal or R2-Alk-O-tosyl (p-toluenesulfonyl radical), where R2 has the meaning given, with Alk having a straight or branched alkylene group Is 3 or 4 carbon atoms, and Hal is a halogen atom (preferably chlorine or bromine) with a compound in which R1 and W have the meanings given and the primary amino group can also be protected by a customary protective group. In an analogous manner, a compound of the formula R2-Alk-NH2, in which R2 and Alk have the meanings given and the amino group can likewise contain a customary protective group, can be used with a compound of the formula in which R1 and W have the meanings given and Hal is a halogen atom (preferably bromine), are reacted. Hydroxyl groups that are present are preferably likewise protected by customary protective groups.

The latter reactions are, for example, with or without Solvent at temperatures between 20 and 2000 C, preferably 50 - 1800 C, carried out, optionally in the presence of acid-binding agents. As a solvent The following can be considered, for example: aromatic hydrocarbons, aliphatic Ketones, ethers, halogenated hydrocarbons, acid amides, alcohols, sulfoxides.

Regarding process b) Process b) can be used without additional solvent or in a suitable solvent or dispersant. as Examples of solvents or dispersants are: Aromatic hydrocarbons such as benzene, mesitylene, toluene, xylene; lower aliphatic ketones such as for example acetone, methyl ethyl ketone; halogenated hydrocarbons such as Chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; Ether like for example Tetrahydrofuran and dioxane; Sulfoxides such as dimethyl sulfoxide; tertiary Acid amides such as dimethylformamide and N-methylpyrrolidone; lower alcohols such as, for example, methanol, ethanol, isopropanol, amyl alcohol, butanol, tert-butanol and so forth. The reaction is carried out, for example, at temperatures from 200 to 2000 C, preferably 50 to 1800 C or 80 to 1200 C, carried out. Will a solution or dispersants are used, one often works at the reflux temperature this means. The reaction often runs even at normal temperature from, or at a temperature between 20 to 500 C.

It can be useful to use one of the starting compounds in excess to use and / or the reaction component of the general formula III in solution or suspended form to the dissolved or suspended form Add reaction component of general formula IV. The molar ratio between the compounds of the general formulas III and IV can be 1: 1 to 1:10 and optionally amount even more.

In carrying out the reaction, ethylene oxide starting compound can be used instead of the ethylene oxide compound (if in formula III X in the form of the hydroxyl group with the neighboring hydroxyl group forms the ethylene oxide ring) also the corresponding one Halohydrin or a mixture of these two compounds (synthesis crude product) can be used.

If appropriate, the reaction can also be carried out in the presence of acid-binding agents Agents such as alkali carbonates, potash, soda, alkali hydroxides or tertiary bases be performed.

If Z or X is an esterified hydroxy group, then act these are reactive esters.

A reactive ester is, for example, one strong organic or inorganic acid, especially a hydrohalic acid, for example hydrochloric, bromic or hydroiodic acid, or a sulfonic acid, such as an aryl or C1-C6 alkyl sulfonic acid, for example of lower alkylbenzenesulfonic acids (p-toluenesulfonic acid). The reaction is carried out using a reactive ester advantageously in the presence of a basic condensing agent or an excess carried out on amine. In particular, agents such as dioxane / water are used as solvents, Dimethylformamide / water or lower saturated aliphatic alcohols in question.

If Z or X is an amino group, way if hydroxyl groups, especially phenolic hydroxyl groups, are present this one of the protective groups already given, for example a benzyl group, contain. If these protective groups are not split off during the reaction they can be used in the manner already indicated after the reaction has ended removed.

The starting materials of the formula III are known or are derived from corresponding keto compounds prepared according to such methods, for example are described in the following references: W.H. Hartung, J.C. Munch, E. Miller and F. Crossly, J. Am. Chem. Soc. 53, 1931, pages 4149-4160 (starting materials III with X = NH2); Houben-Weyl, Methods of Organic Chemistry Volume IV / 1d (1981), Pages 308-310 (starting materials III with X = halogen or another esterified hydroxyl group. The latter compounds can also be used analogously to Houben-Weyl, Methods of Organic Chemie, Volume 5/3 (1962), page 503 ff., Volume 6/2 (1963), page 475 ff. Or Volume 9 (1955) page 426.

The starting materials of the formula IV are known.

Compounds of the formula III which contain an ethylene oxide ring, are known or can be prepared in the customary manner from halohydrides of the formula III, in which X is halogen, can be prepared (see Houben-Weyl, Methods of Organic Chemistry, Volume 6/3 (1965), page 374 and the following): Treatment of the Halohydrins with alkaline agents, e.g. alcoholic KOH for lower ones Temperatures.

The phenolic hydroxyl group is preferably protected and the protecting groups if necessary then removed again.

Regarding process c) The splitting off of protective groups according to this The procedure is carried out under the conditions already specified for this purpose.

The starting materials of the formula V can, for example, according to the method a) and b) can be obtained.

Pharmacological or pharmaceutical information The Compounds are used in the manufacture of pharmaceutical compositions and preparations suitable. The pharmaceutical compositions or drugs contain as active ingredient one or more of the compounds according to the invention, optionally mixed with other pharmacologically or pharmaceutically active substances Fabrics. The pharmaceuticals are produced in a known manner, with the known and customary pharmaceutical excipients as well as other customary carrier and diluents can be used.

Such substances, for example, come as such carriers and auxiliaries in question, in the following references as auxiliaries for pharmacy, cosmetics and adjacent areas are recommended or indicated: Ullmanns Encyklopädie der Technische Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 and ff., H.v. Czetsch-Lindenwald, auxiliaries for Pharmacy and related fields; Pharm. Ind., No. 2, 1961, page 72 and ff .; Dr. H. P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas Cantor KG. Aulendorf in Württemberg 1971.

Examples of this are gelatin, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (e.g. corn starch), gelatin, Gum arabic, alginic acid, tylose, talc, lycopodium, silica (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers, in which the cellulose hydroxyl groups partly with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols are etherified, for example Methyloxypropyl cellulose, Methyl cellulose, hydroxypropylmethyl cellulose), stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated ones (for example Stearates), emulsifiers, oils and fats, especially vegetable (e.g. peanut oil, Castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, Cod liver oil, mono-, di- and triglycerides of saturated fatty acids C12H2402 up to C18 36 and their mixtures), pharmaceutically acceptable mono- or polyvalent Alcohols and polyglycols such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, Mannitol and so on, which may also be etherified, benzyl benzoate, Dioxolanes, glycerine formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12 alcohols, Dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (especially medium viscosity Dimethylpolysiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, Magnesium carbonate and the like.

Substances that cause decay can also be used as auxiliary materials cause (so-called disintegrants) such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, Sodium carboxymethyl cellulose or microcrystalline cellulose. Also can known wrapping materials are used, such as, for example: polyacrylic acid esters, cellulose ethers and similar.

For example, water or physiological solutions are used to produce solutions compatible organic solvents in question, such as Ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulfoxide, fatty alcohols, Triglycerides, partial esters of glycerol, paraffins and the like. For injectables Solutions or suspensions come, for example, non-toxic parenterally acceptable Diluents or solvents in question, such as: 1,3-butanediol, Water, Ringer's solution, isotonic saline solution or even hydrogenated oils including synthetic mono- or diglycerides or fatty acids such as oleic acid.

In the production of the preparations, known and customary Solubilizers or emulsifiers can be used. As a solubilizer and emulsifiers are, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated Sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated Fats, polyoxyethylated oleotriglycerides, linolized oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or 1-methyl-3- (2-hydroxyethyl) -imidazolidone- (2) polyoxyethylated means here that the substances in question Contain polyoxyethylene chains, the degree of polymerization generally between 2 to 40 and in particular between 10 and 20.

Such polyoxyethylated substances can, for example, by reaction of compounds containing hydroxyl groups (for example mono- or diglycerides or unsaturated compounds such as those that contain oleic acid residues) can be obtained with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of oleopotriglycerides are olive oil, peanut oil, castor oil, Sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Fiedler "Lexicon of auxiliaries for pharmacy, cosmetics and related fields "1971, pages 191 to 195).

In addition, the addition of preservatives, stabilizers, Buffer substances, e.g. calcium hydrogen phosphate, colloidal aluminum hydroxide, Flavor corrections, sweeteners, colorings, antioxidants and complexing agents (for example, ethylenediaminotetraacetic acid) and the like are possible.

If necessary, to stabilize the active ingredient molecule with physiological compatible acids or buffers to a pH range of approx. 3 to 7. In general, a pH value that is as neutral as possible to weakly acidic (up to pH 5) is achieved preferred.

As antioxidants, for example, sodium metabisulphite, ascorbic acid, Gallic acid, gallic acid alkyl ester, butylhydroxyanisole, nordihydroguajaretic acid, Tocopherols as well as tocopherols + synergists (substances the heavy metals through complex formation bind, for example lecithin, ascorbic acid, phosphoric acid) for use. Of the The addition of the synergists increases the antioxidant effect of the tocopherols considerably.

Sorbic acid and p-hydroxybenzoic acid esters, for example, can be used as preservatives (for example lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, Phenol, cresol, benzethonium chloride and formalin derivatives are possible.

The pharmaceutical and galenic handling of the invention Connections are made according to the usual standard methods. For example, active ingredient (s) and auxiliary or carrier materials by stirring or homogenizing (for example by means of conventional mixing devices) well mixed, generally at temperatures between 20 and 80 ° C., preferably 20 to 500 ° C., in particular at room temperature is being worked on. Otherwise, reference is made to the following standard work: Sucker, Fuchs, Speiser, Pharmaceutical Technology, Thieme-Verlag Stuttgart, 1978.

The application of the active ingredients or the drugs can on the skin or mucous membrane or inside the body, for example oral, enteral, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal.

The parenteral preparation forms are in particular about sterile or sterilized products.

The addition of other active pharmaceutical ingredients is possible.

The compounds according to the invention show in the anesthetized dog (Circulatory test) a good positive inotropic effect and an increase in cardiac output. For example, in the above-mentioned experimental method, a dose of 0.1 mg / Body weight kg (dog) achieved a 100% increase in heart muscle strength.

The lowest already inotropically effective dose in the one given above Animal experiment is for example 0.1 mg / kg orally 0.01 mgfkg intravenous.

As a general dose range for the inotropic effect (animal experiment as above), for example, 0.1 to 1.0 mg / kg orally, in particular 0.3 0.01 to 0.1 mg / kg intravenously, especially 0.03.

The compounds of the invention are therefore, for example, for Treatment of myocardial insufficiency suitable.

The pharmaceutical preparations generally contain between 0.01 mg to 100 mg, preferably 0.1 to 50 mg of the active component (s) according to the invention.

Administration can, for example, in the form of tablets, capsules, Pills, coated tablets or can be made in liquid form. Come as liquid forms of application for example in question: oily or alcoholic or aqueous solutions as well as suspensions and emulsions.

Preferred forms of use are tablets that are between 5 mg and 50 mg or solutions containing between 0.1% to 5% of the active substance.

The single dose of the active components according to the invention can, for example a) for oral dosage forms between 5 mg and 50 mg, preferably 10 to 40 mg mg, b) for parenteral dosage forms (for example intravenous, intramuscular) between 0.5 mg and 5 mg, preferably between 2 mg and 4 mg.

- (The doses are in each case based on the free base) - For example 1 to 3 tablets containing 10 to 30 mg can be more effective 3 times a day Substance or, for example, in the case of intravenous injection, one ampoule 1 to 5 times a day from 1 to 5 ml content with 0.5 to 5 mg of substance are recommended. When administered orally the minimum daily dose is, for example, 10 mg; the maximum daily dose oral administration should not exceed 100 mg.

For the treatment of dogs and cats, the single oral dose is recommended generally between about 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 according to the invention in the mouse (expressed by the LD 50 mg / kg; Miller and Tainter method: Proc. Soc. Exper. Biol. A. Med.

57 (1944) 261) lies between, for example, in the case of oral administration 400 and 600 mg / kg.

The drugs can be used in human medicine, veterinary medicine as well as in agriculture alone or in admixture with other pharmacologically active substances Substances are used.

Example 1d, W-1- (3-Hydroxy-4-methyl-phenyl) -1-hydroxy-2- (3-phenylpropylamino) propane 4.2 g of 1- (3-benzyloxy-4-methyl-phenyl) -1-oxo-2- (3-phenylpropylamino) propane hydrochloride are dissolved in 80 ml of 90% ethanol with the addition of 0.7 g 10 Zigem palladium-carbon catalyst hydrogenated at 500 C. It is filtered and evaporated, and the residue is dissolved in ethyl acetate. The salt which has crystallized out is filtered off with suction and dried.

Yield: 3.2 g F. of the hydrochloride: 160 - 1610 C.

Preparation of the starting compound: 8.2 g of 1- (3-hydroxy-4-methyl-phenyl) -propanon- (1) are together with 7.6 g of benzyl chloride, 8.4 g of potassium carbonate, 0.28 g of sodium iodide reacted in 35 ml of 95% ethanol at reflux temperature. After six hours The mixture is allowed to cool to the boil, water is added, the mixture is filtered off with suction and crystallized from isopropanol around.

12.5 g of the corresponding 3-benzyloxy ketone are obtained (F .: 55-560 C).

11.5 g of this compound are anhydrous under nitrogen in 80 ml Chloroform at 500 C with stirring within two hours with a solution 7.2 g of bromine in 17 ml of chloroform were added. It is allowed to cool in a stream of nitrogen and evaporated on a rotary evaporator and recrystallized from isopropanol.

This gives 11.2 g of 2-bromo-1- (3-benzyloxy-4-methylphenyl) propanone (1), which melts at 62 - 630 C.

A mixture consisting of 10.0 g of 2-bromo-1- (3-benzyloxy-4-methyl-phenyl) -propanone (1), 4.5 g of 3-phenylpropylamine, 40 ml of ethanol and 3.65 g of triethylamine is 7 hours on Boiled under reflux and then evaporated on a rotary evaporator. One takes the residue is dissolved in water and chloroform, the chloroform phase is separated off and shaken this twice with dilute ammonia solution and twice with water. Of the The extract, dried over potassium carbonate, is evaporated, the residue in ethyl acetate dissolved and acidified with alcoholic hydrochloric acid. The precipitated hydrochloride is suctioned off the next day and recrystallized from isopropanol.

The 1- (3-benzyloxy-4-methyl-phenyl) -1-oxo-2- (3-phenyl-propylamino) thus obtained -propane hydrochloride melts at 175 - 1760 C.

Yield: 5.4 g.

The d,? - compounds of the formula shown in Table 1 are analogous to Example 1 by catalytic hydrogenation of the corresponding protected d, l-ketones of the formula obtained in the presence of a 10% palladium-carbon catalyst. The residue obtained after removing the solvent is in each case recrystallized from isopropanol.

The starting compound for Examples 2 and 3 is prepared analogous to Example 1, with the following change being made: The condensation product des 2-bromo-1- (3-methyl-4-benzyloxy-phenyl) -propanon- (1) with 3-phenyl-propylamine or 1-methyl-3-phenyl-propylamine is not in chloroform but in added a methylene chloride-water mixture and that after evaporation of the methylene chloride The residue obtained is dissolved in acetone and acidified with hydrochloric acid.

Table 1 Example- Alk R F. ° C Yield g Starting solvent Catalyst No. (Hydroketone amount; chloride) reaction temperature 2 - (CH2) 3 -C6H5 173-176 5.8 9 g 150 ml 1 g; 45 ° C 94% Ethanol 3 -CH (CH2) 2- -C6H5 221-222 4.5 9.1 g 150 ml 1 g; 45 ° C CH3 94% Ethanol Example 4 d, l-1- (3-Hydroxy-4-methyl-phenyl) -1-hydroxy-2- (3-fluorophenyl-propylamino) -propane 23.4 g of 1- (3-benzyloxy-4-methyl-phenyl) -1-oxo-2- (3-fluorophenyl-propyl-benzylamino) -propane-p-toluenesulfonate (crude product, mp 140-1420 C are in Added water and excess sodium hydroxide solution and extracted four times with methylene chloride to obtain the base.

The solvent is distilled off and the residue is dissolved in 130 ml Ethanol, acidified with 1N hydrochloric acid and hydrogenated at 600 C with the addition of 2 g of 10 % palladium-carbon catalyst with hydrogen while shaking. After completion the uptake of hydrogen is distilled off and the residue is crystallized out Acetone around. 5.8 g of the hydrochloride with a melting point of 147-1490 ° C. are obtained.

The starting substance is obtained as follows: 30 g of p-fluorophenyl-propyl-benzylamine hydrochloride are stirred with 200 ml of water and excess concentrated ammonia solution. It is extracted four times with methylene chloride and the methylene chloride is distilled away. The residue is dissolved in 240 ml of toluene, 17.9 g of 2-bromo-1- (3-benzyloxy-4-methyl-phenyl) -propanone- <1) added and the resulting solution Boiled under reflux for 18 hours. Place in the refrigerator overnight and suck off the excess HBr salt Starting product from (14.9 g; mp 176-178 ° C).

The toluene filtrate is distilled off in vacuo, the residue with 10% ammonia solution made alkaline and extracted four times with methylene chloride.

The dried methylene chloride solution is evaporated and the residue dissolved in acetone. It is acidified with p-toluenesulphonic acid and the resulting precipitate p-Toluenesulfonate with petroleum ether from (mp 140-142 ° C).

Example 5 d, l-1- (3-methyl-4-hydroxyphenyl) -1-hydroxy-2- [3- (3,4-dimethoxyphenyl) propylamino-7-propane 10.5 g of 3- (3,4-dimethoxyphenyl) propanol tosylate are now added together with 7.7 g of 2,1-3-methyl-4-benzyloxy-norephedrine and 3.65 g of triethylamine in 60 ml of n-butanol implemented. The mixture is refluxed for 15 hours, evaporated in a rotary evaporator and the residue is taken up in a chloroform-water mixture. The phases are separated and the chloroform phase is extracted twice with dilute sodium hydroxide solution and twice with water.

After drying with potassium carbonate, it is filtered, evaporated, dissolved in ethyl acetate and acidified with alcoholic hydrochloric acid. The next day is filtered off with suction and recrystallized from ethanol. 6.6 g of 1- (3-methyl-4-benzyloxyphenyl) -1-hydroxy-2- [3- (3,4-dimethoxyphenyl) propylamino7-propane hydrochloride are obtained, which melts at 198-2000 C.

To split off the benzyl protective group, 5.2 g of the obtained Benzyl compound with the addition of 0.5 g of 10% palladium-carbon catalyst in 55 ml of 90% ethanol are hydrogenated at 50.degree. It is filtered, evaporated and crystallized the residue from isopropanol.

F. of the hydrochloride: 188-1890 C. Yield: 3.3 g.

The d, d -3-methyl-4-benzyloxy-norephedrine can be obtained as follows will: 36.2 g of d, e -3-methyl-4-hydroxy-norephedrine (compare Example 11) are prepared in a from 13.1 g of 85% KOH and 100 ml of ethanol alcoholic potassium hydroxide solution added. It is evaporated in vacuo, 22.8 are added g of benzyl chloride in 220 ml of dimethylformamide and stir for 100 hours at 200 ° C. Now it is evaporated in a rotary evaporator in vacuo, taken up in 130 ml of water and acidified with hydrochloric acid (pH 3). The filtered solution becomes alkaline with sodium hydroxide solution placed and extracted with chloroform. The chloroform phase is dried with it Potassium carbonate, filtered and evaporated. After thorough drying of the residue 35.2 g of d, -3-methyl-4-benzyloxy-norephedrine (F .: 95-960 C, yield: 65 e of theory).

The d, l-compounds of the formula listed in Table 2 are analogous to Example 5 by reacting d, t -3-methyl-4-benzyloxy-norephedrine and the corresponding tosylate of propanol R- (CH2) 3-OH and then splitting off the benzyl protective groups by hydrogenation in 55 ml of 90% ethanol at 50 ° C. in each case Presence of 0.5 g of 10% palladium-carbon catalyst obtained. In Examples 7 and 8, the phenolic hydroxyl group in the starting tosylate is likewise protected by a benzyl group.

In Example 9, starting compound for the hydrogenation of 15 3 g palladium catalyst used (solvent 15 ml water and 300 ml ethanol, Temperature 580 C). The norephedrine compound is used here to manufacture the starting substance with the 3-cyclohexyl propanol tosylate for 45 hours in 320 ml of butanol and 27 ml of triethylamine heated under reflux In Example 10, 17.8 g of starting compound are used for the hydrogenation 1.5 g of catalyst used (120 ml of 90% ethanol, temperature 550 ° C.). For the production the starting substance is the norephedrine compound with the corresponding tosylate and 12.5 ml of triethylamine in 150 ml of ethanol for 32 hours with stirring and reflux heated.

Table 2 Example- R F. 0C Yield Norephedrine Starting Compound Yield Before No u, cu a mlco lffi w 2.5 7.7 - w S WS t (/ nb t78 t7) b) tFs mm dd br I t OH 207-209 175-76 5.8 43.9 X 48 n N OK 00, 11.1 22 N »- ° tg O g N n N At W> »O Example 11 t-1- (3-Methyl-4-hydroxyphenyl) -1-hydroxy-2- (3-phenylpropylamino) propane 9.1 g of -3-methyl-4-hydroxy-norephedrine, 10.0 g of 3-phenylpropyl bromide, 6.1 g of triethylamine and 50 ml of butanol are refluxed for 8 hours. 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 base that remains is dissolved in acetone and acidified with alcoholic hydrochloric acid. The next day it is suctioned off and dried.

F. 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-benzyloxyphenyl) propanone- (1) together with 21.8 g of dibenzylamine, 10.4 g of triethylamine and 200 ml of toluene 12 Boiled under reflux for hours with stirring. 100 ml of water are added and the mixture is separated away and shakes the toluene phase three more times with water. To Drying with potassium carbonate is evaporated and the residue from 50 ml of ethanol recrystallized.

The dibenzyl compound thus obtained (mp .: 77-800 C; yield: 32.7 g) is in an alcoholic solution (200 ml of ethanol and 8 ml of water) at 550 C. hydrogenated with the addition of 2.0 g of 10% palladium-carbon catalyst.

It is filtered, evaporated and dried in vacuo. The yield at d, t-3-methyl-4-hydroxy-norephedrine is 13.5 g.

200 g of this d, -norephedrine base are dissolved in 2 liters of ethanol and with stirring with 276.4 g of (-) - N- (1-methyl-2-phenyl-2-hydroxyethyl) -maleic acid monoamide offset. It is left to stand in the refrigerator overnight and what has crystallized out is filtered off with suction Salt off. It is then recrystallized twice from ethanol. The so obtained 123.6 g of the pure salt [α] D20 + 10.5 ° are mixed with 185 ml of water and 141.5 Stirred 2N NaOH.

After about 5 hours, the product is filtered off with suction and recrystallized from ethanol. 39 g of t-3-methyl-4-hydroxynorephedrine, which melts at 171-173 ° C., are obtained.

[α] 20 (1g / 100 ml methanol): -15.9 ° D Examples for pharmaceutical preparations Example 1 / tablets 1 kg of active ingredient of the compound according to Example 7, with 5 kg of milk sugar and 3 kg of microcrystalline cellulose mixed and mixed with a solution of 0.3 kg of polyvinylpyrrolidone in 1.2 kg of water in granulated in a known manner.

After adding 3.45 kg of microcrystalline cellulose, 2 kg of corn starch, 0.05 kg of highly disperse silica and 0.2 kg of magnesium stearate become tablets weighing 150 mg, a diameter of 7 mm and a radius of curvature of 5 mm pressed. The hardness of the tablets is 4 - 7 kg (Heberlein hardness tester).

Each tablet contains 10 mg of active ingredient.

Example 2 / ampoules 15 g of the compound according to Example 7 are used together with 87.7 g of sodium chloride dissolved in 9 liters of water for injections, the solution made up to 10 liters with water for injections and about a Membrane filter of suitable pore size sterile filtered.

The filtrate is sterilized under aseptic conditions to 2 ml Filled ampoules.

One ampoule contains 3 mg of active substance in 2 ml of solution.

Claims (10)

New 1- (alkyl-hydroxyphenyl) -1-hydroxy-2- (alkylamino) propane patent claims: 01; Compounds of the formula where R1 is a C1-C4-alkyl group, R2 is a phenyl radical which is optionally substituted by halogen atoms, hydroxyl groups, C1-C6-alkyl groups or C1-C6-alkoxy groups or a cycloalkyl radical with 5 which is optionally substituted by C1-C6-alkyl groups or C1-C6-alkoxy groups or represents 6 ring carbon atoms and Alk represents an alkylene group of 3 or 4 carbon atoms and their acid addition salts. 2. Compounds according to claim 1, characterized in that R1 in 4-position and the phenolic hydroxyl group in 3-position or that R1 in 3-position and the phenolic hydroxyl group is in the 4-position. 3. Compounds according to one or more of the preceding claims, characterized in that R1 is a methyl group, Alk consists of 3 carbon atoms and R2 is phenyl or halophenyl. 4. Compounds according to one or more of the preceding claims, characterized in that R2 is a phenyl, a chlorophenyl or a fluorophenyl radical is. 5. Compounds according to one or more of the preceding claims, characterized in that R2 is a phenyl radical or a 4-chlorophenyl or a 4-fluorophenyl radical is. 6. Process for the preparation of compounds of the formula where R1 is a C1-C4-alkyl group, R2 is a phenyl radical optionally substituted by halogen atoms, hydroxyl groups, C1-C6-alkyl groups or C1-C6-alkoxy groups or a cycloalkyl radical optionally substituted by C1-C6-alkyl groups or C1-C6-alkoxy groups with 5 or represents 6 ring carbon atoms and Alk represents an alkylene group of 3 or 4 carbon atoms and their acid addition salts, characterized in that a) a compound of the general formula where R1, R2 and Alk have the meanings given, W is oxygen or a hydroxyl group plus a hydrogen atom, the secondary nitrogen atom and / or phenolic hydroxyl groups can also be protected and where between the secondary nitrogen atom and the group Alk or the grouping -CH (CH3 ) a double bond can also be present, which reduces the Co group and / or a double bond and splits off any protective groups present, or b) a compound of the formula with a compound of the formula R2-Alk-Z IV, where in the formulas III and IV R and Alk have the meanings given, phenolic hydroxyl groups can also be protected, and Z and X are each different and are either an amino group or a protected amino group or denote a hydroxyl group esterified by a strong inorganic or organic acid, such a hydroxyl group in the formula III in unesterified form also being able to form an ethylene oxide ring together with the adjacent hydroxyl group and possibly splitting off protective groups present in the compounds obtained, or c) in a compound the formula wherein R1, R2 and Alk have the meanings given and the secondary nitrogen atom and / or phenolic hydroxyl groups are protected, the protecting groups present by catalytic hydrogenation or by alkaline or acidic saponification, and optionally the compounds obtained by processes a) to c) in the acid addition salts transferred. 7. Compounds of the formula I for use as therapeutic agents. 8. Medicaments containing a compound of the general formula I in addition to customary carriers and / or diluents or auxiliaries. 9. A method for the production of a medicament, characterized in that that a compound of general formula I with common pharmaceutical Carriers or diluents or other auxiliaries processed pharmaceutical preparations or in a therapeutic applicable form is brought. 10. Use of compounds of the general formula I for the preparation of medicines.