CH618958A5 - Process for the preparation of novel secondary acyloxyamines - Google Patents

Description

The present invention relates to a process for the preparation of new secondary acyloxyamines and their salts.

The compounds obtainable according to the invention correspond to the general formula

0

CH — GH--

-CH,

--NH—— Ri

(I)

wherein Zt represents hydrogen or the acyl radical of an organic carboxylic acid and Z2 represents the acyl radical of an organic carboxylic acid, wherein acyl radicals Zt and Z2 are the same or different, and Ra represents an optionally substituted aliphatic, cycloalophatic or araliphatic hydrocarbon radical.

Acyl radicals Zt and Z2 correspond to the formula -C (= 0) -R, in which R denotes an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical, such as optionally substituted lower alkyl, furthermore lower alkenyl or lower alkynyl, optionally substituted mono- or polycyclic cycloalkyl, optionally substituted phenyl or phenyl-lower alkyl, and phenyl-lower alkenyl or phenyl-lower alkynyl. Substitu ent of lower alkyl and lower alkenyl or lower alkynyl are, for. B. optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and / or halogen, such as cycloalkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkenyl and phenyl-lower alkynyl, optionally, for. B. by halogen, substituted lower alkyl, such as lower alkyl or trifluoromethyl, optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy or halogen, and / or functionally modified carboxy, such as esterified carboxy, such as. B. Nie-deralkoxycarbonyl, amidated carboxy, e.g. B. carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, or cyan, where substituted radicals may have one or more substituents in any of the positions suitable for substitution.

Aliphatic hydrocarbon radicals Rj are primarily lower alkyl, but can also be lower alkenyl or lower alkynyl, while cycloaliphatic hydrocarbon radicals Rt z. B. are mono- or polycyclic cycloalkyl. Araliphatic hydrocarbon radicals are in particular phenyl-lower alkyl, also phenyl-lower alkenyl or phenyl-lower alkynyl. Substituents of lower alkyl, and lower alkenyl or lower alkynyl are, for. B. optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy, phenyloxy and / or halogen, optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. B. lower alkoxycarbonyl, amidated carboxy, e.g. B. carbamoyl, N-lower alkyl-carb-amoyl or N, N-di-lower alkylcarbamoyl, or in particular those of cycloalkyl, phenyl-lower alkyl, phenyl-lower alkenyl and phenyl-lower alkynyl z. B. optionally, such as halogen, substituted lower alkyl, such as lower alkyl or trifluoromethyl, optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy, methylenedioxy or halogen, and / or optionally functionally modified carboxy, such as carboxy, esterified carboxy, e.g. B. lower alkoxycarbonyl, amidated carboxy, e.g. B. optionally N-substituted carbamoyl, such as carbamoyl, N-lower alkyl-carbamoyl or N, N-di-lower alkyl-carbamoyl, or cyano, where substituted radicals may have one or more substituents in any of the positions suitable for substitution.

In connection with the present patent application, radicals and compounds labeled "lower" contain up to 7, in particular up to 4, acyl radicals up to 5 carbon atoms.

The general terms used in connection with the present patent application have e.g. B. The following meanings:

Lower alkyl can be unbranched or, especially at the a-carbon atom, branched and is z. As methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, in connection with Ri, isopropyl or tert-butyl and in connection with R z. B. also tert-butyl.

Lower alkenyl contains one or more double bonds and is e.g. B. allyl, 1- or 2-methylallyl or 3,3-dimethylalyl, while lower alkynyl z. B. means propargyl.

3,618,958

Monocyclic cycloalkyl is e.g. B. cyclopropyl, cyclopentyl or cyclohexyl, while polycyclic cycloalkyl z. B. Dicyclo [2,2, llheptyl (norbornyl), bicyclo [2,2,2] octyl or adamantyl, such as 1-adamantyl.

5 Phenyl lower alkyl is e.g. B. benzyl, 1- or 2-phenylethyl, while phenyl lower alkenyl z. B. cinnamyl, and phenyl-lower alkynyl z. B. phenylpropargyl, the radical R z. B. can also be styryl or phenylethynyl.

Lower alkoxy is e.g. B. methoxy, ethoxy, n-propyloxy, isolo propyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy, also n-pentyloxy or neopentyloxy.

Halogen is especially chlorine or bromine, but can also be fluorine and iodine.

Lower alkoxycarbonyl is e.g. B. methoxycarbonyl or 15 ethoxycarbonyl, while N-lower alkyl and N, N-di-lower alkyl-carbamoyl z. B. N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N-ethyl-N-methyl-carbamoyl or N, N-diethylcarbamoyl.

Lower alkoxy-lower alkyl is e.g. B. methoxymethyl, eth-20 oxymethyl, 2-methoxyethyl, 2-ethoxyethyl, l-methoxy-2-propyl, l-ethoxy-2-propyl or l-ethoxy-2-butyl, wherein in connection with the rest Rj lower alkoxy vom Linking carbon atom of the lower alkyl part is preferably separated by at least 2, usually 2-3 carbon atoms.

Phenyloxy lower alkyl is e.g. B. phenyloxymethyl and / or in particular 2-phenyloxyethyl, phenyl in such radicals, for. B. how an aromatic radical in an araliphatic group Rt can be substituted.

30 halogen lower alkyl is e.g. B. fluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl or 2-bromoethyl.

Carboxy lower alkyl is e.g. B. carboxymethyl, 2-carboxy-ethyl or l-carboxy-2-propyl, while Niederalkoxy-carbo-35 nylniederalkyl z. B. methoxycarbonylmethyl, 2-methoxycarbonylethyl, l-methoxycarbonyl-2-propyl, 1-ethoxycarbonyl-2-butyl, l-ethoxycarbonyl-3-butyl, 2-ethoxycarbonylethyl or l-ethoxycarbonyl-2-propyl.

Optionally N-substituted carbamoyl-lower alkyl is 40 z. B. carbamoylmethyl, carbamoylethyl, l-carbamoyl-2-propyl, N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-N-methylcarbamoylmethyl, 2-N-ethylcarbamoyl-ethyl, 2-N, N-N, Dimethylcarbamoylethyl, 1N-methylcarbamoyl-2-propyl or 1-N, N-dimethylcarb-45 amoyl-2-propyl.

Cyan lower alkyl means e.g. B. cyanomethyl, 1- or 2-cy-ethyl, 3-cyanopropyl and l-cyan-2-propyl.

Salts of compounds of formula I are acid addition salts, in particular pharmaceutically usable, non-toxic-50 see acid addition salts with suitable inorganic acids, e.g. B. hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, for. B. 55 formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, emulsified acid, phenonic acid, phenonic acid, phenonic acid, phenonic acid, phenonic acid, phenolic acid, 60% Ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, 4-chorbenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid. As a result of the close relationships between the new compounds in free form and in the form of their salts, the 65 free compounds and the salts are also to be understood as meaning the appropriate salts or free compounds, if appropriate.

The compounds of the present invention can be found in

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4th

Form of isomer mixtures or of uniform isomers, in particular in the form of racemates or optical antipodes.

The new compounds of the present invention have valuable pharmacological properties, in particular cardioselective / 3-receptor-stimulating effects of long duration of action, which can be demonstrated on the basis of corresponding pharmacological experiments. So the new compounds have a positive chronotropic and in particular a positive inotropic effect, which z. B. on the isolated atrium of the guinea pig by increasing the myocardial contractility and the heart rate in each case in a dosage of about 0.003 y / ml to 1 y / ml. On the anesthetized cat, i. v. application of the new compounds in a dosage of 0.003 mg / kg to 1.0 mg / kg show a clear, long-lasting increase in myocardial contractility (rate of pressure increase in the left ventricle) and the heart rate without causing a decrease in arterial blood pressure is coming.

These pharmacological activities characterize the new compounds as cardiotonics, which alone or in combination with other cardiovascular-active compounds, such as. B. cardiac glycosides, in the form of pharmaceutical preparations for the treatment of cardiac insufficiency. However, the new compounds of the present invention can also be used as valuable intermediates for the preparation of other valuable, in particular pharmaceutically active compounds.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Zt is hydrogen or an acyl radical and Z2 is an acyl radical, where acyl radicals Zt and Z2 can be identical or different and for the group of the formula —C (= 0) —R are in which R is lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl, furthermore phenyl or phenyl-lower alkyl, where phenyl can be substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and in which Ra is lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, N. -Lower alkyl-carbamoyl-lower alkyl, N, N-di-lower-alkyl-carbamoyl-lower alkyl or cyano-lower alkyl, and optionally polycyclic cycloalkyl, furthermore preferably means phenyl-lower alkyl or phenyloxy-lower alkyl branched on the a-carbon atom, phenyl optionally by lower alkyl, lower alkoxy, halogen, trifluoromethyl , Lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoy 1, N, N-Diniederalkyl-carbamoyl or cyan may be substituted, and acid addition salts, in particular non-toxic, pharmaceutically usable acid addition salts thereof.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Za is hydrogen or acyl and Z2 is acyl, where the two acyl groups Zt and Z2 can be the same or different and for the rest of the formula —C (= 0 ) —R are where R is lower alkyl having up to 4 carbon atoms, especially methyl, ethyl, isopropyl or tert-butyl, furthermore phenyl, and wherein Ri is primarily lower alkyl having up to 4 carbon atoms, especially isopropyl or tert-butyl , and optionally N-lower alkyl or N, N-di-lower alkyl-substituted carb-amoyl-lower alkyl, e.g. B. carbamoylmethyl, 1-carbamoyl-2-propyl, 1-N-methylcarbamoyl-2-propyl or 1-N, N-dimethylcarbamoyl-2-propyl, or cyano-lower alkyl, e.g. B. cyanomethyl or l-cyan-2-propyl, further preferably branched phenyl-lower alkyl in the lower alkyl part, for. B. l-methyl-2-phenyl-ethyl or 1-methyl-3-phenyl-propyl, carbamoylphenyl-lower alkyl or carbamoylphenyloxy-lower alkyl, e.g. B. 2- (2- or 4-carb

amoylphenyl) ethyl or 2- (2- or 4-carbamoylphenyl-oxy) ethyl means, and acid addition salts, especially non-toxic, pharmaceutically acceptable acid addition salts thereof.

The invention relates primarily to a process for the preparation of compounds of the formula I in which Zi is hydrogen or acyl and Zj is acyl, where acyl radicals Zx and Z2 may be the same or different and represent the group of the formula —C (= 0) —R , wherein R lower alkyl having up to 4 carbon atoms, e.g. B. is methyl, ethyl, isopropyl, or tert-butyl, or phenyl, and Rt is isopropyl or tert-butyl, and acid addition salts, especially non-toxic, pharmaceutically acceptable acid addition salts thereof.

The invention relates in particular to a process for the preparation of the compounds of the formula I shown in the examples, and to their acid addition salts, in particular to their non-toxic pharmaceutically usable acid addition salts.

According to the invention, the new compounds of the formula I or salts thereof are prepared in a manner known per se by adding a compound of the formula

/ • -0-CH2- £ H-CH2-NH-R1 (IX),

where Xt stands for a free or reactive esterified hydroxy group, and Zj has the meaning given above,

or a salt thereof, with a carboxylic acid of the formula Z2-OH (III) or a reactive derivative thereof, and, if desired, converting a free compound obtained into a salt or a obtained salt into the free compound. A mixture of isomers obtained can be separated into the individual isomers.

When a compound of the formula II in which Zt is hydrogen is reacted, in particular when using at least two equivalents of the acylating agent, the phenolic hydroxyl group can be acylated in addition to the introduction of the group —O — Z ^, especially when starting materials are used of formula II, where Xa is hydroxy.

A reactive esterified hydroxy group Xx is e.g. B. with a strong inorganic acid such as a hydrohalic acid, e.g. As hydrochloric acid or hydrobromic acid, or a strong organic, especially alophatic or aromatic sulfonic acid, e.g. B. methanesulfonic acid or p-toluenesulfonic acid, esterified hydroxy group.

A starting material of the formula II, in which Xj stands for a reactive esterified hydroxyl group, is preferably reacted with a salt of the acid of the formula III, z. B. the alkali and alkaline earth metal, preferably lithium, sodium and potassium salts, also magnesium and calcium salts, and ammonium salts with ammonia and amines, preferably with tertiary amines, for. B. triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, pyridine, collidine, quinoline, quinaldine or 4-dimethylaminopyridine, may be considered. This reaction is preferably carried out in the presence of, the rest Xj. activating, primarily polar solvents, especially lower alkanols, or optionally N-lower alkylated lower alkanoic amides, e.g. B. dimethylformamide, also sulfolane, N, N, N ', N'-tetramethylurea or hexamethylphosphoric triamide or mixtures of suitable solvents, to which further inert solvents, such as halogenated hydrocarbons or optionally substituted aromatic hydrocarbons, are optionally added, further in a s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

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Temperature range from about 20 to 150 ° C, and / or under an inert gas, for. B. nitrogen atmosphere.

Compounds of the formula II are preferably used

wherein Xj stands for a free hydroxyl group, with the acid of formula III or a suitable reactive derivative thereof.

The reaction with a free acid of formula III can e.g. B. by heating the reaction components with removal • of water formed, such as to form azeotropic water-solvent mixtures. Suitable solvents are e.g. B. with butanol, benzene or xylene, optionally in the presence of further, preferably esterifying, acidic substances, for. B. conc. Sulfuric acid, thionyl chloride, benzenesulfonic acid, p-toluenesulfonic acid, chlorosulfonic acid, phosphoric acid or perchloric acid works.

Furthermore, acylation with a carboxylic acid can be of formula III in the presence of a condensing agent such as a carbodiimide, e.g. B. N, N'-dicyclohexyl-carbodiimide, or a suitable carbonyl compound, such as carbonyldiimidazole, take place, such reactions being carried out in an inert, anhydrous reaction medium.

However, a starting material of the formula II in which Xj is hydroxy and Zx is usually hydrogen is preferably reacted with a reactive derivative of an acid of the formula III. Such is, in particular, an anhydride, including a mixed or internal anhydride, of such an acid, furthermore a reactive ester, including an organic silyl or stannyl ester, or a reactive amide of such an acid.

A mixed anhydride is e.g. B. an anhydride with a derivative, e.g. B. an ester of halogen, e.g. B. chloroformic acid, such as a chloroformate lower alkyl, z. B. isobutyl ester, further with a hydrohalic acid, for. B. hydrochloric or hydrobromic acid, further formed with hydrochloric acid; reactive derivatives with the latter are the corresponding acid halides, e.g. B. -chloride or -bromide, or acid azides. Internal anhydrides are e.g. B. the ketenes corresponding to the acid of formula III or the suitable hydroxycarboxylic acids corresponding lactones.

Reactive esters of carboxylic acids of formula III are e.g. B. esters with lower alkanols which contain an electron-withdrawing group, such as a cyano group, in the a-position, e.g. B. with cyanomethanol, optionally with, for. B. by nitro or halogen, such as chlorine, substituted phenols or phenyl-lower alkanols, such as benzyl alcohols, for. B. phenol, 4-nitrophenol, 2,3,4,5,6-pentachlorophenol or 4-nitrobenzyl alcohol, or suitable N-hydroxy-carboxamides or imides, e.g. B. N-Hydroxysuccinimide or N-Hydroxyphthali-mid. Suitable silyl and stannyl esters are primarily tri-aliphatic substituted silyl or stannyl esters, such as tri-lower alkyl silyl or stannyl esters, e.g. B. trimethylsilyl or tri-n-butyl stannyl ester.

Reactive amides of acids of formula III are e.g. B. the corresponding N-acyl compounds of azahete-rocyclic compounds, such as 1-acyl-imidazolides or in the 1-and / or 5-position, if necessary, for. B. by lower alkyl, substituted 3-acyl hydantoins, e.g. B. 3-acyl-l, 5,5-trimethyl-hydantoin, and the corresponding N, N-di-acyl amides of carboxylic acids, in particular of lower alkyl carboxylic acids, for. B. formic acid or acetic acid.

The above-mentioned reactive derivatives of a carboxylic acid of formula III can be used as such or under the conditions of the reaction, for. B. from the free carboxylic acid or another derivative thereof in the presence of a suitable, the formation of the reactive derivative, for. B.

an anhydride, or a reactive ester or amide-inducing reagent.

The reaction of starting materials of the formula II, in which X] is hydroxy, with carboxylic acids of the formula III or derivatives thereof is carried out in a manner known per se, usually in the presence of a solvent, it being possible for a suitable esterifying agent to serve as such at the same time, and, if necessary, in the presence of, for example, acid-binding agents and / or catalysts, with cooling io or heating, for example in a temperature range from about -20 to about 150 ° C., in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere.

The reaction with symmetrical and mixed anhydrides, such as acid halides, can be carried out in the presence of agents influencing acylation, z. B. acid-binding agents, such as inorganic and organic bases, further mixtures thereof, or acidic agents (z. B. when using acid halides, z. B. chlorides), such as organic acids, which can also serve as a solvent 20 , used. Inorganic bases are e.g. B. the carbonates, hydroxides or oxides of alkali or alkaline earth metal, and earth metals, for. B. lithium, sodium, potassium, or calcium carbonate, lithium, sodium or potassium hydroxide, or magnesium or calcium oxide, also amines, preferably 25, such as tertiary amines, such as tri-lower alkylamines, for. B. like tri-ethylamine or ethyl-diisopropylamine, 1-lower alkyl-piperidi-ne, z. B. 1-ethyl piperidine, or bases of the pyridine type, e.g. B. pyridine, 4-dimethylamino-pyridine, picoline, collidine, lutidine, quinaldine, quinoline or 4-dimethylamino-quinoline, and 30 mixtures thereof. Suitable organic acids are e.g. B. strong organic carboxylic acids, such as strong, optionally substituted carboxylic acids, e.g. B. trifluoroacetic acid.

To increase the reaction rate and / or lower reaction temperatures, it may be advantageous to add further, preferably catalytically active and primarily acidic substances, such as inorganic acids or derivatives thereof, e.g. Example, hydrogen chloride, sulfuric acid, phosphoric acid, thionyl chloride, perchloric acid, phosphorus oxychloride or phosphorus pentachloride, and also strong or-40 ganic sulfonic and carboxylic acids, eg. Example, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-chlorosulfonic acid or 3-m-nitrobenzenesulfonic acid or trifluoroacetic acid, and also the acids of the formula III corresponding to the anhydrides, furthermore Lewis acids, for. B. fluoroboric acid, and 45 boron trifluoride or its adducts with ethers. In addition, the addition of an acid of the formula III corresponding carboxylic acid salts, such as alkali, alkaline earth or earth metal salts, furthermore from corresponding transition metal, e.g. B. zinc, tin, antimony or lead salts, as well as optionally N-substituted ammonium salts of acids of formula III favorably affect the acylation.

Ketenes as internal anhydrides can usually be used without additional reagents, also in the presence of an acidic condensing agent, and in the presence of a suitable solvent.

The acylation with the aid of reactive amides of acids of the formula III is conveniently carried out in the presence of a condensing agent, such as a basic agent, e.g. B. an anhydrous alkali metal or alkaline earth metal carbo-60 nate, hydroxide or oxide, or especially an alkali metal, alkaline earth metal or Erdmetallamids or-Niederalkan-olats, z. B. sodium or potassium amide, or lithium, sodium, or aluminum methoxide, ethanolate or in particular tert-butoxide.

65 Reactive esters as acylating agents can in the presence of basic reagents, for. B. the above, as well as acidic condensing agents. The latter are u. a. organic sulfonic acids, e.g. B. p-toluene-sul-

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6

fonic acid, also mineral acids, e.g. B. phosphoric acid or a derivative thereof, obtainable by partial hydrolysis of phosphorus oxychloride with water.

If starting materials of the formula II in which Zi is hydrogen are used in the acylation process described above, an acyl group can also be introduced simultaneously with the acyl radical Z2, it being possible for the introduction to take place in stages. Thus, when using an anhydride, such as a halide, of an acid of the formula III in the presence of a base which converts the phenolic hydroxyl group into a hydroxyl group which is in salt form,

where Zj ° has the meaning of Zj or represents a cleavable group, X2 is a hydroxyl group and X3 is a reactive esterified hydroxyl group, such as halogen, e.g. B. chlorine or bromine, or X2 and X3 together form an epoxy group, with a compound of formula

H2N-RÌ (V)

getting produced.

Compounds of the formula I obtainable according to the invention can be converted into other compounds of the formula I in a manner known per se. So you can Solylolyt Zj Solvolytisch, z. B. hydrolytically, such as by treatment with aqueous alkali metal bicarbonate, e.g. B. sodium hydrocarbonate, or by transacylation, for. B. when treated with an easily acylated nitrogen compound, such as an azacylic compound, e.g. B. imidazole, or an optionally, for. B. by lower alkyl, substituted hydantoin, such as 1,5,5-trimethyl-hydantoin, split off and replaced by hydrogen. This transacylation reaction is preferably carried out in the presence of an inert, usually polar solvent, optionally with the addition of a less polar solvent and in a temperature range from about 20 to 150 ° C, preferably 30 to 80 ° C.

As with the manufacturing process, care must also be taken when carrying out the additional steps that undesired side reactions which could result in the conversion of existing groups, in particular the splitting off of an acyl group Zi and / or Z2, are avoided.

The reactions described above can optionally be carried out simultaneously or in succession, and in any order. If necessary, they are carried out in the presence of diluents, condensing agents and / or catalytically active agents, at reduced or elevated temperature, in a closed vessel under pressure and / or in an inert gas atmosphere.

Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts which are also encompassed by the invention, the new compounds or salts thereof also being able to be present as hemi-, mono-, sesqui or polyhydrates thereof. Acid addition salts of the new compounds can be prepared in a manner known per se, e.g. B. by treatment with basic agents such as alkali metal hydroxides, carbonates or -hy-bicarbonates or ion exchangers, in the free compounds and these in turn can be converted into suitable base addition salts with suitable strong basic substances. On the other hand, free bases obtained can be acylated with organic or or a ketene, furthermore a 3-acylated hydantoin first the phenolic hydroxyl group and only subsequently the alcoholic hydroxyl group, while e.g. B. when using anhydrides of acids of formula III in 5 presence of the corresponding acid in a mixture z. B. with sulfuric acid or perchloric acid, or in the presence of organic amines, preferably the alcoholic hydroxy group is first acylated.

The starting materials of formula II are known or may be in a manner known per se, e.g. B. by treating a compound of formula IV,

(IV)

20 inorganic acids, e.g. B. form with the abovementioned acids, acid addition salts. For the production of acids and base addition salts, in particular those acids and bases are used which are suitable for the formation of pharmaceutically usable salts.

25 These or other salts, especially acid addition salts of the new compounds, such as. As picrates or perchlorates, can also be used to purify the free bases obtained by converting the free bases into salts, separating and cleaning them, and releasing the bases 30 from the salts.

Depending on the choice of starting materials and procedures, the new compounds can also be in the form of racemate mixtures 35 as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms.

Racemate mixtures obtained can, due to the physicochemical differences of the diastereoisomers, in a known manner, e.g. B. by chromatography and / or fractional crystallization, separated into the two stereoisomeric (diaste-40 reomeric) racemates.

Racemates obtained can be broken down into the antipodes by methods known per se, e.g. B. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reacting 45 with an optically active substance which forms salts with the racemic compound, in particular acid, and separating the salt mixture obtained in this way, e.g. B. due to different solubilities, in the diastereomeric salts, from which the free antipodes can be released by the action of suitable agents. Particularly common, optically active acids are e.g. B. the D and L forms of tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. It is advantageous to isolate the more effective of the 55 antipodes.

The invention also relates to those embodiments of the method in which a reaction component is in the form of its salt.

The new connections can e.g. B. in the form of pharma-60 medicinal preparations are used which contain a pharmacologically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral, e.g. B. oral, or parenteral-65 len administration. So you use tablets or gelatin capsules, which contain the active ingredient together with diluents, e.g. B. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants,

K

o - // \ - o

CH2 CH CH2 X3

7

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e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets can also contain binders, e.g. B. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium triumcarboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. B. starches, agar, Al-ginsäure or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or have adsorbents, colorants, flavors and sweeteners. The new pharmacologically active compounds can also be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. B. in lyophilized preparations which contain the active substance alone or together with a carrier material, for. B. mannitol, can be prepared before use. The pharmaceutical preparations can be sterilized and / or auxiliary substances, e.g. B. preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically active substances, are known in a manner known per se, e.g. B. by means of conventional mixing, granulating, confectioning, solution or lyophilization processes, and contain from about 0.1 to 100%, in particular from about 1 to about 50%, lyophilisates up to 100% of the active ingredient.

The dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition. The daily doses for oral administration are between about 0.1 and about 2.0 g for warm-blooded animals with a weight of about 70 kg.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.

example 1

To a solution of 5.3 g of racemic 1- (4-hydroxyphe-noxy) -2-hydroxy-3-isopropylaminopropane hydrochloride in 50 ml of trifluoroacetic acid are added 5 ml of acetylbro-mid at 10-15 °. There is gas evolution. After three hours of storage at room temperature, the reaction solution. evaporated under reduced pressure at 30 °. The remaining oil crystallizes when rubbed with ether. The crystals obtained are filtered off with suction, washed with ether and then recrystallized from acetone ether. The l- (4-acetoxyphenoxy) -2-acetoxy-3-isopropylamino-propane-hydrobromide of mp. 156-157 ° is obtained.

Example 2

2.6 ml of pivaloyl chloride are added at room temperature to a solution of 2.6 g of racemic l- (4-hydroxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride in 8 ml of trifluoroacetic acid. There is gas evolution. After storage at room temperature for 48 hours, the reaction solution is evaporated under reduced pressure at 30 °. The remaining oil crystallizes when rubbed with ether. The crystals obtained are filtered off with suction, washed with ether and then recrystallized from acetone ether. The 1- (4-pivaloy! Oxyphenoxy) -2-pivaloyl-oxy-3-isopropylaminopropane trifluoroacetate of mp.

• 112-113 °.

For conversion into the hydrochloride, the trifluoroacetate salt obtained is dissolved in methanol and filtered through a column prepared in methanol from 50 g of Amberlite IRA-400 (chloroid form). After washing and evaporating the filtrate, a colorless oil is obtained which, after recrystallization from acetone, gives the 1- (4-pivaloyloxyphenoxy) -2-pivaloyloxy-3-isopropyl-aminopropane hydrochloride, mp. 169-170 °.

The S - (-) - 1- (4-piva-loyloxyphenoxy) -2-pivaloyloxy-3-isopropylaminopropane or a salt thereof can be obtained in an analogous manner, starting from a corresponding optically active starting material.

Example 3

7.0 g of racemic l- (4-acetoxyphenoxy) -2-acetoxy-3-iso-propylaminopropane hydrobromide and 0.7 g of imidazole are dissolved in 100 ml of methanol and then heated to boiling under reflux for 3-22 hours. Then it is evaporated under reduced pressure and the remaining oil is rubbed with acetone. The crystals obtained are filtered off with suction, washed with acetone and recrystallized from isopropanol. The l- (4-hydroxyphenoxy) -2-acetoxy-3-isopropyl-aminopropane hydrobromide of mp 163-164 ° is obtained.

Example 4

4.3 g of racemic l- (4-pivaloyloxyphenoxy) -2-pivaloyl-oxy-3-isopropylaminopropane hydrochloride and 0.2 g of imidazole are dissolved in 45 ml of methanol and then heated to boiling under reflux for 48 hours. Then it is evaporated under reduced pressure and the remaining oil is rubbed with ether. The crystals obtained are filtered off with suction. After recrystallization from acetone, the 1- (4-hydroxyphenoxy) -2-pivaloyloxy-3-isopropylaminopropane hydrochloride, mp. 133-134 °, is obtained.

In an analogous manner, starting from the corresponding optically active diester, the S - (-) - 1- (4-hydroxyphenoxy) -2-pivaloyloxy-3-isopropylaminopropane or a salt thereof can be prepared.

Example 5

1.0 g of racemic l- (4-acetoxyphenoxy) -2-acetoxy-3-iso-propylaminopropane hydrobromide are dissolved in 50 ml of methanol, 5 g of Amberlite IRA-400 (bicarbonate form) are added at room temperature and 10 Minutes stirred. The ion exchanger is then filtered off and the filtrate is completely evaporated at room temperature under reduced pressure. The remaining oil is dissolved in acetone and neutralized with ethereal hydrochloric acid. Here, crystals separate out.

After recrystallization from isopropanol-acetone, the l- (4-hydroxyphenoxy) -2-acetoxy-3-isopropylaminopropane hydrochloride, mp. 160-161 °, is obtained.

Example 6

A solution of 2.6 g of racemic l- (4-hydroxyphen-oxy) -2-hydroxy-3-isopropylamino-propane hydrochloride in 8 ml of trifluoroacetic acid is mixed with 1.3 ml of piva-loyl chloride at room temperature, a Gas evolution begins.

After standing for 2 hours at room temperature, the reaction solution is evaporated at 30 ° under reduced pressure. The remaining oil is suspended in acetone, small amounts of insoluble matter are filtered off and the filtrate is partially evaporated. The addition of diethyl ether gives the 1- (4-hydroxyphenoxy) -2-pivaloyloxy-3-isopropylaminopropane hydrochloride, mp. 133-134 ° after recrystallization from acetone.

Example 7

The following connections can be made analogously to the procedures described in Examples 1-6:

1- (4-acetoxyphenoxy) -2-acetoxy-3-tert-butylaminopropane, 1- (4-pivaloyloxyphenoxy) -2-pivaloyloxy-3-tert-butylaminopropane,

Prepare l- (4-hydroxyphenoxy) -2-acetoxy-3-tert-butylaminopropane, l- (4-hydroxyphenoxy) -2-pivaloyloxy-3-tert-butylamino-propane, and their salts.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

618 958

Example 8

Analogous to the procedure described in Examples 2 and 4, the following compounds can be started based on the corresponding optically active starting material:

S - (-) - l- (4-pivaloyloxyphenoxy) -2-pivaloyloxy-3-tert-butylaminopropane and

S - (-) -1 - (4-hydroxyphenoxy) -2-pivaloyloxy-3-tert. -Butyl aminopropane or salts of these compounds.

Claims (17)

618 958 2nd PATENT CLAIMS 1. Process for the preparation of new secondary acyl-oxyamines of the formula 0-Zo I 2 ^ • -0-CH2-CH-CH2-NH-R1 (I) • = • wherein hydrogen or the acyl radical of the formula —C (= 0) -R and Z2 denote the acyl radical of the formula —C (= 0) -R, where R in each case represents an optionally substituted aliphatic, cycloaliphatic, aromatic or aliphatic hydrocarbon radical, where acyl radicals Za and Z2 are the same or different, and Rt represents an optionally substituted aliphatic, cycloaliphatic or aliphatic hydrocarbon radical, or salts thereof, characterized in that a compound of the formula y '~ * \ I1 Z -O - * ^ ^ • -0-CH2-CH-CH2-NH-R1 (II) • = • where Xj stands for a free or reactive esterified hydroxy group, and Zj has the meaning given above, or a salt thereof, with a carboxylic acid of the formula Z ^ -OH (III) or a reactive derivative thereof, and, if desired, converting a free compound obtained into a salt or a obtained salt into the free compound. 2. The method according to claim 1, characterized in that a compound of formula II, in which stands for a free hydroxy group, with an anhydride, incl. A mixed or internal anhydride, or with a reactive ester, including an organic silyl or Stannyl ester, or a reactive amide of an acid of formula III. 3. The method according to claim 1, characterized in that an acid halide is used as the reactive derivative. 4. The method according to claim 1, characterized in that one carries out the reaction in an organic acid as a solvent. 5. The method according to claim 4, characterized in that trifluoroacetic acid is used as the solvent. 6. The method according to claim 1, characterized in that a racemate mixture obtained is separated into the two stereoisomeric (diastereomeric) racemates. 7. The method according to claim 1, characterized in that a racemate obtained is broken down into the optical antipodes. 8. The method according to claim 1 for the preparation of compounds of the formula I in which Zt is hydrogen, characterized in that in an obtained compound of the formula I in which Zt is acyl, the acyl radical Zx is split off by hydrolysis or an easily acylated nitrogen compound and replaced by hydrogen. 9. The method according to claim 8, characterized in that imid-azole is used as the easily acylated nitrogen compound. 10. The method according to claim 8, characterized in that one carries out the hydrolysis by means of phenol-formaldehyde resin (Amberlite) (IRA-400) containing methylene sulfonic acid groups in the bicarbonate form. 11. The method according to claim 1, characterized in that a salt of a compound of the formula II or III is used as the reaction component. 12. The method according to any one of claims 1-11, characterized in that compounds of the formula I or io salts thereof are prepared in which Zt and Z2 have the meaning given, where acyl radicals Zj and Z2 for the group of the formula -C (= 0 ) -R are where R is lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl or phenyl or phenyl-lower alkyl, where phenyl can be substituted by lower alkyl, Niels deralkoxy, halogen and / or trifluoromethyl, and wherein Ri is lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl- lower alkyl, carbamoyl-lower alkyl, N-lower alkyl-carbamoyl lower alkyl, N, N-di-lower alkyl-carb-amoyl-lower alkyl or cyano-lower alkyl, optionally poly- 20 means cyclic cycloalkyl, or phenyl-lower alkyl or phenyloxy-lower alkyl, where phenyl may optionally be substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alk-oxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-dinedie-deralkylcarbamoyl or cyano. 25th 13. The method according to any one of claims 1-11, characterized in that compounds of formula I or salts thereof are prepared in which ZJ and Z2 have the meaning given, wherein acyl groups Zt and Z2 for the rest of the formula -C (= 0) —R are where R is lower alkyl of up to 4 30 carbon atoms or phenyl, and wherein Ri is lower alkyl having up to 4 carbon atoms, optionally N-lower alkyl or N, N-di-lower alkyl-substituted carbamoyl-lower alkyl, cyano-lower alkyl, phenyl-lower alkyl, carbamoylphenyl-lower alkyl or carbamoylphenyloxy-lower alkyl. 14. The method according to any one of claims 1-11, characterized in that compounds of formula I or salts thereof are prepared in which and Z2 have the meaning given, wherein acyl radicals Zt and Z2 for the group of 40 are —C (= 0) —R, where R is lower alkyl of up to 4 carbon atoms or phenyl, and Ra is isopropyl or tert-butyl. 15. The method according to any one of claims 1-7 and 11, characterized in that l- (4-acetoxyphenoxy) -2-acet- 45 oxy-3-isopropylaminopropane or salts thereof. 16. The method according to any one of claims 1-7 and 11, characterized in that l- (4-pivaloyloxyphenoxy) - 2-pivaloyloxy-3-isopropylaminopropane or salts thereof. 17. Process according to any one of claims 1-11, characterized in that l- (4-hydroxyphenoxy) -2-acetoxy- 3-isopropylaminopropane or salts thereof. 18. The method according to any one of claims 1-11, characterized in that l- (4-hydroxyphenoxy) -2-pivaloyl- 55 oxy-3-isopropylaminopropane or salts thereof. 19. The method according to any one of claims 1-18, characterized in that obtained compounds of formula I are converted into their non-toxic pharmaceutically acceptable acid addition salts.