DE2530613A1 - AMINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

Dr. Hans-Heinrich Willrath

Dr. Dieter Weber Diploma in Phys. Klaus Seifert

PATENT LAWYERS

D —62 WIESBADEN 7/7/1975 PostfaA 1327 H / βΡ Gustav-Treytag-Straja JS β (0 6121) 3727 2)
Telegram address! Wi-LPATEKT

Nsu? ? osr - -Vv *:

Pcs ^ ach 61 4 3 KH-469-1 · ·

AB Hate
S-431 20 Mölndal 1 (Sweden)

Amine derivatives, processes for their preparation and medicines containing them

Priorities:

on August 11, 1974 in Sweden
Note No.: 7413 789-4

v. 4th June 1975 in Sweden
Note No .: 7506 348-7

The present invention relates to new powerful β-receptors blocking compounds and their preparation and a method for treating symptoms and signs of cardiovascular disease by blocking the heart's β-receptors with the aid of administration of these new compounds to mammals including humans.

The new compounds are those of the general formula

609 819/1275

where R is a hydrogen atom or a methyl group, R is a hydrogen atom, a methyl group / ethyl group, Propyl group, allyl group, methoxy group, propargyloxy group, Cyano group, morpholino group, pyrrolidino group or pyrrolyl group, R denotes a hydrogen atom, denotes a methyl group or ethyl group and R denotes a hydrogen atom or a methyl group, where

2 4
preferably R and R are not both hydrogen atoms.

The new compounds have valuable pharmacological properties Properties.

So they block the ß-receptors of the heart, what comes out of the Termination of the antagonism of tachycardia after an intravenous injection of 0.5 / Ug / kg of d / 1-isoproterenol sulfate in an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg. They block those too vascular ß-receptors / what occurs in the termination of the antagonism of vasodilation after intravenous Injection of 0.5 / ug / kg of d / 1-isoproterenol sulfate an anesthetized cat using an intravenous dose of 0.002 to 2 mg / kg or more. The connections also stimulate the ß-receptors, i.e. they show self-activity

609819/1275. , " ³ "

vity. This property is particularly pronounced in vas— kular ß-receptors, where they expand the peripheral Effect blood vessels.

The new compounds can be used in the treatment of arrhythmias, angina pectoris and hypertension. the peripheral vasodilation is particularly valuable for the last two indications mentioned. You can also use it as a Use intermediates in the manufacture of other valuable pharmaceutical compounds.

Compounds according to the present invention are as follows:

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoy-l-o-methylphenoxypropanol-2,

3- / 2- (4-Hydfoxyphenyl) -l-methyläthylaminoT-l-o-ethylphenoxypropanol-2,

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoT-l-o-propylphenoxypropanol-2,

3- / 2- {4-hydroxyphenyl) -l-methylethylaminoT-l-o-allylphenoxypropanol-2,

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoT-l-o-propargyloxyphenoxy-propanol-2,

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoZ-l-o-cyanophenoxypropanol-2,

3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-raethyl-

phenoxy-propanol-2,

609819/12 75

3- / 2- (4-hydroxyphenyl) -l _f 1-dimethyläthyIamino7-lo-ethy 1-phenoxy-propanol-2,

3- / 2 "- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-propylphenoxy-propanol-2,

3- / 2 "- {4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l ^ o-allylphenoxy-propanol-2,

3- / 2- (4-hydroxyphenyl) -l _f 1-dimethylethylamino7 "lo-propargyloxyphenoxy-propanol-2,

3- / 3 "- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-cyanophenoxy-propanol-2,

3-Ethy1-3- / 2- {4-hydroxyphenyl) -l-methylethylamineV'-l-o-allylphenoxy-propanol-2,

3- / 2 "- (4-hydroxyphenyl) -1-me thy läthy Iamino7-l-o, m-diine thy 1-phenoxy-propanol-2,

3- / 2 * - (4-Hydroxyphenyl) -l-methylethylaminoZ-l-o-methoxyphenoxy-propanol-2,

3-methyl-3- / 2 "- (4-hydroxyphenyl) - 1-methyläthyIamino7-l-oäthylphenoxy-propanol-2,

3-Methy1-3- / 2- (4-hydroxyphenyl) -1-methyläthyIamino7-l-ocyanophenoxy-propanol-2 ,

3-Methy1-3- / 2- (4-hydroxypheny1-1,1-dimethylä methylphenoxy-propanol-2,

3-methyl-3- / 2- (4-hydroxyphenyl) -1,1-dimethylethylamino / -l-oallylphenoxy-propanol-2 and

3- / 2- (4-hydroxyphenyl) -1-methylethylamino7-l-m-methylphenoxypropanol-2.

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Salt-forming acids can be used in the preparation of therapeutically acceptable salts of these compounds. and these are, for example, hydrohalic acids, sulfuric acid, Phosphoric acid, nitric acid, perchloric acid, aliphatic, aiicyclic, aromatic or heterocyclic Carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, emboxylic acid, Methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, Ethylene sulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, Naphthylsulfonic acid or sulfanilic acid, methionine, Tryptophan, lysine, or arginine.

The substances are intended, orally or parenterally, for acute and chronic treatment of the cardiovascular diseases mentioned above to be administered.

The biological effects of the new compounds were tested, and the various experiments carried out are shown and explained below.

The new compounds are obtained according to known methods Methods. So a compound of the general formula II

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-OCH _n CHCHZ R ³

² > 3 II

wherein R, R and R have the above meanings, X one Hydroxyl group and Z denotes a reactive esterified hydroxyl group or X and Z together denote an epoxy group, with an amine of the general formula

'R ^1!

H ₂ NC-CH
CH ₃

wherein R has the above meaning, implemented.

A reactive esterified hydroxyl group is particularly a hydroxyl group that is associated with a "strong inorganic or organic acid is esterified, such as with a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid ' or hydriodic acid, or with sulfuric acid or a strong organic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Thus, Z is preferred Chlorine, bromine or iodine.

This reaction is carried out in the usual way. In the The use of a reactive ester as a starting material is preferably used for production in the presence of a basic one Condensing agent and / or with an excess of an amine instead. Suitable basic condensing agents are, for example Alkali hydroxides, such as sodium or potassium hydroxide, alkali

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carbonates, such as potassium carbonate, and alkali alcoholates, such as Sodium methylate, potassium ethylate and potassium tert-butylate.

Instead, a compound of the general formula III

OCH ₂ CHO _{2 τττ}

\ - / ■ 13.

R ^{4 R.} .-!

OO M

wherein R # R and R have the above meaning, with a Compound of the general formula

Z-CCH

wherein R and Z have the above meaning, are reacted.

This reaction takes place in the customary manner, preferably in the presence of a basic condensing agent and / or one Excess of an amine. Suitable basic condensing agents are, for example, alkali metal alcoholates, preferably Sodium or potassium alcoholate, or also alkali metal carbonates, such as sodium or potassium carbonate.

Instead, a compound of the general formula IV

.-OH

7 IV

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2 4-

wherein R and R are as defined above, with a compound of the general formula V

OR V

Z-Ch ₂ CHCH-NH-CCH ₂ R ³ ™ 3

11 3
in which Z, X, R and R have the above meaning and R is a removable protective group.

This implementation takes place in the usual way. In those cases where reactive esters are used as starting material, can the compound of the formula IV advantageously in the form of its metal phenate, such as alkali metal phenate, preferably be used as sodium phenolate, or one works in the presence of an acidic binder, preferably a condensing agent, which can form a salt of the compound of formula IV, such as an alkali metal alcoholate.

You can also use a compound of the general formula IV

// \\ _ 0H
, 2 ■ ■

2 4

wherein R and R have the above meaning with a compound of the general formula VI

R ³ -CH - [M - CCH ..
1 - ! ! ²
CH - CH "CH-
! ^{l ό} VI

Oh - ..

- 9

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wherein R and R have the above meaning to implement.

This implementation takes place in the usual way. Thus, the reaction is carried out under alkaline conditions in a suitable
Solvent, such as benzyl alcohol, carried out by boiling the reaction mixture for a few hours. It will
the phenol is converted primarily to its metal phenate, such as alkali metal phenate, before it is added to the acetidinol of Formula VI.

In addition, a radical can be split off from a compound of the above formula I in which the nitrogen atom of the amino group and / or the hydroxyl groups carry a removable radical attached to it. Such cleavable residues are special
those that can be split off by solvolysis, reduction, pyrolysis or fermentation.

Residues which can be split off by solvolysis are preferably residues which can be split off by hydrolysis or ammonolysis.

Residues that can be split off by hydrolysis are, for example
Acyl radical, or functionally varied carboxyl groups, such as
Oxycarbonyl radicals, such as alkoxycarbonyl radicals, for example the tert-butoxycarbonyl radical or ethoxycarbonyl radical, aralkoxycarbonyl radicals, such as rfren & lower alkoxycarbonyl radicals, e.g. a carbobenzyloxy radical, halocarbonyl radicals, such as a chlorocarbon radical, furthermore arylsulphonyl radicals, such as fluorosulfonyl radicals, and optionally halogenated sulfonyl radicals, such as the toluenesulphonyl radical

- Io 609819/1275

te lower alkanoyl radicals, such as the formyl, acetyl or trifluoroacetyl radical, or a benzyl radical, a cyano group or a silyl radical, such as a trimethylsilyl radical.

Of the above-mentioned radicals present on the hydroxyl groups which can be split off by hydrolysis, the oxycarbonyl radicals and the lower alkanoyl radicals are preferred or to mention the benzoyl radicals.

In addition to the radicals mentioned above, it is also possible to use double-bonded radicals, which are attached to the amino group by hydrolysis can be split off, such as alkylidene or benzylidene radicals or a phosphorylidene group, such as a triphenylphosphorylidene group, where the nitrogen atom then has a positive charge receives.

Cleavable at the hydroxyl group and the amino group by hydrolysis In addition, radicals are double-bonded radicals, as occur in cases of substituted methylene. As a substituent Any organic radical can be used on the methylene radical, regardless of whether it is hydrolysed or not is which compound is the substituent on the methylene residue. As methylene substituents, for example, aliphatic or aromatic radicals, such as alkyl, as mentioned above, aryl, such as phenyl or pyridyl, are used will. The hydrolysis can be carried out in any conventional manner, expediently in a basic or preferably in an acidic medium.

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Compounds with residues which can be split off by hydrolysis are also the compounds according to the general formula VII

GH ⁵

VII

12 3 4

wherein R, R, R and R have the above meaning and Y

means a carbonyl or thiocarbonyl radical.

The hydrolysis is carried out in an analogous manner, such as in the presence of a hydrolyzing agent, for example in the presence an acidic agent such as a dilute mineral acid, e.g., sulfuric acid or hydrohalic acid, or in the presence basic agents, e.g. in the presence of alkali hydroxides, e.g. sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can be added in a suitable manner with the aid of acidic Agents, for example with the aid of a hydrohalic acid, expediently with hydrobromic acid. Preferably the cleavage takes place using dilute hydrobromic acid, optionally in a mixture with acetic acid. Cyano groups are preferably acidified with the help of hydrobromic acid at an elevated temperature, such as in boiling Hydrobromic acid, according to the "cyanogen bromide method" (von Braun) cleaved. Other radicals, such as a tertiary butoxycarbonyl radical, can be treated under anhydrous conditions with a suitable acid, such as trifluoroacetic acid, split off will. Acidic agents are preferably used in a hydro-

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lysis of compounds of the formula VI used.

Residues that can be split off by ammonolysis are in particular the halocarbonyl residues, like the chlorocarbonyl radical. The ammonolysis can be carried out in the usual way, such as with the aid an amine which contains at least one hydrogen atom bonded to the nitrogen atom, such as with a mono- or di-lower alkylamine, such as methylamine or dimethylamine, or especially ammonia, preferably at an elevated temperature. Instead of ammonia, one can also use an agent that releases ammonia, such as hexamethylenetetramine.

Residues which can be split off by reduction are, for example, an o (-arylalkyl radical, such as a benzyl radical or a C * -aralkoxycarbonyl radical, such as a benzyloxycarbonyl radical, which can be cleaved in the usual way by hydrogenolysis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of hydrogenation catalysts, such as Raney nickel, Further radicals which can be split off by hydrogenolysis are 2-haloalkoxycarbonyl radicals, such as 2,2,2-trichloroethoxycarbonyl radicals or 2-iodoethoxy or 2,2,2-tribromoethoxycarbonyl radicals, which can be split off in the usual way, expediently by metallic reduction (with so-called nascent hydrogen). Nascent hydrogen can be produced by the action of metal or metal alloys, such as amalgam, obtained on compounds that give off hydrogen, such as on carboxylic acids, alcohols or water, with particular Zinc or zinc alloys together with acetic acid

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can be used. The Hydrogenolys.e of 2-haloalkoxycarbonyl residues can also be made using chromium or chromium-II compounds, such as chromium-II-chloride or Chrom-II-ac.etat, take place.

A residue that can be split off by reduction can also be an arylsulfonyl group, be like a toluenesulfonyl group: i the usual way by reduction using nascent Hydrogen, such as with the help of an alkali metal, such as Lithium or sodium, in liquid ammonia, can be split off and expediently split off from a nitrogen atom can be. When carrying out the reduction, account must be taken of the fact that other reducing Groups are not affected.

Residues which can be split off by pyrolysis, especially radicals which can be split off from the nitrogen atom, are, for example, substituted or appropriately unsubstituted garbamoyl groups. Suitable substituents are, for example, lower alkyl groups or Aryl lower alkyl groups, such as methyl or benzyl, or aryl radicals, such as phenyl. The pyrolysis takes place in the usual way, paying attention to other thermally sensitive groups.

Residues that can be split off by fermentation, especially from the nitrogen atom Removable radicals are, for example, substituted but appropriately unsubstituted carbaraoyl groups. Suitable Substituents are, for example, lower alkyl groups or

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Aryl lower alkyl groups, such as methyl or benzyl, or aryl radicals, like phenyl. The fermentation takes place in the usual way, such as with the help of the enzyme urease or with soybean extract at about 20 ° C or slightly higher temperature.

Furthermore, a Schiff's base of the general formula VIII or IX.

OCH ₉ CH-C = NC-CH ₀

OH

VIII

OH

0CH ₀ CH-CH -i 2 ι

CH-

-OH!

IX

or a cyclic tautomer of the formula X corresponding to the formula IX

609 819/127 5

1 O O Λ

are reduced, where R, R, R and R have the above meaning have, but R is not methyl, and where the compounds of the formulas IX and X are also present next to one another can. This reduction is carried out in a conventional manner, such as using a dilute metal hydride, such as sodium borohydride or lithium aluminum hydride, using a hydride such as borane, with formic acid, or by catalytic Hydrogenation, as with hydrogen in the presence: of Raney nickel. With * the reduction one has to pay attention to the fact that other "groups are not affected.

Furthermore, the oxo group in a compound of the general formula XI

g R ¹

^p - "Hr-HC-SH ₉ ^ // \ S

R ³

12 3 4
wherein R, R, R and R are as defined above, are reduced to a hydroxyl group. This reduction is carried out in the usual way, especially using a di-non-metal hydride, as mentioned above, or according to the "Meerwein-Pondorf-Verley method" or a modification thereof, expediently using an alkanol as a reaction component and as a solvent, such as isopropanol , and using a metal alkoxide such as metal isopropoxide, for example aluminum isopropoxide.

Furthermore, in a compound of the general formula XII

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H NH-C-CH ₂ - / \\ - OH ^XI1 3 ru Vm /

• OCH ^ CHOHC

^z '3

ο R CH

13 4 2

wherein R, R and R have the above meanings and X is

2 2

Is a remainder convertible to an R group, X to R

be convicted.

In addition, the oxo group in a compound corresponding to those of the formula I, but which has an oxo group on one Carbon atom bonded to a nitrogen atom, can be reduced to two hydrogen atoms.

These compounds are, for example, those of the formula XIII

^DH : XIII

12 4 3

wherein R, R and R have the above meaning and R is

Means hydrogen atom.

The reduction can be carried out in the manner described above using complex metal hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride. The reaction expediently takes place in an inert solvent, like an ether, e.g. diethyl ether or tetrahydrofuran.

In the usual way, the substituents of the compounds obtained in the end product can be varied, and the sub-

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substituents can be introduced into the compounds obtained, cleaved from these or converted into other substituents in the customary manner.

Depending on the process conditions and the starting material, the end product is obtained either in free form or in Form of its acid addition salt, the acid addition salts also being within the scope of the invention,

as
For example, "basic, neutral or mixed salts as well as hemiamino-, sesqui- or polyhydrates can be obtained". The acid addition salts of the new compounds can be converted into free compounds in a manner known per se, for example by using basic agents such as alkali or ion exchangers On the other hand, the free bases obtained can also form salts with organic or inorganic acids. In the preparation of acid addition salts, preference is given to using acids which form suitable therapeutically acceptable salts. Such acids are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic , alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenyls acetic acid, benzoic acid, p-aminobenzoic acid, antranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, emboxylic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyathanesulphonic acid, jithylenesulphonic acids,

- 18 6 0 9 8 19/1275

Halobenzenesulphonic acids, toluenesulphonic acid / naphthylsul- " fatty acids or sulfanilic acids, methionine, tryptophan, lysine, or arginine.

These or other salts of the new compounds, such as picrates, can be used as cleaning agents for the free bases obtained serve when the free bases are converted into their salts, these are separated and the bases are then released again from the salts will. In view of the close relationship between the new compounds in the free form and in the form of their salts It is understandable that in the entire description, when the free connections are mentioned, the corresponding ones are also mentioned Salts are meant.

The invention also relates to any embodiment of the method, in which one of any compound obtained as an intermediate in any of the process steps goes out and carries out the remaining process stages or in which the process is terminated at any stage or in which a starting material is formed under the reaction conditions or in which a reaction component is optionally used is in the form of their salt.

So you can use an aldehyde of the general formula XIX

OCH ₂ CHGHCHCj ^xix

R ²

609819/12 7 B.

- 19 -

wherein R and R have the above meaning and R is hydrogen atom means with an amine of the general formula

H ₂ NC-CH

wherein R is as defined above, in the presence of a suitable reducing agent such as those mentioned above is to implement. This gives a compound of the general formula VII as an intermediate, which is then according to the Invention is reduced.

An amine of the "general formula III" with an aldehyde or a ketone can also be used in a manner known per se the formula

Ϊη ₃

in the presence of a suitable reducing agent, such as one mentioned above, to form compounds, where R is a hydrogen atom. Receives a compound of the general formula IX or X as an intermediate, which is then reduced according to the invention.

The new compounds can be made depending on the selection of the starting materials and the method are present as optical antipodes or as a racemate, or when they are at least two Containing asymmetric carbon atoms, they can also be called

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609819 / 1.275

Isomer mixture (mixture of racemates) are present.

The isomer mixtures obtained (Racematgeraische) can each
according to the physico-chemical differences of the components into the two stereoisomeric (dtastereoisomeric) pure ones
Racemates can be separated, such as by chromatography and / or fractional crystallization.

The racemates obtained can be separated by known methods, such as by recrystallization from an optically active solvent, with the aid of microorganisms or
by reacting with optically active acids to form salts of the compound and separating the salts thus obtained, such as
due to their different solubility in the diastereomers, from which the antipodes can be released by the influence of a suitable agent. Appropriately usable optically active. Acids are, for example, the L- and D-form of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

Appropriately, those starting materials are used when carrying out 3 reactions according to the invention, leading to groups lead to particularly desirable end products and especially to the end products specifically described and indicated as being preferred.

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The starting materials are known or, if they are new, can be obtained by processes known per se will.

In clinical use, the compounds of the invention are usually administered orally, rectally or by injection administered in the form of a pharmaceutical preparation containing an active component either as a free base or as Pharmaceutically acceptable, non-toxic acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutical carrier.

The mention of the new compounds according to the invention here relates to either the free amine base or the acid addition salts the free base, even if the compounds are described generally or specifically, provided that the accompanying text where such expressions are used, as in the examples, are compatible with this broad meaning is. The carrier can be a solid, semi-solid, or liquid diluent or a capsule. This pharmaceutical Preparations are a further subject of the invention. Usually the amount of active compound is between 0.1 and 95% by weight of the preparation, expediently between 0.5 and % By weight in the case of preparations for injections and between 2 and% by weight in the case of preparations for oral administration.

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In the manufacture of "pharmaceutical preparations that contain a Compounds according to the present invention in the form of dosage units for oral administration can the dug out compound with a solid powdery Carriers, such as with lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin as well as with a lubricant such as magnesium stearate, calcium stearate, Polyethylene glycol waxes or the like, mixed and compressed into tablets. When coated tablets or coated tablets are desired, the tablet core or coated tablet core prepared above can be mixed with a concentrated sugar solution be coated. This solution can, for example, be gum arabic, gelatin, talc, titanium dioxide or the like contain. In addition, the tablets can be mixed with a highly volatile organic solvent or solvent mixture dissolved varnish are coated. A dye can be added to this coating in order to easily intervene To distinguish tablets of different active compounds or with different amounts of the active compounds.

When making soft gelatin capsules (pearl-shaped closed Capsules); which consist of gelatin and, for example, glycerine, or in the manufacture of similar closed ones Capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules can have granules the active compound in combination with a fixed

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contain powdered carriers, such as with lactose, sucrose, Sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared in the form of suppositories, which contain the active Contains substance in a mixture with a neutral fatty base, or they can be made in the form of gelatin rectal capsules which contain the active substance in a mixture with a vegetable oil or liquid paraffin included.

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as solutions, which contain from about 0.2% to about 20% by weight of the active substance described, the remainder being sugar and a Mixture of ethanol, water, glycerine and propylene glycol. If desired, such liquid preparations can be used Contains colorants, flavorings, saccharin and carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be used as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably at a concentration of from about 0.5% to about 0.10% by weight. These solutions can too Contain stabilizers and / or buffering agents and can expediently be accommodated in ampoules of different dosage units. - 24 -

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The production of pharmaceutical tablets for oral ■ use is carried out according to the following method:

The 'solid substances used are based on a certain Grind or sieve particle size. The binder is homogenized and in a certain amount of solvent suspended * -The therapeutic compound and required Auxiliary materials are under continuous and constant Mix blended with the binder solution and moisten so that the solution is uniform without over-wetting any Parts is distributed. The amount of solvent is usually adjusted so that the consistency of the mass is moist Snow reminds. The moistening of the powdery mixture with the binder solution causes the particles to easily adhere to each other into aggregates, and the granulating process is carried out in such a way that the mass passes through a sieve in the form of a stainless steel net with a mesh size of about 1 mm is pressed. The mass is then spread in a thin layer on a floor to put in a drying chamber to be dried. This drying takes place for 10 hours and must be carefully standardized because the water vapor content of the granules is of the utmost importance for the following procedure and for the characteristics of the tablets. Drying in a fluidized bed is also possible. In this case, the mass is not placed on a floor, but poured into a container with a mesh bottom.

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After the drying step, the granules are sieved to obtain the desired particle size. Under certain Powder must be removed under conditions.

The so-called final mixture becomes decomposing, friction reducing and adhesion reducing agents added. After this mixing, the mass should get its correct composition for the tableting stage. '

The cleaned tablet press is provided with a certain set of punches and pressing tools, whereupon the a suitable setting for the weight of the tablets and the degree of compression is tested. The weight of the Tablet is critical to the size of the dosage in each tablet and is based on the amount of therapeutic Means calculated in the granules. The degree of compression affects the size of the tablet, its strength and their ability to dissolve in water. Especially with regard to the latter two properties, the selection of the Compression pressure (Ο, Θ5 to 5 tons) something like a level of equilibrium. When achieved the right attitude is, begins the production of the tablets, which takes place at a rate of 20,000 to 200,000 tablets / hour. The pressing of the tablets requires different times and depends on the size of the attachment.

The tablets are freed from adhering powder in a special device and then placed in closed packaging

809819/1275 -26-

stored until delivery.

Many tablets, especially those that are rough or bitter, are coated. This means that they be provided with a layer of sugar or another suitable coating.

The tablets are usually 'machined with an electronic Packed counter. The different types of packaging consist of glass or plastic bottles, however, boxes, tubes or packaging suitable for special dosages can also be used.

The daily dose of the active substance varies and depends on the route of administration, but can be used as a rule of thumb say that they are at 100 to 400 mg / day, based on the active substance, when administered orally, and at 5 to 20 mg / day mg / day for intravenous administration.

In the following examples the temperatures are in degrees Celsius specified.

example 1

Preparation of 3- / 2 "- {4-hydroxyphenyl) -l-methylethylamino7-l-o-methylphenoxypropanol-2

2.5 g of 1,2-epoxy-3-o-methylphenoxypropane were added with 1.5 g 1- (4-hydroxyphenyl) -2-aminopropane and 25 ml of isopropanol mixed, and the entire solution was 1.5 hours under back

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river heated. The solution was then evaporated in vacuo. The base so obtained was dissolved in acetone and the hydrochloride precipitated in ether using HCl. That The hydrochloride was filtered off and washed with acetonitrile. The yield of 3- / 2- (4-hydroxyphenyl) -l-methylethylamine £ 7-lo-methylphenoxypropanol-2 was 1.4 g, m.p. = 112 ° C. The structure was determined using NMR spectroscopy.

Example 2

3-J2-A 4-hydroxyphenyl) -1-methy Iäthylamino7-lo-ä € hy lphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3- (o-ethyl) -phenoxypropane and 1- (4 -Hydroxyphenyl) -2-aminopropane produced as starting materials. The melting point of its hydrochloride was 142 ° C, its structure was determined by NMR spectroscopy and the equivalent weight.

Example 3

3- / 2- (4-Hydroxyphenyl) -l-methylethylamino / 'l-o-aHylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-allylphenoxypropane and 1- (4-hydroxyphenyl) -2-aminopropane as starting materials. The melting point of the tartrate was 71 ° C. Its structure was determined by NMR spectroscopy and the equivalent weight.

Example 4

3-JjZ- (4-Hydroxyphenyl) -l-methyläthylaminoZ-lo-propargyloxyphenoxy-propanol-2 was according to Example 1 using

6098 19/12 7 5 - 28 -

1,2-epoxy-3-o-propargyloxyphenoxypropane and 1- (4-hydroxyphenyl-2-arainopropane produced as raw materials. The p-hydroxybenzoate was produced.

Example 5

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoZ-l-o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxyphenyl) -1-methylethylamine produced as raw materials. The hydrochloride was obtained as a water-soluble oil, and its structure was determined using NMR spectroscopy.

Example 6

3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-raethylphenoxypropane and 2- (4-hydroxyphenyl) -1,1-dimethyläthylainin produced as raw materials. The hydrochloride was obtained as a water-soluble oil, and its structure was determined using NMR spectroscopy.

Example 7

3- / 7- (4-hydroxyphenyl) -1,1-dimethylethylaminoZ-l-o-ethylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-ethylphenoxypropane and 2- (4-hydroxyphenyl) -1,1-dimethylethylamine produced as raw materials.

The melting point of the hydrochloride was 154 ° C.

- 29 -

609819/1275

Example 8

3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-allylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-allylphenoxypropane and 2- (4-hydroxyphenyl) -1,1-dimethylethylamine produced as raw materials. The melting point of the hydrochloride was 140 ° C.

Example 9

3- / 2 * - (4-Hydroxyphenyl) -1, l-dimethylethylaminoT-S-o-propargyloxyphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-propargyloxyphenoxypropane and 2- (4-hydroxyphenyl) -1,1-dimethylethylamine produced as starting materials.

Example 10

3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxyphenyl) -1,1-dimethylethylamine produced as raw materials. M.p. = 144 ° C (hydrochloride).

Example 11

3- / 2- (4-hydroxyphenyl) -l-methylethylaminoZ-l-o ^ -dimethylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o, m-dimethylphenoxypropane and 2- (4-hydroxyphenyl) -

1-methylethylamine produced as starting materials.

M.p. = 125 ° C (hydrochloride).

- 3o -

609819/1275

- 3ο -

Example 12

3- / 2- (4-hydroxyphenyl) -1-methylethylamino ^ l-o-methoxyphenoxypropanol-2 was according to Example 1 using 1/2-epoxy-3-o-methoxyphenoxypropane and 2- (4-hydroxyphenyl) -1-methylethylamine prepared as starting materials. M.p. = 114 ° C (Hydrochloride).

Example 13

3-Methy1-3- / 2- {4-hydroxyphenyl) -1-methylethylamine ^ -1-o-ethylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-1-methy1-3-o-ethylphenoxypropane and 2- (4-hydroxyphenyl) -1-methylethylamine produced as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined using NMR spectroscopy.

Example 14

3-Methy1-3- / 2- (4-hydroxyphenyl) -l-methylethylamimaT-1-ocyanophenoxypropanol-2 was according to Example 1 using l ^ -Epoxy-l-methyl-S-o-cyanophenoxypropane and 2- (4-hydroxyphenyl) -1-methylethylamine produced as raw materials. The hydrochloride was found to be a water soluble oil obtained and its structure determined using NMR spectroscopy.

Example 15

3-Ethy1-3- / 2- (4-hydroxyphenyl) -1-methylethylamino ^ -l-o-ally1-phenoxypropanol-2-was according to Example 1 using

609819/1275 - 31 -

of l ^ -Epoxy-l-ethyl-S-o-allylphenoxypropane and 2- (4-hydroxyphenyl) -l-methylethylamine produced as raw materials. The hydrochloride was obtained as a water-soluble oil and its structure determined by NMR spectroscopy.

Example 16

3-Methyl-3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-l-omethylphenoxypropanol-2 was prepared according to Example 1 using l _/ 2- ^I epoxy-l-methyl-3-o-methylphenoxypropane and 2- (4-Hydroxyphenyl) -1, 1-dimethylethylamine prepared as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined using NMR spectroscopy.

Example 17

3-Methy1-3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylaminoT-l-oallylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-l-methyl-3-o-allylphenoxypropane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine produced as raw materials. M.p. = 172 ° C (hydrochloride).

Example 18

3- / 2- (4-Hydroxypheny1) -1-methylethylaminoT-1-m-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-m-methylphenoxypropane and 2- (4-hydroxypheny1) -1-methyl-

ethylamine produced as starting materials. M.p. = 150 ° C (hydrochloride).

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609819/1275

Example 19

Preparation of 3- / 1-Methy1-2- (4-hydroxyphenyl) -äthylamino / -l-o-allylphenoxybutanol-2

2.5 g of 2,3-epoxy-lo-allylphenoxybutane were mixed with 1.5 g of 1-methyl-2- (4-hydroxyphenyl) -ethylarain and 25 ml of isopropanol, and the entire solution was refluxed for 100 hours. The solution was then evaporated in vacuo. The base so obtained was dissolved in trichlorethylene and the hydrochloride precipitated in ether using HCl. Water was added and the mixture was titrated with 1M HCl. The pH was determined with a glass electrode and the values were plotted against ml of HCl. At one band on the curve, the water phase was separated, fresh water was added, and the process was repeated until the next band appeared on the curve. This water phase was separated off, _{made alkaline with NH 4} OH and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated. The hydrochloride was precipitated in ether with HCl. The ether was poured off and the product solidified on evaporation in a high vacuum. The yield of 3- / 1-Methy1-2- (4-hydroxyphenyl) -äthylaminoZ-lo-allylphenoxybutanol ^ HCl was

1.6 g. F. = 70 ° C. The structure was determined using NMR spectroscopy certainly.

Example 20

A syrup with a content of 2% (weight per volume) active substance was prepared from the following ingredients:

609819/1275

2530613 G 2.0 G 0.6 G 30.0 G 5.0 G 0.1 G 10.0 ml to 100.0

3- / 2- (4-hydroxyphenyl) -l-methylethylamino / -l-o-methylphenoxypropanol-2 · HCl

Saccharin.

sugar

Glycerin

Flavor

Ethanol, 96%

distilled water

Sugar, saccharin and the ethereal salt were put in 60 g of warm water Dissolved in water. After cooling, glycerin and the solution of the flavoring agents dissolved in ethanol were added. To this Mixture was then added to water up to 100 ml.

The active substance indicated above can of course also be replaced by other pharmaceutically acceptable acid addition salts will.

Example 21

3- / 2- (4-Hydroxyphenyl) -1,1-dimethylethylamino-lo-allylphenoxy / -propanol-2-hydrochloride (250 g) was made with lactose (175.8 g) , potato starch (169.7 g) and colloidal Silicic acid (32 g) mixed. The mixture was moistened with a 10% gelatin solution and granulated through a 12-mesh sieve. After drying potato starch were _r. {160 g), mixed with talc (50 g) and magnesium stearate (5 g), and the mixture thus obtained was pressed into tablets (10 000), each containing 25 mg of substance. The tablets were sold in the market with break lines allowing a dosage other than 25 mg or a multiple thereof when the tablets were broken. - ,,

eO9ai9 / 1275

" ³⁴ " 2530513

Example 22

Granules were made from 3- / 2- (4-hydroxyphenyl) -1-methylethylamino7 "" l-o ~ propargyloxyphenoxypropanol-2-p-hydroxybenzoate (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying stage the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and made up to 10,000 compressed biconvex tablets. These tablets were first made with a 10% alcoholic solution from Shellac and on top with an aqueous solution containing 45% sucrose, 5% gum arabic, 4% gelatin and 0.2% dye overdrawn. Talc and powdered sugar were used to powder after the first five coats. The coating was then coated with a 66% sugar syrup and with a 10% carnauba wax solution in carbon tetrachloride polished.

Example 23

3- / 2 "- (4-hydroxyphenyl) -1, l-dimethylethylaminoZ-S-o -ethylphenoxypropanol-2-hydrochloride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) were used in a sufficient amount dissolved in distilled water to give 100 ml of solution. This solution, which contained 10 mg of active substance per ml, was used to fill ampoules by heating while Sterilized at 120 ° C for 20 minutes.

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609819/1275

Biological effects

The β-receptor blocking agents according to the present invention were tested for their biological properties. All compounds were tested in anesthetized cats (male and female cats weighing 2.5 to 3.5 kg) which had been pretreated with reserpine (5 mg / kg body weight, administered intramuscularly) about 16 hours before the experiments. The animals were pretreated with reserpine in order to switch off the endogenous sympathetic control of the heart rate and the tone of the vascular smooth muscles. The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered ip) and artificially ventilated with room air. A bilateral vagotomy was then performed on the neck. Blood pressure was obtained from a cannulated carotid artery and heart rate was recorded with a cardiotachometer triggered by the electrocardiogram (EKG). The intrinsic β-mimetic activity on the heart was seen as an increased heart rate after administration of the agent. The test compounds were administered intravenously in logarithmically increasing doses. The values obtained were recorded on dose-response _{curves, from which the affinity values (ED 50} ) were determined. At the end of each experiment, high doses of isoprenaline were administered in order to obtain the maximum heart rate response.

The compounds were also tested in conscious dogs. Beagle dogs were trained to keep them calm

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609819/1275

and raised to an aligned position by placing all forefeet on a table for 2 minutes. The arterial blood pressure was registered via a blood pressure transducer, which was connected to the dog at the level of the heart. The heart rate was recorded after the EKG. All dogs were pretreated with methylscopolamine in order to Avoid vagal influences. The recordings were made before and 15 and 75 minutes after administration of the test compound training, first in a lying position for 2 minutes and then in an upright position for 2 minutes. The test connections were given in increasing doses at 2-hour intervals.

The table below shows the affinity values and the ß-mimetic activity in cats treated with reserpine and the effects on blood pressure in dogs of consciousness of the compounds of the present invention. to For comparison purposes, the corresponding values for propanols !, namely {1-isopropylamino-3-U-naphthoxy} -propanol-2f and metoprolol, namely <l-IsopropylaTnino-3- / £ - (2-methoxyethyl) -phenoxy_7-propanol-2) specified.

The table also shows the pA "measured on rats. pA2 - log with concentration of an antagonist, which leads to the fact that the noradrenaline dose has to be doubled in order to obtain the same noradrenaline _{effect as one would get without the antagonist, or pA 2} = log (dr-l) -log ( Antagonist),

- 37 -

609819/1275

where dr is the dose ratio

ED ₅₀ of noradrenaline (antagonist) ED ₅₀ of noradrenaline (control)

and all concentrations are given in mol / 1.

pAp is thus a measure of the O ^ receptor effect, where higher pA ₂ results in a higher VÄ effect.

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609819/1 275

Tabel

link

cat treated with reserpine isoprene blocking self-activity,

ED ₅₀ , mg / kg

MR

Propanol

Metoprotol
At- .
game ^x

3
5
B.
7th

10
11
12th

13th
14th
15th
15th
17th
18th
19th

O ₁ I

0.2

0.07

0.11

0.7

0, Ό4

0.06

0 _f 05.

0.11

0.025

0.24

0.04

0.12

0.3

1.3
2.5
0.2

0.5

PR

Beats / minute

0.1
4.7
0.07
0.15

0.3

0.04

0.09

0 * 04

0.2

0.5

0.5

1.0

3.3

0.6
0.4

0.6

0 0

+ 16

+ 32

+ 33

+ 33

+ 62

+ 38

+ 39

+ 42

+ 6

+ 40

+ 18

+ 40

+ 2

+ 9

+ 3

+ 10

+28 conscious dog, blood pressure in mm HG after 1.5 mg / kg i.v.

lying upright

pA,

+ 5 0 "" _ ι Oil -5 -3 - ω
CO O -22 -19 6.8 ι -40. -3 5 7 ,? - - - 7.2 -40 · ■ -19 6.7 -16 -25 5 j G - - ε, π -40 ■ -20 6.4 0.3 - 6.2 ο _t α 6.6 0.2 ⁷ '

-33

-45

The experiments demonstrate that the tested compounds are strong β-receptor antagonists with or without their own are ß-inimetic activity. The links also lower the blood pressure in conscious dogs is significantly higher than propanolol and metoprolol. The strong hypotensive effect in conscious dogs, the new compounds depend on a vasodilator effect in conjunction with the Blocking of the heart ß-receptors.

609819/1275

Claims (1)

Claims and their pharmaceutically acceptable salts, wherein R is Is a hydrogen atom or a methyl group, R is a Hydrogen atoms, a methyl group, ethyl group, propyl group, Allyl group, methoxy group, propargyloxy group, cyano group, Morpholino group, pyrrolidino group or pyrrolyl group 3
R means a hydrogen atom, a methyl group or an ethyl group and R means a hydrogen atom or a methyl group. 2. amine derivatives according to claim 1, characterized in that 2 4
R and R are not both hydrogen atoms. 3. 3- / 2- {4-Hydroxyphenyl) -1-methylethylaminoZ-1-o-methylphenoxypropanol-2 and its pharmaceutically acceptable salts. 4. 3- / 2- (4-Hydroxyphenyl) -l-methylethylaminoZ-l-o-ethylphenoxypropanol-2 and its pharmaceutically acceptable salts. ⁵ · ³ ~ ^ T-Methyl-2- (4-hydroxyphenyl) -äthylaminoZ-io-propylphenoxy-.propanol-2 and its pharmaceutically acceptable salts. - 41 - 809819/1275 6. 3./2-(4-hydroxyphenyl)-1-methylathylaminoZ"2--o-allylphenoxypropanol-2 and its pharmaceutically acceptable salts. 7. 3- / 2- (4-Hydroxyphenyl) -1-methylethylaminoZ-l-o-p.ropargy 1-oxyphenoxypropanol-2 and its pharmaceutically acceptable salts. 8. 3- / ÜF- (4-hydroxyphenyl) -l-methylethylaminoZ-l-o-cyanophenoxypropanol-2 and its pharmaceutically acceptable salts. 9. 3- / 7- (4-Hydroxyphenyl) -1,1-dimethylethylaminoZ-1-o-methylphenoxypropanol-2 and its pharmaceutically acceptable salts. 10. 3- / 2- (4-Hydroxyphenyl) -1,1-dimethylethylaminoZ-1-o-ethylphenoxypropanol-2 and its pharmaceutically acceptable salts. 11. 3- / 2- (4-Hydroxyphenyl) -1,1-dimethylethylaminoZ-1-o-propylphenoxypropanol-2 and its pharmaceutically acceptable salts. 12. 3- / Σ- (4-hydroxyphenyl) -1,1-dimethylethylaminoZ-l-o-allylphenoxypropanolr2 and its pharmaceutically acceptable salts. 13. 3- / 2- (4-Hydroxyphenyl) -1, l-dimethylethylaminoZ-l-Zo-propargyloxyphenoxy-/ -propanol-2 and its pharmaceutically acceptable Salts. - 42 - 609819/1275 14. 3- / 2- (4-hydroxyphenyl) -lrl phenoxypropanol-2 and its pharmaceutically acceptable Salts. 15. α-Ethyl-S-ZT-methyl-α- (4-hydroxyphenyl) allylphenoxypropanol-2 and its pharmaceutically acceptable salts. . .. · - 16. 3 - / _ T- (4-Hydroxypheny1) -l-methylethylaminoZ-lo, m-dimethylphenoxypropanol-2 and its pharmaceutically acceptable salts 17. 3- / 2- (4-Hydroxypheny 1) -l-methyläthylaminoZ-lo-methoxyphenoxypropanol-2 and its pharmaceutically acceptable salts., IS. 3-Methy 1-3- / 2- (4-hydroxyphenyl) -1-methylethylaminoZ-l-o-ethylphenoxypropanol-2 and its pharmaceutically acceptable salts. 19. 3-Methy 1-3- / 2- (4-hydroxyphenyl) -l-methylethylaminoZ-I-o-cyanoO'-phenoxypropanol-2 and its pharmaceutically acceptable salts. 20. 3 ^ Methy 1-3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylamino-7-l-omethylphenoxypropanol-2 and its pharmaceutically acceptable salts. 21. 3-Methy 1-3- / 2- (4-hydroxyphenyl) -1, l-dimethylethylamino-7-l-oallylphenoxypropanol-2 and its pharmaceutically acceptable Salts. - 43 - 609819/1275 22. 3- / 2- (4-Hydroxyphenyl) -1-methylethy1 amines / -1-m-methylphenoxypropanol-2 and its pharmaceutically acceptable salts. 23. 3- £ T-Methyl-2- (4-hydroxyphenyl) -ethylartin £ 7 ~ l ~ o-allylphenoxybutanol-2 and its pharmaceutically acceptable salts. 24. Process for the preparation of amine derivatives according to claim 1 to 23, characterized in that one a) a compound of the general formula 2 3 4 1 wherein R, R and R have the above meanings, X one Hydroxyl group and Z is a reactive esterified hydroxyl group or 'X and Z taken together is an epoxy group mean, with an amine of the general formula • c wherein R has the above meaning, converts or b) a compound of the general formula ( IV) -OCH ₂ CHdHCHNH ₂ ^RR '- 44 - 609819/1275 2 3 4 wherein R, R and R have the above meaning, with a compound of the general formula wherein R and Z have the above meaning, converts or c) a compound of the general formula 2 4 wherein R and R have the above meaning, with a compound of the general formula . X ¹ R ^1! Z-Ch ₂ CHCHNHC-CH ₂ - ₂ CHCHNHC-CH ₂ -R ³ CH ₂ wherein Z, X, R and R are as defined above or d) a compound of the general formula -OH \ - / ·: R ^4> "~ V O Λ wherein R and R are as defined above, with a compound the general formula - 45 · - 609819/1275 - 45 .1 R-CH - NC-CH = - // ^v > -OH DH wherein R and R have the above meaning, or e) from a compound of the general formula H ₀ CH MUr-f-M - // MHC QH: CH ₃ 2 3
in which R, R and R have the above meanings and where the compound bears a removable radical on the nitrogen atom of the amino group and / or on the hydroxyl groups, or splits off this radical f) a Schiff base of one of the formulas ■ 7 V OH OCH ₂ CHOKCHN = C- [2 R ³ CH, 609819/1275 or "a cyclic one corresponding to the latter compound Tautomer of the general formula OCH. -CH-R ■ ι
■ '! 2 '' NH ■ "\ -oh ^: \H_" , CH- 0
\ H ^ ti 12 3 4
wherein R, R, R and R have the above meaning, where, if R is methyl, the two first-mentioned Schiff's bases can also be present simultaneously with one another, reduced or g) in a compound of the general formula ■ OCH-CCHNHC-CH-V _R 2 R ³ CH ₃ . OH wherein R, R, R and R have the above meaning, the Oxo group reduced to a hydroxyl group or h) in a compound of the general formula K) CH _o CH0HCHNHC-CH = j— / 2 -U r ² ■■ λ π υπ-, 609819/1275 - OH - 47 - 13 4 2 wherein R, R and R have the above meaning and X is a radical that can be converted into R as defined above, X is converted into R ² or i) in a compound according to the formula -CH _o CHQHCHNHC-CH- ('> -CH I ₃ ί ^ = S 2 ^{R CH} 3 but with an oxo group on the carbon atom near the Nitrogen atom, this oxo group to two hydrogen atoms reduced and optionally introduces substituents in all cases or splits off or converts to other substituents, and / or the free bases in their therapeutically tolerable form Salts and / or the salts converted into their free bases and / or the isomer mixtures obtained into their separates pure isomers and / or separates the racemates obtained into their optical antipodes. 25. Medicament containing at least one compound according to claim 1 to 23, preferably together with a customary one pharmaceutically acceptable carrier material. - 48 609819/1 275 - 43 - 26. Medicament according to claim 25, characterized in that it the amine derivatives in an amount of 0.1 to 95 wt .-% contains. 27. Medicament according to claim 25 and 26 for administration by Injection, characterized in that it contains the amine derivatives in an amount of about 0.5 to 20% by weight. 28. Medicament according to claim 25 and 26 for peranteral administration, characterized in that it is an aqueous solution with about 0.5 to 10 wt .-% of at least one water-soluble Is the salt of the amine derivatives. 29. Medicament according to claim 25 and 26 for oral administration, characterized in that it contains the amine derivatives in an amount contains from about 0.2 to 50% by weight. 609819/1 275