CS208731B2 - Method of making the new amines - Google Patents

Abstract

The process is used for preparing the novel amines of the formula (I) <IMAGE> R<1>, R<2> and R<3> are defined in Patent Claim 1. The reactions for preparing the said compounds always take place between primary amines and compounds having a reactive, esterified hydroxyl group or an epoxy group. The novel compounds effectively block beta receptors.

Description

(54) A process for producing new amines

The present invention relates to a process for the production of novel amines of active compounds blocking β-receptors and useful for the treatment of cardiovascular disorders in mammals, including humans.

The new amines produced according to this invention are characterized by the formula I / O _V ² CHOH-CH ² -NH- (CH _{2) n} -X ^X R1 in which ^R1 is methyl, et.hyl ^p ro ^p yl, an ^alkyl, methoxy, tyanmethyl , ^{hydroxypropyl} methyl rox ^y not ^b ar ^P inu

C ^ OC ^ NHCOCHzO- ^{r2 hyd} roxýl, ox ^{meth yl} nebotydrxyyniettyl,

R ^{3 is} hydrogen, hydroxyl, hydroxymethyl or methoxy, n number 2, 3 or 4;

X is -O-.

The novel compounds produced by the process of the invention have valuable pharmacological properties. For example, they block cardiac β-receptors, as shown in the tachycardia antagonist assay after intravenous injection of 0.5 µg / kg d / 1-isoproterenol sulphate and in a cat at an intravenous dose of 0.002 to 2 mg / kg. They also block the vascular β-receptors as manifested in the determination of vasodlatation antagonism following intravenous injection of 0.5 4g / kg d / 1-iooproterenol sulphate to an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg or more. The compounds also have stimulating properties at the .beta.-receptors, i.e. they show a penetrating effect. · This property is particularly pronounced in the case of vascular β-receptors causing dilatation of peripheral blood vessels.

The novel compounds can be used in the treatment of arrhythmias, angina pectoris and hypertension. Peripheral vasodilation is particularly valuable for both of these indications. They can also be used as intermediates in the preparation of other pharmaceutically valuable compounds.

The novel compounds produced by the process of the invention are as follows:

3 - [- (4-hydroxyphenoxy) ethylamino | -1-o-methylphenoxypropionol-2,

3- [2- (4-hydroxy-phenoxy) -methyl-amino] -1-o-ethyl-phenoxy-propanol-2,

3- [2- (4-hydroxyphenoxy) ethylamino] -1-1-propylphenoxypropanol-2,

3- [2- (4-Hydroxyphenoxy) ethylamino] -1-o-allylphenyl: propylprolol-2,1- (4-hydroxyphenoxy) ethylamino] -1-o-propagyloxylenesopropylpropanol-2,3- [ 2- (4-Hydroxyphenoxy) ethylamino] -1-1-kylophenoxypropol-2,3- [2- (4-hydroxyphenoxy) ethylamino] -lo-allyosyl-4-cyano-propane-1,3- [2- ( 4-Hydroxyphenoxy) ethylamino-1- (1-propargylphenyl) propyl] -2,3- [2- (4-hydroxyphenoxy) ethylamino] -1- (1-hydroxyphenoxy) propanol-2,3- [2- (4-hydroxyphenoxy) ethyl] lamino] -1-1-acetyleonylpyrroleool-2,3- [2- (4-hydroxyphenoxy) ethylamino] -1-o-hlyroxyethyl:> χ / phenocχ-prlp (lool-2,3- [2- (4 1-Hydroxyphenylthio) ethlamino] -1-1-ylphenoxypropimol-2,3- [2- (4-hydroxyphenylthio) ethylamino] -1-1-methylphenoxy-1-propyllo-2,3,3- [2- (3-methoxl-4-) methlxyfenoxy) ethylamino] -1-L-iethyllenlxy-propanol-2, 3- [2- (3-bromo-4-hydroxyphenoxy) ethylamino] -o-methoxypyrimidine ^κyl> eno2φlpropanol-2, 3- [2 - '(3 -hydroxymethyl-4-hydroxy-phenoxyl) -ethylamino] -1-o-cyanlenol-propanol-2,3- [2- (3,4-dihydroxyphemethylthio) -hylamino] -1-o-cyanleloxy-p opano0-2,3- [3- (4-hydroxyphenoxy) propylamine (1-l-o-methylphenoxypropyl) -3,3- [4- (4-hydroxyphenyl) -1-allyleol] -1-allyleolOX1-propylpolyl-2 3- [2- (2-4-chllr hydrlxyfeollthio) ehhyaamino] -1 ^ -l-αllllcxlleno -propanno- ^2, 3- [2- (4-aethoxyfenoxy) ethylaaino] -1-L-2-kyaofenlχlpropanol, 3- | 2- (2-Hydroxyphenylphenyl) ethanol] -1-1-cyanophenylpropylpolyol-2,

2- [2- (4-Hydroxy-3-ethoxyphenoxy) ethyl] methyl (3-l-1-kylopheol) cypropalol-2,

3- [2- (3,5-diethoxyphenoxy-ethylamino) -1,1-kyl-n-phenoxy-propolyl-2,3- [2- (4-hydroxy-phenoxy) -ethylamino] -1-1-propyl-phenoxy-propanol-2,3- [2] - (4-Hydroxyphenoxy) ethylamino] -1-o-aethoxyethyllainocarbonylmethylene-phenol-1-POlalol-2,

Acid-forming acids can be used in the preparation of therapeutically useful salts of the compounds. They are hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, hydroxylic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citricore, ascorbic, , hydroxymaine or grape, phenoxy, benzoic, p-alpha-benzoic, anthranilic, p-hydroxybenzolvate, sodium or p-sulfonium, carbon, methanesulfonic, ethanesulfonic, hydrogen sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, sulfonate, Lysine, lysine or arginio.

The substances are intended for oral or parenteral administration for acute or long-term treatment of the above cardiovascular disorders.

The biological effects of the novel compounds as well as the various tests that have been performed are listed and explained below.

The novel compounds can be obtained by methods known per se.

The novel compounds of formula (I), CH ₂ CH ₂ CH ₂ - (CH ₂ ) _n -x (I) wherein R 1 is ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl. or the rest

CH3OC2H4NHCOCH2O-,

3 2 ^, 0 » ^{R h} y ³ rox ^y l, methoxyl, or ^y ydooyyme ^h hyl,

R ³ in the ^y magnesium, H ^yy roo ^y l hy ^ o ^ ^b eethyl not on meth) ^{acryloyl. ,} n numbers 2 to 4a *

X is an -0-, produced by the process according to the finding ^Y, podytata which consists in that a compound of formula III,

Z \ -OCH2CHOHCH ₂ NH 2 _(III J r1 · ^r1, in which my same meaning ^as j and ^k ou ^ya well above stated 3o reacted with a compound of formula

in which

Z represents a reactive esterified hydroxyl group and

3

R, R 4, n, and X have the same meaning as given above.

The reactive esteric hydroxy group is especially a hydroxy group esterified with a strong inorganic or organic acid, preferably a hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, furthermore a sulfuric acid or a strong organic sulfonic acid, for example benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-bromobenzenesulfonic acid. Thus, Z is preferably a chlorine, bromine or iodine atom.

Said reaction is carried out in a conventional manner, preferably in the presence of a basic condensation agent and / or an excess of the amine. Suitable base condensing agents are, for example, alkali metal alcoholates, preferably sodium or potassium alcoholate, or else alkali metal carbonates, for example sodium or potassium carbonate.

The reaction is carried out in an alkanol having 1 to 3 carbon atoms, in an autoclave, with heating at 100 to 130 ° C for 5 to 15 hours.

Depending on the process conditions and starting materials, the end product is obtained either in the form of the free base or in the form of its acid addition salts, which are also included within the scope of formula (I) produced by the process of the invention.

For example, basic, neutral or mixed salts as well as gaming amino, sesqui or polyhydrates can be obtained. Acid addition compounds of the novel compounds can be converted into the free bases in a known manner, for example using basic agents such as alkalis or ion exchangers. On the other hand, the obtained free bases form salts with organic or inorganic acids.

In the preparation of the editorial salts, tartaric acids, which form suitable, therapeutically acceptable salts, are first used. Such acids are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, aliphatic, alicyclic, aromatic or heterocyclic carbooyl or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic acids. , maaine, hydrooymaaine or pyruvic, phenylacetic, benzoic, p-amobenzoic, anthranilic, p-hydrooybenzoic, salicylic or p-aminoosaicylic, embonous, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, sulfonic acid, methionine, tryptophan, lysine or arginine.

These or other salts of the novel compounds, for example picrates, may serve as purifying agents, or the free bases obtained as such may be converted into salts, isolated and the bases released therefrom. In view of the close relationship between the new compounds in the form of the free bases and in the form of their salts, it is to be understood that, where possible, the corresponding salts are included within the term free compounds.

Depending on the choice of starting materials and the method of preparation, the novel compounds occur as optical antipodes or racemates, or (if they contain at least two asymmetric carbon atoms) as a mixture of isomers (a mixture of racemates).

The resulting mixture of isomers (mixtures of racemates), depending on the physicochemical differences of the components, can be separated into both stereoisomeric (diastereomeric) pure racemates, for example by means of chromatography and / or fractional crystallization.

The racemates obtained can be separated by known methods, for example by recrystallization from an optically active solvent, by microorganisms or by reaction with optically active acids which form salts with the compounds, and by separating the thus obtained salts, for example on account of their different solubility, into diastereoisomers release by treatment with a suitable agent. Suitable optically active acids which can be used are, for example, the L- and D-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, the more active moiety is isolated from both isomers.

Suitably, starting materials are used for carrying out the process according to the invention, which in particular provide groups for the end products which are particularly needed, and in particular those end products which are described as particularly advantageous.

The starting materials are known or, if new, can be obtained by known methods.

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

Thus, when reference is made to novel compounds produced by the process of the invention, it refers either to the free base amine or to the acid addition salt of the free base, although the compounds are described generally or individually, unless the text in which these terms are used, e.g. of the embodiments, did not correspond to this broad meaning.

The carrier may be a solid, semi-solid or liquid diluent or capsule. The usual amount of active compound in the preparation is about 0.1 to 99% by weight, suitably from 0.5 to 20% by weight in preparations for injection and from 2 to 50% by weight in preparations for oral administration.

In the manufacture of pharmaceutical compositions containing the compounds of this invention in the form of a dosage unit for oral administration, the selected compound is admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato or corn starch, amylopectin, cellulose derivatives or gelatin, also with a glidant such as magnesium or calcium stearate, polyethylene glycol waxes and the like, and compressed into tablets. If coated tablets are desired, the cores prepared as described above are coated with a concentrated sugar solution, which solution may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like.

In addition, the tablets may be coated with a water-soluble drug in a slightly volatile organic solvent or solvent mixture. A colorant may be added to this coating to more easily distinguish tablets with different active compounds, e.g.

In the manufacture of soft gelatin capsules (spherical capsule capsules, for example of gelatin and glycerin) or in the production of similar capsule capsules, the active compound is mixed with a vegetable oil. Hard gelatine capsules may contain granules of the active compound in combination with a solid powdered carrier such as lactose, sucrose, soobitol, mannitol, starch (such as potato or corn starch or amolepetin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient in admixture with a natural neutral fatty base, or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with rossiin or paraffin oil.

Liquid preparations for oral administration may be presented in the form of syrups or suspensions, for example solutions containing from about 0.2% by weight to about 20% by weight of the active ingredient, the remainder being sugar and a mixture of ethanol. , water, glycerol and propylene glycol. If desired, these liquid preparations may contain coloring agents, flavoring agents and sachaain, and carbonylhydrogen cellulose as a thickening agent.

Solutions for parenteral administration by injection may be prepared 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 10% by weight. These solutions may also contain stabilizing agents and / or pirfers and may be available in amulos in different dosage units.

The preparation of pharmaceutical tablets for oral administration is carried out according to the following procedure.

The solids used are ground to a certain grain size. The binder is homogenized and suspended in a certain amount of solvent. The active ingredient and the necessary auxiliaries are mixed during continuous and uniform mixing with the solution of the binder and moistened so that the solution is distributed uniformly throughout the mass without any parts being wetted. The solvent solvent is usually treated so that the mass has a consistency resembling wet snow. The wetting of the powder mixture with the solution causes the particles to gently adhere together to form an aggregate, and the actual granulation process is effected by passing the mass through a non-stainless steel mesh of mesh size. mm.

It is then dropped in thin layers on trays to settle in the oven. Drying is carried out for 10 hours and the specified conditions must be observed since the moisture content of the granulate is of great importance for the subsequent process and for the properties of the tablets. Drying under fluidic conditions may also be used. In this case, the mass is not placed on a tray but is poured into a container having a sieve bottom.

After drying, the granulate is sieved to obtain particles of the desired size. In certain circumstances, dust is removed.

Disintegrating agents, glidants and anti-adherents are added to the so-called final mixture. After this mixing, the composition should have the correct composition for tabletting.

⁰ The cleaned tabletting machine is scalded with a set of punches and maatic, then the appropriate pressure setting is tested. The weight of the tablet is representative of the dose in each tablet

and calculated in relation to the amount of therapeutically active agent in the granulate. The degree of compression influences the size, strength and disintegration of the tablet. Especially with respect to the latter two properties, the choice of the compression pressure (0.5 to 5 tons) should be well stated. JessiiSe the correct setting is ready to produce tablets that run at 20,000 to 200,000 tablets per hour. Compression of the tablets requires different time and depends on the size of the batch.

The tablets are de-dusted in a separate device and then stored in sealed containers until dispatch.

Some tablets, especially those having an unpleasant or bitter taste, are coated. This is meant to be coated with a layer of sugar or other suitable coating.

Tablets are usually packaged using machines having an electronic computer. Different types of packaging can be glass or plastic cups, but also boxes, tubes and speeial packaging adapted for dosing.

The daily dose of the active ingredient varies and depends on the route of administration, as a rule 100 to 400 mg per day of the active ingredient for oral administration and 5 to 20 mg per day for the intravenous administration.

The following examples illustrate the principle and application of the invention without, however, limiting its scope.

Example 1.

g of c-methylphenol glycidyl ether in 100 ml of ethanol are treated with ammonia gas and the mixture is heated in an autoclave on a boiling water bath for 4 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and hydrogen chloride gas was introduced.

The Hytdoc chloride thus precipitated is filtered off and dissolved in 50 ml of ethanol to which. 2- (4-methoxy- (non-cyclohexyl) phenoxyethyl chloride) and 15 g of potassium carbonate (RgCO4) were added. · Mixtures · will ^also play a ^c autoclave ^p s ^{of 130} ° C and ^d o ^B in ¹⁰ him-ins NACE ^M solvent was evaporated and · ⁿ · ZB ^y tek treated with 100 ml 2NHC1 for one hour at ok from. The aqueous phase was made alkaline with amine and precipitated with ethyl ether. Rozpooutědlo dried over anhydrous potassium carbonates anus (^ CCJ then 1- [2- (4-Hydroxy ^{y y} h day)) xteth laminc ^yl) -3-o-mdiltldonoxýЗ propanoC -2. The base obtained was converted to hydrocClooid, i.e. to 1- [2- (4-h ^y d r)) xyfencxtdtl lrщino ^yl) -3-C-2-meehylfdocxytploplroC hytdocClooid. Melting point 150 ° C.

Example2

Preparation of 3- [2- (4-hydroxyphenethoxy) -dyryrinc] -1o-diethyldonoxypropyl-2

2.5 g of 1,2-dioxo- ^3- o-indolidenoxypropane are mixed with 1.5 g of 2- (4-hydroxyphenoxy) ethylamine and 25 ml of isopropanol and the total solution is refluxed for 1.5 hours. The solution is then evaporated in vacuo. The base thus obtained is taken up in acetone and the hydrochloride is precipitated using hydrogen chloride in ether. The hydride cooride is filtered off and washed with acetone. The yield of 3- [2- (4-hydroxyddncxy) dtlylaminq | -1-o-meilyleenoxtprcpaoolu-2 is 1.5 g. Melting point lydrcch ori ^{1 d} u is ¹ 5 ⁰ ° C. The structural formula was determined by 1 H NMR.

PííIi- U '3- [2- (2-hydroxy phenoxy ^yl) dtlylrilOno) -1-o-methylfenoxyproprnol-2 was prepared according to Example 1 1,2-locSStí dpoxy-3- (o-mdtltl) and 2 eocoxypcopanu - (2-lydroxyddnoxy) dtlylamtnu as Buf · ^{h h} ozíc DTEK. The melting point of the product is 80 ° C. ^The structural formula was determined using NMR and the equivalent of 10 nm. ,

Example 4

3- [2- (2-Methoxy-phenoxy) -ethylamino] -1-o-methyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methyl-phenoxy-propane a. - (2-metloxyfenqχy) ethylaoinu as Buf ^{H H} ozíc ^the battens. The melting point of tartrate is $ 1 ° C. Qu ^to touring pattern was determined, and equivalents ingestion NMR ^ H ^ noVt out.

Example5

3- [2- (4-Methoxyphenoxy) ethylamino-1-q-oethyl: eoxyoxypropanol-2] was prepared according to Example 1 using 1,2-epoxy-3-q-oethyleenoxypropyl and - (4-oethoxyphenyl) ethylacetate as starting materials. The melting point of the hydrochloride is 168 ° C.

Example 6.

3- [2- (3'-Dimethoxyphenyl) ethylamino] -1-o-oethylphenylpropan-2-2 was prepared according to Example 1 using 1,2-epoxy-3-o-oethylphenoxypropane and 2- (3 ₎ 4-dimethoxyethane. ^; ^ jrenoxy) ethylamine as Buf ^H ozícb ^la tek :. ^The temperature of the hydrogen chloride is ¹⁶⁰ . Deň: 32 ° C.

Ex. Ad7

3- [2- (4-Hydroxy-3- (2-phenoxy) -2-methyl-3-o-cyanophenoxypropenol-2) was prepared according to the example with the use of 1,1-epoxy-3-q- kyanfenqχypropanu and 2- (4-hydroxyphenoxy-thylaotnu as ^starting-I C ^{M a} tek. temperature ^Ta in the anus ^ 5 ² ° C.>

Example8

2-, 2- (4-Hydroxyphenoxyylethylamino-1-o-oethoxyphenoxypropanor-2) was prepared according to Example 1 using 1,2-epoxy-3-o-oethoxyphenoxypropane and 2- (4-hydroxyphenoxy) thylaoine as starting materials.

Příkaad9

3- [- (4-Hydrqχyfeeqχy thyPamino ^] -1 ~ q ~ etlyffenoэypropanql - prepared according to Example 1 for _pcouití> --epqχy 3-q and ethyfeeqoxypqopanu - (4-hydrqχyfenoxy) ethylaoieu as starting materials.

Example10

3 - [[(4-Methoxyphenoxy) ethylamino] -1-o-cyanophenylpropanol-2 was prepared according to the example using 1, - epoxy-3-q-cyanophenoxypropane and - (4-oethoxyphenoxypropane). ethylaieu as starting materials. The melting point of the hydrochloride is 134 ° C.

P says and d11

3-Q2- (2-Hydroxyfenqχy) ethylaoieq] -1-q kyaefeeeoxyprqpanoq-2 prepared according to Example 1 for pqqžití 2-epqχy-3-q-kyanfenqχyprqpanu and 2- (2-hydroxyphenoxy-thyleminu as starting ^la tek . Teppota ^l ydrqchlqrtdu point 181 ° C.

Example12

3- [2- (4-Hydroxy-3-oethoxy) -ethylamino] -1-o-cyano-epoxypropanol was prepared as described above. ^Cart with ¹ l ^{per ad} .p ^ q ^ ^Zii ^ ^^ ^children and epoxy-cyano-phenoxy-propane and ^- - ^{(i- y} -hydrqχ -3-methq: l ^{χ χ} enqq jУ ^f) IEH ^h Aamin as starting · substances. Melting point . ly ^d rqchlqrtdu is 78 ° C.

2087 ^ 1

Example 13

3- [2- (3,5-Dimethoxyphenoxy) ethylamino] -1-o-cydenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (3,5-dinethoxyphenoxy) ethylamine as starting materials. The melting point of Uydruchuride is 159 ° C.

Example 14

A syrup containing 2% by weight of the active ingredient is prepared from the following ingredients:

3- [2- (4-Hydroxyphenyl) -11-trans-amino] -11uo-π-ethyl-oxo-propylene-2. HC! 2.0 g saccharin '0.6 g sugar' 30.0 g glycerol 5.0 g flavorings. · 0.1 g ethanol 96% · 10.0 g distilled water to a total volume of 100.0 ml

Dissolve the sugar, sachaain and etheric salt in 60 g of warm water. After cooling, add glycerol and a solution of flavorings dissolved in ethanol. The mixture is then made up to 100 ml with water.

The aforementioned active substances can be replaced by both pharmaceutically acceptable acid addition salts and acids.

Example 15

- ^ - ^ - ^ Hydrox eeyl) - ^1, 1-dimethyl ylethyl ^{u u u} ylrmino 11Oua ^r l ^y lfenux ^yl] -2- ^p rupaar ^{u u u} ydrouh chloride (250 g) · mixed with lactose (175, 8 g), potato starch (169.7 g) and silica for 32 days (32 g). The mixture is moistened with 10% gelatin solution and granulated through sieves of 0.47 mesh / mm. After drying, potato starch (160 g), talc (50 g) and magnesium stearate (5 g) are admixed, and the mixture thus obtained is tableted into tablets (10,000) of 25 mg. to obtain a dose of not more than 25 mg. or its multiples when breaking the tallet. *

Example 16,

The granules are prepared from 3- [2- (4-hydroxyphenyl) 11-methyl-amino] -1-o-poopargyloxyeerluxyprupanol-4-hydroxybenzoate ⁽ 25.0 ^g ), tosyl ( ¹⁷ 5.9 ^g), and α-ω-4-hydroxybenzoate. solution ^of polyvirylpyrrulidone (25 g). After drying, the granules are mixed with talc (25 g), potato starch (40 g) and magnesium tearate (2.50 g) and compressed into 10,000 biconvex (lenticular) tablets.

These tablets were first coated with 10% alcohol shellac, followed by an aqueous solution containing sucrose (45%), gum arabic (5%, gelatin (4%) and color (0.2%)). Five coatings were coated with talc and powdered sugar and then coated with 66% sugar syrup and polished with a 10% solution of carnauba wax in carbon tetrachloride.

Example 17

3- [ ^2- (4-Hydroxyphenyl) -1,1,1-dimethylethylamino] -3-o-ethylfruxypyr- ^p- O-2-hydrochloride (1 g), sodium chloride (0.8 g) and 4-carboxylic acid (0, 1 g) dissolve in sufficient quantity of distilled water per 100 µl of solution

This solution, which contains 10 mg of active ingredient per milliliter, is filled into ampoules which are sterilized at 120 ° C for 20 minutes.

Biological effects

The β-receptor blocking agents of the invention have been tested for their biological properties. All compounds were also tested in anesthetized cats (males and cats weighing 2.5-3.5 kg) pretreated with reserpine (5 mg / kg body weight, intramuscular) about 16 hours prior to the start of the experiment. The animals were pre-treated with reserpine to eliminate endogenous sympathetic regulation of the rate of cardiac activity and vascular smooth muscle tone. Cats were anesthetized with pentobarbitaea (30 mg / kg body weight, i.p.) subjected to artificial air venous misirnooti. A bilateral vagotomy was performed on the neck. The blood pressure was measured from the cannula artery (artheria carotica) and the cardiac activity was recorded by means of an electrocardiogram (1KG) cardiography.

Penetrating e-mimetic efficacy of the heart was determined from increased cardiac activity following drug administration. The test compounds were administered intravenously in logarithmically increasing doses. The obtained values were plotted as a dose response curve from which the affinity values were determined (ED _50). At the end of each experiment, high doses of corn were administered in order to obtain a cardiac activity response.

The compounds were also tested in dogs. kept conscious. Hunter dogs (blagl varieties) were trained to lie still to rise upright by placing their front legs on the table for 2 minutes. Arterial blood pressure was recorded using a blood pressure transducer attached to the dog at heart level. Cardiac activity was recorded by ECG.

All dogs were pre-administered oothyltkopolaoio in order to oddtrain.1 the effect of the vagus. Records were made prior to administration of the test compound and 15 to 75 minutes after administration, first in the sup position for 2 µL and then in the upright position for 2 mimes.

Test compounds were administered at a given dose at two-hour intervals.

The pAg value in rats was also missed. The pAg value is defined as the log concentration of the antagonist, resulting in a doubling of the dose of noradrenaline to achieve the same noradrenaline effect as without the antagonist, or pA2 = log (dr-1) -110 (^115). ), where dr is the dose ratio

ED50 noradrenaline (antagonnsta) dr = 1 · · —- .......—

ED? Q of noradrenaline (control) and all concentrations are given in mdL per liter, i.e. mol / l.

Thus, the pAg value is a measure of the α-receiver effect, where a higher pAg indicates a higher α-effect.

Experiments show that the test compounds are potent receptor antagonists, and are cardilselective agents with or without β-mimetic penetration effect. These compounds also greatly reduce cow pressure in conscious dogs. The hypotensive effect of these novel compounds in conscious dogs depends on the vasodilating effect in combination with cardiac β-receutorl block. The results obtained in the above tests are given in the following Table 1.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of novel amines of the general formula I, r2 O-CH _{2 CHOH-2} -NH- (CH _{2) n} -X- ₃ wherein ^R 'meetyl, ethyl, for ^P-yl, k ^y n,' methoxy kyanmeehyl ^h ydroxymethyl no ^b of CH _{3 2} H oc ₄ nhcoch ₂ o, ρ R. hydrooyl, methoxyl. or hydroxymetřyl, ^R3 is hydrogen hydroxy, ^{h e} hyl ydroxyme not ^{b e} the RNM hooyl n CISO 2, 3 or 4 and X is -O-, characterized in that the compound of formula III, (III) wherein R ^{1 has the} same meaning as given above and is reacted with a compound of the formula wherein R ¹ Z represents a reactive ethoxyterol hydroxyl group and 2 3 R, R., n and X have the same meaning as above.