CS208730B2 - 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

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

The novel amines produced according to the invention are characterized by the general formula I, o-ch ₂ chohch ₂ nh - (s ₂ ) _p -х

Where R is

R ^{1 is} methyl, ethyl, propyl, cyano, methoxy, kaynmethyl, hydroxymethyl or a group

CH.0C _o H.NHC0C'H _o 0-,

3 2 4 2

R is hydroxyl, methoxy or hydroxymethyl, β number 2, 3 or 4 and

The X-O compound of the present invention has valuable pharmacological properties. For example, they block cardiac β-receptors, as demonstrated by the tachycardia antagonist assay after intravenous injection of 0.5 µg / kg d / 1-isoproterenol sulfate to an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg. They also block vascular β-receptors as manifested in the determination of vasodilatation antagonism after intravenous injection of 0.5 µg / kg d / 1-isoproterenol sulfate to an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg or more. The compounds also have stimulating properties at β-receptors, which means that they exhibit a penetrating effect. This property is particularly pronounced for vascular O-receptors causing peripheral vascular dilation.

Novel 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- [2- (4-hydroxyphenoxy) ethylemino] -1-o-methylphenoxy-propanoo-2,

3- [2- (4-hydroxyphenoxy) ethylimino-3-l-o-ethylphenoxy-propeol-2,

3- [2- (4-Hydroxy-phenoxy) -ethyl-amino] -1-o-propyl-phenyl-propyl-2-2,

3- (2- (4-hydroxyphenoxy) ethyl-amino) -1-r-allyl-oxox-1-propanol-2,

3- [2- (4-lydrlxyfenlχy) ethyl ^1-amine 1-L-prlpargyllxyfenl: Xp-prlpθnoO-2

3- [2- (4-Hydroxyphenoxy) ethylaminoo-1-o-cyanophenozoxrPolPnol-2,

3- [2- (4-Hydroxyphenol) '] ^- 4-Amino-11O-allyloxyphenoxy-propanol-2,3,3- [2- (4-hydroxyphenoxy) ethyl-aminol-1-o-propargylphenyl] -propano-2,3- [2- (4-hydroxy-phenoxy) -ethylamino] -. ;] -1-r-Cyanomethylphenyl-piperidin-2,3- (2- (4-hydroxyphenoxy) ethylamino) -1-o-acetylferosopropano-2,3- [2- (4-hydroxyphenoxy) ethylamino]; -1-o-Lydroxymethyl ⁽ 1-phenoxy) -propanol-2,3- [2- (4-halo-2-ylamino) -thienyl] ethyl] -4,8-ylamino; -1-o-cyanophenoxy-propealoo-2,3- [2- (4-hydroxyethylthio-4-ylamino) -1-o-methyl-trifluoromethyl-propanor-2,3- [2- (3-methoxyl-4-ol)] -methoxyphenolxy) ethylpino] -1-o-methylphenoxy-1-chloro-2,3,3- [2- (2-chloro-4-hydroxyphenoxy) ethyl] amino] -1-methoxyphenoxy-4-hydroxypropenol-2,3- [2- (3-hydroxy) 4-hydroxyphenoxy-4-hydroxyphenoxy-1-o-cyanophenoxypropenone-2,3- (2- (3,4-dihydroxyphenenylthio) ethylamino) -1-r-cyanlenepoxypropanor-2,3- (3- (4- (4-hydroxyphenyl) oxy) propyl-1-o-methyl) -4- (4-hydroxyphenoxy) butylamino] -1-r-allyltonoxyl-propanol-2,3 - [2- (2-chloro-4- (1-trifluoromethylphenyl) ethyl) ethyl] -1-o-allyoxyoxyphenoxy γ-propanol-4, 3- (2- (4-methoxy-4-enoxy) -ethylamino] -1,4-cyano-oxo-proppaoro-2,3- [2- (2-hydroxy-phenoxy) -ethyl-amino] -1-l-1 -cyanphenoxylpropanoO-2,3- [2- (4-hydroxy-3-methoxyphenoxy) ethylmino] -1-6-cyanlene-2 (2) -propenoxy-2,3- (2- (3,5-dimethylphenoxy)) tilhllaminol- 1-o-cyanophenoxy-propanol-2,3- (2- (4-hydroxylthnoxy) ethylEmino] -1-1-plrolrolylphenoxypropeno-2-one, and 3- (2-4 4-hydroxydiphenoxy) ethyl-amino) 11o-methoxy yaaminocarbrollmethoxyphenoxylpropanor-2.

Acid-rendering acids can be used in the preparation of therapeutically useful salts of the compounds. These are halide acids, sulfuric, phosphoric, nitric, cis, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or siphonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, lemon, ascorbic, mmlein, haloxy, or grape, phenylacetic, benzoic, p-amiorbensic, anthranilic, p-hydroxybenzylene, salicylic or p-amioosalicilium, methanesulfonate, ethanesulfonenesulfonate, sulfonate, sulfonate, methionine, trifuran, lysine or angina.

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

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

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

The compound of formula I (mentioned in the introductory part of this disclosure) is produced by the process of the invention, which is characterized in that the compound of formula II,

in which ^{r 1} has the same meaning as given above,

X 1 denoted hyrdroxyl a

Z represents a hydroxyl group eeaktivní esterifikovaoou not ^b ox 'and ^{Z p} olečně epojty group consisting of UV ^and says to ^the rea tion of amine ^b t ^s ECN it in ^from fc ^e

in which RI, RI, X and n msa! the same meaning as given in the introductory part of the invention for formula (I).

The reactive hydroxyl group is in particular a hydroxyl group which has been esterified with a strong inorganic or organic acid, preferably a hydrogen halide with an acid such as hydrochloric, hydrobromic or iodide, furthermore sulfuric acid or a strong organic sulfonic acid, e.g. . Thus, Z is preferably chlorine, bromine or iodine. ’(

The reaction is carried out in a conventional manner. When using the reactive ester as the starting material, the preparation is carried out under the addition of a basic condensation agent and / or in the presence of excess amine. Suitable base condensing agents are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal binders such as potassium carbonate, and alkali metal alcoholates such as sodium methoxide, potassium ethylate or potassium t-butylate.

The reaction is carried out in C 1 -C 4 alkanol by boiling the reactants in the solvent under reflux until the compound of formula I is formed, usually for 1 to 12 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 included within the scope of the compounds of the formula produced by the process of the invention.

For example, basic, natural or mixed salts can also be obtained, as well as hemiamino, sesqui, or polyisters. 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 a salt with organic or inorganic salts. acids. In the preparation of the addition salts, it is primarily necessary to use acids which form suitable therapeutically useful salts. Such ^. acids. are, for example, halogenated, sulfuric, phosphoric, nitric, aliphatic, cyclic, hydric or heterocyclic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic, malic acids , tartaric, citric, ascorbic, maleic, hydroxymalein or pyruvic, phenyloctoyl, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosslicylic, embooic, methanesulfonic, ethanesulfonic, tonicity, ethanesulfonic acid halobenzenesulfonic, toluenesulfonic, oephthalosuffonic or sulfanilic acid, mehionine, tryptophan, lysine or argioio.

These or other salts of the novel compounds, for example picrates, may serve as buffing agents, or the free bases obtained as such may be converted into salts, these may be isolated and the bases released therefrom. Because 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 in 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 mixtures of isomers (mixtures of racemates) can be pure racemates, for example by means of chromatography and / or fractional crystallization, depending on the physicochemical differences of the components of the molds for the two diastereomers.

The racemates obtained can be separated by known methods, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids which form salts with the compounds, and by separating the thus obtained salts, for example Suitable optically active acids which can be used are, for example, the La D form of tartaric acid. di-s-tsluylliic acid, malic acid, mandelic acid, camphorsulfonic acid or chioic acid. Preferably, the more active moiety is isolated from both isomers.

Suitably, the starting materials used for carrying out the process according to the invention are those 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 clinker killing, the novel compounds are usually administered orally, rectally, or by injection in the form of pharmaceutical compositions containing the active ingredient either in the free base form or in the form of a pharmaceutically acceptable non-toxic acid addition salt such as hydrochloride, lactate, acetate, sulphate and the like. , in combination with a carrier.

w

Thus, when reference is made to novel compounds produced by the process of the invention, either the free base of the amine or the free base addition salt when referring to the compounds in the form of a lunch or a monolith, refers herein unless the text in which these terms are used, e.g. , did not resist this broad meaning. The carrier may be a solid, semi-solid or liquid diluent or capsule. Typically, the multiplicity of active compounds in the formulation is about 0.1 to 99% by weight, preferably from 0.5 to 20%, by weight in the formulations for injection and from 2 to 50% by weight, in the formulations for oral administration.

In the manufacture of pharmaceutical compositions containing the compounds of the present invention in the form of a dosage unit for oral administration, the selected compound is admixed with a solid powder carrier such as lactose, sucrose, sorbitol, monotolu, starch such as potato or corn starch, Aimyoopekio, cellulose derivatives or gelatin, also with a glidant such as magnesium or calcium stearate, polyethylene glycol waxes and the like, and the mixture is compressed into tablets. If desired, coated tablets with concentrated sugar solution as described herein may be present, for example, gum arabic, gelatin, bridges, titanium dioxide, and the like. Additionally, the tablets may be coated with a varnish dissolved in a slightly volatile organic solvent or a salt solution. A colorant can be added to this coating to easily distinguish tablets with different active compounds or different amounts of active compound present.

In the manufacture of soft gelatin capsules (spherical capsule capsules), such as those made of gelatin and glycerin, or in the manufacture of similar capsule capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol, starch (such as potato or corn starch, or amylopectin), 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 vegetable or paraffin oil.

Liquid preparations for oral administration may be formulated as 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 saccharin and carboxymethylcellulose 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 buffers and may be available in ampoules in different dosage units.

The preparation of pharmaceutical tablets for oral administration is carried out as follows.

The solids used are ground or sieved 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 with the binder solution during continuous and uniform mixing and moistened so that the solution is uniformly distributed throughout the mass without any parts being moistened. The amount of solvent is usually adjusted so that the mass has a consistency resembling wet snow. The wetting of the powder mixture with the binder solution causes the particles to gently adhere together to form an aggregate, and the actual granulation process is carried out by passing the mass through a sieve in the form of a stainless steel mesh having a mesh size of about 1 mm. The mass is then placed in thin layers on trays to dry in an 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 following process and for the properties of the tablets. Fluid drying can 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.

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

The cleaned tabletting machine is provided with a set of dies and dies, and then a suitable pressure setting is tested. The weight of the tablet is critical to the size of the dose in each tablet and is calculated in relation to the amount of therapeutically active agent in the granulate. The degree of compression influences the size of the tablet, its strength and its ability to disintegrate in water. Especially with respect to the latter two properties, the choice of compression pressure (0.5 to tons) should be considered carefully. When the correct setting is ready, tablet production starts at a rate of 20,000 to 200,000 tablets per hour · Compression of tablets requires different Sas and depends on the size of the stick ·

Taabets are freed from adhering dust in a special facility and then - stored in closed containers until dispatch ·

Some tablets, especially those that have an unpleasant or bitter taste, are coated with a coating. This means that they are coated with a layer of sugar or other suitable coating!

The tablets are usually packaged with machines having an electronic counting device. Different types of packaging can be glass or plastic cups, but also boxes, tubes and special packaging adapted for dosing.

The daily dose of the active ingredient varies depending on the route of administration, generally 100 and 400 mg per day of the active compound 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.

He did

Preparation of 3- [2- (4-Hydroxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2

2.5 g of 1,2-ω-oxy-3-o-ethylphenoxy propane are mixed with 1.5 g of 2- (4-hydroxyphenoxy) ethylhrlamine 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 dissolved in acetone and the hydrochloride is precipitated with the aid of hydrogen chloride in ether. The tyrolrohoride is filtered off and washed with acetonitrile. Yield of 3- [2- (4-hydroxyethyl) ethylaino-1-oe. thylphenoxyproparoyl-2 is 1.5 g · The melting point of the hydrochloride is 150 ° C · The structural formula is determined using NMR.

Example 2

3-L2- (2-Isopropylphenyl) ethylamino] -1-o-ethylphenoxy-propanol-2- was prepared according to Example 1 using 1,2-epoxy-3- (o-ethyl) Zoooyl propane and 2- (2- Hydro: χyfzoo: χy) Ethyl6eine as starting material · Melting point of hydrocoride is 80 ° C · Structural formula is determined using NMR and equivalent weight ·

Example 3

3- [2- (2-ethoxyphenoxy) -thiophenyl] -1-o-o-ethylphenoxypropanol-2 was prepared according to Example 1 using 1,2-poly-3-o-methyl-2-oxoxypropane and 2- (2-ethoxyphenoxy) ethyl. The temperature of the tartrate is 91 ° C. The structural formula is determined using NMR and equivalent weight.

Example 1 a d 4

3- [2- (4-Methoxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (4 * methoxyphenyl) ethylamine as starting materials. The hydrochloride melting point is 168 ° C.

Example 1 a d 5

3- [2- (3,4-Dimethoxyphenoxy) ethylamino] -1-methylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (3,4-dimethoxyphenoxy) ethylamine as starting materials. The melting point of the hydrochloride is 160 ° C.

Example 6 _% 3- [2- (4-Hydroxyphenoxy) ethylamine} -3-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxyphenoxy) ethylamine as starting materials. The melting point of the tartrate is 52 ° C.

Example 7

2- [2- (4-4-hydroxyphenoxy) ethylamino] -1-o-methoxyphenoxypropanol-2 was prepared according to Example 1 using 1,2-peroxy-2-methoxy-phenoxypropane and 2- (4-hydroxyphenoxy) ethylamine as starting materials.

Example 8

3- [2- (4-Hydroxyphenoxy) ethylamino] -1-o-ethylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-ethylphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine as starting materials. .

Example 9

3- [2- (4-Methoxyphenoxy) ethylamino] -1-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-methoxyphenoxy) ethylamine as starting materials. . The melting point of the hydrochloride is 134 ° C.

He did

3- [2- (2-Hydroxyphenoxy) ethylamino] -1-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (2-hydroxyphenoxy) ethylamine as starting materials. . The melting point of the hydrochloride is 181 ° C.

Example 11

3- (2- (4-hydroxy-1-methoxyphenoxryethylamino-O-1-cyanophenoxypropanol-S) was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-thyroxy-3-metho)]. The melting point of hydrochloride is 78 ° C.

Example 12

3- [2- (3,5-Dimethoxyphenoxy) ethyl-amino] -1-o-camphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (3,5-dimethoxphenoxy) urlimimine The starting material, m.p.

Example’3

A syrup containing 2% w / v active ingredient is prepared from the following ingredients:

3- C2- ((-hydroxyphenylene-1-methylmino) -1-t-methylphentxypropantlu-2. HCl saccharin sugar glycerol flavor ethanol 96% distilled water to total volume

2,0 g

0.6 g 30.0 g

5.0 g

0.1 g

10,0 g

100.0 ml

Dissolve, saccharin and ether salt are dissolved in 60 g of warm water. After cooling, glycerol and a solution of flavors dissolved in ethanol are added. The mixture was then made up to 100 ml with water.

The above active ingredients may be replaced by certain pharmaceutically acceptable acid addition salts.

Example 4

3- [2- (4-H) -diphenyl-1,1-diethyl-ethyl] -lamin-1-t-aliphanyl] -propylpentyl-2-methylphenyl (250 g) was mixed with aaktzoa (175.8 g), Brm. 169.7 g) and colloidal silicic acid (32 g). The mixture is moistened with 10% gentle disintegration and gantantized through a sieve.

0.47 • mesh / mm. After drying, it is admixed with potato starch (160 g), talc (50 g) and magnesium stearate (5 g) and the thus obtained mixture ae aabexeuue to ai (tl) tl (10,000) of 25 mg. The tablets are placed in a scrubbed irradiated area (to obtain a dose other than 25 mg or multiples thereof when the tablet is broken).

They did.

Granules were prepared from 3-C2- (4-hydroxyphenyl) -1-methylethylamino-3-o-propargrloxyphenoxypropanol-2-p-hydroxybenzoate (250 g), lactose (175.9 g) and alcohol solution of polyvinyl pyrrolidone (25 g). ). After drying, the granules are blended with talc (25 g) potato starch (40 g) and magnesium stearate (2.50 g) and compressed in 10,000 lenticular (lenticular) tablets. These tablets were first coated with a 10% alcohol shellac solution and then with an aqueous solution containing sucrose (45%, gum arabic (5%, gelatin (4%) and coloring agent (0.2%)) after the first five coatings were dusted with talc and powdered sugar. It is then coated with 66% sugar syrup and polished with a 10% solution of carnaul wax in carbon tetrachloride.

Example 16

3- [2- (4-Hydroxyylene-1,1-diene-trifluoromethyl-4-o-ethyl-phenoxy-propanol) · 2-Uydro-fluoride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) ) is dissolved in an iosthanen amount of distilled water per 100 OL solution.

This solution, which contains 10 mg of active ingredient MLL: Li1 ^ l ^ _j) is filled into anmuuí that s ^ <^ i ^ ei ^iL of ^u I ⁱ at this 120 DEG ^C for 20 minutes.

Biological effects.

The β-receptor blocking agents of the invention have been tested for their biological properties. All compounds were tested in anesthetized cats (males and cats weighing 2.5-3.5 kg) pretreated with resonance (5 mg / kg body weight, intamuscular administration) about 16 hours prior to the start of the experiment. Animals were pretreated with adsorption to eliminate endogenous sympathetic regulation of cardiac rate and vascular smooth muscle tone. Cats were anesthetized with uentabarbitane (30 mg / kg body weight, administered i.p) and subjected to artificial air filtration locally. A bilateral vagus was performed on the neck. Blood pressure was measured from a cannulated artery (пг ^ пria carotica), and cardiac activity was recorded using a tri-triachroeter, scanned by ECG.

Penetrating 0 * mimetic activity on the heart was found from increased cardiac activity after drug administration. The test compounds were administered infusively in logarithmically increasing doses. The values obtained were plotted as dose-response curves from which they were determined by affinity values (ED 50). At the end of each experiment, high doses of isrurenaline were administered to recover the isrurenaline. heart rate response.

The compounds were also tested on the surface of conscious dogs. Loving dogs (beagl varieties) were trained to lie still to be lifted 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 scanned by ECG.

All dogs were pre-administered with 010 to maintain the effect of the vagus. Recordings were made before administration of the test compound and 15 and 75 minutes after administration, first in the supine position for 2 minutes and then in the upright position for 2 minutes.

Test compounds were administered in increasing doses at 2 hour iotervals. ·

The pAg value in rats was also measured. The pAg value is defined as the -log concentration of antagonist. substances resulting in the need to double the dose of ooradrenaline to achieve the same norepinephrine effect as without the antagonist, or pAg = log (dr-1) -1ogCantagon. where dr is the ^ED 50 dose ratio of 50 mg / ml (entagoni.sta) dr =

ED50 of noradrenaline (control) and all concentrations are given in moles per liter, i.e. molar / liter. ‘

Thus, the pAg value is a measure of (-rceptor effect), where higher -pAg indicates higher 4-effect.

Experiments have shown that the test compounds are potent receptor antagonists, with or without cardioselective action with β-mimetide. These compounds also significantly reduce blood pressure in conscious dogs. Said hyP ^{on the} activity of these novel compounds in conscious dogs depends on the vasodilatory effect in combination with cardiac (receptor) blockade, and the results obtained in the above tests are given in Table 1 below.

Table !

r ’

Reserpinized cat pAg β-blockade iso- β-blockade iso-- penetration efficiency prenalinového preoalioové dúderiV % 180- cardiac effect- peripheral re- / min prenaUnu to ED ₅₀ 0 lumoo / kg sistence ED50 / omol / kg

-O 4-OH 0.25 1.0 13 18 -CN 4-OCH ₃ 0.22 2.7 7 7 6.4 -OCHgCONHCgH2OCH 4-OH 0.05 1,8 0 0 5.5 -CN 2-OH 1.7 17 35 39 -, 5 -CN _3-OCH3, 4-OH 0.3 3.4 17 27 Mar: -, 8 -CN 3,5-diOCH3 2.9 11 15 Dec 17 -, 5 _3,4-di-OCH3 1.5 5.8 8 11 -, 0 -CH3 2-OCH ₃ 4,5 11 8 8 7.0 -CH3 4-OCH ₃ 0.5 8.2 17 22nd 5.8 -CH3 4-0CHgCHg0CH3 0, - 10.3 25 29 5.8 -CH3 4-CN 1, - 30 12 17 5.9 -CH 4-C ₂ H ₅ 7.9 > -8 15 Dec 17 5, - -CN. 4-OH 0.08 5.5 13 15 Dec -, 3 -CH3 2-OH, 0, - 17 30 29 -, 0

Reserpinized cat

Table 1- continued pA r '

Β-blockade of isoprenaline heart effect

ED? _Q ? -Olol / kg β-blockade of isoprenaline peripheral resistance

ED ₅₀ / uool / kg breakthrough efficiency ú strokes /% iso / oin of proline

-CN

-CH ₂ CN -С ₃ И7

-CH ₂ OH

4-CH 3 OH 0.2 10 + 10 10 5.8 4-0H 0 ', 05 1.6 - + 20 6.6 4-0H 0.02 0.02 0 0 6.2 4-0H 0.02 0.05 17 6.3

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of the novel amines of the general formula (J) (ω-0-СН ₂ СНОНСН ₂ Л1Н4СН ₂ ) пХ ' ^_ ' _R 1 wherein r 1. oetthyl, ethyl, propyl, cyano, oethoxy, cyanmeltyl, hydroxymethyl. or. group CH 3 OC 6 - NHCMI-, R ² a hydroxyl group, ^R3 is hydrogen or discarding hydroxyethyl ^{χ fl,} hydroxymethyl not ^one of œthe ^b ^ l, n CISO 2, 3 or 4, .and X a - is the vomiting thio characterized in that a compound of formula II (II) in the same Neoz ^-J The RNA. known as running above, X ^J i ^ blades ^ r ^ a tyčlroxyl and Z znoená reactive eseerifilovalou iydrosgrlovou group, or X ¹ and ^{Z p} ole ^C No ^ ori е ^ з ^ г group, is reacted with ε-ίη ^ of formula wherein R ² , R ³ , X and ⁿ have the same meaning as given above for formula I. Severogralia, n. P. Plant 7. Most