CS208733B2 - 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 of active compounds blocking β-receptors 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,

in which it means

R ^{* 1 is} methyl, ethyl, propyl, cyano, methoxyl, cyanomethyl, hydroxymethyl or a ch ₃ oc ₂ h ₄ nhcoch ₂ o- group,

R ² hydroxy, methoxy or hydroxymethyl,

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

X -O-,

3

The substituents R and R are bonded in the 2, 3 or 4 position.

The novel compounds produced by the process of the invention have valuable pharmacological properties.

For example, they block the cardiac O-receptors, as shown in 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 A-receptors as manifested in the determination of vasodilatation antagonism after intravenous injection of 0.5 / Ug / kg sulfate - d / 1-Seoproterenol 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 ρ-receptors, ie. appears to have a breakthrough effect. This property is particularly pronounced with vastailial O-receptors causing peripheral vascular dilation.

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- [2- (4-Hydroxy-phenoxy) -ethylamino] -1-o-methylene-phenoxy-pyrimidin-2,3-C 2- (4-hydroxy-phenoxy) -ethylamino] -1-o-ethyl-phenoxy-propnol-2,3- [2- ( 4-Hydroxyphenoxy) -1-o-propenylphenoxypropmoO-2,3- [2- (4-hydroxyphenoxy) thylamino-1-o-allypholoxypropanol-2,3- [2- (4-hydroxyphenoxy) ethylaeinol-1-o] -propargyloxyphenoxyp-proIPnoO-2,3- [2- (4-hydroxyphenylphenyl) ethylamino] -1-1-cyanophenolproponoO-2,3- | [2- (4-hydroxyphenoxy) ethylaino) -1-1-alpha-polyphosphinylpropyl] -2, 3-C 2- (4-hydroxyphenoxy) ethyl amino] -1-no-propan- ^2-one ,

3- [2- (4-Hydroxyphenoxy) ethylamino] -1-1-cyanomethylphenylproponol-2,3- [2- (4-hydroxyphenoxy) ethylamino] -1-1-acetylphenylsulfonylpanol-2,3- [2- (4 4-Hydroxy-phenoxy) -ethyl-im1-l-o-hydroxymethyl-phenoxy-2-chloro-2,3,3- [2- (4-dihydro-thienyl) -ethylamino] -1-o-cyanenyl] -propono-2,3,3-2- (4- hydrwxfeiwl'thi o) ethllamino] -1-o-eethllfeolxy ρrop £ Moo-2, 3- [2- (3-methoxl-4-methoxyphenoxy) ^ethllaeino,] -1-L-eethylfenoχl propano0-2-3- [2-33-Blom-4-ydrlxyfeolxy) ethylaminl] -o-methlxyfeolxy-oгloanol-.2 _I of 3- [2- (3-hydroxymeehhl-4-hydroxyphenoxy) ethylamino] -1-L-kynofeooxy-2-oropanoO 3- [2- (3,4-dihydroxyphenylthio) ethylamino] -1-o-cyanophenoxy-4-propanoO-2,3- [3- (4-hydroxyphenoxy) -1-ethynyl] -1-ethylphenoxy-10-oxo-2, 3- [4- (4-Hydroxyphenoxy) butylamino] -1-1-allyleolo: propano-2, 3- [2- (2-chloro-4-hydroxyphenylthio) ethanol] -1-1-nitro-oyloxyphenyl-2-propylamino-3- 2,3- [2- (4-methoxy-phenoxy) -ethylamino] -1-o-clonophenol-1-propanoO-2,3- [2- (2-hydroxy-phenoxy) -ethoxy] -1-o-cyclo-phenoxy-propano0-2,3- [ 2- (4-Hydroxy-3-methoxyphenyl) ethyl-amino] -1-o-cyclohexyl-propano-2,3- [2- (3,5-dimethoxy-3-phenoxy) ethylamino] -1-o-cyanophenylol- propanoO-2,3- [2- (4-dihydroxyphenoxy) etholainol-1-l-O-pyrrolidinphenol-10-olol-2,3- [2- (4-hydroxyphenoxy) ethylaeinl] -1o-ethoxy-ethylaminocarbonyl-ethyl-o-phenoxy} -phenoxy} -1 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, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as erroneous, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maineic. , hydroxyidanyl or grape, phenylacetate, benzoic, p-aminocarbonyl, anthaloyl, p-hydroxybenzoic, saline or p-amino-molyl, emboonic, methanesulphonic, ethanesulphonic, hydrochloride (meth); Phthalone, ethanol sulfonyl, halobenzene sulfone, toluene sulfone, naphthalene sulfonate or sulfnoil, methine, tryptophan, lysine or arginine.

The substances produced by the process according to the invention are intended for oral or oral administration for the acute or long-term treatment of the aforementioned cardiovascular disorders.

The biological effects of the novel compounds have been tested and various assays that have been performed are set forth and explained below in the description of the invention. .

The novel compounds can be obtained by methods known per se, one of which is set forth below and is the subject of the present invention.

The novel amines of formula I,

in which it means

R? methyl, ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl or a residue of _{3 to 2} h ₄ nhcoch ₂ o-,

R ² hydroxy, methoxy or hydroxymethyl,

R ^{3 is} hydrogen, hydroxyl, hydroxymethyl or methoxy, n numbers 2 to 4 and

X is -O-, which is produced by the process of the invention, characterized in that the compound of formula IV,

in which

R ¹ has the same meaning as indicated above, is reacted with a compound of formula VI,

(VI)

CH ₇ -N

I ^of I

CH-Cl

AND

OH in which

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

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

The reaction is carried out in a conventional manner.

The reaction is carried out in a C 1 -C 4 alkanol by refluxing the reactants in the solvent until a compound of formula I is formed, usually for 1 to 12 hours.

Depending on the process conditions and the 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 according to the invention.

For example, basic, neutral or mixed salts as well as hemiamino, 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 free bases obtained form salts with organic or inorganic acids. In the preparation of the addition salts, it is primarily necessary to use 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, for example carboxylic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic acids. , maaine, hydroxylamine or pyruvic, phenylacetic, benzoic, paminobenzoic, alpha-thiophenol, p-hydroxybenzoic, salicylic or p-amino-aaicylic, embonous, methanesulfonic, ethanesulfonic, ethylsulfonenesulfonate, hydro-benzenesulfonate , toluenesulfonic acid, naphtholene sulfonic acid, or sulfonic acid, mercaptan, tryptophan, lysine or arg.

These or other salts of the novel compounds, for example picrates, may serve as buffers or the free bases obtained as such may be more preferred. in the salts, these are isolated and the base is then released again from these salts. Given the close relatives of the new compounds in the form of the free bases and in the form of their salts, from what has been and will be understood, it is understood that, if possible, the respective salts are included in the term free compounds.

Depending on the choice of starting materials and the method of preparation, the novel compounds are obtained as optical antipodes or racemates or (including at least two asymmetric carbon atoms) as a mixture of isomers (racemic mixture).

The resulting mixture of isomers (mixtures of racemates) can be separated, depending on the physicochemical differences of the constituents, into the two athero-isomeric (racemate) pure racemates, for example, by means of fractional crystallization.

The racemates obtained can be separated by known methods, for example by resolving from an optically active solvent, darkening the microorganisms or by reacting with optically active acids which form salts with the compounds, and separating the thus obtained salts, for example on the basis of their different solubility in the stereoisomers. from which the antipodes are released 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-c-tolvylic acid, malic acid, mmanioic acid, carboxylic sulfonic acid or quinic acid. Preferably, the active part is isolated from both isomers.

It is expedient to use starting materials for carrying out the process according to the invention which, in particular, describe those 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 either known or, if new, can be obtained by known methods.

In clinical use, the novel compounds are administered, usually orally, rectally or by injection, in the form of pharmaceutical compositions which contain the active ingredient either in the form of the free base or in the form of a phthalate-free non-toxic acid addition salt, e.g. in the form of the hydrochloride, acetone, acetate, sulfamate and the like, in co-administration with a pharmaceutical carrier.

Thus, when a change is made to the novel compounds produced by the process of the present invention, either the free amine base or the free base addition salt thereof, although the compounds are described in general or otherwise, unless the text in which these terms are used, for example, in the Examples, this broad meaning has not been met. The carrier may be a solid, semi-solid or liquid diluent or capsule. Usually, the active compound 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 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, -anylopeetin, cellulose derivatives or gelatin. , also with a glidant such as magnesium or calcium stearate, eolyethylene glycol waxes and the like, and compressed into tablets.

The coated tablets were coated with the sugar concentrate as described above, and the solution may contain, for example, gum arabic, gelatin (mothers, TiO 2, and the like).

For a longer time, the tablets may be coated with varnish dissolved in a slightly volatile organic solvent or solvent mixture. A colorant can be added to this coating to easily distinguish tablets with different active compounds or different amounts of direct active compound.

In the production of soft gelatin capsules (capsule-like 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. The hard gelatine capsules may contain granules of the active compound in combination with a solid powder carrier such as lactose, sucrose, sortotol, starch (such as opaque potato or corn starch or amolouette), cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented in the form of suppositories which stabilize the active ingredient in admixture with a natural neutral base, or in the form of green rectal capsules, which contain a plurality of particles. : and active substance in admixture with or гШМйпО ^parnf0no, oil Well.

Oral liquid preparations may be formulated as syrups or suspensions, opiate solutions containing from about 0.2% to about 20% ammonium, the remainder being sugar and a mixture of ethanol, water, glycerol and erupylloglycule. If desired, these liquid preparations may contain coloring agents, flavoring agents, saccharin, and carbuxes (n-ethylcellulose as an excipient).

Solutions for injection by the earenteral administration may be prepared as an aqueous solution of a water-soluble faroacetic acid acceptable salt of the active compound, preferably at a concentration of about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and / or buffers and may be available in various dosage units.

The preparation of pharmaceutical tablets for peroral administration is carried out as follows:

The solids are ground or sieved to determine the grain size. The active ingredient and the necessary auxiliaries are mixed during continuous and continuous stirring with a binder solution and moistened, so that the solution is dispersed in the mass in a uniform manner without any of them being present. Moisture of the solvent is usually adjusted so that the mass has the consistency of wet snow, and the wetting of the powder mixture with the eoillin solution causes the particles to be slightly mixed together to form an aggregate and the actual granulation process is carried out by The mass is extruded through a mesh of blackened mesh having a mesh size of about 1 mm and then placed in thin layers on trays to be divided and dried in a drying oven for 10 hours. The moisture content of the granules is of great importance for the process and the properties of the tablets. e eouιCStu also be drying under fluidized bed conditions. In this case the mass is not put on a tray but is poured into a container having a sieve bottom.

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

Disintegrants, glidants and antiadhesives are added from the so-called final mixture. After this mixing my mass have the right composition for tabletting.

The cleaned tabletting machine is provided with a set of punches and maaric, and then a suitable pressure setting is tested. Tablet size is critical to the dose level 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 characteristics, the choice of compression pressure (0.5 to 5 tons) should be well considered. When the correct setting is ready, tablet production starts at a rate of 20,000 to 200,000 tablets per hour. Compressing the tablets requires different time and depends on the size of the stick.

The tablets are freed from adhering dust 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 means that they are coated with a layer of sugar or other suitable coating.

Tablets are usually packaged using 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 substance varies and depends on the mode of administration; as a rule, it is 100 to 400 mg per day of active ingredient for oral administration and 5 to 20 mg per day for intensive administration.

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

Example 1

0.116 mol of o-meehylfenolu was mixed with 0.080 mole of 1- ^г '2- (4-methyl · thtxymeehhtyfeeoty) etnhУL sietiUiotlu-3, 0.500 moles of benzylalcohol and 0.003 moles of KOH. The mixture was refluxed under stirring for 6 hours at 140 ° C, then cooled and extracted with 2N hydrochloric acid.

The aqueous phase was allowed to stand for one hour at ambient temperature, then basified and finally extracted with chloroform. After drying and evaporation, the residue was dissolved in ether and hydrogen chloride in ether was added. The hydrohalide is stripped off and washed with acetone. 3- [2- (4-Hydroxy-4-dienododano -anolamino) -1-o- (methyl-phenoxy) -propanol-2 hydodohoride has a melting point of 150 ° C.

Example 2

3- [2- (2-Hydroxyenthoxy) ethylamino] -1-o-methylphenoxypropanol-2 was prepared according to Example 1 using 1,2-eptxy-3- (1-methoxyphenyl) phonoxypropane and 2- (2-hydroxyOenthoxy) ethylamine as starting materials. The melting point of the hydrochloride is 80 ° C. The structural formula was determined using NMR and equivalent mass.

Example 3

3- [2- (2-Methoxy-enenoxy) -ethylamino] -1-t-methyl-pentyl-pyrazol-2 was prepared according to Example 1 using 1,2-epoxo-3-o-men-indophenoxydopropane and 2- (2-methoxy-oenoxy) -ethlamine as starting material. Fabric. The melting point of the tartrate is 91 ° C. The structural formula was determined using NMR and equivalent.

Example 4

3- [2- (4-Methoxyphenoxy) ethylaminol-1-o-methylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylennoxypropane and 2- (4-epoxyphenyl) -1-phthylamine as the title compound. . gaiters. Mp ^d ydrochlori ^h at 168 ° C.

Example5

3- [2- (3,4-Dimethyl-phenoxy) -phenylamino-1-u-methyl-phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methyl-phenoxy-propane and 2- (3,4-dihydro-phenoxy) -propanol. : ^ j ^ yfe ^ (^ 3 ^ J ^) <^ 1 ^ 1 ^ 2 ^ ^{j nu} muzzle as the starting L ^ix. Melting ^ ^h ydrochlor her ^ID at ¹⁶⁰ ° C.

Example6

3- [2- (4-Hydroxyffnuxy) etlLylaminu] -3-Okkyanfenoxyprupanol BC-2: synthesized according to Example 1 potuití 1,2-epoxy-3-o-kyanfenoxypropanu and 2- (4-lydroxyffnuxy) ftlylaminu as výchozíc ^{h lát} e ^k . ^The temperature of ^melting in water is 52 ° C.

Example7

2- [2- (4-Hydroxyphenuxyl) ethylamino] -. Alpha.-methoxyphenuxyprupanoO-2 was prepared according to Example 1 using 1,2-epuxyl-3-o-methoxyphenoxypropane and 2- (4-hydroxyphenoxy) thylamine as starting material. substances.

Example8

3- [2- (4-Hydrofluoro-phenoxy) -phthyramine-1-u-ethyl-phenoxy-propanoo-2 was prepared according to Example 1 with the substitution of 1,2-phpoxy-3-o-phthyffenoxypropane and 2- (4-hydroxyphenoxy-ethylanine) - i.

Example9

3- [2- (4 ^- and ^H UXY fnoxy ^f) et ^h ylamino] - ^{1 y} n -OH ^{f 's} for ^p fnux anol-2 were prepared ccording ^P Example 1 and 1,2-potuití fpoxy 3 -o-kyaeffenoxy for Mr and 2- (4-mftloxyfenoxy) ftlylaminu as Buf ^{H M a} ozíc ^to te. ^The temperature of the pools of tyrdride is ¹³⁴ ° C.

Example10

3- [2- (2-Hydroxyffuxy) ethyl-amino-1-o-cyalphenethoxyprupanol-2 was prepared according to the example using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (2-hydroxyphenyls) ethylylamine starting materials. The melting point of the hydrochloride is 181 ° C.

Examples

3- [2- (4-Hydroxy-3-methylphenylphenoxy) ethylamine] -1-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4- hydroxy-3-mfthoxyffeoxχ) et.tylaminu as ozíc Buf ^{H M a} Tek. Melting pools ^l ydrochloridu is 7 ^{to 8} ° C.

Example12

3- [2- (3-Dieflhoxyphenuxyl) phthylamine] -100-cyanophenoxypropanol-2 was prepared according to Example 1, substituting 1,2-epoxy-3-o-caynphenoxypropane and 2- (3,5-dimphthoxypheuxyl) ethyl ethylene as starting materials. The melting point of the lydruchluid is 159 ° C.

Example 13

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

3- [2- (4-hydroxyphenyl) -1-methylamino] -1-o-methylphenoxypropanol-2. HCl 2.0 g saccharin 0.6 g sugar 30.0 g glycerol 5.0 g flavor 0.1 g ethanol 96% 10.0 g distilled water to a total volume of 100.0 ml

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

The above active substances may be replaced by other pharmaceutically acceptable acid addition salts.

Example

3- [2- (4-Hydroxyphenyl) -1,1-dimethylethylamino-1-o-allylphenoxy] propanol-2-hydrochloride (250 g) was mixed with lactose (175.6 g), potato starch (169, 7 g) and colloidal silicic acid (32 g). The mixture is moistened with a 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 (10,000) in 25 mg tablets. The tablets are marketed with a score line to obtain a dose other than 25 mg or multiples thereof when the tablet is broken.

Example 15

Granules are prepared from 3- [2- (4-hydroxyphenyl) -1-methylethylamino] -1-o-propargyloxyphenoxypropanol-2-p-hydroxybenzoate (250 g), lactose (175.9 g) and alcohol solution of polyvinylpyrrolidone (25 g) ). After drying, the granules are mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and compressed into 10,000 biconvex tablets. These tablets were first coated with a 10% alcoholic shellac solution followed by an aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and a colorant (0.2%). After the first five coatings, they are 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-Hydroxyphenyl) -1,1-dimethylethylamino] -3-o-ethylphenoxypropanol-2-hydrochloride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) were added. Dissolve in sufficient quantity of distilled water per 100 ml 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 anaesthetized cats (males and cats weighing 2.5 to 3 kg) pretreated with reserpine (5 mg / kg body weight) about 16 hours prior to the start of the experiment. The animals were pretreated with reserpine to eliminate endogenous sympathetic regulation of the rate of cardiac activity and vascular smooth muscle tone. Cats were anesthetized with pentobarbital (39 mg / kg body weight, i.p.), subjected to artificial venom-air air. A bilateral vagotomy was performed on the neck. Blood pressure was measured from a cannulated artery (artheria ca ^ tica) and cardiac activity was recorded by an electrocardiogram (ECG) type psoriasis karstist.

Cardiac breakthrough β-Rnimette activity was found to be enhanced by cardiac activity following drug administration. Test compounds were administered intravenously in logarithmically increasing doses. The values obtained were plotted as dose-response curves from which affinity values were determined (Ο ^ θ). At the end of each experiment, high doses of isoprenaline were administered to obtain a mexican response heart activity.

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

All dogs were pre-treated with ethyl scopolaein ₁ to eliminate the effect of the vagus. Recordings were made before administration of the test compound and 15 and 75 minutes after the underload, first in the supine position for 2 minutes and then in the upright position for 2 minutes.

Test compounds were administered at increasing doses at 2 hour intervals.

The rat value was also measured. The p-value is defined as the log concentration of the anotonic agent, resulting in a need to increase the dose of the oral agent to achieve the same nonsradrenaline effect as without the aotaosic agent, or pA2 = 10 (Sr-1) -log (aotaosic). where dr is the dose ratio

Εϋ ^ θ nsraSrenalin (antagonnsta) dr = ---------------------------------——

EDtjQ nsraSrenaline (control) and all concentrations - are given in moles per liter, ie moo / l.

Thus, the pA2 value is a measure of the T-receptor effect, where higher pA2 indicates a higher α-effect.

Experiments have shown that the test compounds are potent receptor antagonists, being carisselectic with or without p-mimetide penetration effect. These compounds also significantly reduce blood pressure in conscious dogs. Said hypo-enzymatic effect of these novel compounds in conscious dogs depends on the vasodilatory effect in conjunction with carboxy-β-receptor blockade. The results obtained in the above tests are given in Table 1 below.

Table

2

R R Reserpinized cat from pA “β-blockade O-blockade Penetration efficacy of isoprenaline isoprenaline Arusts / oin% io-heartbeat effect of peripheral reed junol / kg assist • 5 đд / uool / kg

IN/ 4- OH 0.25 1.0 13 18 -CN 4-OCHj 0.22 2.7 7 7 ,4 6.4 -OCHgCONHCg ^ OC ^ 4-OH 0.05 1,8 0 0 5.5 -CN 2-OH 1.7 17 35 39 6.5 -CN _3-OCH3, 4-OH 0.3 3.4 17 27 Mar: 6.8 -CN 3,5-dOOCH3 2.9 11 15 Dec 17 6.5 -CHj 3,4-diOCH3 1.5 5.8 8 11 6.0 -CHj 2-OCHj 4,5 11 8 8 7.0 -CHj 4-OCHj 0.5 8.2 17 22nd 5.8 -CHj 4- ^ O ^ CH ₂ CH ₂ OCH ₃ 0.6 10.3 25 29 5.8 -CHj 4-CN 1.6 30 12 17 5.9 -CHj ⁴ -c ^2H ₅ 7.9 > 68 15 Dec 17 5.6 -CN 4-OH 0.08 5.5 13 15 Dec 6.3 -CHj 2-OH 0.6 17 30 29 6.0 -CN 4 -CH ₂ OH 0.2 10 + 10 10 5.8 -CHgCN 4-OH 0.05 1.6 +20 6.6 - ^C ₃ ^Hy 4-OH 0.02 0.02 0 0 6.2 -ch ₂ oh 4-OH 0.02 0.05 17 6.3

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of the novel amines of the general formula (I) in which: R ^! oottyl, ethyl, propyl, cyano, mothoxyl, kyanmotřyl ^h thereafter quick match ydroxymothyl CH3OC2H4NHCOCH2O ·, R ^{2 hydroxy} or a hy mothoxyl Kym ^^ ^^, ^R3 is hydrogen ^hyd roxyl, or TH ydroxymothyl ^h ^ ^l (I) 1 1 n number 2, 3 or 4 a X is an -O-, wherein the compound of formula IV wherein ^R1 has the same meaning as in ^DE No ^above, is reacted with a compound of formula VI (VI) v'němž 2 3 R, R ^J , X are as defined above.