CS208734B2 - 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 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

(I) in Nemi zněměné R 'is methyl, ethyl, ^p ro ^p yl, an ^alkyl, methoxy, ^alkyl anmethyl, hy ^d rox ^{y b} no methyl group on

CH3OC2H4NHCOCH2O- ^{R2 hy} dro:) ςn. ^, neto hydroxymethyl, n number 2, 3 or 4 and

Zb X ^y tek -0-.

The novel compounds produced by the process of the invention have valuable pharmacological properties. For example, they block cardiac β-receptors, which is manifested in the determination of tachycardia antagonism after intravenous injection of 0.5 µg / kg d / 1-issprstert sulphate anesthetized cat, at an intravenous dose of 0.002 and 2 mm / kg. They also block vascular e-receptors, which appears to be a pM determination of vasodilation antagonism after intravenous injection of 0.5 µg / kg d / 1-isoprsterensulfate anesthetized cat, at an intravenous dose of 0.002 and 2 µg / kg or more. The compounds also have stimulatory properties at the e-receptors, i.e. they show a penetrating effect. This property is particularly pronounced for vascular β-receptors and peripheral vascular dilatation.

The novel compounds can be used in the treatment of arrhythmias, angina pectoris and hypertension. Peripheral vasodilation is particularly valuable in 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) ethylamino] -1-o-methylphenoxypropenol-2,3- (2- (4-hydroxyphenoxy) ethylamino] -1-1-ethyphenoxypropanol-2,3-C2- (4-hydroxyphenyl) oxy Ethylamino] -1-1-propylphenoxypropanoO-2,3-C2- (4-hydroxyphenyl) ethylamino] -1-o-allyphenoxypropanol-2,3-1- (4-hydroxyphenoxy) ethylamino-1-o-propargyloxypheno trans-Propanol-2- _> 3- [2- (4-hydroxyphenyl) ethylamino] -1-o-cyanophenoypropano-2, 3- [2- (4-hydroxyphenylolyl) ethylamino] -1-o-allyoyloxyphenoyl-propanol-2 ,.

3-1 2- (4-Hlyroyylphenoxy) ethylamino] -1-1-propylparoyl-loyl-propyl-2,3,3- [2- (4-Hlyroyylphenoxy) ethylaminol-1-o-cyclohexylphenoxy] -propanol-2,3-L2 - (4-Chlorophenyl) ethllaminol-1-o-acetylphenoyypropanol-2,3-12- (4-hydroxyphenoloyl) ethllaminol-1-1-hydroxyphenylolphenolylpiperidine-2,3-L2- (4-hydroxyphenolthio) ethylamino o-Cyanophenoyypropimol-2,3- (2- (4-hydroyyphenylthio) ethylamino) -1-1-methylphenol) propanol-2,3- [2- (3-methyl-4-methylphenylthio) ethllamino] -1 -1-Methylphenyl-propanol-2,3-12- (3-bromo-4-hydroxy-phenoxy) -ethylamino] -1-methyl-phenoxy-propanol-2,3-L- (3-hydroxy-4-hydroxy-4-hydroxy-phenoxy) -ethylaminol -1-o-cyanophenoyl-pgopanol-2,3-12- (3,5-dimethylamino-1-o-cyano-phenoxy) -popopanoO-2,

3-13 -. (ROP 44tlirlУlf phenoxy ^ ^ ^ amino] -! Aethylfenoyy 4o-2-propanol _with 3- £ 4- (4-tyiroyyfenoyy) butylamino] -1404allyfeonoxlpropanoO-2, 3- [2- (2-chllr 4-Hlylyphenylthio) ethylthio [14,44] allyloxy] -phenoxy-4-propano [2,3-b] [eta] &lt; 3 &gt; -O-cyanophenol-2-ylpropeno [2,3-d] [2- (2-Chlorophenoxy) ethylamino] -1-octyl-4-yl-propano-1,3,3- (4-trifluoromethyl-34-methoxyphenooyyethylamino) -1-o-claololyl-propanol-2,3- (2- ( 3,54-ethoxyphenoxy Ethylamino] -1-o-claophenolyl-propeno-2,3,3- (44higlylphenyl) ethylamino] -1-o-pyrrolyffenoylpropanol-2,3- (44-thiylylphenyl) ethylamino] -1- o-methoxyethylamiocarbonyllaeehole-propenol-2.

Acid-rendering acids can be used to prepare 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 formic acid, sulfuric, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic. , rhamine, hydroxyamlein or grape, phenylacetic, benzoic, p-aalol-benzoic, anthranyl, p-pyrlyl-benzoic, salicyl or p-amiolsalicyl, ammonium, sulfane, ethanesulfonic, sulfenesulfonate, sulfenesulfonate, sulfenesulfonate, sulfenesulfonate, sulfenesulfonate, hooío, tryptophan, lysine or эг £ 1о.

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

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

The novel compounds can be identified by methods known per se, one of which is described previously.

in which ^R1 is methyl, ethyl, propyl, cyano, methoxy-l, cyanomethyl, hydroxymethyl or CH ₃ oc ₂ H ₄ NHCOCH ₂ O-,

R ² . Hydroxyme or Hydroxymethyl,

R ³ is hydrogen hydroxy tydrox ^^ ^ ^b mttiyl not the MMT-ho-l, n 2,. 3 or 4 a

X is -O-, which is produced by the process of the invention, which comprises reacting a compound of formula Va,

och ₂ chohch ₂ nh (CH ₂ ) _n Z (Va) wherein

Z is a reactive hydroxyl group and ^{r 1} and n have the same meaning as given for ^a compound of formula (IVa),

(IVa) in which:

3

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

The esterified esterified hydroxyl group is, in particular, a hydroxyl group esteeified 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, 4-broebetiethylsulfonate tolutnsulfonooé. Thus, the substituent Z is preferably a chlorine, bromine or iodine atom.

This reaction is carried out in a conventional manner. In those cases where reactive esters are used as starting materials, it is expedient to use the compounds of the general formula IVa in the form of an added metal phenolate, for example an alkali metal phenolate, preferably sodium phenolate; optionally working in příoomnooti agent used ^ aícího acid, preferably present at a condensing agent capable of forming a salt with the compound of formula IVa, such as an alcohol altalic ^к éУo metal.

The reaction is carried out in C 1 -C 3 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 according to the invention.

For example, basic, neutral or mixed salts as well as hemiamino, sesqui or polyhydrates can be obtained. The 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 alkali 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, it is primarily necessary to use acids which form suitable therapeutically useful salts. Such acids are, for example, hydrohalic acids, sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic acids. , maleic, hydroxymmaein, or pyruvic, phenylacetic, benzoic, p-aminobeenoo. anthranilic, p-hydroxybenzoic, salicylic or p-amino-aicylic, embonic, methanesulfonic, ethanesulfonic, hydro-acethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesuffonic or sulfanilic acids, meehionine, tryptophanin, tryptophanin.

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, these may be isolated and the base subsequently liberated 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 at least two asymmetric carbon atoms) are present as a mixture of isomers (mixture of r, acema).

The resulting mixtures of isomers (mixtures of racemates) can be separated, depending on the physicochemical differences of the constituents, into the two stereoisomeric (diastereoomeric) pure racemates, for example by means of crystallography 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 separation of the salts thus obtained, for example on account of their different solubility, into diastereoisomers release the antipodes by treatment with a suitable agent. Suitable optically active acids which can be used are, for example, the La D form of tartaric acid, di-f-tartaric acid, malic acid, mmndic acid, clphasulfonic acid or quinic acid. Preferably a portion of both isomers is more actively isolated.

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

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 compositions which contain 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, sulfamate and the like. in conjunction with a pharmaceutical carrier.

Thus, when reference is made to novel compounds produced by the process of the invention, either the free base of the amine or the acid addition salt of the free base is mentioned here, even though the compounds are described generally or singly, unless the text in which these terms are used, for example, in the exemplary embodiments, this broad meaning is not contemplated. The carrier may be a solid, semi-solid or liquid diluent or capsule. Typically, the onofi 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.

For preparing pharmaceutical compositions containing the compounds of this invention in the form of dosage units for oral application the selected compound is mixed with a solid pulverulent _t, the carrier, such as lactose, saccharose, sorbitol, mannitol, starches such as potato or corn starch, ammlopektin ,. 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 by the above-described concentrated sugar solution are coated, which solution may contain, for example, gum arabic, gelatin, maize, titanium dioxide and the like. For longer, the tablets may be coated with soluble 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 sizes of the active compound.

In the manufacture of soft gelatin capsules (bead sealed capsules), such as those made of gelatin and glycerin, or in the manufacture of similar sealed 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 powder carrier such as lactose, sucrose, sorbitsl, malatol, starch (such as potato or corn starch, or neylopsetin), 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 use may be formulated. in the form of syrups or suspensions, for example solutions containing from about 0.2% mono- to about 20% of the active ingredient, the remainder being sugar and a blend of ethanol, water, glycerol and propylene glycol. If desired, these liquid formulations may contain colorants, flavoring agents and saccharin and carboxyin-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 buffers and may be available in non-aqueous form. 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 homogeneous and suspended in a particular solvent. The active ingredient and the necessary excipients are mixed during continuous and uniform mixing with the binder solution and moistened so that the solution is uniformly dispersed in the hammer without any parts being moistened. Typically, the Mn solvent is adjusted so as to:. that the mass has a consistency reminiscent of wet snow. The wetting of the powder mixture with the ash 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 of stainless steel mesh having a mesh size of about 1 mm. . The emm is then placed in thin layers on trays to dry in an oven. Sieving is carried out for 10 hours and care must be taken. The moisture content of the granulate is of great importance for the process and the properties of the tablets. Fluid drying can also be used. In this case, the mass is not put on the tray, but is · poured into the tray that my sieve bottom. ,

After drying, the granulate is mixed to obtain the desired particle size. Dust is removed under certain sieves.

Disintegrants, glidants and aitiades are added to the so-called final mixture.

After this, the composition should have the correct composition for tabletting. The cleaned tabletting machine is scalded with a set of dies and dies, and a suitable pressure setting is tested.

Hmmonoot tablets are critical to the size of the dose in each tablet and are 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. ¹

Certain tablets, particularly those that have 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 that have an electronic computer. 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 and depends on the route of administration, as a rule 100 to 400 mg of the active ingredient per day for oral administration and 5 to 20 mg daily for intravenous administration.

The following examples illustrate. and the invention without, however, its scope.

ø kl a d 1

244 g of sodium are dissolved in 100 ml of ethanol, followed by addition of 12.4 g of 4-methooy phenol and then 25.3 g of 1- (2-chloroethylmino) -3- (2-cyanophenoxy) propanol-2. The mixture was heated in an autoclave on a boiling water bath for 10 hours. It is filtered and the filtrate is evaporated to dryness. The residue was heated with 2N hydrochloric acid for 1 hour at room temperature and extracted with ether, then the aqueous phase was basified with ammonia and extracted with ether. This ether phase is vysiuSí over anhydrous magnesium sulfate (MgSO₄) to afford 1-12- (4-m ^ t ^h ox; ^: ^phenoxy) et ^h ylae ⁱ nc | - ^- - ⁽² - ^- yan ^phenoxy -propan ^! - ^ ^k esters are reversible, ^{d P} e at their h ^{y d} drochhori and isolated, its melting point is 134 ° C.

Example 2

3- (2- (2-Hydroxyphenoxy) ethyl) amino-1-o-ethylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-2- (p-methyl) phenoxypropane and 2- (2-hydroxyphenoxy) ethylamine starting material, m.p. hydrochloride 80 DEG C. The structural formula was determined using NMR and equivalent heotnoots.

Example 3

3- (2- (2-Methoxyphenoxy) ethylamino) -1-o-ethylphenoxypropanol-2 was prepared according to Example 1 using 1'-epoxy 4-o-methylphenoxypropane and 2- (2-methoxyphenoxy) ethylaine as starting materials. The tartrate melts at 91 DEG C. The structural formula is determined using NMR and equivalent weight.

Example 4.

3- [2- (4-Methoxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylennoxypropane and 2- (4-methoxyphenol) et. , hylamine as starting materials. Melting point ¹⁶⁸ ° C.

Example5

3- [2- (3,4-Dimethoxymethylflyylamino ⁾ -1-methylphenoxyprop (eluU-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methyleneoxypropane and 2- (3,4-dienoxy) ^ ^ eastern dimethylamine as their compounds. ^T emperature hydrochtortou point is ¹⁶⁰ ° C.

He said a d6

3- [2- (4-Hydroxyphenoxy) ethyl] amino] -3-o-oyaneenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-u-ceraerphenoxypropyl and - (4-lydruxyphenoxy) Ethlylamine as starting material. The melting point of the tartrate is 52 ° C.

Example-7

2- [2- (4-hydroxyphenoxy) -ethylamine hydrochloride · e] 11u ₀ _ _m ethoxyfenoxypřop8noU.-2 prepared according to Example 1 for the slaughter of 1,2-epoxy-3-o-methoxyfenoxypropanu and - (4-lydruxyfenoxy) ethylamine as starting materials.

He said a d8

3- [(2- (4-Hydroxyphenoxy) ethylaminoo-1-o-etlyffenoxyprupanol-2] was prepared according to Example 1 using 1,2-epoxy-3-o-ethyphenoxypropane and 2- (4-hydroxyphenoxy) thylamine as starting material. substances.

Example9

3 - [- (4-MethoxχfenooχУethylamino] -1-o-kyaefenoxyprupanol-2 prepared according to Example 1 using 1 - epoxy-3-o-kyanfenoxypropaeu and - (4-methuxyfenu> χy) etlylaminu as Buf ^H ozíc tetek ^h. EP ^{T p} ^ drochtoridu ot.a reading is ¹³⁴ ° C.

Example10

Γ-3 - (- HydruxyfeeoxyУethylamino] -1-u-kyaefenuxypropanoO-- prepared according to Example 1 using 1 - epoxy-3-o-kyaefenoxypropaeu and - (- lydruxyfeeoxy) etlylaminu as Buf ^{H H} ozíc The temperature of the drug was ¹⁸¹ ° C.

Example11

3- [2- (4-Hydroxy-3-methyl-3-methoxyphenoxy) -hlamino] -1-u-cyanophenoxypropanol was prepared according to Example 1 using 1-epo-3-o-cyano-phenoxypropyl and - (4-lydruxy) -3 - metloxyfenouχ)) thllaminu Avid® se ^{h h} ozíc substances. mp ^{l l} ydruch urīdu is ⁷⁸ ° C.

Example12

3- ^[- - (3, ⁵ zeta ^e houχ enouχ ^yl) -1-ethylamino ^u u ^- k ^{y y} anfeeox propanol, ^- was prepared according to Example 1 1 - epuxy-3-o-2- and kyaeďenoxypropanu (3,5-dimethoxyphenoxy) thylamine starting material, m.p. 159 ° C.

206734

Example 13

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

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

Dissolve sugar, saccharin and ether salt 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 substances may be replaced by other pharmaceutically acceptable acid addition salts.

Example 14

3- [2- (4-Hyddoxyxy) -1,1-dimethylethylamino-1-o-allyphenoxy] propanol-2-hydrochloride (250 g) is mixed with lactose [175.8 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) is added. talc (50 g) and magnesium stearate (5 g) and the mixture thus obtained is tableted to tablets (10,000) of 25 mg each. The tablets are marketed with a score line (in order to obtain a dose other than 25 mg or multiples thereof when the tablet is broken).

Example 15

Granules were prepared from 3-L2- (4-hydroxyphenyl) -1-methylamino] -1-o-poopaggyloxyphenoxypropanol-4-hydroxybenzoate (250 g), lactose (175.9 g) and polyvinylpyrrolidone alcohol solution (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 dye (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 · 6 ’

3- [2- (4-Hydroo-sphernda) -1,1-dimethylethylamino] -3-o-ethylphenoxypropanoO-2-hydro-alcohol (1 g), sodium chloride (0.6 g) and ascorbic acid (0.1 g); and dissolve in sufficient amount of distilled water per ~ 100 ml solution.

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

Biological effects

The β-receptor bleaching 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 resorpine (5 mg / kg body weight, intaamusloillary) about 16 hours prior to the start of the experiment.

The animals were pretreated with resorpine to eliminate endogenous symptomatic regulation of cardiac rate and vascular smooth muscle tone. The cats were anaesthetized with pentobarbital (30 mM / kg body hmoOnooSi, administered ip), artificial veenilaci subjected to air at the neck by a bilateral Vago ^<iome. Blood pressure was detected from a cannulated artery (artheria carotica) and cardiac activity was recorded using an electrocardiogram reader (ECG).

Penetrating e-mimetic activity on the heart was found from increased cardiac activity after drug administration. Test compounds were administered intrameenoses in logarithmically increasing doses. The values obtained were plotted as dose-response curves from which affinity values (ED? Q) were determined. At the end of each experiment, high doses of prenene were administered to obtain a maximal cardiac response.

The compounds were also tested in conscious dogs. Loving dogs (beagl varieties) were rehearsed to calm Ichghi to rise to an upright position by resting 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 with methyltkopolxmin to eliminate the reaction. influence of vagu. Recordings were made before administration of the test compound and 15 and 75 minutes after administration, first in the supine position for 2 and then in the upright position for 2 minutes.

Test compounds were administered at increasing doses at two-hour intervals. ‘

The pAg value in rats was also measured. The pAg value is defined as the log of the antagonist dose concentration, resulting in a need for a dose of ooradrenalysis to achieve the same ooralreoaline effect as without the antagonist, or pA2 = log (lr-1) -0og (antagoo), where dr is the dose ratio

ED ^ ₀ osadadraliol (antagonnsta) d ^r 'ED ^ q''osradrenoaiou (control) and all concentrations are given in moles per liter, ie moo / l.

Thus, the pAg value is a measure of the d-receptor effect, where higher pAg means a higher X-effect.

Attempts to test compounds are potent receptor antagonists, with cardiotectives with or without p-mimetic penetration effect. These compounds also significantly reduce blood pressure in conscious dogs. The effect of these novel compounds in conscious dogs depends on the vasodilatory effect correlated with the cardiac 3-receptor blockade. The results obtained in the above tests are given in Table 1 below.

0

Table

ОН _r 2

R ¹

Reserpinized cat

O-blockade of soprenaline cardiac effect ED ^ / um ol / kg β-blockade of isoprenaline punches / oin peripheral resistsncs

ED 50 / itnol / kg efficiency of% isoprenaline

PA2

-O 4-OH 0.25 1.0 13 18 -CN 4-OCHj 0.22 2.7 7 7 6.4 - ^ OCHgCONHCgHzjOCHj 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-diOCH3 2.9 1 1 15 Dec 17 6.5 -CHj 3,4-diOCH3 1.5 5.8 8 1 1 6.0 -CHj 2-OCHj 4,5 1 1 8 8 7.0 -ch ₃ 4-OCH ₃ 0.5 8.2 17 22nd 5.6 -CHj 4- [CCH 2 CH 2 O 4] + 0.6 1θ, 3 25 29 5.6 -ch ₃ 4-CN. 1.6 30 12 17 5.9 -ch ₃ 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 -CH ₂ CN 4-OH 0.05 1.6 +20 6.6 ^-C 3 ^H 7 4-OH 0.02 • 0.02 0 0 6.2 -CHgOH 4-OH 0.02 0.05 17 6.3

*

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of the novel azines of formula I, O-CH ₂ CHOHCH ₂ NH- (CH (I)) 1 1 wherein R 'is methyl, ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl or a residue CH ₃ oc ₂ H ₄ NHCOCH ₂ O-, ^{R 2,} l-hydroxy, methoxy or hydroxymethyl, ^R is hydrogen, dro ^ ^^ ^ droxymethyl nt ^b o methoxyl, n number 2, 3 n or 4 a X is -O-, wherein the reaction reacts a compound of formula Va, (Va) wherein Z is a reactive hydroxyl group, ^R1 macI an equal importance ^to the utan I above with a compound of formula IVa,> 2 HX (IVa) R 'in which 2 3 R ^c , R ^j and X have, inter alia, the same meaning as given above. Severography. n. p., <plant 7. Most