CS202037B2 - Process for preparing new p-hydroxyphenoxypropanolamines - Google Patents

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (18) DESCRIPTION OF THE INVENTION PATENT 202037 (11) (B2) (51) Int. Cl.3 (22) Registered 14 02 75 C 07 C 87/127 (21) (PV 5580-78) OFFICE AND DISCOVERY (32) (31) (33) Priority from 14 0'2 74 (7401958- 9) Sweden (40) Published 31 03 80 (45) Published 15 08 83

(72) CARLSSON ENAR INGEMAR, KUNGSBACKA, PERSSON NILS HENRYAutor of the invention ALFONS. DALBY, SAMUELSSON GUSTAV BENNY ROGER, MOLNLYCKE and WETTERLIN KJELL INGVAR LEOPOLD, SANDBY (Sweden) (73) AB HANDLE, MOLNDAL (Sweden)

Patent proprietor (54) Method for producing new p-hydroxyphenoxypropanolamines

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of new? -Hydroxyphenoxypropanolamines, a potent?

These novel compounds, which are substituted p-hydroxyphenoxypropanolamines, have the general formula I and CH 2 OH -OH, - C = O, NH 2 - C = O, OC 2 H 5

OH

OR (I) or

Wherein R is cycloalkyl of not more than 6 carbon atoms or R3 is R2; —C — R4 — I! CH 3 wherein R 2 is hydrogen or hydroxyl wherein R 4 is any of the following or when R 2 is hydroxyl, and R 3 is selected from the group consisting of

202037 202037

or or when R 2 is hydroxyl, and R 3 is selected from the group consisting of hydrogen and methyl, R 1 is selected from the group consisting of hydrogen and benzyl.

The cycloalkyl group R is preferably C 5 -C 6 cycloalkyl, such as cyclopentyl and cyclohexyl.

Many heart diseases are accompanied by such extensive myocardial damage that cardiac insufficiency occurs. The essential component of cardiac insufficiency treatment is a substance with a positive inotropic effect on the heart, ie, a substance that enhances contractility and / or one that has a positive synchronotropic effect on the heart, ie, that increases the heart rate. The most commonly used drugs currently include anthropogenic glycosides with an inotropic effect. However, preparations containing foxglove glycosides have deficiencies in the therapeutic aspect. They also have a narrow therapeutic breadth. If their doses exceed the appreciable dose, they exhibit positive innocuous activity, inducing, for example, heart arrhythmias. The requirement for drugs with a positive effect to replace or supplement the annular preparations is obvious. According to the results obtained in animal experiments, the compounds produced by the method of the invention are just such agents. The positive effect of these compounds depends on the activation of adrenergic receptors controlling heart contractility.

The novel compounds of the invention are: 1- (2-phenyl-2-hydroxy-1-methylethylamino) -3-p-hydroxyphenoxypropanol-2, ethyl ester of 3- (3-p-hydroxy) -phenoxy-2-hydroxypropylamino) -butyric acid, 3- (3-p-hydroxy-phenoxy-2-hydroxypropylamino) -butyric acid amide, 1- (hydroxy-tert-butylamino) -3-p-hydroxy-phenoxypropanol-2,1 - (2-p-hydroxyphenyl) -1-methylethylamino-3- (3-hydroxyphenoxypropan-2, 1- [2- (p-hydroxyphenyl) -1,1-dimethylamino] -3- -hydroxyphenylpropanol-2, 1 - [(2-p-chlorophenyl) -1-methylethylamino] -3-p-hydroxyphenoxypropanol-2,1-cyclopentylamino-3-p-hydroxyphenoxypropanol-2, 1- (2- (p-hydroxyphenyl) -1,1-dimethylethylamino) -3- (o-chloro-p-hydroxyphenoxy) propanol-2 The following salt-forming acids may be used to prepare the therapeutically useful salts of these compounds: halogenoic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acid acetic acid, propionic acid, janitic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxy maleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-amino-salicylic, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, ethylene sulphonic acid, benzenesulphonic acid halogenated, toluenesulphonic acid, naphthyl sulphonic or sulphanilic acid, methiomine , tryptophan, lysine or argimin.

These compounds are intended to be administered orally or parenterally in acute achronic treatment of heart failure, especially heart ventricular failure (a disease caused by a reduction in ventricular contractility below the healing heart), such that the myocardium, at each fiber length, can induce tension or to shorten the load is worse enough to be reflected in circulation. Accordingly, the compounds of the invention are intended to improve the manifestations and symptoms of heart failure such as dyspnoea, cyanosis, pulmonary edema, elevated pulmonary pressure, liver enlargement, and peripheral edema.

Compounds produced by the method of the invention may be used alone or in combination with other drugs, such as administration of annular glycosides and diuretics. These compounds, in combination with other drugs, can also be used to treat cardiogenic shock, accompanied by a reduction in arterial pressure, which often complicates myocardial infarction.

Another use of these compounds lies in the treatment of bradycardia, i.e., under the conditions of slow heart rhythm where the therapeutic value of compounds with a weak positive chronotropic effect in combination with positive inotropic activity can be assumed.

The biological activity of the novel compounds has been tested; the various tests performed will be explained and explained below.

Example A-Adrenergic effects of isoprenaline and the compounds of the present invention.

Tests on anastetized cats after previous administration of reserpine 202037 6

WITH

Chronotropic (heart rate) and vaso-dilatation effects: Reserpine (5 mg / kg body weight intramuscularly) was administered to cats of an average weight of 3 kg approximately 16 hours prior to the test, eliminating fully reflex sympathetic control of the heart and vascular tone If the cats were anesthetized with Mebumal 30 mg / kg body weight ip, they were started by summation and both stray nerves were cut and the blood passing through the femoral artery was passed through the catheter and pumped back into the distal vessel. the perfusion pressure was perfused and constant flow, and the perfusion pressure was registered The constant flow perfusion pattern is the fusion pressure directly proportional to the peripheral resistance of the vascular backbone.

The circulation of blood in the leg was interrupted by ligation. The heart rate was a registered ECG triggered cardiometer. The compounds were administered intravenously in ascending doses and the dose-dependency curves - heart rate and va-sodiumlation response curves were registered. In Table I, the ED 50 values, ie the doses found, which give a 50% maximal effect are given. Next, the ratio of the ED50 (vasodilatation / ED 50 for heart rate) was determined. The dose ratio of> 1 shows a selective cardiac effect. The reported values represent the average of 4 experiments.

Table 1

Merger- Affinity ED 50 / xg / kg (cardiac number vasodilated latency according to examples)

Selectivity Penetration efficiency ED 50 vasodilator_max. 100% ED 50 heart rate isoprene 0.05 0.01 0.2 100 I 30> 1000> 33 100 II 30> 1000> 33 86 III 62> 1000> 16 78 IV 32> 1000> 31 86 V 11> 1000 > 90 100 VI 10> 1000> 100 97 VII 32> 1000> 100 87 VIII 28> 1000> 35 87

Compounds I to VIII exhibit about 1/200 or less chronotropic activity of isoprenaline but less than 1 / 100,000 of its vasodilatory activity. The heart rate response after α-filling of the compounds of the invention is 80% or maximum of the isoprenaline response.

The novel compounds are prepared by a process according to the invention which is based on the fact that the compound of the formula IV

OH (IV) wherein R 1 is as defined above is reacted with a compound of formula V, Z-CH 2 CHCH 2 -NH-R (V),

AND

X 1 is the reactive esterified hydroxy group and x 1 is hydroxy or Z and x 1 together form an epoxy group.

This reaction is carried out in the usual manner. In such cases, when the reactive esters are used as the starting material, the compound of the formula (IV) can be suitably used in the form of its phenolates, such as alkali metal phenolates, preferably sodium phenolates, or in the presence of an acid-binding agent, preferably a condensing agent. which form a salt with a compound of formula IV, such as an alkali metal alcoholate. The above reactions are carried out in a conventional manner in the presence of diluents, condensation and / or catalytic agents at low, room or elevated temperatures and can be carried out in a sealed vessel. Depending on the method of preparation and starting material, the final product is obtained either in free form or in addition salt form, which is within the scope of the invention.

For example, basic, neutral or in which 202037 the mixed salts may be obtained in the form of a chemo, sesqui or polyhydrate. The acid addition salts of the novel compounds can be converted into the free compounds in a manner known per se, for example by basic agents such as alkali or ion exchange resins. On the other hand, the free bases obtained can form salts with organic and inorganic acids. Acids for the preparation of the acid salts are those which form a suitable therapeutically useful salt. Examples of such acids are hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxyleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid , ethylene sulfonic, halogenated benzenesulfonic acids, toluenesulfonic, naphthyl sulfonic or sulfanilic acid, methionine, tryptophan, lysine or argin.

Other salts of the novel compounds, such as, for example, borates, can be used to purify the free bases by converting the free bases obtained into salts which are separated and the base is liberated from the salts. In accordance with the close relationship between the novel compounds and the free salt form and salts thereof, the term "free compounds" and the corresponding salts are to be understood as possible.

The novel compounds, depending on the choice of starting material and method of manufacture, may be present in the form of antipodes or racemates, or if they contain at least two asymmetric carbon atoms, may be present as mixtures of isomers (racemate mixtures J).

Mixtures of isomers (racemate mixtures) may be separated into both stereoisomeric (diastereomeric) pure racemates, e.g. by chromatography and / or fractionated crystallization, depending on the physicochemical differences of the components.

The racemates thus 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 formed with the compound and by partitioning the salts obtained, for example, by the different solubility of the diastereomers from which -to release antipodes with suitable reagents. Suitable optically active acids are, for example, the L- and D-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Isolation of the more active component from the biphasic is preferred. In order to carry out the reactions according to the invention, suitable starting materials are used which lead to the groups of the desired end products, and in particular to the final products which are specified and refined. The starting materials are known or, if they are new, they can be obtained in a manner known per se. In clinical practice, the compounds of the present invention are administered orally, rectally or by injection in the form of pharmaceutical compositions containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic addition salt such as hydrochloride, lactate, acetate a sulfamate or similar combination with a suitable pharmaceutical carrier.

The compounds of the invention disclosed herein meet both the free ammonium bases and the acid addition salts of the free bases, whether described generally or specifically, although the context in which such compounds are exemplified, such as those exemplified, may not be consistent with this broad scope. known. Solid, semi-solid, liquid wafers or wafers are used as carriers for these compounds. The amount of active ingredient is between 0.1 and 95% by weight. weight of the preparation, suitably between 0.5 and 20% by weight. in injectable preparations and between 2 and 50% by weight. in oral preparations. In formulations of pharmaceutical compositions containing a compound of the invention in the form of dosage units for oral administration, the selected compound may be mixed with suitable carriers such as lactose, sucrose, sorbitol, mannitol, starch, potato starch, corn starch, and the like. , amylopectin, cellulose derivatives or gelatin, as well as glidants such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like and can be tableted. If coated tablets are desired, the prepared core may be coated with a concentrated sugar solution, such as gum arabic, gelatin, talc, titanium dioxide and the like. Furthermore, they can be coated with a varnish dissolved in a highly volatile organic solvent or solvent mixture. To this end, a dye may be added to make it easy to distinguish tablets with different active compounds or with different amounts of active compound. In soft gelatin-bead formulations that consist of gelatin and, for example, glycerin or a similarly closed wafer composition, the active compound is mixed with the vegetable oil, and the gelatin wafers may contain granules of the active compound in combination with a solid carrier. such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amlylpectin), cellulose derivatives or gelatin, the dosage unit for rectal administration may be presented in the form of suppositories which they contain the active ingredient in admixture with neutral citrus bases, or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing about 0.2% by weight. 20 wt. the active compounds described herein, the remainder consisting of sugar, a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain flavoring agents (saccharin) and carboxymethylcellulose (as filler).

Injectable solutions for parenteral administration may be prepared as aqueous solutions of water-soluble pharmaceutically acceptable salts of the active compound, preferably at a concentration of from about 0.5% to 0.1% by weight. and / or buffers and are available in various injectable dosage forms. The preparation of pharmaceutically acceptable tablets for oral administration is carried out according to the following procedure:

The solids are ground or screened to a specific particle size. The binder is homogenized and suspended in a certain amount of solvent. The drug and the necessary adjuvants are mixed by continuous and constant mixing, along with the solution containing the surfactant, and moistened to such an extent that the solution is uniformly distributed throughout the mass without any particulate being wetted. The amount of solvent is adjusted so that the obtained mass becomes consistently reminiscent of wet snow. Moisturizing the mixture with a binder solution with the reagent causes the particles to aggregate slowly and form an aggregate that is extruded through a mesh of 1 mm stainless steel mesh. The mass is then placed in a thin layer and dried on a sieve in a drying box. This drying lasts 10 hours and needs to be carefully standardized, since the moisture content of the granulate is of decisive importance for the following procedure and shape of the tablets. A fluidized bed drying process may also be used. In this case, the mass is not placed on the dryer, but placed in a container which has a meshed bottom.

After the drying step, the granules are sieved to obtain the desired particle size. Under certain circumstances, dust must be removed. Degradation, anti-friction and antiadhesive agents are added to the so-called final mixture. After this treatment, the composition should have a suitable composition for tabletting.

The cleaned tabletting machine is provided with suitable dies and dies, whereupon preparation for the desired tablet weight and compression rate is tested. The weight of the tablets is decisive for the dose size in each tablet and is calculated from the amount of therapeutic agent present in the granulate. The degree of compression affects the size of the tablets, their strength and their disintegration in water. In particular, due to the two last properties of the compression pressure selection (5 to 50 MPa), when the tableting machine is adjusted, the preparation of the tablets starts at a rate of 20,000 to 200,000 tablets per hour.

The tablets are freed from adhering dust by a special device and then stored in sealed containers until shipped. Some tablets, especially those that have a bitter or bitter taste, are coated. It is said that they are coated with a layer of sugar or some other suitable coating.

Tauiers are usually packaged on a device combined with a tube computer. The packaging consists of glass or plastic bottles, but also boxes, tubes, and containers adapted to special dosages.

The daily doses of the active substance are variable and depend on the mode of administration, but as a general rule, for oral administration, 100 to 400 mg per day and 5 to 20 mg per day for intravenous administration. The following description of the invention will be made without limiting it to the invention. The temperature is given in degrees Celsius. EXAMPLE 1 2.4 g of sodium are dissolved in 100 ml of ethanol and 21.7 g of 1- [2- (p-chlorophenyl) -1-methylethylamino] -3-chloropropane-2-ol are added. 0 g of p-benzyloxyphenol. The mixture was heated in an autoclave in a boiling water bath for 15 hours. Then the solution was filtered and the filtrate evaporated to dryness.

The residue was acidified with 2 N HCl and extra 202037 11 12 ether, whereupon the aqueous phase was basified with 2N sodium hydroxide and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, and after isolation the 1- [2- (p-chlorophenyl) -1-methylethylamino] -3- (p-benzyloxyphenoxy) propan-2-ol was obtained hydrogenated and isolated as in Example 1. It has a melting point of 122 ° C. Example 2

3 - [(3-p-Hydroxyphenoxy-2-hydroxy) propylamino] butyric acid ethyl ester was prepared according to Example 1 using 1,2-epoxy-3-p-benzyloxyphenoxypropane and 3-aminobutyric acid ethyl ester as starting materials. tek. The base obtained in the form of a water-soluble oil, the structure was confirmed by the NMR-spectra with moles. weight. Example 3

3- (3-p-Hydroxy-phenoxy-2-hydroxypropylamino-butyric acid amide was prepared according to Example 1 using 1,2-epoxy-3-p-benzyloxy-phenoxypropane and 3-aminobutyric amide as starting materials. The base was obtained as water-soluble oil, its structure was determined by NMR-spectra and equivalent weight determination Example 4 1- (Hydroxy-tert-butylamino) -3-p-oxy-phenoxypropan-2-ol was prepared according to Example 1 using 1 2-epoxy-3-p-benzyloxy-phenoxypropane and 2-amino-2-methylpropan-1-ol as starting materials The p-hydroxybenzoic acid salt was prepared by a steplot of 190 ° C. Example 5 1- ( 2-p-Hydroxyphenyl) -1-methylethylamino) -3-p-oxyphenoxypropan-2-ol was prepared according to Example 1 using 1,2-epoxy-3-p-benzyloxyphenoxypropane and 2-p -hydroxyphenyl-1-methylethylamine as starting materials. The melting point of the prepared hydrochloride is 192 ° C. Example 6 1- [2- (p-Hydroxyphenyl) -1,1-dimethylethyl-amino-3-p-hydroxy-phenoxypropan-2-ol was prepared according to Example 1 using 1,2-epoxy-3-p-benzyloxy-phenoxypropane and 2 -p-hydroxyphenyl-1,1-dimethylethyl-amine as other substances. The melting point of the hydrochloride was 219 ° C. Example 7

By the method of Example 1 above, 1- [2-phenyl-2-hydroxy-1-methyl-ethylamino] -3-p-hydroxy-phenoxy-propanol-2 having a melting point of 163 ° C was prepared. Its structure was determined using NMR. Example 8 1-Cyclopentylamino-3-p-hydroxy-phenoxy-propan-2-ol was prepared according to Example 1 using 1,2-epoxy-3-p-benzyloxy-phenoxypropane and cyclopentylamine as starting materials. Melting point of the hydrochloride is 165 ° C. Example 9 1 - [(2-p-Hydroxyphenyl) -1,1-dimethylethylamino] -3-p-chloro-p-hydroxyphenoxypropan-2-ol was prepared according to Example 1, using 1, 2 epoxy-3-o-chloro-p-benzyloxyphenoxy-propane and 2-p-hydroxyphenyl-1,1-dimethyl-ethylamine as starting materials. Example 10

A syrup containing 2% by volume of the active ingredient was prepared from the following components: 1- (2-phenyl-2-hydroxy-1-methylethylamino) -3-p-hydroxyphenoxypropan-2-ol hydrochloride saccharin sugar glycerin taste corrector ethanol 96% distilled water 2.0 g0.6 g 30.0 g5.0 g 0.1 g 10.0 billion 100.0 ml

The sugar, saccharin and ether salt are dissolved in 60 ml of warm water. After cooling, the glycerin and the flavor corrector are dissolved in ethanol. The mixture is then diluted with water to 100 ml. The above active substances can be replaced by other pharmaceutically acceptable acid addition salts. Example 11 1- (2-p-Hydroxyphenyl-1,1-dimethylethylamino-3-p-hydroxyphenoxypropan-2-ol hydrochloride (250 g) was mixed with lactose (175.8 g), starch (169 g). 7 g) and colloidal silicon dioxide (32 g), wetted with 10% gelatin solution and granulated with 12 mesh, potato starch (160 g), talcum (50 g) and magnesium stearate (5 g) and the resulting mixture is tabletted (10,000 tablets) containing 25 mg of the substance each Tablets intended for practical use are coated so that the dosage can be varied and administered at or above 25 mg.

The granulate was prepared from 1- (hydroxy-tert-butylamino) -3-p-hydroxyphenoxypropan-2-ol

Claims (1)

20 213 as a salt with p-hydroxybenzoic acid (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying, the granules are mixed with a plate (25 g), potato starch and magnesium stearate (2.50 g) and tabletted in 10,000 tablets of biconvex shape. These tablets are first coated with a 10% alcoholic shellac solution followed by an aqueous 45% sugar solution, 5% arabic gum solution, 4% solution and 0.2% dye. Talc and sugar were used to dust after the first 5 trains. The coating was then coated with 66% sugar syrup and polished with 10% of a process for the preparation of new p-hydroxyphenoxy-propanolamines of the formula I (I) wherein R is cycloalkyl of up to 6 carbon atoms or R3 of R2 II —C— Wherein R 2 is hydrogen or hydroxyl, wherein R 4 is one of the radicals —OH, -C = O, I NH 2 —c = 0, 10 O 2 H 5 when R 2 is hydrogen, and wherein R 4 is one of the geverograph residues, n is a 37 14 carnauba wax in carbon tetrachloride. EXAMPLE 13 1-Cyclopentylamino-3-p-hydroxyphenoxy-propan-2-ol hydrochloride (1.0 g, 0.8 g of sodium chloride and 0.1 g of ascorbic acid dissolved in sufficient amount to distill off to give 100 ml of solution) This solution, which contains 10 mg of active substance in each ml, was filled into ampoules, which were sterilized by heating to 120 ° C for up to 20 minutes. when R 2 is hydroxyl and R 3 is selected from the group consisting of hydrogen and methyl, R 1 is selected from the group consisting of hydrogen and benzyl, and physiologically acceptable salts of these compounds, wherein the compound of formula IV (IV) wherein R 1 has the same meaning as above, is reacted with a compound of general formula V X 4 I -CH 2 CHCH 2 NHR (V) wherein R is as defined above and X 1 is hydroxy and Z is reactive esterified hydroxy or X 1 and Z taken together form an epoxy group, whereupon, if desired, the obtained isomer mixtures are separated into the pure isomers, and / or the racemates obtained are separated into the optical antisense, and / or the free base obtained is converted into its physiological harmless salts or salts obtained are converted to the appropriate bases. source 7, Mps |