CS250682B2 - Method of s(-)-3-(3-acetyl-4-/3-tertiary butylamino-2-hydroxypropoxy/-phenyl)-1,1-diethylurea production - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts. 1. Claims (for the Contracting State AT) Process for the preparation of S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts, characterised in that a) the racemate of the formula see diagramm : EP0155518,P10,F1 in the form of the base is reacted with an enantiomer of a chiral resolving acid in a suitable organic solvent, the mixture of the two diastereomeric salts formed in this manner is separated by fractional crystallisation, and, after separating each diastereomeric salt which contains the laevorotatory enantiomer of the compound of the formula I in the S configuration, is reconverted into the free base or a pharmaceutically acceptable addition salt and the resolving acid is recovered, or b) S(+)-3-[3-acetyl-4-(2,3-epoxypropoxy)-phenyl]- 1,1-diethylurea of the formula see diagramm : EP0155518,P10,F2 is reacted with tertiary butylamine in the presence of water at room temperature or with gentle heating to a maximum of 40 degrees C, and then the laevorotatory enantiomer of the compound of the formula I thus obtained is converted as required into a pharmaceutically acceptable addition salt.

Description

The present invention relates to a process for the preparation of S- [-] -3- [3-acetyl-4- (3-tert-butylamino'-2-hydroxypropoxy) phenyl] -1,1-diethylurea, otherwise called S - (-) - Celiprolol is a pharmaceutically active substance which, in particular in the form of the hydrochloride, can be formulated into pharmaceutical compositions.

German Patent Specification No. 2,458,624 describes, inter alia, 3- [3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) phenyl] -1,1-diethylurea (Celiprolol). of formula I

Of H ^X t (2.rC.

(I) as a receptor blocking agent.

(Blockers are substances with valuable pharmacological properties which are of great importance in the treatment of heart disease and circulation, such as angina, myocardial infarction, heart rhythm disorders or elevated blood pressure.

It is also known from the German Patent Specification No. 2,458,624 that Celiprolol has a pronounced cardioelective (β-receptor blocking effect), without the usual cardiac depressant side effects being observed.

In the structure of the compound of formula (I), a cross-referenced carbon atom in the backbone is the center of the chirality so that Celiprolol can exist in the form of two optical antipodes.

Furthermore, it is also known from European Patent Application No. 15 480 and from Nature, 210, 1336 ff that in the case of (--locators such as Mopirotol, i.e. O-isopropylamino-3 - ((t-methoxxxphenoxx)) - -propanol or propranolol, i.e. 1-isoprr) pylamine-3R (1-inaphthyloxy) is associated with blocking activity of the .beta.-receptors predominantly with the levorotatory enantiomer of the compound, whereas the dextrorotatory enantiomer has only little or no activity at the .beta.-receptors. Other advantageous pharmacological properties have hitherto always been associated with levorotatory forms (-Ы | Окёsmeгт

It has now been found that left-handed enantiomeric · mer celiprolol not only has a stronger effect ^(ECE II-Ptoro, but also unexpectedly high effect on the expansion of the bronchi.

Accordingly, the present invention provides a process for the preparation of S- (-) - 3- [3-, _ac- ethyl-4- (3-tert-butylamine)

-2-Hydroxypropoxy] phenyl] -1,1-diethylurea of S- [-] - Celiprolol and its hydrochloride acid addition salts, characterized in that it is reacted with S (-H-3- [3-acetyl-4]). - (2,3-epoxy for poxy) phenyl] -1,1-diethylcarbonyl of formula II

c-cw ₃

O-CHfCH-CH

The tert-butyl amine in the presence of water at room temperature or heated to 40 ° C and the thus obtained laevorotatory enantiomer of compound I is optionally converted to its hydrochloride acid addition salt.

In carrying out the reaction, the tert-butylamine is preferably mixed with water, for example in the same amount, slowly adding the epoxide of formula II in the S configuration and at room temperature or heating to at most 40 ^° C, preferably at most 30 ° C. The reaction is allowed to proceed. The levorotatory enantiomer of Celiprolol thus obtained can then be converted by acid treatment to a pharmaceutically acceptable addition salt, with hydrochloric acid being preferred. Since the product obtained in this reaction is identical to the product obtained in the resolution of the racemate obtained after the salt formation in terms of chemical and physical properties, it is possible to proceed in this manner. In both ways, products are obtained which have the same rotation, the same NMR spectrum and other properties.

Of the starting materials, only the racemate S (44 -3- [3-acetyl-4- (2,3-epoxypropoxy) eeoyl] -1H-diethylurea) of the formula II has been described so far in German Patent Specification No. 2,458,624. The dextrorotatory form of this compound, which has the S configuration and is required for the preparation of S- (-) -CelipTol, is obtained, for example, from WL Nelson, JE Wennerstnom and SR Sankar in J. Org., Chem. 6, 1977, pages 1 006-1012 of S (+) -2,2-dimethyl-4- (p-tosyloxymethyl) 1,3-dioxolane and 3- (3-acetyl-4-hydroxyphenyl) - 1,1-diethylurea or by the method of G. Zolss, Drug Res. 33, 2 (1983) by reacting 3- (3-acetyl-4-hydroxyphenyl) -1,1-diethylurea with < 1 > The rotation value of S (4 -) - 3- (3-acetyl-4- (2,3-ep (oxypropoxy) phenyl) -1,1-diethyl-10-oxo is [c] 5C ^{22 22} = -j-12.60 (c = 2.8 in acetone).

The designations R (rectum) and S (sinisterj, which is indicated throughout the application to express the absolute configuration) are in accordance with "Experientia", Vol. 12, pp. 81-94 (1956).

Surprisingly, pharmacological investigations of the compound of the present invention have shown that, besides the expressed cardioselective blocking effect on the β-formulas, surprisingly, the β-β-Celiprolol has a further pharmacodilating effect. especially in anesthetized cats in which the bronchial tone, bronchial elevation has been increased by intravenous infusion of serotonin by the following method:

Cats of both sexes weighing 2.5 to 4.8 kg are anesthetized with pentobarbital. A cannula is inserted into the trachea and the pchrudinic cavity of each cat. A pneumntachograph is used to register the tidal volume in the trachea, and a device capable of measuring the pressure difference is used to measure the transpulmonary pressure in the trachea and the pleural cavity.

These signals are converted to an analog computer each time they are inhaled and converted to a Raw Resistance value in the lungs. To measure blood pressure and heart rate, probes in the right femoral artery and in the femoral artery are used.

The animals are paralyzed with galliin dithiodide (Flaxedil) and mechanical breathing is introduced. In order to demonstrate the bronchodilator effect of the substance, it is necessary to increase the cat's bnoinchial tenus, which is normally low. This can be done by sustained intravenous infusion of serotonin (5-HT) at a rate of 40 µg / kg / min. S (-) - C 1 H 3 -phenyl, R (+) -C 6 H -prolol and (R, S) -cellipolol are administered at a dose of 5 mg / kg intravenously during the senotonin infusion.

The bnonchial tone variations are converted to Raw resistance values, with the value at the beginning of the Celiprolol infusion being assumed to be 100%.

In a series of 13 experiments, it was shown that only S (- J-Celiprclol had in all cases a significant and long-lasting bronchial effect, on average, -c ^ · 52 +18%. When R (+ J-Cerprolol was administered) The bronchial tdnus had recovered to its original value for only a few minutes of bronchodilation, and in about a quarter of the cases, the bronchoconstrictor effect was completely undesirable, with a maximum value of 260. Raw 260%. as in the case of R (+) -Celipnolol, pulmonary resistance was increased to baseline after a short period of bronchodilation.

This result was not to be expected, since beta blockers are known to generally increase respiratory resistance and are therefore contraindicated in patients suffering from bronchial asthma or another disease that results in airway narrowing.

Based on these unexpected pharmacological effects, S (- J-CeUprolel, produced by the method of the invention) can be used to treat cardiac and circulatory diseases without risk, particularly in those patients in whom β-blocking agents have previously been unusable due to a constructive disease respiratory tract, particularly for the treatment of elevated blood pressure, angina pectoris, cardiac rhythm disorders with an increase in the rate of this rhythm and the like, all of which lead to undesirable circulatory stress and are probably caused by catecholamines.

The cardioselective, β-receptor blocking effect was investigated by measuring the effect of S (β-Celiprolol on the positive effect of isoprenaline compared to racemic Cellprolol).

The effect of test substances on tachycardia induced by Isoprenaline is a well established way to determine the effect of substances with B-adrenergic blocking action. The less active the tachycardia caused by isoprenaline is the more potent the test substance is when the test substance is administered. The experiment was performed as follows:

Male rats and females weighing 200-300 g were anesthetized with pentobarbitalein at a dose of 30 mg / kg intraperitaneously. The test substance was also administered mtrapertoneally at a dose of 40 mg / kg. 15 minutes for the intraperitoneal administration of the test compound, 10 µg / kg of isoprenaline was also administered intraperitoneally. When soprenaline is administered without prior administration of the test substance, the increase in heart rate induced by 100 µg / kg is 146 beats per minute. The amount of Celiprolol was determined to halve this increase in heart rate. This value was

S (- - Ceiprolol

0.1 to 0.3 mg / kg of (R, S) -Celipnolol

0.76 mg / kg.

Thus, in this test, S (-) - β-Cel / prolol has twice the effect of the racemate, which allows to significantly reduce the dose to be administered to the patient.

The invention will be illustrated by the following examples:

··

Example 1

To a mixture of 0.86 ml of t-butylamine and 0.86 ml of water is added 250 mg of 8 (+ - 3- (3-acetyl-4- (2,3-epoxypropoxy) phenyl) -1,1-diethylurea at The excess t-butylamine was then distilled off in vacuo without heating, the residue was diluted with water and the precipitated base was extracted with chloroform, and the chloroform solution was dried over sodium sulfate and then evaporated to dryness in vacuo.

The residue obtained is treated with 1.5 ml of acetone, cooled to 0 DEG C. and crystallized after inoculation for 5 hours. The crystalline product formed is collected by suction filtration and dried.

A total of 225 mg of S (-) - Cellprolol was obtained.

[Α] 589 ²² : —6.3 ° (c = 10% in CHCl 3)

CD-spectrum:

CD (in ethanol):

Delta epsilon32o: ± -0.08

Delta epsioon355: —0.25

Production of hydrochloride:

12.0 g of S (-) -Celiprolol are dissolved at 20 DEG C. in 54 ml of acetone, a calculated amount of 4N hydrochloric acid is added and the resulting crystalline product is filtered off with suction after 2 hours at 4 DEG C. and washed with acetone. and dried.

Yield: 11.2 g of S (-) -Cellprolol hydrochloride [io] 589 ²⁵ : -7.4 ° (c = 10% in methanol)

M.p .: 187-188 ° C

Analysis:

calculated

H, 8.24; N, 10.1%; O, 15.4%.

8.5% Cl;

found

57.5% C,. 8.5% H, 9.9% N, 15.6% O,

8.5% Cl.

Example 2

The process of Example 1 was repeated except that the mixture was stirred at 10, 20, 30 and 40 ° C for 6 hours. The yield of S (-) -Celiprolol is at 218mg ° C 225mg ° C 211mg ° C 184mg.

Claims (1)

A process for the preparation of S (-) - 3- [3-acetyl-4- (3-tert-butyl) -mino-2-hydroxy-oxo-y-thiophen-2-yloxy] -oxa (S) - (-) - C 1 -prolol] phenyl I -1,1-diethylnoic acid of the formula I OF THE INVENTION and its hydrochloric acid addition salts, characterized in that S (±) -3- [3-acetyl-4- [2,3-epoxypropoxy] phenyl] -1,1-ethylurea is reacted with the formula II O II Z ^H S ^C 2_ HN-C-N o-ch-ch-brick-n and. i Z OH (I) with tert-butylamine in the presence of water at room temperature or with heating to a maximum of 40 ° C, whereupon the reaction is carried out. the levorotatory enantiomer of the compound of formula I thus obtained is optionally converted into its addition salt by treatment with hydrochloric acid.