DE3324785A1 - PHARMACEUTICAL PREPARATION WITH SYNERGISTIC ANTI-HYPERTENSIVE EFFECT - Google Patents

Description

description

The invention relates to a pharmaceutical preparation or a medicament which is a combination of two Contains active ingredients, namely indapamide and 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman.

Indapamide or N- (3-sulfamoyl-4-chlorobenzamido) -2-methylindoline or also 4-chloro-N- (2-methyl-1-indolinyl) -3-sulfamoylbenzamide is in Example 1 of FR-PS No. 69.06023 (published under the number 2.003.311 has been described) as a diuretic, which is particularly suitable for the treatment of arterial hypertension is.

8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman (and its addition salts) is in Example 2 of FR-PS No. 71.11445 (published under the number 2.092.004 where it is stated that this compound has cardiovascular and particularly β-blocker properties having.

It has now been found that a combination of the two Above mentioned compounds developed surprising synergistic effects, the simultaneous therapeutic Application of these compounds allows.

The invention therefore relates to a pharmaceutical preparation which contains an active ingredient combination of indapamide and 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman or a pharmaceutically acceptable addition salt thereof, these two Ver "'ndungen in the form of the racemate or the optical Isc ..eren can be present, as well as therapeutic Compatible binders, door materials and / or contains auxiliary substances.

For the sake of simplicity, consider the compound 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman hereinafter abbreviated as "THPT".

The compounds used in the present invention were individually and in combination with respect to functional inhibition the membrane adenylate cyclase investigated.

Since the work of Sutherland et al. (Adenyl cyclase 1.

Distribution, preparation and properties, J. Biol. Chem. (1962) 237, 1220-1227) the red blood cells of the pigeon are known for their strong adenylate cyclase activity. The tests were carried out on erythrocyte phantoms (opened cells), which were obtained from the blood of the Strasser pigeons according to the method of R. Salesse and J. Garnier ("Effects of drugs on pigeon erythrocyte membrane and asymmetric control of adenylate cyclase by the lipid bilayer ", Biochem. Biophys. Acta (1979) 554, 102-103) have been manufactured.

The suspensions obtained were in a hypotonic for 20 minutes Buffer incubated with a volume of the product to be tested at the desired final concentration. The adenylate cyclase activity was determined by the method of L. Birnbaumer et al. (J. Biol. Chem. (1969) 244, 2468-3476) and J. Ramachandran and V. Lee (Biochem. Biophys. Res. Commun. (1970) 41, 358-366).

The final concentrations of the reagents were: 2 mM ATP, of which 1 μ Ci / Λ- ³ ^ / Ρ ATP, 4 mM theophylline, 10 mM phosphocreatine, 0.5 g / l creatine kinase, 7.5 mM MgCl- / 10 mM tromethamine HCl ("Tris", HCl), pH = 7.4.

The total volume was 75 μΐ with a cell number of

about 10 per tube.

The production of cyclic! AMP (AMPc) was either stimulated by 0.05 mM isoproterenol in the presence of 0.1 mM GTP or by 10 mM sodium fluoride. The connection was added in the required final concentration.

The reaction was stopped after 15 minutes at 37 ^C C by addition of 300 μΐ 0.5N hydrochloric acid and a treatment for 3 minutes on a boiling water bath. The tubes were then removed from the water bath and the contents were neutralized with 300 μl, 65N imidazole.

After centrifugation (10 min, 4000 g) were 500 μΐ the supernatant liquid applied to an activated neutral alumina column and with 2.6 ml of 10 mM Imidazole (pH = 7.5) eluted. The columns have an AMPc yield of 95%.

The radioactivity of the samples was then used in a scintillation counter (Packard Tricarb) of the Cerenkov effect after adding 10 ml of an aqueous 1% o solution of 7-amino-1,3-naphthalenedisulfonic acid measured on the eluate (counting yield = 65%).

Then, on a logarithmic scale, three concentrations above and three concentrations below the concentration determined in which one in the rat in vitro in the mesenteric artery a 50% inhibition of vasoconstriction caused by norepinephrine observed.

The results are the mean of three examinations given in pmoles of cyclic AMP, which has been formed per minute and per mg of M .nbranphosphoiipide. 35

It should be noted that indapamide and THPT in this

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Test to inhibit the activation of isoproterenol or sodium fluoride-stimulated adenylate cyclase by decreasing the amount of AMPc formed. The nature of the observed effect on the formation of AMPc depends on the concentration of the compound used. For this purpose, the active concentration of each compound _{causing an inhibition of 25% (CA 35} ) or 50% (CA ₅₀ ) and then that of the mixture of these compounds at these concentrations was determined graphically: 10

Indapamide (MW = 365.89): CA ₃₅ = 9 χ ΙΟ " ⁵ mol / l

CA ₅₀ = 3 10 ~ ⁴ mol / l

THPT, HCl (MW = 331.90): CA ₃₅ χ = 1.2 10 ^-5 mol / l CA ₅₀ = 7 x 10 ^-5 mol / l

In the table below are the percentages of inhibition indicated that achieved with each of the four mixtures of the two compounds at the stated concentrations have been:

THPT 25% THPT 50%

TABEL

Indapamide 25%

45%
62%

Indapamide 50%

62%

75%

It can be seen that the inhibition achieved with the mixture of the two compounds is markedly greater than those that can be achieved with the compounds used individually. For example, one achieves with a mixture from 9 χ 10 ~ mol / l indapamide and 1.2 χ 10 mol / l

-4 THPT an inhibition of 25%, which can only be achieved with 2.5 χ

Mol / l indapamide or reached with 5 χ 10 ~ ⁵ mol / l THPT,

d. that is, about 3 to 4 times the amount of the compounds

is required if these are used separately. The two effects, which correspond to an inhibition of 25%, thus multiply to an overall effect that leads to an inhibition of enzyme activity by 45% leads.

Since THPT is known as a ß-blocker, it was the most inhibiting Effect of this compound on the adenyl cyclase combined with an extracellular ß-receptor foreseeable On the other hand, however, it was surprising that an antihypertensive diuretic such as indapamide had a similar effect exercises and that in particular the activity of these two compounds interacts. In fact they show Dose / response curves of these compounds and in particular

their CA ₂₅ and CA _5Q values that there is a multiplicative synergistic effect.

AMPc is a second intracellular messenger that triggers cellular functions. By inhibiting adenyl cyclase it is thus possible to slow down the hyperactivity states of the cell that occur in hyperthyroidism, hypertension and hypersensitivity etc. occur. As a result the synergistically effective combination of active ingredients of the present invention is particularly indicated for Treatment of ß-dependent hyperactivities, how to get them in which hypertension occurs, especially in cases of severe arterial hypertension with renal insufficiency or with other diseases such as hyperthyroidism.

The pharmaceutical preparations according to the invention are preferably administered orally and can be in the form of tablets, coated tablets, gelatin capsules, Suspensions etc. are present. You can in particular 0.8 to 3 mg indapamide and 3 to 12 mg THPT or a pharmaceutically acceptable addition salt thereof as well as for

the usual binders and carrier materials for the oral administration form and / or contain adjuvants and can be taken once or twice a day.

The following example serves to further explain the invention.

example

To make a 90 mg tablet, use the the following components:

1.25 mg indapamide 5.00 mg 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman hydrochloride 0.90 mg of stearic acid

3.00 mg sodium carboxymethyl starch 33.38 mg microcrystalline cellulose 35.75 mg lactose 10.00 mg calcium hydrogen phosphate 0.27 mg colloidal silicon dioxide 0.45 mg magnesium stearate

This tablet can be coated. 25th

Claims (3)

Dr.-Ing. H. LiSKA, Dipl.-Pnys. Ur. d. ± recrrcex HtM / cb 8000 MÜNCHEN 86 PO Box 860 820 MDHLSTRASSE 22 TELETON (O »9) 98 03 52 TELEX 5 22621 TELEGRAM PATENTJFEICKMANN MÖNCHEN ADIR 22 Rue Gamier 92200 Neuilly sur Seine / France Pharmaceutical preparation with patented synergistic antihypertensive effect 1. Pharmaceutical preparation containing a combination of active ingredients from indapamide and 8- (3-tert-butylamine-2-hydroxypropoxy) thiachromane or a pharmaceutically acceptable addition salt thereof, these two compounds may exist in the form of the racemate or the optical isomers, as well as therapeutically acceptable ones Binders, carrier materials and / or auxiliaries. 2. Pharmaceutical preparation according to claim 1, characterized in that it is 0.8 up to 3 mg indapamide and 3 to 12 mg 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman or an addition salt thereof. 8 ζ, ν ^: ε ε 3. Pharmaceutical preparation according to claim 2 for administration by the oral route, characterized that they contain 1.25 mg of indapamide and 5 mg of 8- (3-tert-butylamino-2-hydroxypropoxy) -thiachroman contains hydrochloride.