DE3324785C2 - Pharmaceutical preparation with synergistic antihypertensive effect - Google Patents

Abstract

Pharmaceutical preparation for the treatment of hypertension, containing an active ingredient combination of indapamide and 8- (3-tert-butylamino-2-hydroxypropoxy) -thiachroman or one of its pharmaceutically acceptable addition salts, it being possible for the two compounds to be in the form of the racemate or the optical isomers , as well as therapeutically compatible binders, carrier materials and / or auxiliaries. The two active ingredients of this preparation develop a synergistic effect.

Description

The invention relates to a pharmaceutical preparation or a medicament which is a combination contains two 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-methyll-indolinyl) -3-sulfamoylbenzamide is described in Example 1 of FR-PS No. 69 06 023 (which has been published under the number 20 03 311) as a diuretic, which is particularly suitable for the treatment of arterial hypertension.

8- (3-terL-butylamino-2-hydroxypropoxy) thiachroman (and its addition salts) is in Example 2 of FR-PS No. 7111445 (which under the number 20 92 004) where it is stated that this compound is cardiovascular and in particular has / f-blocker properties.

It has now been found that a combination of the two above-mentioned compounds is surprising synergistic effects developed, the simultaneous therapeutic application of these compounds enables.

The invention therefore relates to a pharmaceutical preparation which comprises an active ingredient combination Indapamide and 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman or a pharmaceutically acceptable one Addition salt thereof, these two compounds in the form of the racemate or the optical Isomers can be present, as well as therapeutically acceptable binders, carrier materials and / or contains other excipients.

For the sake of simplicity, consider the compound 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman in the following abbreviated as »TliPT«.

The compounds used according to the invention were individually and in combination with respect to the functional Inhibition of membrane adenylate cyclase investigated.

Since the work of Sutherland et al. (Adenyl cyclase 1. Distribution, preparation and properties, J. Biol. Chem. (1962) 237, 122-227) is the red blood cell the pigeon is known for its strong adenylate cyclase activity. The investigations were carried out on erythrocyte phantoms (opened cells) carried out based on the blood of the Strasser pigeons according to the Method by R. Salesse and J. Garnier (Effects of drugs on pigeon erythrocyte membrane and asymmetry control of adenylate cyclase by the lipid bilayer ", Biochem. Biophys. Acta (1979) 554, 102-103).

The suspensions obtained were in a hypotonic buffer with a volume of 20 minutes the product to be investigated is incubated at the desired final concentration. The determination of the adenylate cyclase activity took place according to 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- ³² ] Ρ ATP, 4 mM theophylline, 10 mM phosphocreatine, 0.5 g / l creatine kinase,

7.5 mM MgCl ₂ , 10 mM tromethamine HCl ("Tris", HCl), pH = 7.4.

The total volume was 75 μ! with a cell count of about 10 ⁸ per tube.

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

The reaction was after 15 minutes at 37 ° C by adding 300 μΐ 0.5 η hydrochloric acid and a Treatment interrupted for 3 minutes on the boiling water bath. Then the The tube was removed from the water bath and the content was neutralized with 300 μΙ 1.65 η imidazole.

After centrifugation (10 min, 4000 g), 500 μl of the supernatant liquid was activated applied neutral aluminum oxide column and with

2.6 ml of 10 mM imidazole (pH = 7.5) eluted. The columns have an AM Pc yield of 95%.

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

Then on a logarithmic scale, three concentrations above and three concentrations below the concentration determined at which a 50% ige Inhibition of norepinephrine-induced vasoconstriction observed.

The results are given as the mean of three tests in pmoles of cyclic AMP, which has been formed per minute and per mg of membrane phospholipids.

It is found that indapamide and THPT in this test the activation of isoproterenol or Inhibit sodium fluoride-stimulated adenylate cyclase by decreasing the amount of AMPc formed. the The type of effect observed on the formation of AMPc depends on the concentration of the compound used away. For this purpose, the active concentration of each compound that inhibits 25% (CA25) or 50% (CA50) and then that of the mixture of these compounds at these concentrations graphically determined:

Indapamide (MW = 365.89):
CA ₂₅ = 9 xlO- ⁵ mol / l
CA ₅₀ = 3 XlO- "mol / l

THPT ₁ HCl (MW = 331.90):
CA ₂₅ = 1.2 xlO- ⁵ mol / l
CA ₅₀ = 7 xlO- ⁵ mol / l

In the table below are the percentages the inhibition reported with each of the four mixtures of the two compounds in said Concentrations have been reached:

Tabel

Indapamide 25%

Indapamide 50%

TH PT 25%
TH PT 50%

45%
62%

62%
75%

ίο

1.25 mg indapamide

5.00 mg 8- (3- butylamino-2-hydroxy-

propoxyjthiachroman hydrochloride

0.90 mg of stearic acid

3.00 mg sodium carboxymethyl starch

33.38 mg of microcrystalline cellulose

35.75 mg of lactose

10.00 mg calcium hydrogen phosphate

0.27 mg colloidal «silicon dioxide

0.45 mg Magncsium stearate

This tablet can be coated.

It can be seen that the inhibition achieved with the mixture of the two compounds is markedly stronger than that which is brought about with the compounds used individually. For example, was achieved with a mixture of 9 χ 10 ^-5 mol / l and 1.2 indapamide χ 10- 'mol / l THPT an inhibition of 25%. which can only be achieved with 2.5 10- "mol / l indapamide or with 5 χ ΙΟ- ⁵ mol / l THPT, ie that about 3 to 4 times the amount of the compounds is required if these are used separately Both effects, which correspond to an inhibition of 25%, thus multiply to form an overall effect which leads to an inhibition of the enzyme activity by 45%.

Since THPT is known as a / blocker, it was inhibitory Effect of this compound on adenyl cyclase combined with an extracellular / receptor predictable. On the other hand, however, it was surprising that an antihypertensive diuretic such as indapamide exerts a similar effect and that in particular the activity of these two compounds interacts. Indeed, the dose / response curves of these compounds, and in particular their CA25- and CA50 values that it is a multiplicative synergistic Effect acts.

AMPc is a second intracellular messenger that triggers cellular functions. By inhibiting the Adenyl cyclase can thus slow down the hyperactivity states of the cell, which in hyperthyroidism, hypertension and hypersensitivity etc. occur. Accordingly, the synergistically effective combination of active ingredients of the present invention is special indicated for the treatment of / -dependent hyperactivity, as found in hypertension, especially in cases of severe arterial hypertension with renal insufficiency or in others 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. In particular, they can contain 0.8 to 3 mg of indapamide and 3 to 12 mg of THPT or a pharmaceutically acceptable one Addition salts thereof and binders and carrier materials customary for oral administration and / or contain adjuvants and can be taken once or twice a day.

The following example serves to further explain the invention.

example

The following ingredients are used to make a 90 mg tablet:

Claims (2)

Patent claims: 1. Pharmaceutical preparation containing an active ingredient combination of indapamide and 8- (3-tert-butylamino-2-; iydroxypropoxy) thiachroman or a pharmaceutically acceptable addition salt thereof, these two compounds in Form of the racemate or the optical isomers can be present, as well as therapeutically acceptable Auxiliary materials. 2. Pharmaceutical preparation according to claim I for administration by the oral route, characterized in that that they contain 1.25 mg of indapamide and 5 mg of 8- (3-tert-butylamino-2-hydroxypropoxy) thiachroman hydrochloride contains