FR2529785A1 - PHARMACEUTICAL COMPOSITION BASED ON INDAPAMIDE AND 8- (3-TERTBUTYLAMINO 2-HYDROXYPROPOXY) THIACHROMAN - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION CONTAINING A COMBINATION OF INDAPAMIDE AND 8- (3-TERT-BUTYLAMINO-2-HYDROXYPROPOXY) -THIACHROMAN OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE ADDITIONAL SALTS, EACH OF THESE TWO COMPONENTS, WHICH HAVE BEEN POSSIBLE OPTICAL ISOMER AS WELL AS A THERAPEUTICALLY COMPATIBLE EXCIPIENT OR VEHICLE. THE TWO CONSTITUENTS OF THIS COMPOSITION ACT SYNERGETICALLY. TREATMENT OF HYPERTENSION.

Description

1 -

  The present invention relates to a composition

  pharmaceutical composition containing a combination of two

  active ingredients, indapamide and 8- (3-tert-butylamino)

  2-hydroxypropoxy) -thiachromanne. Indapamide, or N- (3-sulfamoyl 4-chlorobenzene)

  mido) 2-methylindoline, or 4-chloro N- (2-methyl-1-

  indolinyl) 3-sulfamoyl-benzamide, has been described in Example 1 of French Patent No. 69 06023 (published under No. 2,003,311) as a particularly usable diuretic

  in the treatment of high blood pressure.

  8- (3-tert-butylamino-2-hydroxypropoxy) -thia-

  chromanne (or its addition salts) is described in the following

  No. 2 of French Patent No. 71,114,445 (published under the

  No. 2 092 004) which indicates cardio-

  vascular, especially beta-blocking.

  Now, we have now found that both

  Previous compounds have associated properties

  unexpected energy sources, predicting their use

  simultaneous therapeutic use.

  The invention therefore relates to a pharmaceutical composition

  containing an association of indapamide and 8-

  (3-tert-butylamino-2-hydroxypropoxy) -thiachromanne or a pharmaceutically acceptable addition salt thereof, each of which may be in racemic form or optical isomer, and an excipient or

  therapeutically compatible vehicle.

  2 - For convenience, 8- (3-tert-butylamino

  2-hydroxypropoxy) -thiachromanene will be referred to as "THPT" above.

  after. Pharmacological study The compounds studied according to the invention

  have been tested on functional inhibition of adeno-

  late cyclase menbranaire alone and in combination.

  The red blood cell of pigeon is known for its high activity adenylate cyclase since the work of

  SUTHERLAND et al. (Adenyl cyclase 1 Distribution, first

  paration and properties, J Biol Chem (1962) 237: 1220-

  1227) The experiments were carried out on erythrocyte ghosts (open cells) prepared from Strasser pigeon blood according to the technique of

  SALESSE R and GARNIER J, "Effects of drugs on pigeon ery-

  thrombocyte membrane and asymmetric control of adenylate cyclase by lipid bilayer "(Biochem Biophys Acta

(1979) 554: 102-103).

  The suspensions obtained were incubated

  twenty minutes in hypotonic buffer with a volume of

  duit tested to the desired final concentration

  Adenylate cyclase activity assays have been

  made according to the method of BIRNBAUMER L et al (J.

  Biol Chem (1969) 244: 2468-3476) and RAMACHANDRAN J; LEE V (Biochem Biophys Res Commun (1970) 41:

358-366).

  The final concentrations of reagents were ATP 2mM, of which 1t Ci del 32 Jp ATP, theophylline 4mM, phosphocreatine 10mM, creatine kinase 0.5g / l, Mg Cl 2 7.5mM, tromethamine, H Cl ("TRIS", HCl) 10 mM, pH = 7.4-4. The total volume was 75 microliters and the

  number of cells per tube about 108.

  The production of cyclic AMP (AM Pc) was stimulated either by isoproterenol 0.05 m M in the presence of 0.1 m M GTP, or by sodium fluoride 10 m M On

  added the compound to the required final concentration.

  The reaction was stopped after 15 minutes

  at 37 C by the addition of 300 microliters of hydrochloric acid

  drique 0.5 N and a passage of 3 minutes in a boiling water bath The tubes were then removed from the water bath by neutralizing the contents by 3090 microliters of imidazole

1.65 N.

O

  After centrifugation (10 min, 4000 g) 500 micro-

  1 liter of the supernatant was poured onto a column of activated neutral alumina and eluted with 2.6 ml of imidazole mM, p H = 7.5. These columns have a yield of AM Pc of%.

  The radioactivity of the samples was

  in a "Packard Tricarb" scintillation counter, using the Cerenkov effect after addition to the eluate of 10 ml of a 10% aqueous solution of acid

  7-amino-1,3-naphthalene disulfonic acid (yield of

65%.

  We have established, according to a

  three concentrations above and three concentrations below the concentration for which, in vitro, the mesenteric artery of rats is observed to have a half-inhibition of vasoconstriction.

induced by norepinephrine.

  The results are given as the average of

  three picomole trials of cyclic AMP produced by half

  nute and per milligram of membrane phospholipids.

  It is found that indapamide and THPT are subject to

  This test inhibits the activation of adenylate cyclase

  Isoproterenol or sodium fluoride: the amount of AM Pc produced decreases The nature of the effect observed on the production of AM Pc depends on the concentration of the compound used. each compound producing an inhibition of 25% (CA 25) and 50% (CA 50) then that of their mixtures at these concentrations: Indapamide (MW = 365.89): CA 25 = 9 × 10 -5 mol / l CA 50 = 3 × 10 mol / 1 THPT, HCl (MW = 331.90): CA 25 = 1.2 × 10 -5 mol / l CA 50 = 7 × 10 -5 mol / l The following table was collected the inhibition percentages obtained with each of the 4 mixtures of the two compounds at these concentrations:

BOARD

Indapamide 25% Indapamide 50%

THPT 25% 45% 62%

THPT 50% 62% 75%

  It is found that the inhibition obtained with the mixture of the two compounds is clearly greater than that obtained with each separately. For example, with a mixture at concentrations of 9 × 10 -5 mol / l of indapamide and 1.2 × 10-5 mol / l of THPT gives 45% inhibition, which is only reached with 2.5 × 10 -4 mol / l of indapamide or with 5 × 10 -5 mol / l of THPT, that is, approximately 3 to 4 times the necessary amount of each of the compounds taken separately. The two effects corresponding to 25% inhibition multiply in terms of the overall effect and result in a 45% inhibition of

the activity of the enzyme.

Discussion:

  THPT is known as a beta-blocker, its activity

  Inhibitory activity on adenyl cyclase associated with an extracellular beta receptor was predictable by

  however, it was unexpected that an antihypertensive diuretic

  tensor such as indapamide has a similar activity

  and especially that the activity of these two compounds is conjugate: indeed, the dose / activity curve of these compounds and in particular their CA 25 and CA 50 show

  that they act synergistically multiplier.

  AM Pc is a second intracellular messenger triggering the start of cellular functions By inhibiting adenyl cyclase, it slows down all states of hyperactivity as they exist in hyperthyroidism, hypertension, hypersensitivity, etc. Consequently, the combination of the two compounds acting in synergy according to the invention is particularly indicated for the treatment of beta-dependent hyper-activities such as are found in hypertension, in particular in the case of hypertension. renal hypertension, or in hyperthyroidism. The pharmaceutical compositions according to the invention are preferably administered orally, and may be in the form of tablets, tablets or tablets.

  coatings, gelules, suspensions, etc. They may

  in particular from 0.8 to 3 mg of indapamide, and from 3 to

  12 mg of THPT or a pharmaceutically acceptable salt thereof

  acceptable excipients or vehicles for the oral form, and may be

  administered in one or two daily doses.

EXAMPLE: TABLET 90 mg.

Indapamide 1.25 mg

  8- (3-tert-butylamino-2-hydroxypropoxy) hydrochloride

  thiachromanne 5.00 mg Stearic acid 0.90 mg Carboxymethyl Sodium Starch 3.00 mg Microcrystalline Cellulose 33.38 mg Lactose 35.75 mg Calcium Hydrogen Phosphate 10.00 mg Colloidal Silica 0.27 mg Magnesium Stearate 0.45 mg

This tablet can be coated.

7-

Claims (3)

  1 Pharmaceutical composition containing an associa-   indapamide and 8- (3-tert-butylamino-2-hydroxy-   propoxy) -thiachromanne or a phar-   maceutically acceptable, each of these two compounds   may be in a racemic form or an isomer   tick, as well as an excipient or therapeutic vehicle compatible.   Pharmaceutical composition according to Claim 1, characterized in that it contains from 0.8 to 3   mg of indapamide and 3 to 12 mg of: 8- (3-tert-butyl)   2-hydroxypropoxy) -thiachromanene or an addition salt thereof.   3 Pharmaceutical composition for administration   oral administration according to claim 2, which is   preserved by the fact that it contains 1.25 mg of indapamide   and 5 mg of 8- (3-tert-butylamino-2-hydroxyhydrochloride) propoxy) -thiachromanne.