JPH0250084B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a pharmaceutical composition for the treatment of β-dependent hyperactive states containing a combination of two active substances, indapamide and 8-(3-tert.-butylamino-2-hydroxypropoxy)-thiachroman. Indapamide, alternatively N-(3-sulfamoyl-4-chlorobenzamide)-2-methylindoline, alternatively 4-chloro-N-(2-
Methyl-1-indolinyl)-3-sulfamoylbenzamide is described in Example 1 of French Patent No. 69.06023 (published as No. 2003311) as a diuretic that can be used in particular for the treatment of arterial hypertension. 8-(3-tert.-butylamino-2-hydroxypropoxy)-thiachroman (or its acid addition salt) is disclosed in French Patent No. 71.11445 (No.
2092004) is described in Example 2,
Shows cardiovascular properties, especially β-blocking properties. However, it has now been found that the two above compounds, when in combination, have unexpected synergistic properties that allow their simultaneous therapeutic use. Therefore, the present invention provides indapamide and 8-
(3-tert.-butylamino-2-hydroxypropoxy)-thiachroman, or a combination of one of its pharmaceutically acceptable addition salts, and also a therapeutically compatible excipient or carrier. Regarding the composition, each of the two compounds can be in racemic or optical isomeric form. For convenience, 8-(3-tert.-butylamino-2-
Hydroxypropoxy)-thiachroman is hereinafter referred to as "THPT". Pharmacological Studies The compounds studied according to the invention were tested alone and in combination for functional inhibition of membrane adenylate cyclase. Pigeon red blood cells are prepared by SUTHERLAND et al. [adenyl, cyclase 1. destruction, preparation,
and, properties (Adenyl cyclase 1.
distribution, preparation and properties),
The Journal of Biological Chemistry (J.Biol.Chem.), (1962) 237:1220
~1227)], their significant adenylate cyclase activity is known. The experiment was carried out using the method of SALESSE R. and GARNIER J.
Drugs, On, Pidgeon, Erythrocyte, Membrane, And, Asymmetric, Control, Of, Adenylate, Cyclase, By, The, Lipid, Bilayer” (“Effects of
drugs on pigeon erythrocyte membrane and
asymmetric control of adenylate cyclase by
the lipid bilayer”), Biochem.Biophys.Acta,
(1979), 554:102-103) on red blood cell ghosts (open cells) prepared from the blood of Strasser pigeons. The resulting suspension was incubated with 1 volume of test product in a hypotonic buffer at the desired final concentration for 20 minutes. Adenylate cyclase activity was determined by Birnbaumer
L.) et al. [J.Biol.Chem. (1969) 244:3468-3476],
and RAMACHANDRAN
J.); Lee (LEE V.) [Biochemical, &
Biophysics, Research, and Communication (Biochem.Biophys.Res.Commun.) (1970)
41:358-366]. The concentration of the reagent has [a _- ³² ]P ATP 1μCi
ATP 2mM, theophylline 4mM, phosphocreatine 10mM, creatine kinase 0.5g/l,
Mgcl ₂ 7.5mM, Tromethamine HCl [“TRIS” HCl]
It was 10mM and PH=7.4. The total capacity is 75 microliters and 1
The number of cells per tube was approximately ¹⁰⁸ . The production of cyclic AMP (cAMP) is
Isoproterenol in the presence of GTP 0.1mM
Stimulation was performed either with 0.05 m or with 10 mM sodium fluoride. Compounds were added to the required finality. The reaction was stopped after 15 minutes at 37°C by adding 300 microliters of 0.5N hydrochloric acid and placing the mixture on a boiling water bath for 3 minutes. Remove the tube from the water bath and empty the contents.
Neutralized with 300 microliters of 1.65N imidazole. After centrifugation (10 min, 4000 g), supernatant 500 g
Inject the microliters onto a neutral activated alumina column and add 2.6 ml of imidazole (10 mM,
It was eluted at pH=7.5). The columns had a cAMP yield of 95%. The radioactivity of the sample was measured using a scintillation counter “Packard, Tricarb”.
After adding 10 ml of a 1% aqueous solution of 7-amino-1,3-naphthalenedisulfonic acid to the eluate, measurements were made using the Cerenkov effect (counting yield 65%). Logarithm According to the scale, three concentrations above and below the concentration at which half inhibition of norepinephrine-induced vasoconstriction can be observed in rat mesenteric arteries in vitro were determined. is expressed in picomole of cyclic AMP induced per minute and per mg of membrane phospholipid.
It can be seen that THPT inhibits the activation of adenylate cyclase stimulated by isoproterenol or sodium fluoride:
be guided. The amount of cAMP decreases. be observed
The nature of the effect on cAMP production depends on the concentration of the compound used. 25% (AC ₂₅ ) and
The active concentration of each compound leading to 50% (AC ₅₀ ) inhibition was determined graphically and then that of their mixture at those concentrations: Indapamide (molecular weight = 365.89): AC ₂₅ = 9 x 10 ^-5 mole /: AC ₅₀ = 3 × 10 ^-4 mole / THPT HC (molecular weight = 331.90): AC ₂₅ = 1.2 × 10 ^-5 mole / AC ₅₀ = 7 × 10 ^-5 mole / The following table shows the two compounds at these concentrations. 4
The percent inhibition obtained with each of the species mixtures is shown.

[Table] It can be seen that the inhibition obtained with the mixture of the two compounds is clearly superior to the inhibition obtained with each compound separately. For example, indapamide 9×10 ^-5 mole/and THPT1.2×
45% inhibition was obtained with the mixture at a concentration of 10 ^-5 mole/indapamide, which was 2.5 x 10 ^-4 mole/
, or THPT 5 x 10 ^-5 mole/, ie the required amount of each of the compounds when taken separately is about 3 to 4 times larger. The two effects corresponding to 25% inhibition are therefore multiplied into their total effect and result in a 45% inhibition of the activity of the enzyme. Discussion Since THPT is known as a β-blocker,
Its inhibitory activity against adenyl cyclase in combination with extracellular β-receptors is predictable. On the contrary, it would not be expected that antihypertensive diuretics such as indapamide would have similar activities and above all that the activities of the two compounds would be combined; in fact, the dose/activity curves of those compounds , and especially those AC ₂₅ and
AC ₅₀ indicates that it operates in multiplication and reduplication. cAMP is the second intracellular messenger that triggers the initiation of cellular functions. By inhibiting adenyl cyclase, all conditions of cellular hyperactivity, such as those present in thyroid hyperactivity, hypertension, irritability, etc., are reduced. the result,
The combination of two compounds acting in synergy according to the invention is useful in hypertension, especially in cases of severe arterial hypertension together with renal failure, or in disorders such as thyroid hyperactivity. It is especially prescribed for the treatment of hyperactive states of dependence. Pharmaceutical compositions according to the invention are preferably administered by the oral route and may be in the form of tablets, coated tablets, capsules, suspensions and the like.
They are, in particular, from 0.8 to 3 mg of indapamide;
and 3 to 12 mg of THPT or one of its pharmaceutically acceptable addition salts, and may also contain conventional excipients or carriers in oral forms, and they may be administered once or twice daily. . Example 90 mg tablet Indapamide 1.25 mg 8-(3-tert.-butylamino-2-hydroxypropoxy)-thiachroman hydrochloride 5.00 mg Stearic acid 0.90 mg Sodium carboxymethyl starch 3.00 mg Microcrystalline cellulose 33.38 mg Lactose 35.75 mg Calcium hydrogen phosphate 10.00mg Colloidal Silica 0.27mg Magnesium Stearate 0.45mg This tablet may be coated.

Claims (1)

Claims: 1. Indapamide and 8-(3-tert.-butylamino-2-hydroxypropoxy), each of which can be in racemic or optical isomeric form. ) - A pharmaceutical composition for the treatment of β-dependent hyperactive conditions containing a combination of thiachroman, or a pharmaceutically acceptable acid addition salt thereof, and also a therapeutically compatible excipient or carrier. 2 Interpamide 0.8 to 3 mg, and 8-
Pharmaceutical composition according to claim 1, characterized in that it contains from 3 to 12 mg of (3-tert.-butylamino-2-hydroxypropoxy)thiachroman or one of its acid addition salts. 3 Indapamide 1.25 mg and 8-(3-tert.-
Pharmaceutical composition intended for administration by the oral route according to claim 2, characterized in that it contains 5 mg of butylamino-2-hydroxypropoxy)-thiachroman hydrochloride.