JPS5927813A - Medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention utilizes two active substances, indapamide (indapamide);
mi+ie) and 8-(3-tert,-butylamino-2-hydroxypropoxy)-thiacro.

PHARMACEUTICAL COMPOSITIONS CONTAINING A COMBINATION OF MAN.

Indapamide, or N-(6-sulfamoyl-4
-chlorobenzamide)-2-methylindoline, or alternatively 4-chloroμmN-(2-methyl-1-indolinyl)=3-sulfamoylbenzamide, is disclosed in the French Patent No. No. 69.06023 (published as No. 2.003,311), Example 1.

8 (3-tert,-butylamino-2-hydroxypropoxy)-thiachroman (or its acid addition salt)
is French Patent No. 71.11445 (No. 2,092
9 and exhibits cardiovascular properties, particularly β-blocking properties.

However, it has now been found that the two above-mentioned compounds, when in combination, have unexpected complementary properties that allow their simultaneous therapeutic use. (3-te
rt, -ditylamino-2-hydroquine propoxy)-
With respect to pharmaceutical compositions containing a combination of theachroman, or a pharmaceutically acceptable salt thereof, and also a therapeutically compatible excipient or carrier, each of the two compounds may be in racemic or optical form. It is possible to be in isomeric form.

For convenience, 3-(3-tert,-butylamino-2-
Hydroxypropoxy)-thiachromanwo, hereinafter referred to as "T"
HPT”.

Pharmacological Studies The compounds studied according to the invention were tested alone and in combination for functional inhibition of membrane adenylate 2-ase.

Pigeon red blood cells are sub-2nd (SUTHFiRLAN)
D) etc. [adenyl, cyclase 1. Destribution, Preparation Simin, And, Floparties (A
denyl cyclase 1. Distribution
ion.

preparation ancl property
es), Zu, Journal, Op, Zu, BioNissical, Kumist v-(,T,Biol, Chern, )
, (1962) 237: 1220-1227)), the 7-denylate cyclase activity of these Kana p is known. The experiment was carried out using Salles (5ALESSf).
iR, ) and Garnier (,GARN KRJ,
) Method [6 Effects, Of, Drugs, On, Vision, Erythrocyte, Menplan, And, Asymmetry, Control, Of, Adenylate, Cyclase, Pi, Zu, Lipid, Pilayer” (“E
ffec,ta ofdrugs on pigeon
erythrocyte membrane and
asymmetric control-of-ade
nylate cyclase by the 1ipi
d bilayer”), Biochem, Eiophys,
Acta (1979), 554:102-103)
Ghosts of red blood cells (open cell) prepared from blood of Strasser pigeons according to
cell)].

The resulting suspension was mixed with one portion of the test product in a hypotonic buffer.
volume and the desired final concentration for 2°. Adenylate cyclase activity was determined by Birnbaumer et al. [J, Blo.
l, chem, (1969) 244:246El? ~6
476], and Ramachandran (RAMAOHAN)
DRAN J, ) ; LEE V, ) [
Biochem, Biophysical, Research, Communication (Biochem, Bioph)
ys, Res.

C! Ommun, ) (1970) 41:358-666
``The decision was made in accordance with J.

The concentration of the reagent is (a ”2.l P ATP iμo
A T P 2 mM with i, theophylline 4m
M,, Phosphocreatine 1QmM, RiL'7f7 key)
--ze0. ! M/l.

MgO427,5mM, ) 0 Metamine HO4[
'TR Engineering S' HO7) 1Q mM, pH=7.
It was 4.

The total capacity is 75 microliters, and one tube is 9
The number of cells was approximately 108.

Generation of cyclic AMP (cAMP)
Q, i isoproterenol in the presence of 0.0 mM
Stimulation was performed with either 5mM or 10mM thorium fluoride. Compounds were added to the required final concentration.

The reaction was stopped after 15 minutes at 67°C by adding 600 microliters of 0.5N hydrochloric acid and placing the mixture on a boiling water bath for 6 minutes. The tube was then removed from the water bath and the contents neutralized with 300 microliters of 1.65N imidazole.

After centrifugation (10 min, 4000 g), supernatant 1y, 5
oo microliters were injected onto a neutral activated alumina column and imidazole 2.6-(10mM, p
H=7. b) was eluted. Those columns are cAMP
The yield was 95 cm.

The radioactivity of the sample was measured using a scintillation counter "Paracard" and "PackardTrick".
After adding 1% aqueous solution 10 of 7-amino-1,6-naphthalenedisulfonic acid to the eluate, measurement was performed using the selencon effect (Oθrθnkovθeffect) (counting yield 65%).

According to a logarithmic scale, in vitro, a half-inhibition of norepinephrine-induced vasoconstriction can be observed in rat mesenteric arteries above 38 degrees and below 6 degrees.
The concentration was determined.

Results are expressed as the average of 6 experiments and in picomole of cyclic AMP induced per minute and membrane phospholipid concentration.

Based on this test, it was found that indapamide and THPT inhibit the activation of adenylate cyclase stimulated by isoproterenol or thorium fluoride: the amount of cAMI' induced decreases. The nature of the observed effect on cAMP production is
It depends on the af of the compound used. 25chi (A"r5
) and 50% (AC30) inhibition of each compound leading to inhibition was determined graphically and then that of their mixture at those concentrations: indapamide (molecular weight =
365.89): AC2, = 9 X Io' mo1e/tA 0
5o= 3 X IQ' mole/ LTHPT
mat (molecular weight = 3.31.9 CJ): AC2
5= 1.2 x 10-5mo1e/AAC50=
7 X IQ-5mo:he/ The following table shows the percent inhibition obtained with each of the four mixtures of the two compounds at those concentrations.

It can be seen that the inhibition obtained with the mixture of the two compounds in Table 2 is clearly superior to the inhibition obtained with each compound separately. For example, indapamide 9 × 10”-5m
o1e 7 t and THPT 1.2 X IQ-”
45% inhibition was obtained with the mixture at a concentration of mole/l, which
mo:he /4 or THPT 5 X 10-
This is achieved only by δmol'lθ/l, ie the required amount of each of the compounds when taken separately is about 6 to 4 times higher. Two effects corresponding to 25% inhibition are therefore multiplied by 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 in particular their AC2, and AC5° indicate that multiplication acts on the additive sum.

cAMP is the second intracellular messenger that triggers the initiation of cellular function. By inhibiting adenyl cyclase, all cellular activity conditions, such as those present in thyroid activity, hypertension, irritability, etc., are reduced. As a result, a combination of two compounds acting in synergy according to the invention may be encountered in hypertension, especially in cases of severe arterial hypertension together with renal failure, or in disorders such as thyroid dysfunction. It is particularly prescribed for the treatment of more β-dependent hyperactive conditions.

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 may contain, in particular, from 0.8 to 6 q of indapamide and from 6 to 12 q of THPT or one of its pharmaceutically acceptable salts, and also the usual excipients or carriers in oral form; and those li 1 or 2 a day
Example 90 - Tablet Indapamide 1.25 Stearic acid 0.90 Sodium carboxymethyl starch 3.00
~Microcrystalline cellulose 33.38
~Lactose 35.75
Calcium hydrogen quinate 1o, o
o Cutucolloid silica 0.27
■Magnesium stearate 0.45q
The tablet may be coated.

Agent Asamura Hao

Claims (2)

[Claims] (1) Indapamide and 8-(3-tert,-butylamino-2-hydroxypropoxy)-, in which each of the following two compounds can be in the form of a di-semiconductor or an optical isomer. A pharmaceutical composition containing a combination of thiachroman, or a pharmaceutically acceptable acid addition salt thereof, and also a therapeutically compatible excipient or carrier. (2) Indapamide 0.8 to 6■, and 8
-(3-tert,-butylamino-2-hydroxypropoxy)thiachroman or one of its acid addition salts from 6 to 12 ■ Pharmaceutical composition 0 according to claim 1 ( 3) Indapamide 1.2
A pharmaceutical composition intended for administration by the oral route according to claim 2, characterized in that it contains 5WII and 8-(3-tert.-ditylamino-2-hydroxypropoxy)-thiachroman hydrochloride 5.