LU86290A1 - PHARMACEUTICAL COMPOSITIONS BASED ON 3-AMINOPROPOXYINDOLES - Google Patents

Description

- 1 - fc *

The present invention relates to pharmaceutical compositions based on 3-aminopropoxyindoles.

The invention relates in particular to pharmaceutical compositions containing the compounds of formula I

r 0CH2CHCH2NH-C (CH,), I 3 (I)

(© CX

H ^ in which R represents hydrogen or a benzoyl group, in the form of the base or in the form of a macharically acceptable phar-15 acid addition salt.

R preferably represents a benzoyl group; the corresponding compound of formula I is known by the common name of bopindolol.

The compounds of formula I and their salts are powerful agents for blocking β-adrenergic receptors. They are described for example in Belgian patent n ° 734,126 and German patent application n ° 2635209.

It is known that agents for blocking β-adrenergic receptors can be used for example for the prophylaxis and treatment of cardiovascular disorders such as hypertension, arrhythmia and angina pectoris. Such agents are generally administered, for example orally, several times a day due to their limited duration of action. Thus, pro-pranolol is normally administered orally at a daily dose of between about 80 and about 480 mg divided into two doses during the day when it comes to the treatment of hypertension, and has a daily dose between about 10 and about 160 mg divided into three or four doses during the day when it comes to the treatment of angina pectoris. As for the other 35 indications such as arrhythmia, migraine, etc., the drug is normally administered orally several times a day (see Modem Drug Encyclopedia and Therapeutic Index, AJ Lewis, Ed. Yorke Medical Books, 1981, page 824). For pindolol, the daily oral dose can be between 5 and 15 mg in the form of a single dose, or between 20 and 30 mg administered in a single dose or in two or three doses when it is 'acts of the treatment of hypertension; for other indications, the daily dose is generally between 10 and: 30 mg administered in two or three individual doses or in a single dose in a prolonged release form (see Sandoz Index 1984-1986, p. 149).

Likewise, it is known from Belgian Patent No. 734,126 that the compound of formula I in which R represents hydrogen, can be administered at a daily dose of between approximately 0.5 and approximately 50 mg. This patent gives an example of a tablet containing 5 mg of active substance.

The Applicant has now found, quite surprisingly, that the compounds of formula I in the base form or in the form of a pharmaceutically acceptable salt can be administered at intervals greater than 24 hours, for example every two days or well once or twice a week, even when not in an extended release form.

The exceptionally long duration of activity of the compounds of formula I was demonstrated, for example, in the following clinical trial:

For this trial, eight male patients with previously untreated high blood pressure were selected who had a diastolic blood pressure (PAD) between 95 and 125 mm Hg and a systolic blood pressure (PAS) such as blood pressure mean (MAP) is greater than 117 mm Hg for an age between 30 and 39 years and greater than 127 mm Hg for an age between 40 and 65 years. The average age was 54 years (age group 35-63 years) and the average weight was 87 kg (weight range 67.1-114 kg). The trial was carried out as part of a long-term study of bopindolol, comparing double-blind for 6 weeks 1 mg bopindolol administered once daily and 8 mg administered once per week. Blood pressure (PAS and PAD) and heart rate (HR) were measured after 10 minutes of rest in the supine position and 2 minutes in the upright position. The preparations to be tested were taken in the morning for three-week periods in the form of capsules containing either 1 mg of bopindolol to be taken daily, or 8 mg of bopindolol to be taken at the start of the week, followed by placebo capsules. The means + ESM 10 (standard error of the mean) were calculated according to conventional methods. The statistical meanings of the differences between the values obtained under treatment and those obtained under placebo were calculated by analysis of variance followed by the Student's t-test. The differences were considered significant when p was less than 0.05.

When comparing blood pressure and heart rate in a seated position measured after administration of different doses, it can be seen (see table on the next page) that during treatment with bopindolol 8 mg 20 administered once a week blood pressure was maintained at a satisfactory profile compared to the results obtained by administering 1 mg bopindolol daily. At the end of the three treatments, the blood pressure was 146 * 5/97 ^ 4, 141 * 6/90 * 5 and 143Î7 / 96 + 5 mm Hg when bopindolol was administered at a dose of 8 mg at start of each week. The corresponding values of blood pressure were 139/97/4, 142 ± 6/95 + 5 and 143Î4 / 92 + 4 mm Hg when bopindolol was administered at a daily dose of 1 mg. No significant difference was noted in terms of heart rate (see table 30).

"- 4 - TABLE 1". : »Per day • | ggf * TABLE * ----- * per week i 7 ° · .4— w 50 J *

O

u_ 10,160 *; ^ ^ £ £ 120 - * “» ·> <> Η> Ι ~ φ) = Η 80 * 11 t I ...

^ 2 4 7 ^ 24 7 ^ 24 7 day week "* week 2 week 3 20 Blood pressure (BP) and heart rate (HR) while seated during treatment with bopindolol 1 mg once weekly or of 8 mg once a week (taking the tablets is indicated by arrows) The values indicated are the mean tESM of PAD, PAS and FC (n - 8).

"- 5 -

Few side effects were observed and they were all well tolerated. The frequency of side effects was not different during placebo treatment.

The comparison of the results obtained with a single daily intake and a single weekly intake shows that a single weekly intake, which is well tolerated and which does not undesirably reduce the heart rate and the blood pressure during the peak effect, allows regulation of blood pressure.

10 This exceptional and unexpected tolerance makes it possible to administer the entire weekly dose in a single dose or in two semi-weekly doses. In addition, overdose by incorrect administration at short intervals is unlikely.

It is therefore possible to administer a compound of formula I 15 at intervals greater than 24 hours, for example every other day or once or twice a week.

This is quite surprising. Indeed, blockers of fi-adrenergic receptors such as propranolol or timolol generally only act for a few hours and must therefore be administered at least once or twice a day or be put into a release form. prolonged. However, sustained release forms can only prolong the effect of the drug up to a certain limit, generally up to 24 hours, since they are only effective at best for the time necessary for formulation to get into the gastrointestinal tract. In addition, these sustained-release forms are expensive and difficult to prepare, and it is not easy to achieve constant plasma levels.

It is only recently that Ton has developed agents for blocking β-adrenergic receptors such as nadolol, having intrinsic activity extending over more than about 24 hours. Those in the field do not seem to have considered at all the possibility of using an antihypertensive agent having an activity extending over a long period in a form allowing its administration at even less frequent intervals, that is to say - say once or twice a week.

V, - 6 -

What has been mentioned above obviously has far-reaching implications. Thus, for example, for young subjects suffering from mild hypertension and having to undergo treatment for life, therapeutic adherence can be improved considerably with weekly treatment compared to daily treatment. In addition, it is not necessary to use an extended-release form, which decreases the influence from one patient to another, for example linked to a diet or to gastrointestinal function, on the pharmacokinetic properties. 10 of the formulation.

The present invention therefore relates to pharmaceutical compositions suitable for administration at intervals greater than 24 hours in the treatment of cardiovascular disorders, and which comprise a compound of formula I as defined above, in the form of the base or in the form of a pharmaceutically acceptable salt. These compositions will be designated hereinafter the "compositions of the invention".

The compositions of the invention allow a new approach to the prophylaxis and therapy of disorders usually treated with agents blocking β-adrenergic receptors, in particular cardiovascular disorders such as hypertension.

For the above-mentioned use, the total weekly dose will be between approximately 4 and approximately 32 mg, conveniently in divided doses 1 to 4 times per week in the form of unit doses suitable for oral or non-oral administration. containing from about 1 to about 32 mg of active substance in association with a solid or liquid pharmaceutical carrier or diluent, or in a sustained release form if it is desired to further extend the duration of drug activity. A weekly dose is for example between about 4 and about 10 mg, in particular between about 4 and about 8 mg. For bi-weekly administration, the doses mentioned above are reduced by half; the total bi-weekly dose * - 7 - will therefore be between approximately 2 and approximately 16 mg, preferably between approximately 2 and 5 mg, in particular between approximately 2 and approximately 4 mg.

The preferred compound of formula I is that in which R 5 represents a benzoyl group.

The compositions of the invention may contain the compounds of formula I in the form of the base or in the form of a pharmaceutically acceptable salt, preferably in the form of an acid addition salt, for example in the form of hydrogenomalonate, mixed with a pharmaceutical carrier or diluent. These salts have the same order of activity as the bases and can be easily prepared according to conventional methods.

The compositions of the invention may be presented, for example, in the form of a capsule, a transdermal system or a tablet. The preferred compositions are those intended for oral or transdermal administration.

The invention also relates to the use of a unit dose suitable for administration at intervals greater than 24 hours in the prophylaxis and treatment of disorders generally treated with receptor blocking agents (3-adrenergics, in particular cardiovascular disorders such as hypertension, comprising between approximately 1 and approximately 32 mg of a compound of formula I.

What has been mentioned previously further indicates that the compounds of formula I are perfectly suitable for use in combination with long acting diuretics. However, you cannot use just any diuretic. It goes without saying that the latter will preferably be a relatively long-acting diuretic. Several known diuretics, such as hydrochlorothiazide, chlorthalidone, meto] azone, amiloride, indapamide, etc. have a duration of action greater than 6 hours. It has, however, been found that two diuretics with a particularly long duration of action, namely chlorthalidone and indapamide, are particularly suitable for use in combination with a compound of formula I.

The invention therefore also relates to a pharmaceutical composition comprising a compound of formula I as defined above, in the form of the base or in the form of a pharmaceutically acceptable acid addition salt, and chlorthalidone or 5 11indapamide. These compositions will hereinafter be referred to as "combinations of the invention".

Chlorthalidone and indapamide are perfectly suitable for use in combination with a compound of formula I in the treatment of hypertension. The onset of action is slow enough to avoid acute diuresis during the first two hours after administration, but the duration of action, which is relatively long for a diuretic, is nevertheless short enough to avoid diuresis during night.

The two active ingredients are preferably used in the form of a fixed combination. Here too, the compatibility of the active ingredients is surprisingly good. In fact, the development of a fixed suit is never a trivial matter, particularly when it comes to treating hypertension which, by its very nature, affects a large, very heterogeneous population of patients. In fact, these patients metabolize the active ingredients at a variable speed, which results in a continuous variation in the proportion of the constituents. It follows that the intensity of the therapeutic activity also varies continuously, and it is therefore important to choose constituents with compatible pharmacodynamic profiles with regard to criteria such as the effect of first hepatic passage , etc.

Bopindolol is preferably used as the β-blocker. As a diuretic, chlorthalidone is preferably used. The composition containing the two active ingredients can be administered, for example once a day, or at longer intervals, for example every other day or once or twice a week, preferably once a day. .

- 9 -

The compounds of formula I can be present in the combination in the form of the base or in the form of salt, for example in the form of hydrochloride, fumarate, hydrogen malonate, etc., preferably in the form of hydrogen malonate.

5 Few side effects have been observed with this combination when used in the treatment of hypertension. No orthostatic hypotension has been observed and the symptoms usually associated with the treatment of hypertension such as dizziness, headache, ringing in the ears, general tiredness, etc., are minimal. Surprisingly, the duration of antihypertensive activity is long.

Although it is known that β-adrenergic blocking agents reduce blood pressure in subjects suffering from hypertension, the combinations of the invention could not have been expected to have such favorable activity.

The invention also relates to a pharmaceutical composition containing a combination of the invention, suitable for enteral or parenteral administration, for example in the form of tablets, dragees, etc., preferably in the form of tablets. To prepare these compositions, the combination is worked with conventional organic or inorganic adjuvants pharmacologically inert such as lactose, starch, polyvinyl-pyrrolidone, stearic acid, sorbic acid, talc, methylcellulose, alcohols, glycerin, etc. The compositions may further contain suitable sweeteners, colors, flavoring agents, etc.

For the aforementioned use in combination with chlorthalidone or Vindapamide, the exact dose will obviously depend on the compound used, the mode of administration and the treatment desired. However, satisfactory results are generally obtained when the β-adrenergic blocking agent is administered at a dose corresponding to a daily dose of approximately 0.1 to approximately 2 mg, preferably approximately 0.5 to About 1 mq, in combination with a dose corresponding to the diuretic to a daily dose of about 1 to about 50 mg; for chlorthalidone, the daily dose will preferably be between approximately 2.5 and approximately 50 mg, more particularly between approximately 10 and approximately 50 mg, more particularly between approximately 12.5 and approximately 25 mg; for 11 Indapamide, the daily dose will preferably be between approximately 1 and approximately 5 mg, more particularly between approximately 1 and approximately 2 mg.

These compositions will preferably be administered in the morning.

10 The two active ingredients are therefore normally present in a β-adrenergic / diuretic blocking weight ratio of between approximately 1: 500 and approximately 2: 1, preferably between approximately 1: 100 and approximately 1: 1, more specifically, for chlorthalidone , preferably between about 1: 500 and about 1: 1.25, more particularly between about 1: 500 and about 1: 5, more especially between about 1: 250 and about 1: 6.25, especially about 1:20; for indapamide, this ratio will preferably be between approximately 1:50 and approximately 2: 1, more particularly between 1:20 and approximately 2: 1, more particularly approximately 1: 2.

The following examples illustrate the present invention without in any way limiting its scope.

A) Administration of a single active ingredient once or twice a week in cardiovascular therapy Example 1: Composition suitable for weekly administration in cardiovascular therapy

Hard gelatin capsule containing: mg

Bopindolol (hydrogen malalonate) 10.184 30 (= 8 mg base)

Lactose 191,066

Corn starch 140.0

Silica (Aerosi r ^ OO, Degussa) 1.75

Stearic acid 7.0 35 _ 350.0 - 11 -

Example 2 Composition suitable for weekly administration in cardiovascular therapy

Tablet containing: mg 5

Bopindolol (hydrogen malalonate) 12.73 (= 10 mg base)

Lactose 91.55

Corn starch 12.8 10 Hydroxypropyl methylcellulose 6.5 (Pharmacoat 603®, Shinetsu)

Red iron oxide 0.055

Malonic acid 0.21

Hydrogenated castor oil (Cutina HR®) 1.95 15 Carboxymethyl starch sodium 4.2 (Primojel®) _

Tablet diameter: 9 mm 130.0 - 12 -

Examples 3 and 4: Compositions suitable for administration once or twice a week in therapy 5 Tablet containing: Example 3 Example 4 (1 time (2 times a week) week) (mg) (mg) 10 Bopindolol (hydrogenenomalonate) 10.184 5.092 (= 10 or 5 mg base)

Lactose 166.29 147.306

Corn starch 22.0 19.0

Hydroxypropylmethylcellulose 11.0 9.5 15 (Pharmacoat 603®, Shinetsu)

Red iron oxide 0.0906 0.08

Malonic acid 0.0254 0.022

Hydrogenated Castor Oil 3.3 2.85 (Cutina HR®) 20 Sodium Carboxymethyl Starch 7.11 6.15 (Primojel®)

Total 220 190 25 Tablet diameter: 9 mm 8 mm - 13 -

EXAMPLES 5 TO 8: C ° position _ suitable__ for administration in cardiovascular therapy

Hard gelatin capsule containing: 5 the ingredients mentioned in examples 1 to 4 respectively, except that the bopindolol is replaced by an equivalent molar amount of 4- (3-tert-butylami no-2-hydroxypropoxy) -2-methyli ndole ( compound of formula I in which R represents hydrogen) in the form of hydrogenenomalonate.

B) Administration of a combination of two active ingredients Examples 9 and 10: Çompositions_pour_Vadministrâtion_par ^ une_fois_par_jour in the treatment of hypertension

Tablet containing: Example 9 Example 10 (rng) (mg) 20 Lactose (200 mesh) 130.61 118.11

Hydroxypropylmethylcellulose 9.00 9.00

Corn starch 18.00 18.00

Bopindolol (hydrogenomalonate) 1.273 1.273 - (= 1 mg base) 25 Chlorthalidone (base) 12.50 25.0

Red iron oxide 0.076 0.076

Malonic acid 0.021 0.021

2.70 hydrogenated castor oil. 2.70 (Cutina H F®) 30 Sodium carboxymethyl starch 5.82 5.82

Total 180.00 180.00

Tablet diameter: 8 mm s - 14 -

Example 11; Composition for administration for example once-a-day in the treatment of 11 hypertension 5 Tablet containing: mg

Lactose (200 meshes) 140.61

Hydroxypropylmethylcellulose 9.00

Corn starch 18.00 10 Bopindolol (hydrogen malalonate) 1.273 (= 1 mg base)

Indapamide (base) 2.50

Red iron oxide 0.076

Malonic acid - 0.021 15 Hydrogenated castor oil (Cutina HFT ^) 2.70

Sodium carboxymethyl starch 5.82

Total 180.00 20 Tablet diameter: 8 mm

Examples 12, 13 and 14: stration by 2 * 2 ™ 2] 2_222_i2i2-22L: i22r_i !! 2Ds the “treatment of hypertension 25

L

Tablet containing: the ingredients mentioned in Examples 9, 10 and 11 respectively, except that the bopindolol is replaced by an equivalent amount of 30 molar of 4- (3-tert-butylamino-2-hydroxypropoxy) -2-methyl-indole in the form of hydrogenomalonate (i.e. in an amount corresponding to 0.76 mg base).

Claims (12)

1. A pharmaceutical composition suitable for administration at intervals greater than 24 hours in the treatment of cardiovascular disorders and comprising a compound of formula I OR 0CH2CHCH2NH-C (CH3) 3 ^ ecx N ^ CH, H 3 in which R signifies hydrogen or a benzoyl group, in the form of the base or in the form of a pharmaceutically acceptable acid addition salt, in association with a pharmaceutical diluent or vehicle. 2. A composition according to claim 1 for the prophylaxis or treatment of disorders usually treated with blockers of β-adrenergic receptors. 3. A composition according to claim 1, in the form of a single dose comprising from 1 to 32 mg of a compound of formula I as defined in claim 1, in the form of the base or in the form of a pharmaceutically acceptable acid addition salt. 4. A composition according to claim 1, comprising the compound of formula I in which R signifies a benzoyl group. 5. A composition according to claim 1, for administration once every two days or once or twice a week. 6, - A unit dose suitable for administration at intervals greater than 24 hours in the treatment of cardiovascular disorders and containing, per unit dose, from 1 to 32 mg of a compound of formula I such as defined in claim 1, in base form or in the form of a pharmaceutically acceptable acid addition salt, in combination with a pharmaceutical carrier or diluent. 7. A pharmaceutical composition comprising: a) a P> -adrenergic receptor blocking agent of formula I specified in claim 1, in the form of a base or in the form of a pharmaceutically acceptable acid addition salt, and b) a diuretic chosen from chlorthalidone and indapamide. 8. A composition according to claim 7, comprising bopindolol as a blocking agent for β-adrenergic receptors. 9. A composition according to claim 7 or 8 comprising chlorthalidone as a diuretic, 10. A composition according to claim 7 or 8 comprising indapamide as a diuretic. 11. A composition according to claim 7, comprising from 0.1 mg to 2 mg of component a) and from 1 mg to 50 mg of component b). 12. A composition according to claim 7, £ characterized in that the weight ratio of component a) to. component b) is between approximately 1: 500 and approximately 2: 1. 13. A composition according to claim 9, characterized in that the weight ratio of component a) to chlorthalidone is between approximately 1: 500 and approximately 1: 1.25. 14, - A composition according to claim 10, J - 17 - 4 * characterized in that the weight ratio of component a) to indapamide is between about 1:50 and about 2: 1. 15.- A composition according to any one of claims 7 to 14, characterized in that it is in the form of a fixed composition. 15.- Products and processes in substance as above described with reference to the examples cited.