MC2019A1 - COMBINED ANTI-HYPERTENSIVE PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

Pharmaceutical combination preparations containing a beta -blocker of the formula <IMAGE> and a pyridazodiazepine of the formula <IMAGE> in which R, R<1>, R<2>, R<3>, R<4> and R<5> have the meaning stated in claim 1, have a pronounced lowering effect on blood pressure without increasing the heart rate and are accordingly suitable for controlling or preventing hypertension and its sequelae.

Description

10 The present invention relates to a combined pharmaceutical composition suitable for the treatment of hypertonia and which contains certain alkylamino-alkoxy-phenylic/-naphthyl or -indolylic derivatives and certain pyridazodiazepines.

15 The phenyl, naphthyl, and indolelylic derivatives in question are known beta-blockers. Among other things, they have marked antihypertensive activity and can be used to treat hypertension of all degrees of severity. 20 Similarly, the pyridazodiazepines in question are known ACE inhibitors also suitable for treating hypertension; they have a blood pressure-lowering effect without increasing heart rate (see German patent application 25 DE-OS 3 317 290).

The simultaneous application of a beta-blocker and an ACE inhibitor has already been described in the scientific literature. In Clinical Science/ 61_/ 441s-444s (1981), Amery et al. reported that in 30 patients whose high blood pressure was being treated with Captopril, the additional administration of Propranolol resulted in a further reduction in blood pressure. However, this observation could not be subsequently confirmed. For example, in Journal of Cardiovascular Pharmacology/ 1, pages 35

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82-87 (1985) MacGregor et al. report that in their studies, the additional administration of Propranolol to patients treated with Captopril for prolonged periods did not cause a further decrease in blood pressure. These authors offer as a possible explanation for the lack of a further decrease in blood pressure the fact that, probably, beta-blockers and ACE inhibitors, at least in part, have the same mechanism of action, namely the inhibition of the renin-

angiotensin, so that no additive effect can be expected from combination therapy. Since then, this opinion has been adopted by specialists [cf. Eur. J. Clin. Pharmac. 32_, 229-235 (1987)] and this is the reason why, at present, combination therapy of beta-blockers and ACE inhibitors cannot be recommended in cases of hypertonia [cf. Journal of Cardiovascular Pharmacology, 9_t Suppl. 3, 2-5 (1987)].

There is a need for a pharmna-20 ceutic combination adopted without difficulty by the greatest possible number of patients, the administration of which leads to a decrease in blood pressure without a simultaneous increase in heart rate and in which the doses of the individual components are reduced, which would allow the undesirable side effects encountered with monotherapy at the necessary doses to be avoided.

It has been observed within the framework of the present invention that, upon administration of the combination according to the invention of a beta-blocker and an ACE inhibitor, the number of patients responding to treatment

was significantly more important than in the case of monotherapies, and the hypotensive properties of the two individual components resulted not only in additive effects but, in some cases, even in potentiation, so that the active doses of the two

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Individual components can be reduced. It was also observed/which could not have been foreseen/ that there was simultaneously a considerable prolongation of the duration of action.

5. The antihypertensive combination according to the invention therefore has the following advantages:

1. The number of patients responding to treatment is significantly increased;

2. the quantities of active substances to be administered 10 are reduced;

3. Undesirable side effects are eliminated or greatly reduced;

4. The heart rate is not affected;

5. The duration of action is prolonged, and

15 6. a regular stock price is achieved.

The invention therefore relates to a new combined pharmaceutical composition for the treatment of hypertension, containing a beta-blocker of general formula

20

OH

I

ROCH2CH-CH2NHCH(CH3)2 I

25 in which R represents a phenyl group possibly substituted by lower alkenyloxy, (lower alkoxy)-lower alkyl/ (aminocarbonyl)-lower alkyl or (lower alkoxy)-(lower alkoxy)-lower alkyl groups, or a naphthyl, indolyl 30 or dihydroxytetrahydronaphthyl group,

and a pyridazodiazepine with the general formula

3

-4-

r\ /R4

• - ■ • 0

/ v,/ \

\ « i II

\# / \y

R^-ÇH-NH7 5 ÎOOR3 COOR2

in which R"'" represents an inf-2 aryl-alkyl group

rieur, R and R each represent hydrogen or a

4 5

10 lower alkyl group and R and R each represent hydrogen or together form an oxo group/ the active substances being in the state of free bases/ hydrates or salts acceptable for pharmaceutical use.

15 The term "lower" as used in this description applies to groups which contain from 1 to 4 carbon atoms.

The aryl group of a lower aryl-alkyl group is a phenyl group that can be mono- or poly-substituted with halogens (i.e., fluorine, chlorine, bromine, or iodine) and can be lower alkyl groups, lower alkoxy groups, trifluoromethyl groups, phenyl groups, and analogs. Examples of lower aryl-alkyl groups include benzyl, 4-chloroben-25, 2-phenylethyl, 3-phenylpropyl, 3-(4-chlorophenyl)propyl, 3-(4-methoxyphenyl)propyl, 4-phenylbutyl, and analogs.

The relative proportions by weight between the beta-blocker and pyridazodiazepine are advantageously from approximately 0.5:1 to 500:1, preferably from 1:1 to

50:1 and even better from 1:1 to 5:1/ for free bases, these relative proportions depending on the nature of the beta-blocker and pyridazodiazepine used.

The daily dose to be administered using the 35 combination is advantageously 5 to 320 mg for

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The beta-blocker and pyridazodiazepine doses are 1 to 5 mg. Generally, the total daily dose of beta-blocker and pyridazodiazepine is a maximum of 325 mg. When using a 5-hydrate or a salt acceptable for pharmaceutical use, these values are adjusted accordingly.

The invention therefore aims to:

- a combination of a beta-blocker of formula I and a pyridazodiazepine of formula II;

10 - a pharmaceutical composition containing a beta-blocker of formula I and a pyridazodiazepine of formula II;

- the preparation of a pharmaceutical composition which is characterized by the fact that it is put into a form

15 galenic administration a mixture of a beta-blocker of formula I and a pyridazodiazepine of formula II;

- the use of a combination of a beta-blocker of formula I and a pyridazodiazepine of formula II 20 or a pharmaceutical composition containing a beta-

formula I blocker and formula II pyridazodiazepine for the treatment or prevention of diseases, in particular circulatory diseases, and especially for the treatment and prevention of 25 hypertonia and its consequences, for example heart failure, without increasing heart rate.

Among the beta-blockers that are particularly suitable are those conforming to the formula 30 I, in which R represents an alpha-naphthyl, indole-4-yl, 2-allyloxyphenyl, 4-methoxyethylphenyl, 4-aminocarbonylmethyl, 4-isopropyloxyethyloxymethylphenyl, or 6,7-dihydroxy-5,6,7,8-tetrahydronaphtho-l-yl group. Beta-blockers with the formula I, in which R represents an alpha-naphthyl, indole-4-yl, or 2-allyloxyphenyl group,

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4-Aminocarbonylmethyl or 4-Isopropyloxyethyloxymethylphenyl are particularly suitable.

The most suitable representatives of the group of formula I beta-blockers are Propranolol and Bisoprolol.

The pyridazodiazepines that are particularly suitable are those that meet the formula II

in which R represents an inferior aryl-alkyl group

2, 3

rieur, R represents a lower alkyl group/ R

4 5

10 hydrogen and R and R represent hydrogen or together form an oxo group.

The most popular pyridazodiazepines are those that conform to formula II in which R"'"

2

represents a lower phenyl-alkyl group, R a

3 4 5

15 lower alkyl group and R/R and R hydrogen.

The most appropriate representative of the pyridazodiazepine group of formula II is 9(S)-[1-(S)-ethoxycarbonyl-3-phenylpropylamino]-octahydro-10-oxo-6H-pyridazo[1/2-a][1/2]diazepine-1(S)-carboxylic acid 20 (hereafter referred to as Cilazapril).

The most popular combination according to the invention is a combination of Cilazapril and Bisoprolol, due to the following properties which characterize the two active substances:

25 - the pharmacokinetic profile is similar/ i.e. there is high bioavailability and a long elimination period;

- there is a long duration of action (i.e., a single daily administration is sufficient);

30 - there is a high specificity of the two active substances with respect to their respective pharmacological point of attack/ and

- There is high activity of both active substances and a potency roughly equivalent to the oral dosage

35 of the free databases.

%

For these reasons, the two active substances Cilazapril and Bisoprolol are especially suitable for therapeutic use in the form of a fixed combination.

It is advantageous to use propranolol and bisoprolol as pharmaceutically acceptable salts, while cilazapril is either as a pharmaceutically acceptable salt or as a hydrate. Generally, the combination contains propranolol as hydrochloride or bisoprolol fumarate and cilazapril as monohydrate or hydrobromide. Preferably, the relative weight proportions of the beta-blocker and pyridazodiazepine are approximately 20:1 to 50:1 for the combination of propranolol and cilazapril, and approximately 1:1 to 5:1 for the combination of bisoprolol and cilazapril, both proportions being relative to the free bases.

Using the combination according to the invention and with small doses of active substances, a regular and persistent decrease in blood pressure can be achieved without an increase in heart rate, with, simultaneously, good tolerance by the patient and low toxicity for the patient.

The advantageous hypotensive activity, at least additive, of the combination according to the invention, compared to those of the two individual components, as well as the good response of patients to these combinations, were able to be demonstrated in the two experimental trials on humans described below, with a combination of Cilazapril and Propranolol, these trials having been carried out in accordance with the Declaration of Helsinki in the Venice version.

A) Six healthy male subjects, who had previously given their written consent to participate in the trials, participated in this 4-way crossover study

routes, which was carried out according to the double-blind principle and comprised the following four treatment sections, each lasting 7 days, with in all cases a break of more than 7 days between the various treatment sections:

(1) placebo plus placebo

(2) 2.5 mg Cilazapril plus placebo

(3) 120 mg Propranolol plus placebo

(4) 2.5 mg Cilazapril plus 120 mg Propranolol.

To ensure no subject experienced health problems, each patient's medical history was recorded before the start of the study, and they underwent a general examination along with the following checks: ECG (12 leads) and laboratory tests of hemoplastic, hepatic, and renal function. The most important laboratory parameters were also checked in each case at the beginning and end of the breaks between individual treatment sections and no pathological signs were revealed.

On each of trial days 0 through 6, subjects were required to fast, meaning they had not eaten, drunk, or smoked since the previous evening. After 5 minutes of seated rest, systolic and diastolic blood pressure and pulse were measured. Subjects were then allowed to eat breakfast, receive their medication under supervision with 100 ml of tap water, and were allowed to return home. On trial day 7, subjects were also required to fast; however, the examinations were performed with the subject lying down with their torso elevated at a 15° angle. After 15 minutes of rest lying down in each case, blood pressure and pulse were measured at intervals of -2, 1, 2, 6, 8, and 24 hours.

Measurements taken during the 7-day period at the minimum concentration of the preparations in the plasma did not reveal any differences.

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important differences between the various medications, whereas at

ÔÏÏÎB

On day 7, we were able to observe clearly different activities.

In the case of Propranolol monotherapy, 5 a decrease in systolic and diastolic blood pressure of approximately 7 mm Hg and a decrease in heart rate of approximately 8 beats/min were observed.

In the case of cilazapril monotherapy, systolic and diastolic blood pressure decreased almost as much as in the case of propranolol monotherapy (approximately 7 mmHg), and the heart rate increased by about 5 beats/min. In the case of combination therapy with propranolol and cilazapril, blood pressure decreased more significantly than with the individual administration of each component, and the maximum mean decrease in blood pressure was approximately 15 mmHg. Furthermore, on treatment day 7, the significant decrease in blood pressure was observed for more than 8 hours after tablet administration. As for heart rate, in the case of combination therapy, it was neither decreased nor increased.

The results obtained in the experimental trials on human subjects described above concerning blood pressure are reported in Table 25 below.

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Systolic blood pressure values in mm Hg at

"th . -, i

7-day trial

(1) placebo plus placebo subject/hr

-2

1

2

6

8

24

1

107

113

102

107

111

120

2

113

109

112

112

112

122

3

106

107

106

105

108

104

4

115

111

114

121

119

121

5

120

112

118

136

124

142

6

118

111

120

122

124

100

average value

113

111

112

117

116

118

AND*

2

1

3

5

3

6

(2) 2/5 mg of

Cilazapril plus placebo

subject/hr

-2

1

2

6

8

24

1

96

102

84

92

88

108

2

115

113

111

110

112

134

3

105

100

97

102

100

106

4

110

108

106

116

124

120

5

112

118

108

116

114

112

6

117

111

115

106

108

126

average value

109

109

104

107

108

118

AND*

3

3

5

4

5

4

(3) 120 mg of

Propranolol plus placebo

subject/hr

-2

1

2

6

8

24

1

107

104

103

104

102

116

2

119

108

113

114

112

128

3

101

110

99

96

103

112

4

113

104

106

112

114

108

5

120

111

108

122

112

112

6

103

100

108

112

104

112

average value

111

106

106

110

108

115

AND*

3

2

2

4

2

3

(4) 2/5 mg of

Cilazapril plus

120 mg of Propranolol

subject/hr

-2

1

2

6

8

24

1

105

96

82

98

102

106

2

115

112

108

108

112

122

3

100

94

97

88

100

100

4

118

110

103

102

112

132

5

116

110

109

90

80

114

6

114

124

102

108

102

122

average value

111

108

100

99

101

116

AND*

3

5

4

4

5

5

* AND = standard deviation.

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Diastolic blood pressure values in mm Hg

on the 7th day of

'essay

(1) placebo plus placebo

subject/hr

-2

1

2

6

8

24

1

65

71

66

67

72

82

2

71

67

74

63

64

68

3

73

62

78

63

72

72

4

75

76

72

76

79

72

5

80

86

80

83

68

68

6

77

64

71

68

74

70

average value

74

71

74

70

72

72

AND*

2

4

2

3

2

2

(2) 2/5 mg of

Cilazapril plus placebo

subject/hr

-2

1

2

6

8

24

1

63

63

54

58

52

78

2

78

80

77

52

62

64

3

69

62

66

57

64

78

4

75

72

69

68

72

66

5

76

72

73

76

78

72

6

75

82

73

64

66

88

average value

73

72

69

63

66

74

AND*

2

3

3

4

4

4

(3) 120 mg of

Propranolol plus placebo

subject/hr

-2

1

2

6

8

24

1

67

56

58

50

64

74

2

78

64

68

54

54

76

3

67

74

75

64

62

76

4

75

66

71

56

80

78

5

74

68

67

76

79

72

6

72

52

64

58

50

78

average value

72

63

67

60

65

76

AND*

2

3

2

4

5

1

(4) 2/5 mg of

Cilazapril plus

120 mg of

Propranolol

subject/hr

-2

1

2

6

8

24

1

69

52

52

50

54

72

2

70

70

68

52

54

72

3

65

66

65

51

50

60

4

72

58

65

62

66

72

5

82

81

80

58

49

72

6

71

64

68

55

59

76

average value

72

65

66

55

55

71

AND*

2

4

4

2

3

2

* AND = standard deviation.

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B) 10 male and 3 female subjects, aged 43 to 62 years and weighing 64 to 106 kg, suffering from essential hypertonia, participated in this crossover study which comprised the following three treatment sections, 5 of each lasting 3 weeks, with sections (1) and (2) being exchanged according to the group:

(1) 2/5 mg of Cilazapril

(2) 120 mg of Propranolol

(3) 2/5 mg of Cilazapril plus 120 mg of Propranolol. 10 With the exception of 3 patients, no patient received antihypertensive medication for at least 2 weeks prior to the start of a 2-week placebo treatment. At this time/ diastolic blood pressure/ sitting/

was 95 to 120 mmHg. The 15 patients were then freely divided into two groups, the first of which was treated

One group was initially treated with Cilazapril, and the other with Propranolol. After the 3-week treatment period, the medications were switched between the two groups. During the treatment periods, all measurements were taken 2 hours after administration, with blood pressure measured while the subject was seated.

Cilazapril monotherapy resulted in a mean decrease in diastolic blood pressure of approximately 8 mmHg, and propranolol resulted in a decrease of approximately 9 mmHg, while combination therapy resulted in a decrease in blood pressure of approximately 19 mmHg. Four patients responded to cilazapril monotherapy and two out of 13 patients to propranolol monotherapy, while 10 out of 13 patients responded to combination therapy. In this study, "response" to therapy refers to a decrease in diastolic blood pressure to below 90 mmHg.

These results show, with reference to example 35 of the combination of Cilazapril with Propranolol, that

C

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The combination according to the invention has unexpected advantageous properties. Considering the prior art, it could not be expected that the combination of beta-blockers with 5-pyridazodiazepines would lead to such an advantageous hypotensive effect.

The combination according to the invention is generally administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, it can also be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of solutions for injection. For the preparation of tablets, coated tablets, dragees, and hard gelatin capsules, inert pharmaceutical excipients of mineral or organic nature can be used with the combination according to the invention. Among these excipients, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used, for example, for tablets, dragees, and hard gelatin capsules.

Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, etc.; however, depending on the physical nature of the active substance, in some cases it may even be possible to eliminate all excipients in soft gelatin capsules.

Suitable excipients for the preparation of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose and similar excipients.

C

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Suitable excipients for injection solutions include, for example, water, alcohols, polyols/glycerol/vegetable oils/ etc.

5 Suitable excipients for suppositories include, for example, natural or hydrogenated oils/ waxes/ fats, semi-liquid or liquid polyols and similar excipients.

Pharmaceutical compositions may, in addition to containing preservatives, solubilizing agents, stabilizers, wetting agents, emulsifying agents, sweeteners, colorings, flavorings, salts used to modify osmotic pressure, buffers, coating agents, or antioxidants, they may also contain other substances with therapeutic activity.

The following examples illustrate the invention.

Example 1

20. Preparation of hard gelatin capsules with the following composition:

Cilazapril, monohydrate 2.61 mg *)

Propranolol hydrochloride 136.89 mg **)

lactose powder 33.50 mg

25% lactose crystallized 101.00 mg, white corn starch 20.00 mg, talc 5.00 mg, magnesium stearate 1.00 mg

Total 300.00 mg

30 *) corresponding to 2/5 mg of anhydrous Cilazapril **) corresponding to 120 mg of Propranolol base. Preparation instructions: Vigorously mix the active substance Cilazapril with the lactose powder. To this pre-mixed solution, add the active substance Propranolol.

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Crystallized lactose, white corn starch, talc, and magnesium stearate are mixed together. The powdered mixture is then placed in capsules of size 1.

5 Example 2

Preparation of tablets with the following composition:

Cilazapril/ monohydrate 2/61 mg *)

Propranolol hydrochloride 136/89 mg **)

10 lactose powder 120/00 mg white corn starch 40/50 mg polyvinylpyrrolidone 4/00 mg white corn starch 40/00 mg talc 5/00 mg

15 magnesium stearate 1/00 mg

Total 350/00 mg

*) corresponding to 2/5 mg of anhydrous Cilazapril **) corresponding to 120 mg of Propranolol base Preparation procedure 20 The active substances are mixed with powdered lactose and white corn starch. The mixture is moistened with an aqueous solution of polyvinylpyrrolidone and kneaded; the mass is formed into granules, which are then dried and sieved. The granules are mixed with white corn starch (second part), talc, and magnesium stearate, and pressed into tablets of the required size.

Example 3

Preparation of hard gelatin capsules

30

35

The following composition:

Cilazapril/ monohydrate

2.61

mg

*)

Bisoprolol fumarate (2:1)

5/89

mg

** )

lactose powder

80/50

mg

crystallized lactose

110.00

mg

white corn starch

50.00

mg

-16-

talc 30/00 mg magnesium stearate 1.00 mg

Total 280.00 mg

*) corresponding to 2.5 mg of anhydrous Cilazapril **) corresponding to 5.0 mg of Bisoprolol base Preparation instructions

The active substances, Cilazapril monohydrate and Bisoprolol fumarate (2:1), are mixed with powdered lactose (first part) and sieved. To this preliminary mixture, lactose (second part), crystalline lactose, white corn starch, talc, and magnesium stearate are added. The powdered mixture is then placed in size 2 capsules.

Example 4

15. Preparation of coated tablets with the following composition:

Tablets

Cilazapril, monohydrate 2.61 mg *)

Bisoprolol fumarate (2:1) 2.95 mg **)

20g lactose powder 227.44 mg white corn starch 100.00 mg polyvinylpyrrolidone 10.00 mg talc 5.00 mg magnesium stearate 2.00 mg

25 Total/tablet 350.00 mg

*) corresponding to 2.5 mg of anhydrous Cilazapril **) corresponding to 2.5 mg of Bisoprolol base Varnish layer:

hydroxypropylmethylcellulose 2.80 mg

30 talc 2.00 mg polyethylene glycol 6000 0.80 mg titanium dioxide 0.20 mg red iron oxide 0.20 mg

Total for the varnish layer: 6.00 mg; Total for one coated tablet: 356.00 mg

O

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Preparation procedure

Tablets

The active substances are mixed with powdered lactose and white corn starch (first part). The mixture is moistened with an aqueous solution of polyvinylpyrrolidone and kneaded. The resulting mass is formed into granules, dried, and sieved. The granules are mixed with white corn starch (second part), talc, and magnesium stearate, and pressed into tablets of appropriate size.

Tablet coating

Hydroxypropylmethylcellulose and polyethylene glycol 6000 are dissolved in demineralized water 15 (first part). The following are introduced into this solution:

Under agitation, a suspension of talc, titanium dioxide, and red iron oxide in water (second part) is mixed. The varnish suspension is sprayed onto the cores in a coating drum. The coated tablets are then dried.

•k "k ★

<

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X 12 849 DV 4019/104

Claims (17)

DEMANDS 1. A method for preparing a pharmaceutical composition characterized in that a 5. Form of galenic administration: a mixture of a beta-blocker with a general formula OH I 10 ROCH2CH-CH2NHCH(CH3)2 I in which R represents a phenyl group possibly substituted by lower alkenyloxy, (lower alkoxy)-alkyl, (aminocarbonyl)-15 lower alkyl or (lower alkoxy)-(lower alkoxy)-alkyl groups, or a naphthyl, indolyl or dihydroxytetrahydronaphthyl group, and a pyridazodiazepine with the general formula 5 4 20 R \ /R • — • • •/X Y \ /N\ /* ii • i ■ • • - R1-ÇH-NH/ 6 i00R3 COOR2 25 in which R"*" represents an inf-2 aryl-alkyl group 3 rieur, R and R each represent hydrogen or a 4 5 lower alkyl group and R and R each represent hydrogen or together form an oxo group, 30 in the state of free bases, hydrates or salts acceptable for pharmaceutical use. 2. A method according to claim 1, characterized in that the relative weight proportions between the beta-blocker and pyridazodiazepine are 0.5:1 to 35,500:1, for free bases. -19- 3. A method according to claim 2, characterized in that the relative proportions by weight are 1:1 to 50:1. 4. A method according to claim 3, characterized in that the relative proportions by weight are 1:1 to 5:1. 5. A method according to any one of claims 1 to 4, characterized in that a mixture of 5 to 320 mg of a beta-blocker is administered as a daily dose. 10 and 1 to 5 mg of a pyridazodiazepine or equivalent amounts of a hydrate or salt acceptable for pharmaceutical use. 6. A method according to any one of claims 1 to 5, characterized in that a beta-blocker is used 15 formula I in which R represents an alpha-naphthyl, indole-4-yl, 2-allyloxyphenyl, 4-methoxyethylphenyl, 4-aminocarbonylmethylphenyl, 4-isopropyl-oxyethoxymethylphenyl or 6,7-dihydroxy-5,6,7,8-tetra-hydronaphtho-l-yl group. 20 7. A method according to claim 6, characterized in that Propranolol or Bisoprolol are used as formula I beta-blockers. 8. A method according to claim 7, characterized in that it uses as a beta-blocker 25 formula I Bisoprolol. 9. A method according to any one of claims 1 to 8, characterized in that a pyridazodiazepine of formula II is used, in which R represents an aryl- group 2 lower alkyl, R represents a lower alkyl group, 3 4 5 30 R hydrogen and R and R each represent hydrogen or together form an oxo group. 10. A method according to claim 9, characterized in that a pyridazodiazepine of formula II is used in which R represents an inferior phenyl-alkyl group 2 3 35 rieur, R represents a lower alkyl group, and R , -20- 4 5 R and R each represent hydrogen. 11. Process according to claim 10/ characterized in that the 9(S)-[1(S)-ethoxycarbonyl-3-phenyl-propylamino]-octahydro-10-oxo-6H-pyridazo[l/2a][1/2]-diazepine-1(S)-carboxylic acid is used as the pyridazodiazepine of formula II. 12. Process according to claim 11/ characterized in that the 9(S)-[1(S)-ethoxycarbonyl-3-phenyl propylamino]-octahydro-10-oxo-6H-pyridazo[1/2a][1,2 J-diazepine-1(S)-carboxylic acid is in the salt or hydrate state. 13. Process according to claim 12/ characterized in that the 9(S)-[1(S)-ethoxycarbonyl-3-phenyl propylamino]-octahydro-10-oxo-6H-pyridazo[1/2a][1/2J-diazepine-1(S)-carboxylic acid is in the form of hydrobromide or monohydrate. 14. A process according to any one of claims 1 to 13/ characterized in that Propranolol is in the hydrochloride form or Bisoprolol in the fumarate form. 15. Use of a composition obtained according to any one of claims 1 to 14 for the treatment or prevention of diseases. 16. Use of a composition obtained according to any one of claims 1 to 14 for the treatment or prevention of circulatory diseases. 17. Use of a composition obtained according to any one of claims 1 to 14 for the treatment or prevention of hypertonia and its pathological consequences without increasing heart rate. O R 1*G* i W A. t'en pagçs "containing -4— References ... word added rfiotrayé