NZ228379A - Pharmaceutical composition comprising an n-(2,3-dihydroxy propyl) isopropyl amine b-blocker derivative and a pyridazodiazepine derivative - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £28379 Patents Form No. 5 Prio.i^ Xowi^tete Specie ' "."■>■ CSsss: {5).Ok>)^W>^. - PubUcaiien Date: - S.OJHJ9$..... mat, fco: ). Jouroat 22 8 37 9 NEW ZEALAND PATENTS ACT, 1953 No.: Date.

COMPLETE SPECIFICATION ANTI HYPERlEJJSlVE C0M BlNAT/OfS WE, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSHCAFT 124-184 Grenzacherstrasse, Basle, Switzerland a Swiss company hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page -la-) ('*** ^ — \CX_— RAN 4019/104 The present invention is concerned with a pharmaceutical combination preparation, which is suitable for 5 the treatment of hypertension, containing certain alkyl-aminoalkoxy-phenyl, -naphthyl or -indolyl derivatives as well as certain pyridazodiazepines.

The aforementioned phenyl, naphthyl and indolyl 10 derivatives are known fi-blockers. They exhibit, inter alia, a pronounced antihypertensive activity and can be used in the treatment of hypertension of all degrees of severity.

Similarly, the aforementioned pyridazodiazepines are known ACE inhibitors which are also suitable for the treatment of hypertension; they have a blood pressure--lowering activity without increasing the heart rate (see New Zealand Patent Specification No. 204130.

The simultaneous administration of a B-blocker and an ACE inhibitor has already been described in the scientific literature. Amery et al. report in Clinical Science, 61. 441s-444s (1981) that in patients, whose high blood 25 pressure is treated with captopril, a further lowering of the blood pressure could be achieved by the additional administration of propranolol. This finding could, however, no longer be confirmed later. Thus, for example, MacGregor et al. in Journal of Cardiovascular 30 Pharmacology, 7. S82-S87 (1985), report that in their investigations the additional administration of propranolol to patients treated over a long period of time with captopril brought about no further lowering of the blood pressure. As a possible explanation for the absence Kbr/13.2.89 * • 4 JUL 1991 i 22 8379 of a further lowering of the blood pressure the authors state that probably fi-blockers and ACE inhibitors - at least to some extent - have the same mechanism of action, namely inhibition of the renin angiotensin system, 5 wherefore in the case of a combination therapy an additive effect can not even be expected. This opinion has prevailed since then in the scientific circles [see Eur. J. Clin. Pharmac., 32., 229-235 (1987)] and therefore in the case of hypertension a combined therapy of 13-blockers 10 and ACE inhibitors cannot even today be recommended [see Journal of Cardiovascular Pharmacology, 9., Suppl. 3, 2-5 (1987) ] .

There exists the need to provide a pharmaceutical 15 combination to which as far as possible all patients respond, the administration of which leads to a lowering of the blood pressure without simultaneously increasing the heart rate and in which the dosage of the individual components is reduced and undesired side-effects which 20 occasionally appear in the case of the required dosing in monotherapy can be suppressed.

In the scope of the present invention it can be established that, with the administration of the 25 combination in accordance with the invention of a 6-blocker with an ACE inhibitor, significantly more patients respond to the treatment than in the case of the monotherapies and the blood pressure-lowering properties of the two individual components are not only additive, 30 but are even partially potentiating, whereby the effective dosages of the two individual components can be reduced. In addition, it could not have been foreseen that at the same time the duration of activity would also be lengthened considerably.

Accordingly, the antihypertensive combination in accordance with the invention has the following advantages 22 8 37 1. The number of patients who respond to the treatment increased significantly; 2. the amounts of active substances to be administered are reduced; 3. undesired side-effects are eliminated or greatly reduced; 4. the heart rate is not influenced; . the duration of activity is lengthened and 6. a uniform course of efficacy is achieved.

The inventon is therefore concerned with a pharmaceutical combination preparation for the of hypertension, containing a B-blocker of the formula OH I ROCH^CH-C^NHCH ( CH3 ) wherein R signifies phenyl, which is optionally substituted by lower-alkenyloxy, lower-alkoxy-lower--alkyl, aminocarbonyl-lower-alkyl or lower-alkoxy--lower-alkoxy-lower-alkyl, or naphthyl, indolyl or dihydroxytetrahydronaphthyl, and a pyridazodiazepine of the general formula novel treatment genera 1 22837# 1 / \ II R I H-NH' OOR2 6 i00R3 1 2 3 wherein R signifies aryl-lower-alkyl, R and R 4 5 each signify hydrogen or lower-alkyl and R and R each signify hydrogen or together signify an oxo group, whereby the active substances are present either in the g form of their free bases, their hydrates or their pharma-ceutically usable salts.

The term "lower" used in this description relates to residues which have 1-4 carbon atoms.

The aryl residue in aryl-lower-alkyl is a phenyl group which can be mono- or multiply-substituted by halogen (i.e. fluorine, chlorine, bromine or iodine), lower-alkyl, lower-alkoxy, trifluoromethyl, phenyl and the like.

Examples of aryl-lower-alkyl groups are benzyl, 4-chloro-benzyl, 2-phenylethyl, 3-phenylpropyl, 3-(4-chloro-phenyl)propyl, 3-(4-methoxyphenyl)propyl, 4-phenylbutyl and the like.

The weight ratio of B-blocker to pyridazodiazepine conveniently amounts to about 0.5:1 to 500:1. preferably 1:1 to 50:1, especially 1:1 to 5:1, with respect to free base(s), with the weight ratio depending on the fl-blocker and pyridazodiazepine used. 22 8379 Advantageously, the dosage to be administered by means of the combination per day amounts to 5-320 mg of a fl-blocker and 1-5 mg of a pyridazodiazepine. In general, the total amount of a fl-blocker and a pyridazodiazepine to 5 be administered daily amounts to a maximum of 325 mg. If a hydrate or a pharmaceutically usable salt is employed, then the above values must be altered appropriately.

Objects of the present invention are therefore a combination of a fl-blocker of formula I and a pyridazodiazepine of formula II; a pharmaceutical preparation, containing a fl-blocker of formula I and a pyridazodiazepine of formula II; 15 - the manufacture of a pharmaceutical preparation, which comprises bringing a mixture of a fl-blocker of formula I and a pyridazodiazepine of formula II into a galenical dosage form; the use of a combination of a fl-blocker of formula I 20 and a pyridazodiazepine of formula II and. respectively, of a pharmaceutical preparation containing a fl-blocker of formula I and a pyridazodiazepine of formula II for the control or prevention of illnesses, especially of circulatory disorders, 25 particularly in the control or prevention of hyper tension and its consequential disorders, such as e.g. heart failure, without increasing the heart rate.

Especially suitable fl-blockers are those of formula I 30 in which R signifies a-naphthyl, indol-4-yl, 2-allyl-oxyphenyl, 4-methoxyethylphenyl, 4-aminocarbonylmethyl, 4-isopropyloxyethyloxymethylphenyl or 6,7-dihydroxy--5,6,7,8-tetrahydronaphth-l-yl. Those fl-blockers of formula I in which R signifies a-naphthyl, indol-4-yl, 35 2-allyloxyphenyl, 4-aminoearbonymethyl or 4-isopropyi-oxyethyloxymethylphenyl are particularly suitable. 22 8379 Propranolol and bisoprolol are the most suitable representatives from the group of fl-blockers of formula I.

Especially suitable pyridazodiazepines are those of 1 2 formula II in which R signifies aryl-lower-alkyl. R . . 3 . . . 4 signifies lower-alkyl, R signifies hydrogen and R and R each signify hydrogen or together signify an oxo group.

Particularly suitable pyridazodiazepines are those of formula II in which R1 signifies phenyl-lower-alkyl, 2 3 4 5 R signifies lower-alkyl and R . R and R signify hydrogen. 9(S)-[1-(S)-Ethoxycarbony1-3-phenylpropylamino]octa- hydro-10-oxo-6H-pyridazo[1,2-a][1.2]diazepine-l(S)--carboxylic acid (referred to hereinafter as cilazapril) is the most suitable representative from the group of pyridazodiazepines of formula II.

The most preferred combination in accordance with the invention is a combination of cilazapril with bisoprolol having regard to the following properties which are characteristic of the two active substances: Similar pharmacokinetic profile, i.e. a high bioavailability and long elimination half life; long duration of activity (i.e. only one dosage daily); high specificity of the two active substances for 30 their respective pharmacological targets; high efficacy of the two active substances as well as approximate equipotency based on the oral dosaging of the free bases.

For the above reasons the two active substances cilazapril and bisoprolol are especially well suited for a therapeutic use in the form of a fixed combination. £28379 Conveniently, propranolol and bisoprolol are present as pharmaceutical^ usable salts, while cilazapril is present as a pharmaceutically usable salt or hydrate. As a rule, in the combination propanolol is present as the 5 hydrochloride and bisoprolol is present as the fumarate, and cilazapril is present in the form of the corresponding monohydrate or hydrobromide. Preferably, the weight ratio of JB-blocker to pyridazodiazepine in the combination of propanolol with cilazapril amounts to about 20:1 to 50:1 10 and in the combination of bisoprolol with cilazapril amounts to about 1:1 to 5:1, based on the free bases.

By means of the combination in accordance with the invention there can be produced with low active substance 15 dosages a regular and long-lasting lowering of the blood pressure without increasing the heart rate with simultaneously good compatibility and low toxicity.

The advantageous, at least additive blood pressure-20 -lowering activity of the combination in accordance with the invention compared with that of the two individual components as well as the favourable response of patients to this can be demonstrated in the two human-experimental trials using a combination of cilazapril with propanolol 25 described hereinafter, which were carried out in conformity with the Declaration of Helsinki in the version of Venice.

A) Six healthy male volunteers, who prior to the trial 30 had given their written agreement thereto, took part in this 4-way cross-over study which was carried out according to the double-blind procedure and comprised the following 4 phases of treatment each lasting 7 days, whereby a break of >7 days was introduced between each of 35 the individual phases of treatment; 22 8 3 7 9 (1) Placebo plus placebo (2) 2.5 rag of cilazapril plus placebo (3) 120 mg of propranolol plus placebo (4) 2.5 rag of cilazapril plus 120 mg of propranolol.

In order that no volunteer should suffer a health risk, before the beginning of the study the case history was ascertained from each of the volunteers and they were subjected to a general examination which was associated 10 with the following controls: ECG (12 derivations) as well as laboratory investigations of the haematic, hepatic and renal functions. The most important laboratory parameters were also checked in each case at the beginning and at the end of the breaks between the individual phases of 15 treatment and did not indicate abnormality of any kind.

The volunteers were required in each case to fast at the trial stages 0 to 6. i.e. they were required neither to eat. drink nor smoke since the previous evening. After 20 a 5 minutes rest break while seated systolic and diastolic blood pressure and pulse were measured. Subsequently, the volunteers could take breakfast, and the medication was administered to them with 100 ml of tap water under supervision and they were sent home. On trial day 7 the 25 volunteers likewise fasted; the examinations were. however, carried out in the reclining position with 15° raised upper body. After in each case a rest break of 15 minutes in the reclining position blood pressure and pulse were measured at the points in time -2, 1, 2, 6, 8 30 and 24 hours.

The measurements effected in the case of the minimum plasma concentration of the preparations during the 7 days period revealed no substantial difference between the 35 various medications, while on the 7th day clearly visible different effects could be observed. 228379 In the case of the monotherapy with propranolol a decrease in the systolic and diastolic blood pressure by about 7 mmHg and a decrease in the heart rate by about 8 beats/minute took place. In the case of the monotherapy 5 with cilazapril systolic and diastolic pressure fell almost as much as in the case of the monotherapy with propranolol (about 7 mmHg), while the heart rate increased by about 5 beats/minute. In the case of the combination therapy with propranolol and cilazapril the blood pressure 10 fell more strongly than in the case of the individual administration of the two components and the average maximal lowering of the blood pressure amounted to about 15 mmHg. Moreover, on day 7 of the treatment the strong lowering of the blood pressure can be observed over more 15 than 8 hours after tablet intake. The heart rate is neither lowered or increased in the case of the combination therapy.

The results obtained with respect to blood pressure 20 which are obtained in the human-experimental trial described above are compiled in the following Tables. 22 8 3 Systolic blood pressure values in mmHa on the 7th trial dav (1) Placebo plus placebo Volunteer/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 4 115 111 114 121 119 121 120 112 118 136 124 142 6 118 111 120 122 124 100 Average 113 111 112 117 116 118 SEM * 2 1 3 3 6 (2) 2.5 ma Cilazapril plus placebo Volunteer/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 4 110 108 106 116 124 120 112 118 108 116 114 112 6 117 111 115 106 108 126 Average 109 109 104 107 108 118 SEM * 3 3 4 4 (3) 120 ma Propranolol plus placebo Volunteer/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 4 113 104 106 112 114 108 120 111 108 122 112 112 6 103 100 108 112 104 112 Average 111 106 106 110 108 115 SEM * 3 2 2 4 2 3 (4) 2.5 ma Cilazapril plus 120 ma propranolol Volunteer/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 4 118 110 103 102 112 132 116 110 109 90 80 114 6 114 124 102 108 102 122 Average 111 108 100 99 101 116 SEM * 3 4 4 * SEM = Standard Error Mean. 22 837 Diastolic blood pressure values in mmHa on the 7 tl trial dav (1) Placebo plus placebo Volunteer/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 80 86 80 83 68 68 6 77 64 71 68 74 70 Average 74 71 74 70 72 72 SEM * 2 4 2 3 2 2 (2) 2.5 ma Cilazapril plus placebo Volunteer/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 76 72 73 76 78 72 6 75 82 73 64 66 88 Average 73 72 69 63 66 74 SEM * 2 3 3 4 4 4 (3) 120 ma Propranolol plus placebo Volunteer/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 OK 4 75 66 71 56 80 78 C.O 74 68 67 76 79 72 6 72 52 64 58 50 78 Average 72 63 67 60 65 76 SEM * 2 3 2 4 1 (4) 2.5 ma Cilazapril Plus 120 ma propranolol Volunteer/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 82 81 80 58 49 72 £ u 71 64 68 55 59 76 tib Average 72 65 66 55 55 71 SEM * 2 4 4 2 3 2 * SEM = Standard Error Mean. 22 8 37 B) Ten male and three female patients with an essential hypertension, aged 43-62 years and weighing 64-106 kg, took part in this cross-over study which comprised the following three phases of treatment each lasting 3 weeks, 5 with phases (1) and (2) being exchanged for each group: (1) 2.5 rag of cilazapril (2) 120 mg of propranolol (3) 2.5 mg of cilazapril plus 120 mg of propranolol.

With the exception of three patients no patient received a blood pressure-lowering medication for at least 2 weeks before the beginning of a two-week treatment with placebo. After this time the diastolic blood pressure in 15 the seated position lay between 95 and 120 mmHg. Then, the patients were divided by selection into two groups. whereby one of the groups was treated firstly with cilazapril and the other was treated firstly with propranolol. After the treatment period of three weeks the 20 medication in the two groups was exchanged. During the phases of treatment all measurements were carried out 2 hours after administration, with the blood pressure being measured in each case in the seated position.

The monotherapy with cilazapril brought about an average lowering of the diastolic blood pressure by 8 mmHg and that with propranolol brought about an average lowering of the diastolic blood pressure by 9 mmHg, while the combination therapy brought about a lowering of the 30 blood pressure by 19 mmHg. 4 patients responded to the monotherapy with cilazapril and 2 of 13 patients responded to that with propranolol, while 10 of 13 patients responded to the combination therapy. In this study a lowering of the diastolic blood pressure to below 90 mmHg 35 was defined as "response" to the therapy. 228 379 These results, presented by way of example for the combination of cilazapril with propanolol, show the unexpectedly advantageous properties of the combination in accordance with the invention. With the knowledge of the 5 state of the art it could not have been expected that the combination of fi-blockers with pyridazodiazepines would show such an optimal blood pressure-lowering activity.

The combination in accordance with the invention is 10 generally administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. 15 in the form of injection solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules, a combination in accordance with the invention can be processed with 20 pharmaceutically inert inorganic or organic excipients. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc; depending on the nature of the active substance no excipients are. however, generally required 30 in the case of soft gelatine capsules.

Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose and the like.

Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. 22 8 37 9 Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.

The following Examples illustrate the invention.

Example 1 Manufacture of hard gelatine capsules of the following composition: Cilazapril monohydrate Propranolol hydrochloride Powd. lactose Cryst. lactose White maize starch 25 Talc Magnesium stearate *) corresponding to 2.5 mg 30 **) corresponding to 120 mg Manufacturing principle 2.61 mg *) 136.89 mg **) 3 3.50 mg 101.00 mg .00 mg .00 mg 1.00 mg Total 300.00 mg of anhydrous cilazapril of propranolol (base) The cilazapril active substance is mixed intensively 35 with powd. lactose. This pre-mixture is mixed with the propranolol active substance, cryst. lactose, white maize 22 8 379 starch, talc and magnesium stearate. The powder mixture is filled into size 1 capsules.

Example 2 Manufacture of tablets of the following composition: Cilazapril monohydrate Propranolol hydrochloride 10 Powd. lactose White maize starch Polyvinylpyrrolidone White maize starch Talc Magnesium stearate Total 2.61 rag *) 136.89 mg **) 120.00 mg 40.50 mg 4.00 mg 40.00 mg .00 mg 1.00 mg 350.00 mg *) corresponding to 2.5 mg of anhydrous cilazapril **) corresponding to 120 mg of propranolol (base) Manufacturing principle The active substances are mixed with powd. lactose and white maize starch. The mixture is moistened with an 25 aqueous solution of polyvinylpyrrolidone and kneaded; the resulting mass is granulated, dried and sieved. The granulate is mixed with white maize starch (2nd portion), talc and magnesium stearate and pressed to tablets of suitable size.

Example 3 Manufacture of hard gelatine capsules of the following composition: Cilazapril monohydrate 2.61 mg *) Bisoprolol fumarate (2:1) 5.89 mg **) 22 8 3 Powd. lactose Cryst. lactose White maize starch Talc Magnesium stearate 80.50 mg 110.00 mg 50.00 mg 30.00 mg 1.00 mg Total 280.00 mg *) corresponding to 2.5 mg of anhydrous cilazapril **) corresponding to 5.0 mg of bisoprolol (base) Manufacturing principle The active substances, cilazapril monohydrate and bisoprolol fumarate (2:1), are mixed with powd. lactose 15 (1st portion) and sieved. This pre-mixture is mixed with the lactose (2nd portion), cryst. lactose, white maize starch, talc and magnesium stearate. The powder mixture i filled into size 2 capsules.

Example 4 Manufacture of coated tablets of the following composition: Tablet: Cilazapril monohydrate 2 . 61 mg Bisoprolol fumarate (2:1) 2 .95 mg Powd. lactose 227 . 44 mg White maize starch 100 .00 mg Polyvinylpyrrolidone .00 mg Talc .00 mg Magnesium stearate 2 .00 mq Total/tablet 350 .00 mg *) corresponding to 2.5 mg of anhydrous cilazapril **) corresponding to 2.5 mg of bisoprolol (base)

Claims (19)

- 17 - 22 8 379 Coating layer: Hydroxypropylmethylcellulose Talc 2.80 mg 2.00 mg 0.80 mg 0.20 mg 0.20 mg 6.00 mg 5 Polyethylene glycol 6000 Titanium dioxide Red iron oxide Total/coating layer Total/coated tablet 3 5 6.00 mg 10 Manufacturing principle Tablets 15 The active substances are mixed with powd. lactose and white maize starch (1st portion). The mixture is moistened with an aqueous solution of polyvinylpyrrolidone and kneaded; the resulting mass is granulated, dried and sieved. The granulate is mixed with white maize starch 20 (2nd portion), talc and magnesium stearate and pressed to tablets of suitable size. 6000 are dissolved in deionized water (1st portion). A suspension of talc, titanium dioxide and red iron oxide in water (2nd portion) is stirred into the solution. The coating suspension is sprayed onto the tablets in a 30 drageeing pan. The coated tablets are subsequently dried. Coating of the tablets 25 Hydroxypropylmethylcellulose and polyethylene glycol 35 228379 - 18 - what we claim is:

1. A pharmaceutical preparation, which contains a 5 fl-blocker of the general formula OH roch2ch-ch2nhch(ch3)2 10 wherein R signifies phenyl, which is optionally substituted by lower-alkenyloxy, lower-alkoxy-lower--alkyl, arainocarbonyl-lower-alkyl or lower-alkoxy--lower-alkoxy-lower-alkyl, or naphthyl, indolyl or 15 dihydroxytetrahydronaphthyl, and a pyridazodiazepine of the general formula 20 R\ /r4 • - — — • • // \ /N\ /" II • — .M ■— • • R1-CH-NH// - & i00RJ coor' 2 25 1 2 3 wherein R signifies aryl-lower-alkyl, R and R 4 5 each signify hydrogen or lower-alkyl and R and R each signify hydrogen or together signify an oxo group, 30 in the form of their free bases, their hydrates or their pharmaceutically usable salts^ and wherein the weight ratio of fl-blocker to pyridazodiazepine amounts to 35 1:1 to 50:1 with respect to free base(s). - 19 - 228870

2. A preparation according to claim 1/ wherein the 5 weight ratio amounts to 1:1 to 5:1.

3. A preparation according to claim 1 or 2, which contains 5-320 mg of a fl-blocker and 1-5 mg of a pyridazodiazepine or equivalent amounts of a hydrate or of 10 a pharmaceutically usable salt as the daily dosage.

4. A preparation according to any one of claims 1-3, which contains a fl-blocker of formula I in which R signifies a-naphthyl. indol-4-yl. 2-allyloxyphenyl. 15 4-methoxyethylphenyl, 4-aminocarbonylmethylphenyl, 4-isopropyloxyethoxymethylphenyl or 6,7-dihydroxy-5,6,7.8--tetrahydronaphth-l-yl.

5. a preparation according to claim 4, which 20 contains propranolol or bisoprolol as the fl-blocker of formula I.

6- A preparation according to claim 5, which contains bisoprolol as the fl-blocker of formula I. 25

7, A preparation according to any one of claims 1-6, which contains a pyridazodiazepine of formula II in which 1 2 R signifies aryl-lower-alkyl, R signifies lower- 3 4 5 -alkyl, R signifies hydrogen and R and R each 30 signify hydrogen or together signify an oxo group.

8. A preparation according to claim 7, which contains a pyridazodiazepine of formula II in which R1 2 signifies phenyl-lower-alkyl. R signifies lower-al.ky-1 ^ 35 and R". R" and R~ each signify hydrogen. /£*** if ^ \l o\ .f-4 SEP 1992** .Qj -til 228379 10 - 20 -

9. A preparation according to claim 8, which contains 9(S)-[1(S)-ethoxycarbony1-3-phenylpropylamino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1.2]diazepine-l(S)~ -carboxylic acid as the pyridazodiazepine of formula II.

10. A preparation according to claim 9, wherein the 9(S)-[1(S)-ethoxycarbony1-3-phenylpropylamino]octahydro--10-oxo-6H-pyridazo[1.2-a][1,2]diazepine-1(S)-carboxylie acid is present as a salt or hydrate.

11. A preparation according to claim 10, wherein the 9(S)-[1(S)-ethoxycarbony1-3-phenylpropylamino]octahydro--10-oxo-6H-pyridazo[l,2-a][1.2Jdiazepine-l(S)-carboxylie acid is present as the hydrobromide or monohydrate.

12. A preparation according to any one of claims 1-11, wherein propranolol is present as the hydrochloride or bisoprolol is present as the fumarate. 20

13. A preparation in accordance with any one of claims 1- 12, —> for the control or prevention of hypertension and its consequential disorders without increasing the heart rate. 25

14. A process for the manufacture of a preparation in accordance with any one of claims 1-13, which process comprises bringing a mixture of the two active substances into a galenical dosage form. 15 - 5 DEC 1981 - 21 - 228370

15. The use of a fl-blocker of formula I in combination, with an ACE inhibitor of formula II for the manufacture of a preparation according to any one of claims 1-14. 10

16. A pharmaceutical preparation as claimed in ?ny one of claims 1 to 3 substantially as hereinbefore defined with reference to any example thereof. 15

17. A process as claimed in claim 14 substantially as hereinbefore defined with reference to any example thereof.

18. A pharmaceutical preparation as claimed in any one of claims 1 to 13 and 16 when prepared by a process as claimed in claim ' 14 or 17.,■ - * 20

19 . The use as claimed in claim 15 substantially as hereinbefore defined with reference to any example thereof. DATED THIS DAY OF <S^p\ 19°( a. j. park & son , q PER/f/7 AGENTS FOR THE APPLICANT'S 30