AU616249B2 - Antihypertensive combination - 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

S F Ref: 88830 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION 6162(ORIGINAL)

(ORIGINAL)

FOR OFFICE USE: Class Int Class Complete Specification Lodged: So Accepted: Published: Priority: S Related Art: Name and Address of Applicant: Address for Service: F Hoffmann-La Roche Co Aktiengesellschaft Grenzacherstrasse 124-184 4002 Basle

SWITZERLAND

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia SComplete Specification for the invention entitled: Antihypertensive Combination The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/5 I ___WI

-I-

RAN 4019/104 Abstract Pharmaceutical combination preparations, containing a B-blocker of the formula

OH

ROCH CH-CH NHCH(CH3) 2 2- 2^ H(C 3 o 00 0 0 0 0400 0 0a a a 00 O 0 a 0 0 00 0 0 0 0 0 0 040 0.4«0 0 and a pyridazodiazepine of the formula R R 4 R H-NH/ 5 COOR 3

OOR

1 2 3 4 5 wherein R, R R R R and R have the significance given in claim 1, have a pronounced blood pressure-lowering aktivity without increasing the hearth rate and are, therefore, useful for the control or prevention of hypertension and its consequential disorders.

L

RAN 4019/104 The present invention is concerned with a pharmaceutical combination preparation, which is suitable for the treatment of hypertension, containing certain alkyl- A aminoalkoxy-phenyl, -naphthyl or -indolyl derivatives as well as certain pyridazodiazepines.

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

15 Similarly, the aforementioned pyridazodiazepines are 0 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 German Offenlegungschrift 3317290).

The simultaneous administration of a B-blocker and an ACE inhibitor has already been described in the scientific 0oo<' literature. Amery et al. report in Clinical Science, 61, 441s-444s (1981) that in patients, whose high blood S 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, 0 however, no longer be confirmed later. Thus, for example, o s0a" MacGregor et al. in Journal of Cardiovascular Pharmacology, 1, S82-S87 (1985), report that in their Sinvestigations 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 ~lliYLIIY I.-ii i-a~ 15 2 of a further lowering of the blood pressure the authors state that probably B-blockers and ACE inhibitors at least to some extent have the same mechanism of action, namely inhibition of the renin angiotensin system, wherefore in the case of a combination therapy Pn 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 3-blockers and ACE inhibitors cannot even today be recommended [see Journal of Cardiovascular Pharmacology, 9, Suppl. 3, (1987)].

o°o There exists the need to provide a pharmaceutical 0 oo o 15 combination to which as far as possible all patients respond, the administration of which leads to a lowering 0 :o e 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 occasionally appear in the case of the required dosing in monotherapy can be suppressed.

O 0 o* In the scope of the present invention it can be 0. 00 established that, with the administration of the 6 0 0 25 combination in accordance with the invention of a 8-blocker with an ACE inhibitor, sigDificantly more o, patients respond to the treatment than in the case of the monotherapies and the blood pressure-lowering properties o00 of the two individual components are not only additive, 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: i; s !i^ i 1- 3 1. The number of patients who respond to the treatment is 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 invention is therefore concerned with a synergistic composition for the treatment of hypertension, comprising a 3-blocker of the general formula

OH

I

ROCH2CH-CH2NHCH(CH3) 2 wherein R signifies phenyl, which is optionally substituted by lower-alkenyloxy, lower-alkoxy-lower-alkyl, aminocarbonyl-loweralkyl or 'ower-alkoxy-lower-alkoxy-lower-alkyl, or naphthyl, indolyl or dihydroxytetrahydronaphthyl, and a pyridazodiazepine of the general formula *o 0 0000 -'3 rN R 1-H-NH

OR

R R 0 t! c R 3 wherein R signifies aryl-lower-alkyl, R 2 and R 3 each signify hydrogen or lower-alkyl and R 4 and R 5 each signify hydrogen or together signify an oxo group, whereby the active substances are present either in the form of their free bases, their hydrates or their pharmaceutically usable salts, together with a pharmaceutically acceptable carrier, adjuvant, excipient and/or diluent.

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

1463 TM&/1463y

I

I

P 4 The aryl residue in aryl-lower-alkyl is a phenyl group which can be mono- or multiply-substituted by halogen fluorine, chlorine, bromine or iodine), lower-alkyl, lower-alkoxy, trifluoromethyl, phenyl and the like. Example of aryl-lower-alkyl groups are benzyl, 4-chlorobenzyl, 2-phenylethyl, 3-phenylpropyl, 3-(4-chlorophenyl)propyl, 3-(4-methoxyphenyl)propyl, 4-phenylbutyl and the like.

The weight ratio of 3-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 P-blocker and pyridazodiazepine used.

StI rtm I o ara n, 0 a 0 0 0 o~ so o o os v J <'iT 0 ,0Ms/l463y l~~i7 iQ1 i

K::

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j Advantageously, the dosage to be administered by means of the combination per day amounts to 5-320 mg of a 3-blocker and 1-5 mg of a pyridazodiazepine. In general, the total amount of a B-blocker and a pyridazodiazepine to 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 S a combination of a 3-blocker of formula I and a pyridazodiazepine of formula II; a pharmaceutical preparation, containing a B-blocker S" of formula I and a pyridazodiazepine of formula II; wo3o S 15 the manufacture of a pharmaceutical preparation, which comprises bringing a mixture of a B-blocker of formula I and a pyridazodiazepine of formula II into a galenical dosage form; the use of a combination of a B-blocker of formula I and a pyridazodiazepine of formula II and, respectively, of a pharmaceutical preparation 04 containing a B-blocker of formula I and a pyridazoo* diazepine of formula II for the control or prevention a Q, of illnesses, especially of circulatory disorders, S 25 particularly in the control or prevention of hypertension and its consequential disorders, such as e.g.

heart failure, without increasing the heart rate.

<o Especially suitable B-blockers are those of formula I in which R signifies a-naphthyl, indol-4-yl, 2-allyloxyphenyl, 4-methoxyethylphenyl, 4-aminocarbonylmethyl, 4-isopropyloxyethyloxymethylphenyl or 6,7-dihydroxy- -5,6,7,8-tetrahydronaphth-l-yl. Those B-blockers of formula I in which R signifies c-naphthyl, indol-4-yl, 2-allyloxypheny], 4-aminocarbonylmethyl or 4-isopropyloxyethyloxymethylphenyl are particularly suitable.

6 Propranolol and bisoprolol are the most suitable representatives from the group of B-blockers of formula I.

Especially suitable pyridazodiazepines are those of formula II in which R 1 signifies aryl-lower-alkyl, R 2 signifies lower-alkyl,

R

3 signifies hydrogen and R 4 and R 5 each signify hydrogen or together signify an oxo group.

Particularly suitable pyridazodiazepines are those of formula II in which R 1 signifies phenyl-lower-alkyl, 2 3 4 5 R signifies lower-alkyl and R R and R signify hydrogen.

a p 9(S)-[l-(S)-Ethoxycarbonyl-3-phenylpropylamino]octahydro-10-oxo-6H-pyridazo[l,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 S invention is a combination of cilazapril with bisoprolol 94 ,tn °having regard to the following properties which are characteristic of the two active substances: S S Similar pharmacokinetic profile, i.e. a high bioavailability and long elimination half life; S- long duration of activity only one dosage daily); high specificity of the two active substances for 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.

I_ 7 Conveniently, propranolol and bisoprolol are present as pharmaceutically usable salts, while cilazapril is present as a pharmaceutically usable salt or hydrate. As a rule, in the combination propanolol is present as the 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 B-blocker to pyridazodiazepine in the combination of propanolol with cilazapril amounts to about 20:1 to 50:1 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 o o° 15 dosages a regular and long-lasting lowering of the blood pressure without increasing the heart rate with simultaneously good compatibility and low toxicity.

0 o0 o 0 The advantageous, at least additive blood pressure- -lowering activity of the combination in accordance with the invention compared with that of the two individual 0. components as well as the favourable response of patients ~o to this can be demonstrated in the two human-experimental o trials using a combination of cilazapril with propanolol described hereinafter, which were carried out in conformity with the Declaration of Helsinki in the version o, of Venice.

oo A) Six healthy male volunteers, who prior to the trial had given their written agreement thereto, took part in Sthis 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 the individual phases of treatment: Si 4i 8 Placebo plus placebo mg of cilazapril plus placebo 120 mg of propranolol plus placebo mg of cilazapril plus 120 mg of propranolol.

0 00 0 0 0 0000 S0r 0 000 0 0000 o o a

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0000 000 000000 0 0 ot I o 0 13 00 0 0 0o 0 00 00 0 o o o 0 00 0 0 0 0 0 I o od 0 0000 0 0 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 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 volunteers likewise fasted; the examinations were, however, carried out in the reclining position with 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 1, 2, 6, 8 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 various medications, while on the 7th day clearly visible different effects could be observed.

~n 1 9 9 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 with cilazapril systolic and diastolic presoure fell almost as much as in the case of the monoth.Lapy 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 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 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 which are obtained in the human-experimental trial described above are compiled in the following Tables.

4 S e 3 fiI 10 *n I S (ii S Systolic blood pressure values in mmHq on the 7th trial day 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 5 3 6 2.5 mg 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 15 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 5 4 5 4 120 mq 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 4a 00 s0 O O *0o 04Oi 4 4.7,4 4D 2.5 mg Cilazapril plus 120 mq 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 5 4 4 5 SEM Standard Error Mean.

rr wherein R signifies aryl-lower-alkyl, R 2 and R 3 each signify hydrogen or lower-alkyl and R 4 and R 5 each signify hydrogen or together signify an oxo group, in the form of their free bases, their hydrates or their pharmaceutically ./2 III- 11 Diastolic blood pressure values in mmHg on the 7th trial day Placebo plus placebo Volunteer/hr. 8 24 71 73 77 71 67 62 76 86 64 66 74 78 72 80 71 67 63 63 76 83 68 70 3 82 68 72 72 68 72 2 Average 74 71 74 SEM 2 4 2 2.5 mq Cilazapril plus placebo Volunteer/hr.

8 24

I,

4t Average SEM 120 mg Propranolol plus placebo Volunteer/hr.

1 44a 4 4 a 4 d4 ro 58 68 75 71 67 64 67 2 50 54 64 56 76 58 60 4 8 24 64 74 54 76 62 76 80 78 79 72 50 78 65 76 5 1 6 Average SEM 72 72 2 o 00 0 4 2.5 mg Cilazapril plus 120 mq propranolol Volunteer/hr. 8 24 69 72 82 71 72 2 52 70 66 58 81 64 65 4 52 68 65 65 80 68 66 4 50 52 51 62 58 55 55 2 54 54 50 66 49 59 55 3 72 72 72 72 76 71 2 Average SEM SEM Standard Error Mean.

;j !1 1 6-' 12 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, with phases and being exchanged for each group: 2.5 mg of cilazapril 120 mg of propranolol 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 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 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.

MS e4 The monotherapy with cilazapril brought about an average lowering of the diastolic blood pressure by 8 mmHg °no and that with propranolol brought about an average o lowering of the diastolic blood pressure by 9 mmHg, while the combination therapy brought about a lowering of the blood pressure by 19 mmHg. 4 patients responded to the monotherapy with cilazapril and 2 of 13 patients responded to that with proprano±ol, while 10 of 13 patients responded to the combination therapy. In this study a lowering of the diastolic blood pressure to below 90 mmHg was defined as "response" to the therapy.

I

13 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 state of the art it could not have been expected that the combination of B-blockers with pyridazodiazepines would show such an optimal blood pressure-lowering activity.

The combination in accordance with the invention is 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, Soo' e.g. in the form of suppositories, or parenterally, e.g.

15 in the form of injection solutions.

4 0 8499 Sce For the manufacture of tablets, coated tablets, Cdragees and hard gelatine capsules, a combination in S *accordance with the invention can be processed with pharmaceutically inert inorganic or organic excipients.

Lactose, maize starch or derivatives thereof, talc, 00 0 oo 0 stearic acid or its salts etc. can be used as such 0 00 excipients e.g. for tablets, dragees and hard gelatine S0o o 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 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.

'^a.w^as'taM** 14 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 agen 2, 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: 0 04 04 0 4444 0 rf 414 0 4 4 40UI 4 4 4O r 44 Cilazapril monohydrate Propranolol hydrochloride Powd. lactose Cryst. lactose White maize starch 25 Talc Magnesium stearate 2.61 mg 136.89 mg 33.50 mg 101.00 mg 20.00 mg 5.00 mg 1.00 mq 300.00 mg Total corresponding to 2.5 mg of anhydrous cilazapril corresponding to 120 mg of propranolol (base) Manufacturing principle The cilazapril active substance is mixed intensively i with powd. lactose. This pre-mixture is mixed with the propranolol active substance, cryst. lactose, white maize 15 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 Powd. lactose White maize starch Polyvinylpyrrolidone White maize starch Talc 15 Magnesium stearate 2.61 mg 136.89 mg 120.00 mg 40.50 mg 4.00 mg 40.00 mg 5.00 mg 1.00 mq 350.00 mg 4 44 #4f C 4 Total corresponding to 2.5 mg of anhydrous cilazapril corresponding to 120 mg of propranolol (base) 44ff 4 ft I1 44L 4 4l 4 4.e4 0 4 *0 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 Bisoprolol fumarate (2:1) 2.61 mg 5.89 mg

B

s I iI g I 1~ ;1

A

16 Powd. lactose Cryst. lactose White maize starch Talc Magnesium stearate 80.50 mg 110.00 mg 50.00 mg 30.00 mg 1.00 mq 280.00 mg Total corresponding to 2.5 mg of anhydrous cilazaprii corresponding to 5.0 mg of bisoprolol (base) Manufacturing principle o 00 0 00, 0 0 0 t 44* 9 The active substances, cilazapril monohydrate and bisoprolo fumarate 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 is filled into size 2 capsules.

Example 4 Manufacture of coated tablets of the following composition: 25 Tablet: Of,' 4 0 t o o 0 0o 0 0 Cilazapril monohydrate Bisoprolol fumarate (2:1) Powd. lactose White maize starch Polyvinylpyrrolidone Talc Magnesium stearate 2.61 mg 2.95 mg 227.44 mg 100.00 mg 10.00 mg 5.00 mg 2.00 mg 350.00 mg Total/tablet corresponding to 2.5 mg of anhydrous cilazapril corresponding to 2.5 mg of bisoprolol (base) i I 1_L__ 17 Coating layer: Hydroxypropylmethylcellulose Talc Polyethylene glycol 6000 Titanium dioxide Red iron oxide Total/coating layer Total/coated tablet 2.80 mg 2.00 mg 0.80 mg 0.20 mg 0.20 mq 6.00 mg 356.00 mg Manufacturina orinciole 4 t 0 3 t 00 1 I000 0. 0t 0000 0 0 00 0 09 00 00 0 0 0 0 0 0 04 ata 0 fi- S00 0 0 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 (2nd portion), talc and magnesium stearate and pressed to tablets of suitable size.

Coating of the tablets 25 Hydroxypropylmethylcellulose and polyethylene glycol 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 drageeing pan. The coated tablets are subsequently dried.

1

Claims (14)

1. A synergistic pharmaceutical composition, comprising a P-blocker of the general formula OH ROCH 2 CH-CH 2 NHCH(CH 3 2 I wherein R signifies phenyl, which is optionally substituted by lower-alkenyloxy, lower-alkoxy-lower-alkyl, amirocarbonyl-lower- alkyl or lower-alkoxy-lower-alkoxy-lower-alkyl, or naphthyl, indolyl or dihydroxytetrahydronaphthyl, and a pyridazodiazepine of the general formula S /R 4 II OOR 2 wherein R signifies aryl-lower-alkyl, R 2 and R 3 each signify hydrogen or lower-alkyl and R 4 and R 5 each signify hydrogen or together signify an oxo group, in the form of their free bases, their hydrates or their pharmaceutically useable salts, together with a pharmaceutically acceptable carrier, adjuvant, excipient and/or diluent.

2. A composition according to claim 1, wherein the weight ratio of P-blocker to pyridazodiazepine amounts to 0.5:1 to 500:1 with respect to free base(s). 30 3. A composition according to claim 2, wherein the weight ratio amounts to 1:1 to 50:1.

4. A composition according to claim 3, wherein the weight ratio amounts to 1:1 to 5:1. A composition according to any one of claims 1 to 4, which contains 5 to 320 mg of a P-blocker or a hydrate or a pharmaceutically useable salt thereof and 1 to 5 mg of a pyridazodiazepine or a hydrate or a pharmaceutically useable salt thereof. i S'i -TMS/1463y 19

6. A composition according to any one of claims 1 to 5, which contains a p-blocker of formula I in which R signifies a-naphthyl, indol-4-yl, 2-allyloxyphenyl, 4-methoxyethylphenyl, 4-aminocarbonyl- methylphenyl, 4-isopropyloxyethoxymethylphenyl or 6,7-dlhydroxy-5,6,7,8- 5 tetrahydronaphth-l-yl.

7. A composition according to claim 6, which contains propranolol of bisoprolol as the P-blocker of formula I.

8. A composition according to claim 7, which contains bisoprolol as the P-blocker of formula I.

9. A composition according to any one of claims 1 to 8, which contains a pyridazodiazepine of formula II in which R signifies aryl-lower-alkyl, R 2 signifies lower-alkyl, R 3 signifies hydrogen and R 4 and R 5 each signify hydrogen or together signify an oxo group. A composition according to claim 9, which contains a pyridazodiazepine of formula II in which R 1 signifies phenyl-lower-alkyl, R 2 signifies lower-alkyl and R 3 R 4 and R each signify hydrogen.

11. A composition according to claim 10, which contains 9(S)-[1-(S)-ethoxycarbonyl-3-phenylpropylamino]octahydro-10-oxo-6H- 20 pyridazo[l,2-al[l,2]diazepine-1(S)-carboxylic acid as the pyridazodiazepine of formula II.

12. A composition according to claim 11, wherein the 9(S)-[1-(S)-ethoxycarbonyl-3-phenylpropylamino]octahydro-10-oxo-6H- pyridazo[l,2-al[1,2]diazepine-1(S)-carboxylic acid is present as a salt S 25 or hydrate.

13. A composition according to claim 12, wherein the 9(S)-[C-(S)-ethoxycarbonyl-3-phenylpropylamino]octahydro-10-oxo-6H- pyridazo[l,2-al[1,2]diazepine-1(S)-carboxylic acid is present as the hydrobromide or monohydrate. 30 14. A composition according to any one of claims 1 to 13, wherein propranolol is present as the hydrochloride and bisoprolol is present as the fumarate.

15. A process for the manufacture of a composition in accordance with any one of claims 1 to 14, which process comprises bringing a mixture of the two active substances into a galenical dosage form.

16. A method for the treatment or prophylaxis of circulatory disorders or hypertension and its consequent disorders without increasing T 16 t.,TMS/1463y L fTii 20 the heart rate in a patient requiring said treatment or prophylaxis, which method comprises administering to said patient an effective amount of a composition according to any one of claims 1 to 14.

17. A synergistic pharmaceutical composition for the treatment or prophylaxis of circulatory disorders or hypertension and its consequent disorders without increasing the heart rate in a patient requiring said treatment or prophylaxis, which composition is substantially as herein described with reference to any one of Examples 1 to 4.

18. A method for the treatment or prophylaxis of circulatory disorders or hypertension and its consequent disorders without increasing the heart rate in a patient requiring such treatment or prophylaxis, which method comprises administering to said natient an effective amount of a composition according to claim 17. DATED this SIXTH day of AUGUST 1991 F Hoffmann-La Roche Aktiengesellschaft Patent Attorneys for the Applicant SPRUSON FERGUSON C C 4e 4 3 sg\A LI 4 -4 U T