GB2084017A - Pharmaceutical compositions, effective against coronary heart disease and hypertension - Google Patents

Abstract

Pharmaceutical composition containing as active agents A) a calcium antagonist of a 4 - (2,1,3-benz - oxa- or thia-diazolyl) - 1,4 - dihydro pyridine type and B) a beta -blocker and/or a vasodilating nitrate, effective against coronary heart disease and hypertension.

Description

SPECIFICATION Pharmaceutical compositions, effective against coronary heart disease and hypertension The invention relates to new pharmaceutical compositions effective against coronary heart disease and hypertension, and to their production and use.

The present invention provides a pharmaceutical composition containing as active agents A) a compound of formula I,

wherein R1 is hydrogen, (C1-8) alkyl, hydroxy (C2-,) alkyl, (C3,) alkoxyalkyl, (C3-6) alkenyl, (C3-6) alkinyl, (C3-7) cycloaalkyl, (C4-8)cycloalkylalkyl, (C7-8)phenylalkylor (C9-12)phenylalkenyl, the phenylring being unsubstituted or independently mono-, di- or trisubstituted by halogen, hydroxy, (C1-4) alkyl or (C1-4) alkoxy, R2 and R5, independently, are hydrogen, (C1-6) alkyl, (C7-10)phenylalkyl, (C3-7)cycloalkyl or (C4-8) cycloalkylalkyl, R3 and R4, independently are CN, COOR7, COR,, S(O)nRg,

n isO, 1 or 2, R7, Ra and Rg independently are (C1-6) alkyl, (C3-,) alkenyl, (C3-,) alkinyl, (C3-7) cycloalkyl, (C4-8) cycloalkylalkyl, hydroxy (C2-,) alkyl, (C3-6) alkoxyalkyl, hydroxy (C4~8) alkoxyalkyl, amino (C2~6) alkyl, (C1-4) alkylamino (C2-,) alkyl, di[(C,~4 )alkyl] aminoalkyl, phenyl, (C7-10) phenylalkyl, a 5-or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen oxygen or sulphur and which may contain additionally 1, 2 or 3 ring nitrogen atoms, or (C,~4) alkyl substituted by a 5-or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and which may contain additionally 1,2 or 3 ring nitrogen atoms, A is (C1,) alkylene, R10and R11 independently are (C1-6)alkyl, (C3-6) alkenyl or (C3-,) alkinyl, (C3-7) cycloalkyl, (C4-,) cycloalkylalkyl, hydroxy (C2-6) alkyl, (C3-,) alkoxyalkyl, hydroxy (C4-3) alkoxyalkyl, amino (C2,) alkyl, (C1~4) alkylamino (C2,) alkyl, di[C1-4) alkyl aminoalkyl, phenyl, (C7 1O) phenylalkyl, or Rlo and R11 together with the nitrogen atom form a 5-, 6- or7-membered heterocyclic ring, which may contain a further heteromember selected from oxygen, sulphur and a group =N-R,2, wherein R12 is (C1-4) alkyl, and R, is hydrogen, halogen, (C,~4) alkyl, (C,~4) alkoxy, (C1-4) alkylthio, (C,~4) alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, (C,~4) alkylamino, di [ (C1-4) alkyl] amino, (C1-5) alkanoylamino, (C2-5) carbalkoxy, aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, (C1-4) alkylsulfamyl or di [(C,~4) alkyl] sulfamyl, and X is oxygen or sulphur, in free base or in a pharmaceutically acceptable acid addition salt form and B) a p-adrenoceptor blocking agent and/or C) a vasodilating nitrate, hereinafter referred to as a composition of the invention.

The components A), B) and C) of the composition are generally known. Particularly the compounds of formula I are known from e.g. European Patent Publication No. EP 150 (application No. 78100165.6), U.K.

Patent Publication No. 2041 358 (application No.

7943112) and U.K. Patent Publication No. 2037766 (application No.7943113).

In any of the above radicals for active component A) of formula I, alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 to 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in COOR7 is preferably not attached to the a-carbon atom and is preferably attached to the distant terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably has an ethylene or propylene moiety substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino respectively. The alkyl moiety of cycloalkylalkyl is conveniently methyl.Halogen means fluorine, chlorine or bromine and is especially chlorine. Cyc loalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl or cyc lohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in R, or COOR7 is preferably not in the a,ss position. Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is convenientyl allyl or 2-methylallyl. Alkinyl is conveniently propinyl.

Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl. When R1 is optionally substituted phenylakyl, the phenyl group is prefer ably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same.

When R7, R, or R9 contain a heterocyclic ring this may be for example furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tet razoly], pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpholinyl ortriazinyl.

When R10 and R11 together with the nitrogen atom to which they are bound, for a heterocyclic ring, this is preferably saturated and may be for examle pyrrolidine, piperidine, piperazine, N-alkylpiperazine, morpholine, azepane, diazepane or Nalkyl-diazepane.

R2 is conveniently identical to R5.

R6 is conveniently halogen, alkyl or alkoxy, or hydrogen and is conveniently adjacent to the dihydropyridine moiety.

As components A) the following compounds of formula I, wherein y indicates the position of the dihydropyridine moiety, may be used.

Compound Rl R3 R3 R5 R6 X y No. 1 2 l H CH3 CN COO-i-Bu CH3 H 0 4 2 H CH3 COOC2H5 SO2CH3 CH3 H 0 4 3 H CH3 CN COOC2H5 CH3 H 0 4 4 H CH3 CN COOC2H5 CH3 H S 4 5 H CH3 CN COOCH2CH(CH3)2 CH3 H S 4 6 H CH3 COOCH3 COC6H5 CH3 H 0 4 CH3 7 H CH3 COO(CH2)2N/ COOC2H5 CH3 H 0 4 CH2C6R5 /CH3 8 H CH3 COO(CH2)2N COOC2H5 CH3 H S 4 CH2C6H5 9 H CH3 - COO(CH2)2N(CH3)2 COO (CR2) 2N(CH3)2 CH3 H 0 4

Compound R1 R2 - R3 R4 R5 R6 X y Np, 10 H CH3 COO(CH2)2N(CH3)2 COO(CH2)2N(CH3)2 CH3 H S 4 11 H CH3 COO(CH2)2N(CH3)2 COOC H CH3 H 0 4 12 H CH3 COO(CH2)2N(CH3)2 COOC2Hg CH3 H S 4 /CR3 13 H CH3 COO(CH2)2N COOC2H5 CH3 H S 5 CH2C6H5 /CH3 14 H -CR3 COO (CH2) 2N COOC2H5 CH3 H 0 5 CH2C6H5 CH3 15 H CH3 COO /CR3 COOCH3 CH3 H O 4 L\ CH2CsH5 16 H A COOC2H5 COOC2H5 CH3 H O 4 17 H A COOCH3 COOCH3 CH3 H 0 4 18 H A COOCH3 COOCH3 t H O 4 Compound R1 R2 R3 R4 R R X No.

19 H t COOC 2R5 COOC2H5 A H O 4 20 H CH3 coo(CH2)2 C6H5 COOCH3 CH3 H 0 4 21 H CH3 COOCH3 COOCH2CsH5 CH3 H 0- 4 22 H CH3 COOC2H5 COOC2H5 CH3 H 0 4 23 H CH3 COOC 2R5 COOC2H5 CH3 H S 4 24 H CH3 C0OC(CR3)3 COOC(CH3)3 CR3 H S 4 25 H CH3 COOCH3 .COOCH3 CH3 7-C1 0 4 26 H CH3 COOCH3 COOCH3 CH3 H S 4 27 H CH3 COOC2H5 C00C2R5 CH3 5-OCH3 S 4 28 H CH3 COOC2H5 COOC2H5 CH3 7-C1 S 4 29 H CH3 COOC2R5 COOC2H5 CR H S 5 30 H CH3 COOC2H5 COOC2H5 CH3 4-C1 S 5 Compound R1 R2 R3 R4 R5 R6 X y No.

31 H CH3 COC(CH3)3 COC(CH3)3 CH3 H S 4 32 H CH3 COCH3 COCH3 CH3 7-Cl O 4 33 H CH3 COCH3 COCH3 CH3 H S 4 34 H CH3 COC2H5 COC2H5 CH3 5-OCH3 S 4 35 H CH3 COC2H5 COC2H5 CH3 7-C1 S 4 36 H CH3 COC2H5 COC2H5 CH3 H S 5 37 H CH3 COC2H5 COC2H5 CH3 4-C1 S 5 38 H CH3 COCH3 COCH3 CH3 H 0 4 39 H CH3 COCH3 COOC2H5 CH3 H 0 4 40 H CH3 COCH3 COOC2H5 CH3 H S 4 41 H CH3 COOCH3CH(CH3)2 COOCH3 CH3 H 0 4 42 H CH3 COOCH3 COOCH3 CH3 H 0 4

Compound R1 R2 R3 R4 R5 R6 X y No.

43 H CH3 COOC2H5 COOC2H5 CH3 H 0 5 44 H CH3 COOCH2CH(CK3)2 COOC2H5 CH3 H S 4 45 H CH3 CoocH2cH(cH3)2 COOC25 CH3 H 0 4 46 H CH3 COOC(CH3)3 COOC(CH3)3 CH3 H 0 4 47 H CH3 COOCH2CH(CH3)2 COOCH2CH(CH3)2 CH3 H 0 4 48 H CH3 COO(CH2)20C2H5 COOC2H5 CH3 H 0 4 49 H CH3 COO(CR2)20C2H5 COOC2H5 CH3 H S 4 50- H CH3 COO (CH2) 20C2Hg COOC2H5 CR3 H S 5 51 H CH3 COOCH(CH3)2 COOCH3 CH3 H 0 4 52 H CH3 00(CH2)20CH3 COOCH3 CH3 H ' 0 4 53 H CH3 COO(CH2)2OCH(CH3)2 COOCH3 CH3 H 0 4 54 H CH3 COO(CH2)2C2H5 COOCH3 CH3 H 0 4 55 H CH3 COO < COOCH3 CH3 H 0 4 56 H CH3 CoO(CH;)2oCH3 COOCH(CH3)2 CH3 H 0 4 Compound No.R1 R2 R3 R4 R5 R6 X Y 57 H CH3 COOCH3 COOC2H5 CH3 H O 4 58 CH3 CH3 COOC2H5 COOC2H5 CH3 H O 4 59 n-C3H7 CH3 COOC2H5 COOC H CH3 H 0 4 Preferred compositions of the invention contain a component A-) of formula I in which R, is hydrogen or (C1-6)-alkyl or R2 and R5 independently are (C1-6)alkyl or the dihydropyridine ring is in position 4 of the benzoxa- or -thia diazolyl moiety orX is oxygen or R6 is hydrogen or R3 and R4 independently are COOR, COR8or

in which R7,, R8' R10' R11 and A are as defined above.

However, R, is preferably (C1~6) alkyl, (C3-6) alkoxyalkyl, (C-7) cycloalkyl or (C7-10) phenylalkyl, R8 is preferably (C1-6) alkyland preferably one of R10 and R11 is (C1-6) alkyl and the other (C7-10) phenylalkyl and-A is preferably (C1-2) alkylene.

Particularly preferred components A) are such of formula la,

wherein R1a is hydrogen or (C1-6) alkyl, R2a and R3a independently are (C1-6) alkyl R3a and R4a independently are COOR7a' COR, or

in which R7a is (C1-6) alkyl, (C3-6) alkoxyalkyl (C3-7) cycloalkyl or (7-10) phenylalkyl, R8a is (C1-5) alkyl, one R10a and R11a is (C1-6) alkyl, the other is (C7-10~phenylakyl alnd Aa is (C1-2)alkylene.

In the components A) of formula la, preferably one of R3a and R4a is COOR7, and the-other is COR8a'

orCOOR7,, in which Fl7,, R8,, A,, Rica and R,1a are as defined above.

If both R3a and R4a independently are COOR7,, preferably one of R3a and R4a is (C2-7) alkoxycarbonyl and the other is (C4~7) alkoxyalkoxycarbonyl, (C4-8) cycloalkoxycarbonyl, (C8-11) phenylalkoxycarbonyl or (C2-7) alkoxycarbonyl. If one of R3a and R4a is (C2-7) alkoxycarbonyl, and the other is (C5-7) alkoxyalkoxycarbonyl or (C4-7) alkoxycarbonyl, preferably at most one of the terminal alkoxy groups having at least 4 carbon atoms is branched. Preferred as active components A) are the compounds having the compounds Nos. 7,21,22,39,41,45,48,51,57 and 59.

Especially preferred-are the compound Nos. 21, 22, 51, 54 and 55, particularly 22.

A suitable ss-adrenoceptor blocking agent B) is e.g.

a compound having an

side chain attached through the oxygen thereof directly to an aryl moiety, or a

side chain attached through the 1-carbon atom thereof directly to an aryl moiety.

The aryl moiety may be, for example, of up to 10 carbon atoms, e.g, phenyl or naphthyl, e.g. 4-indolyl or 1-naphthyl, and may contain one ortwo heteroatoms, e.g. nitrogen as in indolyl or nitrogen and sulphur as in thiazolyl. The-aryl moiety may also have one or two ring substituents, e.g. acetyl, allyl, allyloxy, aminocarbonylmethyl, cyano, methyl chloro, methoxy, methoxyethyl, amido, hydroxy, nitro, propinyloxy, (C1-4) alkanoylamino, methylsulfamoyl, morpholino, methylthio, oxo and tetrahydrofurylmethyloxy substituents.

The aryl moiety may also have an alkyl chain between two adjacent carbon atoms, thereby forming a saturated ring. For example, the aryl moiety nucleus may be tetralone ortetraline.

The amino group of the

side chain conveniently has a branched chain alkyl substituent of 3 to 7 carbon atoms, e.g. isopropyl or tert-butyl.

Examples of suitable known blocking agents are Acebutolol, Alprenolol, Atenolol, Bufetolol, Bunitrolol, Bunolol, Bupranolol, Labetalol, Metaprolol, Nadoxolol, Oxprenolol, Pargolol, Procinolol, Propranolol, Talinolol, Timolol, Tiprenolol, Tolamolol, Toliprolol, Trimepranol.

Preferred as active agents B) are compounds interfering little with myocardial contractile function and having little effect on heart rate, e.g. compounds possessing some degree of intrinsic sympathomimetic activity.

Especially interesting compounds are: 4 - (2 - hydroxy -3 - isopropylaminopropoxy) indole (Pindolol) and 4 - (2 - benzoyloxy - 3- tert - butvlaminoprnpoxy) -2 - methylindole (LT).

Preferred as active components C) are known (C1~6) aliphatic alcohol esters of nitric acid. Especially preferred are (C3-6) aliphatic polyol esters of nitric acid, such as glyceryl trinitrate and mannitol hexanitrate, particularly erythrityl tetranitrate and pentaerythritol tetranitrate, especially isosorbide dinitrate.

Active agents A) and B) may be in the free base form or in salt, e.g. in acid addition salt form.

The new composition may be prepared by a process comprising formulating component A) with component B andlor component C), in a state of purity sufficient for pharmaceutical acceptability. Conventional pharmaceutical excipients including carriers and diluents, may also be formulated therewith.

Preferred is a composition containing components A) and B).

The composition of the invention exhibits pharmacological activity in animals and is therefore indicated for use as a pharmaceutical, e.g. for therapy. In particular, the composition of the invention exhibits a calcium-antagonistic effect, as indicated in standard tests, e.g. as follows: An inhibition of the calcium-induced contraction of isolated dog coronary arteries suspended in a depolarizing solution is observed at a concentration of about 10-'OM to about 106M M of active agent A) (method of Godfraind and Kaba, Brit J. Pharm. 36 [1969] 549-560) The composition containing components A) and B) exhibits additionally a blocking effect on the adrenergic preceptors as indicated in the following standard test In the isolated, spontaneously-beating guinea pig atrium (method of K. Saameli,Helv. PhysibL Acta [1967] CR 219-CR 221) inhibition of the positive inotropic effect of adrenaline is observed at a bath concentration of about 10-9 to about 106M of active agent B).

The composition containing components A) and C) exhibits in addition to the calcium-antagonistic effect an arterial and venous smooth muscle relaxing effect, as indicated in the hemodynamic standard test with the open chest cat in the form of a reduction of preload-and afterload.

The composition containing component A) and component B) and/or component C) exhibits antihypertensive activity, as indicated by a blood pressure lowering activity in standard tests.

For example, the composition exhibits a blood pressure lowering effect in the Grollman rattest[see A. Grollman, Proc. Soc. Expt. Biol. and Med. 57,104 (1944)] as well as in tests carried out in a similar way in spontaneously hypertensive rats on s.c. administration offrom 0.1 to 10 mg/kg animal body weight of the composition.

The composition of the invention is therefore hindi; cated for use in the treatment of coronary heart disease, e.g. Angina pectoris, and hypertension.

An indicated oral daily dosage of active component A), e.g. compound No.22 is from about 5 mg to about 200 mg, particularlyfrom about5to about 100 mg, conveniently administered in divided doses 2 to 4times a day in unit dosage form containing from about 1.25 mg to about 100 mg, particularly from about 1.25 to about 50 mg of the compounds or in sustained release form.

An indicated preferred weight ratio of active agent A) to active agent B), calculated on the free base moiety thereof, is from about 100:1 to about 1 :10, particularly from about 100:1 to about 1:1, preferably from about 50:1 to about 5:1.Thus for compound No.22 and LTa preferred range is from about 100:1 to about 1:1, especially about 50:1. For compound No.22 and Pindolol a preferred range is from about 10:1 to about 1 :10, particularly from about 10:1 tol:1,especiallyabout7:1.

An indicated preferred weight ratio of component A) to component C), calculated on the free base of component A), is from about 1:3 to about 10:1, particularly about 10:3. For compound No.22 and isosorbide dinitrate the preferred range is from about 1:3 to about 10:3, particularly from about 1:3 to about fro:1, especially about 10:3.

An indicated preferred weight ratio of component A) to component B) to component C), calculated on the free bases of components A) and B), is from about 2:20 to about 0.2 :24 to about 2:10.

For compound No.22, Pindolol and isosorbide dinitrate, the preferred weight ratio is from about 2:20 to about 1:1.5 to about 2:6, particularly about 7:1.5:6. For compound No.22, LTand isosorbide dinitrate, the preferred weight ratio is about 70:2:60.

Conveniently components A) and B) and/or C) are administered in the form of a pharmaceutical composition comprising a compound offormula I in free base form or in pharmaceutically acceptable acid addition salt form, and a p-adrenoceptor blocking agent in free base form or in pharmaceutically acceptable salt, e.g. acid addition salt form, and/or (C1-6) aliphatic alcohol ester of nitric acid, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution or a tablet.

It has now been found that the composition of the invention surprisingly does not lead to the unfavourable effectsthatcan be expected on the basis of the components A), B) and C) when taken alone. For compositions containing components A) and B), surprisingly no clinical observations can be made which indicate that the combination of a P-adrnnergic blocking agent and a calcium antagonist generally may be-highly dangerous.

It is known that P-adrenergic blocking agents as well as standard calcium antagonists such as Ver apamil and Nifedipine have some degree of car diodepressant effect It was therefore to be expected that their use in combination would be dangerous since an interaction in any heartthatdoes not have much functional reserve might precipitate conges tive heart failure. This condition of insufficient func tional reserve is difficult to exclude completely and is common in patients with severe coronary heart dis ease.

It has therefore generally been stated that patients should not be simultaneously treated with a calcium antagonist and an adrenergic blocking agent. For the combination of Nifedipine and an adrenergic blocking agent very conflicting opinions have been expressed.

Thus cardiovascular accidents have been reported in cases of concomittant administration of Vepar pamil and a blocking agent (Witchitz, S. et al., Nouv. Presse Med. 4 [1975] 337) and of Nifedipine and Atenolol (G. Mottle et al., Nouv. Presse Med. 9 [1980] 379). Great caution in such simultaneous administration has generally been recommended (K.E. Wirth,Med. Welt 29 [1978] 413).

However, to our surprise it has now been found that the dosage of active agent A) necessary to produce a significant cardioepressant effect is several orders of magnitude higher than the dosage effective in producing a potent calcium antagonistic effect.

This observation was arrived at as follows: First the potency of calcium antagonism was determined on coronary arteries in vitro: Mongrel dogs of either sex weighing between 15 and 30 kg were anaesthetized by rapid i.v. injection of pentobarbitone (50 mg/kg) and killed by i.v. injection of 100 ml of air. The heart was removed and placed in a modified Krebs-Henseleitsolution (mM): NaCI 118, KCI 4.7, MgSo41.2, CaCI2 2.5, KH2PO4 1.2, NaHCO2 25, glucose 11, at 37 C, gassed with 95% 2-5% CO2. Branches of the ventral interventricular artery (about 500 to 1000 11Lm outer diameter) were dissected and cut into helical strips, approximately 1 to 3 mm wide and 10 mm long.

The strips were suspended in 10 ml organ baths containing Krebs-Henseleitsolution at370C gassed continuously with 5% CO2 in oxygen. Changes in the tension of the strips were recorded isometrically with electromechanical transducers (Statham model UC 3) and a potentiometric recorder. At the beginning of the experiments the strips were stretched to an initial tension of 500 mg and then allowed to equilibrate for 120 to 180 minutes in the bathing medium. Thereafter the Krebs-Henseleit solution was replaced by a solution containing 100 mM KCI in equimolar repiacement for NaCI. Cumulative response curves for CaC12 were established, using the method described by Van Rossum, J.M.,Arch.

Intern. Pharmacodyn. 143 (1963) 299. The duration of exposure to a particular concentration depended on the time to reach equilibrium (the maximum response reached with that particular concentra tion). Thus there was no fixed interval at which the concentration of the agonist was increased. Com po nent A) or Verapamil was added 30 min. before the first administration of CaCI2. The effects were expre ssed as percentage of the preceding response to nM CaCI2. In all experiments at least one strip was used as control.

The pA2 values obtained were 10.5 for compound No.22 and 7.8 for Verapamil.

Then the effects on contractility of paced guinea pig left arteria in vitro was measured; Guinea pigs of either sex weighing 250 to 400 g were killed by a blow on their heads and the left atrium was rapidiy dissected from the heart and suspended ina modified oxygenated Tyrode solu tion at 30"C. The preload was adjusted to 1 g, rectan gular impulses of 10 msec. at a rate of 1 Hz were used for pacing through a platinum cathode attached to the lower end of the tissue. The tension developed was measured isometrically with a Statham UC 3 transducer.

Compound No. 22 or Verapamil was added to the bath in increasing amounts.

The highest dose of compound No. 22, 0.444 CLM, reduced the contractile force to 56% of its baseline value. With Verapamil a comparable reduction was obtained at about 1.4,aM.

These results should be compared with the results obtained on coronary arteries. In the case of com pound No. 22 there is an about 10'000 fold difference between the concentration mentioned and the pA2 of Ca-antagonism whereas for Verapamil this difference is only about 100 fold. This shows that com pound No. 22 is about 100 times less cardiodepressantthan Verapamil for a similar degree of calcium antagonism. Due to this, selectively component A) can be combined with agents that have negative influences on myocardial contractility, e.g. beta blockers. Secondly, it has been found that a combi nation of active agent A) with an active agent B) has unexpected non-additive properties for these undesirable side-effects.

This observation was arrived at in the anaethetized open chest cat as follows: The microsphere method as described in 1967 by Rudolph, A.M. and Heymann, M.S. in Circ. Res. 21 (1967) 163 and modified by R.P. Hof, F. Wylerand G.

Stalder, Basic Res. Cardial. 75, 747-756 (1980) was used. Cardiac output was calculated from the flow signal of an electromagnetic flow meter since the calibration factors indicated bythe producer of the flow probes did not apply to cat aortic blood flow, these probes were calibrated at the end of each experiment with a microsphere injection, using the reference flow method of Buckberg, G.D. et al.,J. of Applied Physiology 31 (1971), 598-604. This consists in sampling blood at a known flow rate into a syringe, which can be regarded as "an external organ".

This sampling is done during the time of microsphere circulation. The number of microspheres in the syringe is then determined and cardiac output can be calculated as follows: Nj CO=Q5x N5 where-CO is cardiac output, Os is flow to the syringe, N 1 is the number of spheres injected and N5 is the number of spheres in the syringe.

Cats of 2 to~4 kg of body weight were anaesthetized with chloratose urethane (43 and 430 mg/kg) and ventilated with a Loosco M.K.II infant ventilator with positive end-expiratory pressure. Catheters were inserted into the femoral artery and vein.The thorax was dpened through the left fourth intercosttal space,the aorta was freed of its adventitia and.an -electromagnetic flow probe was placed around it The electromagnetic flow signal bandits first derivative, acceleration of the blood in the aorta, mean.aor-- tic flow, phasic-and mean aortic blood pressure, heart rate and megan right artial pressure were recorded on a Beckmann R612 8 channel recorder.

For flow measurements a Narco RT500 flowmeter was used. Differentiation was performed by a HSE 401 differentiator Theflowsignal, which is a measurement ofthe velocity of blood in the aortic root was electronically integrated to obtain mean aorticflow. At the same time this signal was fed into the differentiator mentioned. The output of the differentiator, acceleration of blood in the aorta, is an indicator of myocardial function and was used instead of dp/dt (R.R. Rushmer, Circulation 29 [1964] 268, G.C.

Van den Bos et al.. Cardiovascular Research 7 [1973] 834), applied to cats by R.P. Hof and-A. Hof,Journal of Pharmacological Methods, accepted for publication in 1981.At the end of the experiments the cats were dissected and the organs or samples of tissue placed in counting vials. The samples were counted in a Packard Mod. 9012 gamma counter with a 1024 channel pulse height analyser. Component A), e.g.

compound No.22 was dissolved in polyethyleneg glycol 400.1 ml plus ethanol 1 ml per milligram of active substance and administered intravenously at a dose of 43 yg/kg i.v.. Coronary blood flow was markedly increased. The experiment was then repeated, with LT being infused intravenously at the dose of 50 jllg/kg. After a stabilisation time of 60 minutes, compound No.22 was then administered exactly as described above to obtain results strikingly similar to those without pretreatment.Thus, the magnitude ofchange and-time course of all relevant general hemodynamic parameters indicative of myocardial contractility, such as acceleration of blood and cardiac output, were comparable in cats not pretreated and in cats pretreated with the-p adrenoceptor blocking agent, which means that the combination of components A)-and B) is a non-additive one, since ,8-blockers are known to diminish coronary blood flow;The same was observed with retard to heart rate. The adequacy of beta blockade was checked by comparing the effects of a test dose of isoproterenol 0.05 /lglkg before, to the effects of 0.1,ag/kg after the betablockade.All isoproterenol effects were completely or almost completely suppressed by the dose of LT used.

Additionally there can be established that a diminuation of the coronary blood flow, caused by a component B), is compensated by a component A) and an increase of the preload caused by component A) is compensated by component C).

The simultaneous. administration of an active agent A) and an active agent B) and/or C) is therefore unexpectedly safe.

The combination of the invention can be used, surprisingly, without untoward cardiodepressant effect, e.g. in cases of hypertension and especially in cases of coronary disease that do not respond satisfactorilywhen either active agent A) or active agent B) or active agent C) is administered alone.

It isto be appreciated that the beneficial effects of the combination may also be obtained when active agents A) and B) and/or C) are administered separately, in analogous manner two that indicated above, e.g. in-the form of pharmaceutical compositions.

Thus a therapeutically effective amount of active agentA) and of active agent B) and/or C) may be administered to a subject in need of such treatment.

If desired the active agents. may be ordered in a pack to facilitate administration of a particular dosage regimen, e.g. in a particular order in a blister pack.

A suitable composition may consist of a pack containing separately active agents A) and B) and/or C) until required for concomitant administration, con veniently together with instructions for the concomitant administration of a predetermined amount of active agent A) and a predetermined amount of active agent B) and/or C).

The following compositions may be formulated using standard encapsulating ortabletting techniques and are useful for oral administration 2 to 3 times a day for the treatment of coronary heart disease or hypertension.

EXAMPLES Example 1 Ingredient Capsule (mg) Compound No.22 (in free base form) 25.0 Pindolol (in free base form) 5.0 Lactose 158.0 Polyvinyl pyrrolidone 7.5 Magnesium Stearate 3.0 Silica. (colloidal) 1,5 Total 200.0 Example 2 Ingredient Capsule ,(mg) Compound No. 22 35.0 isosorbide dinitrate 30.0 Pindolol a 7.5 Lactose 58.0 Mannitol 150.0 Corn Starch 15.0 Silica (colloidal) 1.5 Magnesium stearate 3.0 Total 300.0 Example 3 Ingredient Capsule (mg) Compound No.22 35.0 Isosorbide dinitrate 30.0 Lactose 65.5 Mannitol 150.0 Corn Starch 15.0 Silica (colloidal) 1.5 Magnesium Stearate 3.0 Total 300.0 Example 4 Ingredient Tablet (mg) Compound No. 22 (in free base form) 25.0 Pindolol (in free base form) 5.0 Polyvinylpyrrolidone 15.0 Lactose 185.2 Corn Starch 30.0 Talcum 6.0 Silica (colloidal) 0.8 Magnesium stearate 3.0 Total 225.0 Example 5 Ingredient Tablet (mg) Compound No.22 35.0 Isosorbide dinitrate 30.0 Pindolol 7.5 Lactose 53.5 Mannitol 150.0 Corn Starch 15.0 Polyvinylpyrrolidone K30 6.0 Magnesium stearate 3.0 Total 300.0 Example 6 Ingredient Tablet (mg) Compound No. 22 35.0 Isosorbide dinitrate 30.0 Lactose 61.0 Minnitol 150.0 Corn Starch 15.0 Polyvinylpyrrolidone K 30 6.0 Magnesium stearate 3.0 Total -300.0 Example 7 Compound No. 22 in the formulations of Examples 1-6 may bd replaced by compound No.41 to obtain formulations for similar uses.

Example 8 Compound No. 22 in the formulations of Examples 1-6 may be replaced by compound No. 51 to obtain formulations for similar uses.

Example 9 Pindolol in the formulations of Examples 1,2,4 and 5 may be replaced byan amount of 1 mg of LTto obtain formulations for similar use.

Claims (20)

1. A pharmaceutical composition containing as active agents A) a compound of formula I,

wherein R1 is hydrogen, (C1-8) alkyl, hydroxy (C2-6) alkyl, (C3-6) alkoxyalkyl, (C3-6) alkenyl, (C3-6) alkinyl, (C3-7) cycloalkyl, (C4-8) cycloalkylalkyl, (C4-8) cycloalkylalkyl, (C7-9) phenylalkyl or (C1-12) phenylalkenyl, the phenyl ring being unsubstituted or independently mono-, di- or trisubstituted by halogen, hydroxy, (C1-4)alkyl, or (C1-4)alkoxy, R2 and R5' independently, are hydrogen, (C1-6) alkyl, (C7-10)phenylalkyl, (C3-7)cycloalkyl or (C4-8) cycloalkylalkyl, R3 and R4 independently are CN, COOR7, CORa' S(O)nR6,

nisO,1 or2, R7, R8 and R9 independently are (C1-12) alkyl, (C3-6) alkenyl, (C3-6) alkyl, (C3-7) cycloalkyl, (C4-8) cycioal kylalkyl, hydroxy (C2-6) alkyl, (C3-12) alkoxyalkyl, hyd roxy (C4-8) alkoxyalkyl, amino (C2-6) alkyl, (C1-4) alkylamino (C2-6) alkyl, di [C1-4) alkyl] aminoalkyl, phenyl, (C7-10) phenylalkyl, a 5-or 6-membered heterocyclic ring containing one heteratom selected from nitrogen, oxygen or sulphur and which may contain additionally 1,2 or3 ring nitrogen atoms, or (C1-4) alkyl substituted by a 5- or 6-membered heterocyclic ring containing one heteroatom selected from nitrogen, oxygen or sulphur and which may contain additionally 1,2 or 3 ring nit rogen atoms, A is (C1-5) alkylene, R10 and R11 independently are (C1-6) alkyl, (C3-6) alkenyl or {C3~6) alkinyl, (C3 7) cycloalkyl, (C4-8) cyc loalkylalkyl, hydroxy (02-6) alkyl, (C3-6) alkoxyalkyl, hydroxy(C4-8) alkoxyalkyl, di[(C1-4)alkyl]aminoal kyl, phenyl, (C7-10) phenylalkyl, or R10 and R11 together with the nitrogen atom form a 5 -, 6- or7-membered heterocyclic ring, which may contain a further heteromember selected from oxygen, sulphur and a group =N-Rt2, wherein Rt2 is (C1-4) alkyl, and R6 is hydrogen, halogen, (C1-4) alkyl, (C1-4) alkoxy, (C1-4 alkylthio, (C1 -4) alkylsulfonyi, trifluoromethyl, nitro, hydroxy, azido, amino, (C1-4) alkylamino, di [C1-4)alkyl]amino, (C1-5)alkanoylamino, (C2-5)carbalkoxy, aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, (C1 4) alkylsulfamyl or di [(C ~4) alkyl] sulfamyl, and X is oxygen or sulphur, in free base or in a pharmaceutically acceptable acid addition salt form and B) a ss-adrenoceptor blocking agent and/or C) a vasodilating nitrate.

2. A composition of claim 1 containing as a componentA) a compound offormula la

in which Ria is hydrogen or (C1-6) alkyl, R28 and Flea are independently (C1-6) alkyl, R3a and R4a independently are COOR7,, COR, or

in which R7a is (C1-6) alkyl, (C35) alkoxyalkyl, (C3-7) cycloalkyl or (C7-10) phenylalkyl, Flea is (C1-5) alkyl, one of R10a and Riia is (C1-6) alkyl the other is (C7-10) phenylalkyi and Aa is (C1-2) alkylene.

3. A composition of claim 2, in which both R3a and R4a independently are COOR7a in which R7a is defined as in claim 2.

4. A composition of claim 3, in which R3a and R4a independently are (C2-7) alkoxycarbonyl.

5. A composition of claim 1, containing as a component A) 4-(2, 1,3 - Benzoxadiazol -4-yl) - 1,4 - dihydro - 2,6 - di i methyl - pyridine - 3,5 - dicarbox ylic acid-diethylester.

6. A composition of claim 1, containing as a component B) Pindolol.

7. A composition of claim 1, containing as a component C) isosorbide dinitrate.

8. Acomposition of claim 1, consisting of a component A) and a component B) as active agents.

9. A composition of claim 1, consisting of a com- ponentA), a component B) and a component C) as active agents.

10. A composition of claim 8, wherein the weight ratio of components A) and B) is from about 100:1 to about 1 :10.

11. A composition of claim 8, consisting of 4 (2, 1, ; 3-Benzoxadiazol-4- yl)-1,4-dihydro-2, 6- dimethyl - pyridine -3,5 - dicarboxylic acid diethylester as a component A) and Pindolol as a component B).

12. Acomposition ofclaim 11,whereinthe weight ratio of components A) and B) is from about 10:1 to about 1:10.

13. Acomposition of claim 9, consisting of 4- (2, 1.3-Benzoxadiazol-4 -yl)-1,4-dihydro-2, 6- dimethyl - pyridine - 3, 5 - dicarboxylic acid diethylester as a component A), Pindolol as a component B) and isosorbide dinitrate as a component C).

14. A composition of claim 13, wherein the weight ratio of com ponents A), B) and C) is from about 2:20 to about 1:1.5 to about 2:6.

15. A pharmaceutical composition according to claim 1, substantially as hereinbefore described with reference to any one of the Examples.

16. A composition according to any one of the preceding claims in unit dosage form.

17. Process for the preparation of a pharmaceutical composition which comprises bringing the components A) and B) and/or C), mentioned in claim 1, into synergistic association.

18. A method of treating coronary heart disease e.g. angina pectoris or hypertension which comprises administering a therapeutically effective amount of a composition of claim 1.

19. A pack containing A) a pharmaceutical composition comprising a compound of formula las defined in claim 1, and separately B) a pharmaceutical composition comprising a ,B-adrenoceptor blocking agent and/or C) a pharmaceutical composition comprising a vasodilating nitrate together with instructions for administering a predetermined amount of active agentA) and a predetermined amount of active agent B) and/or of active agent C).

20. The steps, features, compositions and compounds referred to or indicated in the specification andlor claims of this application individually or collectively, and any and all combinations or any two or more of said steps or features.