GB2038178A

GB2038178A - Antithrombotic therapeutic composition

Info

Publication number: GB2038178A
Application number: GB7850360A
Authority: GB
Original assignee: Parcor SARL
Current assignee: Parcor SARL
Priority date: 1978-12-29
Filing date: 1978-12-29
Publication date: 1980-07-23
Also published as: IE48883B1; FR2445142B1; DE2951669A1; FR2445142A1; IL58816A; IE792280L; GB2038178B; BE880885A; JPS5592318A; IT7951222A0; IT1162497B; IL58816A0; JPS6150925B2; DE2951669C2

Abstract

Anti-thrombotic pharmaceutical compositions comprise a pyridine derivative of the formula: <IMAGE> in which: X represents oxygen or sulfur; R represents a phenyl or benzoyl group which may be substituted by more halogen, straight- or branched-chain C1-6 alkyl or alkoxy groups, nitro, amino, sulfonylamino, carboxy, C1-6 alkoxycarbonyl, cyano, phenyl, hydroxy C1-6 alkyl, methylene-dioxy or ethylene-dioxy groups: or R may be an alpha -naphthyl or thienyl group; R1 represents hydrogen, halogen, hydroxy, a straight- or branched-chain C1-6 alkyl or alkoxy group or a phenyl group; R<1> represents a C1-6 alkyl group; and n is an integer from 1 to 15; wherein R1 may have different meanings in each radical CHR1 when n is greater than 1, or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof: together with a beta-receptor blocking agent (e.g. propranolol metoprolol, atenolol, acebutolol, pindalol,timolol, bupranol, bunolol, alprenol, and oxprenolol). The preferred compound (I) is ticlopidine hydrochloride.

Description

SPECIFICATION Antithrombotic therapeutic composition This invention relates to a therapeutic composition having an antithrombotic activity comprising, as active ingredient, a combination of a compound having anti-blood-platelet-aggregating properties and of a compound having beta-receptor blocking properties.

The compound having anti - blood - plateletaggregating properties is selected from the pyridine derivatives having the formula:

in which: X represents oxygen or sulfur; R represents a phenyl or benzoyl group which may carry one or more substituents selected from halogen atoms and the straight- or branched-chain lower alkyl groups, the straight- or branched-chain lower alkoxy groups, the nitro, amino, sul fonyla mi no, ca rboxy, lower al koxyca rbonyl, cyano, phenyl, hydroxy(lower)alkyl, methylene-dioxy and ethylene-dioxy groups; an a-naphthyl group or a thienyl group; R, represents a hydrogen or halogen atom or a hydroxy group, a straight- or branched-chain lower alkyl group, a straight- or branched-chain lower alkoxy group or a phenyl group;R' represents a lower alkyl group and n is an integer from 1 to 15; and the symbols R, may have different meanings in each radical CHR1 when n is greater than 1; and the pharmaceutically acceptable acid addition salts and quaternary ammonium derivatives of said derivatives.

By "lower alkyl" and "lower alkoxy" are meant here groups having 1-6 carbon atoms and particularly 1-4 carbon atoms.

The above derivatives, the processes for their preparation and their therapeutic applications are described, particularly in French Patents and published applications Nos. 2,215,948; 2,345,150 and 2,336,932.

Non-limiting Examples of derivatives of the formula (I) useful in the therapeutic composition of this invention include: 5 - (2 - chloro - benzyl) - 4, 5,6,7 tetrahydrothieno [3, 2 - ci pyridine, (ticlopidine); 5 (3, 4, 5 - trimethoxybenzyl) - 4, 5, 6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - (4 - methoxy - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 hydroxy - 2 - phenyl - ethyl) - 4, 5, 6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - p.chlorobenzyl - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 p.chlorobenzyl - 4, 5, 6, 7 - tetrahydro - furo [3, 2 - c] pyridine; 5 - (3, 5 - dimethoxy - benzyl) - 4, 5,6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - (3,4, 5 trimethoxy - benzyl) - 4, 5, 6,7 - tetrahydro - furo [3, 2 - ci pyridine; 5 - (3 - methoxy - benzyl) - 4, 5,6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - (3 - methyl - benzyl) - 4, 5, 6, 7 - tetrahydro - furo [3, 2 - c] pyridine; 5 - (4 methyl - benzyl) - 4, 5, 6, 7 - tetrahydro - furo [3, 2 - c] pyridine; 5 - (2 - fluoro - benzyl) - 4, 5, 6,7 - tetrahydrothieno [3, 2 - ci pyridine; 5 - (3,4 - dichloro - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 - phenyl - ethyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 ci pyridine; 5 - (2 - phenyl - ethyl) - 4, 5, 6,7 - tetrahydro - furo [3, 2 - ci pyridine; 5 - (1 - methyl - 2 hydroxy - 2 - phenyl - ethyl) - 4, 5, 6, 7 - tetrahydro - thieno , 2 - c1pyridine; 5 - (2 - methyl - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (3 methyl - benzyl) - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 c] pyridine; 5 - (4 - methyl - benzyl) - 4, 5,6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - (4 - fluoro benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (2, 6 - dichloro - benzyl) - 4, 5,6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 - nitrobenzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (4 - hydroxy - benzyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 - p.hydroxyphenyl - 2 - hydroxy - ethyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (2 - p.methoxyphenyl - 2 - hydroxy - ethyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (2 - p.chlorophenyl - 2 - hydroxy - ethyl) - 4, 5,6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 - hydroxy 2 - o.methoxyphenyl - ethyl) -4,5,6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - (2 - hydroxy - 2 m.methoxyphenyl - ethyl) - 4, 5, 6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - (3 - o.chlorophenyl - 3 - hydroxypropyl) - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 ci pyridine; 5 - (1 - phenyl - ethyl) - 4,5,6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (3 - hydroxy - 3 - p.nitrophenyl - propyl) - 4, 5, 6,7 - thieno [3, 2 - c] pyridine; 5 - (3 - hydroxy - a - phenyl - propyl) - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (2 benzoyl - ethyl) - 4, 5, 6,7 - tetrahydro - thieno[3, 2 - c] pyridine; 5 - 0 - bromobenzyl - 4, 5,6,7 - tetrahydro thieno [3, 2 - c] pyridine; 5 - p.nitrobenzyl - 4, 5, 6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - (3 - chloro - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 pyridine; 5 - (3 - hydroxy - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2 p.fluorophenyl - 2 - hydroxy - ethyl) 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2,5 dimethoxy - 2 - phenyl - 2 - hydroxy - ethyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (2,3,4 trimethoxy - benzyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - benzyl - 4,5, 6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - (2 - methoxy - benzyl) - 4, 5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine;; 5 - (3, 4dimethoxy - benzyl) - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 - c] pyridine hydrochloride; 5 - [3 - (4 - fluoro benzoyl) - propyls 4, 5, 6, 7 - tetrahydro - thieno [3, 2 c] pyridine hydrochloride; 5 - o - methoxycarbonylbenzyl - 4, 5,6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - o - carboxybenzyl - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - 0 - methoxycarbonylbenzyl - 6 - methyl - 4, 5,6, 7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (a - naphthyl - methyl) - 4, 5, 6,7 tetrahydro - thieno [3, 2 - ci pyridine; 5 - [(5 - chloro - 2 - thienyl) methyl] - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - [2 - hydroxy - 2 - (2 - thienyl) ethyl-] 4, 5, 6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - 0 - cyanobenzyl - 4, 5,6,7 - thieno [3, 2 ci pyridine; 5 - (3,4 - methylenedioxy - benzyl) 4, 5, 6, 7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - [2 - (4 - bis - phenyl) - 2 - hydroxy - ethyl] - 4, 5,6,7 - tetrahydro thieno [3, 2 - ci pyridine; 5 - 0 - hydroxy - methyl ben zyl - 4,5,6,7 - tetrahydro - thieno [3, 2 - ci pyridine;; 5 - benzhydryl - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - c] pyridine; 5 - (1 - 0 - chlorophenyl - butyl) - 4, 5, 6,7 tetrahydro - thieno [3, 2 - c] pyridine; 5 - (1 - 0 - chlorophenyl - pentyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine; 5 - (1 -0 - chlorophenyl - propyl) - 4, 5,6,7 - tetrahydro - thieno [3,2 - c] pyridine; 5 - (1 - o - chlorobenzyl - ethyl) - 4, 5, 6, 7 - tetrahydro - thieno [3, 2 - c] pyridine; and 5 - (1 - phenyl - ethyl) - 4, 5, 6,7 - tetrahydro - thieno [3, 2 - ci pyridine.

The compound having beta-blocking properties is selected from the following compounds of the formulae (II) and (ill).

A first family of compounds of this type is that represented by the formula (II)

in which: R2 represents a mono- or polycyclic, carbo- or hetero-cyclic radical which exhibits at least a ring of aromatic character and which is attached to the oxygen atom by a ring carbon atom, preferably of the aromatic ring; R3 is hydrogen orthe acyl radical of an organic carboxylic acid; and R4 represents an optionally substituted aliphatic, cycli-aliphatic or araliphatic hydrocarbon radical; and their pharmaceutically acceptable inorganic or organic acid addition salts.

The carbocyclic radicals R2 are typically phenyl radicals and also optionally partly saturated bicyclic (e.g. naphthyl, indanyl) or polycyclic (e.g. fluorene) radicals.

The heterocyclic radicals R2 may contain one or more nitrogen, oxygen or sulfur atoms. They are optionally partly saturated monocyclic (pyridyl, pyrimidyl) or bicyclic (indolyl, quinolyl) radicals.

Said radicals R2 may be substituted with at least an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, an optionally esterified or etherified hydroxy or mercapto group, or an acyl, carboxy, nitro, optionally substituted amino, or oxo group.

The acyl radicals R3 are typically the corresponding radicals of the organic carboxylic acids, particularly lower alkanoyl or benzoyl.

The aliphatic hydrocarbon radicals R4 are typically straight- or branched-chain lower alkyl groups; the cycloaliphatic radicals are typically cycloalkyl groups, and the araliphatic radicals are typically lower phenylalkyl groups.

Non-limiting Examples of compounds of the formula (I) useful in the therapeutic composition of this invention are given below: 1 - isopropylamino - 3- [(1) - naphthyloxy] - propanol (propranolol); (+) 1 - isopropylamino - 3 [4 - (2 - methoxy - ethyl) - phenoxyi - 2 - propanol (metoproiol); 2-[4- (2- hydroxy-3- isopropylamino - propoxy) - phenyl] acetamide (atenolol); 3' - acetyl 4' - (2 - hydroxy - 3 - isopropylamino - propoxy) butyranilide (acebutolol); 1 - (4 - indolyl - oxy) - 3 (isopropylamino) - 2 - propanol (Pindolol); (-) - 1 - (tert.butylamino) - 3 - [3 - (4 - morpholino - 1,2, 5 thiadiazol - 3 - yl) oxy] - 2 - propanol (timolol); 1 (Tert.butylamino) - 3 - (2 - chloro - 5 - methyl phenoxy) - 2 - propanol (bupranolol); (+) - 5 - [3 - (tert.butylamino) 2 - hydroxy - propoxyt 3,4 dihydro - 2H - naphthalenone (bunolol); 1 - (2' - allyl phenoxy) - 3 - isopropylamino - 2 - propanol (alprenolol); and 1 - (2 - allyloxy - phenoxy) - 3 isopropylamino - 2 - propanol (oxprenolol).

The second family of the compounds having blocking properties is that represented by the formula (III)

in which R2, R3 and R4 have the meanings given for the formula (II) and Rs is hydrogen or a lower alkyl radical and their pharmaceutically acceptable inorganic or organic acid addition salts.

The compounds of the formula (III) useful in the therapeutic composition of this invention include particularly: 2 - isopropylamino - 1 - (1 - naphthyl) ethanol; 2 - tert.butylamino - 1 - (2, 5 - dimethoxy phenyl) - ethanol; 1 - (3, 4- dichlorophenyl) - 2 - isopropylamino - ethanol; 2 - isopropylamino - 1 - (4 - nitro - phenyl) - propanol; 2 - isopropylamino - 1 - (4methylsulfonylaminophenyl) - ethanol; 1 - (4 - car- bamoyl - 3 - hydroxyphenyl) - 2 - tert.butylamino ethanol; and 2 - tert.butylamino -1 - (1,2,3,4 tetrahydro - 5 - naphthyl) - ethanol.

Compounds of above formulae (II) and (III) are described in published French patent application n" 2296430.

The combination constituting the active ingredient of the therapeutic composition of this invention exhibits a synergistic effect which will be evidenced by means of the following illustrative Example which gives the results of a toxicological and pharmacological investigation effected with compositions of this invention comprising, as compound having anti blood - platelet- aggregating properties, ticlopidine hydrochloride having the formula:

and, as compounds having beta-blocking properties: (a) propanolol having the formula:

(b) acebutolol having the formula:

(c) metoprolol having the formula:

and (d) atenolol having the formula:

I - TOXICOLOGICAL INVESTIGATION Said investigation related to: 1. Acutetoxicityofticlopidine hydrochloride (LD > o rat'kg:: p.o. 1938 mg; i.p. 291 mg; LD50 mice/kg p.o.777 mg; i.p. 532 mg), of propranolol (LD5kg: p.o. 35 mg in the male and 45 mg in the female), of metoprolol (LD50 rat/kg: p.o. 4070 mg; i.v. 70.1 mg; LD50 mice/kg: p.o. 2380 mg; i.v. 74.6 mg), of acebutolol and of atenolol (LD50rat'kg: p.o. > 3000 mg; i.v. > 50-60 mg; LDsO mice/kg: p.o. > 2000 mg, i.v. > 100 mg) and of the combination of this invention.

2. Chronic and delayed toxicity, 3. Local and systemic tolerance, and it was found that the composition of this invention, on administration by gastric intubation, is per fectytolerated underthe conditions of the experiment without inducing any local or systemic reaction.

The toxicity of the composition of this invention is the same as that of its components and, in this respect, no potentiation phenomenon was found to occur.

I I+HARMACOLOGICAL INVESTIGATION This investigation concerned myocardial necrosis induced in animals under severe stress conditions which may be reproduced by infusion of adrenalin.

Mongrel dogs of either sex, weighing about 10 kg, were distributed into 15 groups of 5 animals each: except for one group of untreated dogs (controls, Group I), the other groups were orally administered the test material, twice a day, for4 days, respectively: Group II: 50 mg/kg ticlopidine hydrochloride Group III: 100 mg/kg ticlopidine hydrochloride Group IV: 50 mg/kg ticlopidine hydrochloride + 5 mg propranolol/kg Group V: 100 mg ticlopidine hydrochloride + 10 mg propranolol/kg Group Vl: 50 mg ticlopidine hydrochloride + 25 mg acebutolol/kg Group VIII: 100 mg ticlopidine hydrochloride + 50 mg acebutolol/kg Group VEIL: 50 mg ticlopidine hydrochloride + 10 mg metoprolol/kg Group /X: 100 mg ticlopidine hydrochloride + 20 mg metoprololikg GroupX: 50 mg ticlopidine hydrochloride + 5 mg atenolol/kg Group XI: 100 mg ticlopidine hydrochloride + 10 mg atenolol/kg Group XII: 10 mg propranolol/kg Group XIII: 50 mg acebutolol/kg Group XIV: 20 mg metoprolol/kg Group XV: 10 mg atenolol/kg.

Eighteen hours afterthe last treatment, the dogs were anesthetized with pentobarbital (25 mg/kg, i.v.); a catheter was placed in the femoral artery, the blood pressure was recorded via a STATHAM P 23 GD sensor and the ECG was recorded (D, and D2) with a RACIA polygraph. The adrenalin was infused by the cephalic route at a dosage of 4 g/kg/mn at a rate of 2 ml/mn for 4 hours.

Arterial blood samples were taken before and after the end of the infusion to effect the blood-platelet counts.

The animals were freed from the catheters and were allowed to wake up. The animals which survived 7 days later were sacrificed and autopsied; the hearts were cut out and examined macroscopically priortotaking samplesforthe histological examination. Any macroscopic anomalies are rated according to the following code (Table I) which was established arbitrarily and which takes into account the extent of the damages (p. 10).

The following results were obtained: Blood-platelet count: The blood-platelet count effected immediately prior to and after adrenalin infusion shows a 32.4% decrease in the controls (Group I). In contrast, in the treated animals, the count tends to increase, with the exception, however, of those which were administered only,B-blocking compounds: Group II: + 14% Group VIII: + 15.1% Group lil: + 13.2% Group IX: + 16.8% Group IV: - 18% Group: + 16.5% Group: + 20% Group Xl: + 18.2% Group: + 17% GroupXII :-20.0% Group Vll: + 19.5% Group XIII :-24.1% Group XIV : - 17.4% Group XV : - 27.6% Survival time: The number of animals that survived on the 7th day after adrenalin perfusion is reported below: (p.

11): TABLE I

\ Extent of the Entirely Large Numerous Some 1 small Parts involvement hemorragic hemorragic hemorragic hemorragic hemorragic observed \ areas points points or necrotic < point Pericardium 5 4 3 2 1 Left ventricle 5 4 3 2 1 Exterior Right ventricle 5 4 3 2 1 Left auricle 5 4 3 2 1 Right auricle 5 4 3 2 1 Left ventricle 5 4 3 2 1 Right ventricle 5 4 3 2 1 Cavities Left Au ricle 5 4 3 2 1 Right auricle 5 4 3 2 1 Group l: 2/5 Group VIII :4/5 Group ll :3/5 Group IX: 5/5 Group 111:4/5 GroupX :4/5 Group IV : 4/5 Group XI :5/5 Groups 5/5 Group XII : 2/5 Group VI :4/5 Group Xlil: :2/5 GroupVII : 5/5 Group XIV :2/5 GroupXV :2/5 Macroscopic lesions: It is found that the treated animals reach necrosis scores (calculated according to the above Table) of a markedly lesser magnitude than the controls; the necrosis scores of the animals administered only blocking compounds are substantially identical with those of the controls: Group 18.0 Group VIII: :3.0 Group II :6.8 Group IX: 1.8 Group lit: 4.8 GroupX:2.6 Group IV: 2.8 Group XI 1.0 Group :2.2 Group XII:15.4 Group :3.7 Group XIII 19.6 Group VII 3.4 Group XIV:16.1 Group 13.4 It may be concluded, from the set of results obtained, that intravenous perfusion of adrenalin induces in the controls serious disorders which are essentially shown buy a drop of the number of blood-platelets and by a myocardial involvement of necrotic type. In contrast, pre-treatment with ticlopidine hydrochloride provides significant protection against myocardial necrosis, improves the survival time and increases the number of bloodplatelets.Said results are enhanced when ticlopidine hydrochloride is combined with a blocking material, both products thus functioning according to a synergistic effect. It should be noted that the p-blocking materials, when administered individually, have no effect on the blood-platelet count which is found to decrease, on the survival time which is identical with that of the controls, and on the macroscopic lesions which are substantially identical with those of the controls.

The pharmacological investigation reported above shows the usefulness of the combination of a compound having anti - blood - platelet- aggregating properties with a compound having p-blocking properties, said combination exhibiting valuable antithrombotic properties.

In view of this antithrombotic activity, the combination of this invention may be advantageously used in human and veterinary medicine.

The active ingredients are generally used together with a therapeutically administrable carrier. Thus, the composition may advantageously be formulated as tablets, coated tablets and capsules for oral administration; and as suppositories for rectal administration. Generally, each unit dose will contain 0.05-0.200 g of anti - blood - platelet- aggregating material and 0.010-0.150 g of blocking material. The daily dosage regimen may vary from 0.050 to 1 .0-g for the anti - blood - platelet- aggregating material and from 0.01 9 two 0.600 g forthep-blocking material.

Non-limiting Examples of pharmaceutical formu lations of the composition of this invention are given below.

1-Tablets Ticlopidine hydrochloride ......................... 0.200 g Propranolol ........................................ 0.030 g Excipients: starch, lactose, stearic acid, talc, sufficient to make 1 0.400 g tablet 2-Coated tablets Ticlopidine hydrochloride ......................... 0.150 g Acebutolol ........................................ 0.150 g Excipients: corn starch, dicalcium phosphate, shellac, gelatin, granulated suger, talc, titanium dioxide, carnauba wax, sufficient to make one 0.650 g coated tablet.

3 - Capsules Ticlopidine hydrochloride ......................... 0.180 g Propranolol ........................................ 0.025 g Excipients: stearicacid,talc,sufficientto make 1 capsule 4 - Capsules Ticlopidine hydrochloride ......................... 0.150 g Acebutolol ........................................ 0.150 g Excipients: talc, stearic acid, sufficient to make 1 capsule 5 - Capsules Ticlopidine hydrochloride ......................... 0.200 g Metoprolol ........................................ 0.150 g Excipients: talc, lactose, sufficient to make 1 cap sule 6 - Capsules Ticlopidine hydrochloride ......................... 0.100 g Atenolol ........................................ 0.050 g Excipients: talc, stearic acid, sufficient to make 1 capsule.

In view of its antithrombotic properties, the composition of this invention reduces the risk of accidents in patients suffering from thrombo-embolic diseases.

Thus, it is applicable, for preventive or curative purposes, in the accidents related to a thrombotic process, particularly when the latter involves the blood-platelets in its development; the composition of this invention is particularly useful in patients in which there is a risk of development or of relapse of a coronary or cerebral ischemic accident or of any vascular ischemic episode.

Claims

1. Therapeutic composition comprising, as active ingredient, a combination of (a) a pyridine derivative of formula:

in which: X represents oxygen or sulfur; R represents a phenyl or benzoyl group which may carry one or more substituents selected from halogen atoms and the straight- or branched-chain lower alkyl groups, the straight- or branched-chain lower alkoxy groups, the nitro, amino, sulfonylamino, carboxy, lower alkoxycarbonyl, cyano, phenyl, hydroxy (lower) alkyl, methylene-dioxy and ethylene-dioxy groups; an a-naphthyl group or a thienyl group; R, represents a hydrogen or halogen atom or a hydroxy group, a straight- or branched-chain lower alkyl group, a straight- or branched-chain lower alkoxy group or a phenyl group;R' represents a lower alkyl group and n is an integerfrom 1 to 15; and the symbols R, may have different meanings in each radical CHR, when n is greater than 1, or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof and (b) a compound having beta-receptor blocking properties, and a therapeutically administrable carrier.

2. Therapeutic composition according to claim 1 in which said pyridine derivative is 5 - (2 - chloro benzyl) - 4, 5,6,7 - tetrahydro - thieno [3,2 - c] pyridine or its hydrochloride.

3. Therapeutic composition according to claim 1 or 2 in which said compound having beta-receptor blocking properties is a compound of formula:

in which: R2 represents a mono- or polycyclic, carbo- or hetero-cyclic radical which exhibits at least a ring of aromatic character and which is attached to the oxygen atom by a ring carbon atom, preferably of the aromatic ring; R3 is hydrogen orthe acyl radical of an organic carboxylic acid; and R4 represents an optionally substituted aliphatic, cyclo-aliphatic or araliphatic hydrocarbon radical or a pharmaceutically acceptable acid addition salt thereof.

4. Therapeutic composition according to claim 3, in which said compound having beta-receptor blocking properties is 1 - isopropylamino - 3 -[1 - naph thyloxyi - 2 - propanol, (+) 1 - isopropylamino - 3-4 -(2- methoxy ethyl)- phenoxy]-2- propanol, 2-4 - (2 - hydroxy - 3 - isopropylamino - propoxy) phenyl] - acetamide or3' - acetyl - 4' - (2 - hydroxy - 3 - isopropylamino - propoxy) - butyranilide.

5. Therapeutic composition according to claim 1 or2 in which said compound having beta-receptor blocking properties is a compound of formula:

in which R2, R3 and R4 have the meanings given in claim 3 and R5 is hydrogen or a lower alkyl radical or a pharmaceutically acceptable acid addition salt thereof.

6. Therapeutic composition according to any one of the preceding claims in the form of unit doses containing each 0.05 g - 0.200 g of compound (a) and 0.010g-0.150g of compound (b).

7. Therapeutic composition as claimed in claim 1, substantially as described with reference to the Examples.