FR2690342A1 - Synergistic compsn. to prevent ventricular arrhythmias - contains di:aza bi:cyclo nonane and pyridyl methyl sulphonyl aminobenzoyl piperidine - Google Patents

Abstract

The pharmaceutical prod. contains cpd. A - a blocker of the brief leaving current of cardiac potassium, (as defined by Dukes and Morad Am. J. Phsiol. 257: H1746-H1749, (1989)) and cpd. B - a specific blocker of the rectifier channel of deferred cardiac potassium, (as defined by Follmer and Colatsky, Circulation 82:288 - 293, (1990)), the two cpds. being administered simultaneously or sequentially. Cpd. A is pref. 3,7-di(cyclo propylmethyl)-9,9-tetramethylene- 3,7-diazabicyclo-(3.3.1)-nonane, or one of its salts and solvates, in US 4 550 112. Cpd. B is pref. 1-(2-(6-methyl-2-pyridyl) ethyl)- 4-(4-methyl sulphonyl amino benzoyl)-piperidine or one of its salts and solvates, described in EP 235752. USE/ADVANTAGE - The cpds. act synergistically to prevent arrhythmias, esp. ventricular arrhythmias. The cpds. may be given by any route - orally, parenterally, or topically - the unit dose of each being 0.1-500 mg, pref. 2 - 50 mg. The daily dosage is most often in the range 50-2000 mg for an adult. At these doses the cpd. do not show any toxic effect.

Description

 The present invention relates to a pharmaceutical product and its use in medicine.

 U.S. Patent No. 4,550,112 describes 3,7-di (cyclopropylmethyl) -9,9-tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane and its use as an antiarrhythmic agent: it is known that this product acts by non-specific blockage of the transient current output of cardiac potassium (It).

 European Patent Application Publication NO 235752 describes 1- (2- (6-methyl-2-pyridyl) ethyl) -4- (4methylsulfonylaminobenzoyl) -piperidine and its use as an antiarrhythmic agent: it is known that this product acts by specific blockage of the delayed cardiac rectifying potassium channel (IK).

 We have now discovered that, surprisingly, 3,7-di (cyclopropylmethyl) -9.9 tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane and 1 (2- (6-methyl-2 -pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) -piperidine, when combined, act synergistically in the prevention of arrhythmias and in particular ventricular arrhythmias.

 The present invention therefore relates to a pharmaceutical product containing a compound which acts by blocking the passing current of cardiac potassium outflow (Compound A) and a compound which acts by specifically blocking the defective rectifying cardiac potassium channel (Compound B).

 The pharmaceutical product is suitable for both simultaneous and sequential administration of Compound A and Compound B, with preference being given to simultaneous administration.

 The present invention also relates to the application of the above compounds as medicaments for the treatment of arrhythmias in mammals, such as humans, characterized in that an effective and non-toxic amount of Compound A and Compound B is administered. .

 The present invention further relates to the use of Compound A and Compound B for the manufacture of a pharmaceutical product useful for the treatment of arrhythmias.

 A compound of general formula I, described in patent N 4550112 of the United States, constitutes a compound A according to the present invention.

 A compound of general formula I, described in European patent, publication number 235752, constitutes a compound B according to the present invention.

 Preferably, compound A is 3,7 di (cyclopropylmethyl) -g, s-tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane or a pharmaceutically acceptable salt of this derivative and / or a pharmaceutically acceptable solvate of this derivative.

 Preferably, compound B is 1- (2- (6 methyl-2-pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) - piperidine or a pharmaceutically acceptable salt of this derivative and / or a pharmaceutically acceptable solvate of this derivative.

 A particular treatment consists of the treatment of cardiac arrhythmias and in particular ventricular arrhythmias.

 Appropriate treatments also include symptomatic and prophylactic treatments.

 To remove any ambiguity, a compound "which acts by blocking the passing current of cardiac potassium outflow" is a compound which has the activity defined by Dukes and Morad in Am. J. Physiol 257: H1746-H1749, (1989). Standard experimental methods for demonstrating such activity can be used, for example those described in the Dukes and Morad reference cited above.

To remove all ambiguity, a compound "which acts by specifically blocking the deferred rectifying cardiac potassium channel" is a compound which has the activity defined by Follmer and Colatsky in
Circulation 82: 288-293, (1990). Standard experimental methods for demonstrating such activity can be used, for example those described in the reference Follmer and Colatsky cited above.

 Compound A and Compound B can be administered in the form of a single pharmaceutical composition containing effective amounts of the two active ingredients. It is also possible to administer the two active ingredients in the form of two separate pharmaceutical compositions, to be used simultaneously or sequentially.

 The pharmaceutically acceptable salts of 3,7 di (cyclopropylmethyl) -9,9-tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane include the salts described in US Pat. No. 4,550,112, in particular the hydrochloride, and preferably dihydrochloride.

 The pharmaceutically acceptable salts of 1 (2- (6-methyl-2-pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) -piperidine include the salts described in patent EP235752, in particular the hydrochloride, and preferably the hydrochloride .

 Pharmaceutically acceptable solvates include those described in US Pat. Nos. 4,550,112 and EP235,752, for example hydrates.

The method of synthesis of Compound A and Compound
B necessarily varies with the particular nature of compounds A and B, but standard synthesis methods are generally used. For example if Compound A is 3,7-di (cyclopropylmethyl) -9,9-tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane or one of its pharmaceutically acceptable salts, and / or one of its pharmaceutically acceptable solvates, the synthesis method used is generally that which is described in US Patent No. 4,550,112. Similarly, if Compound B is 1 (2- (6-methyl-2-pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) -piperidine or one of its pharmaceutically acceptable salts, and / or one of its pharmaceutically acceptable solvates, the synthetic method used is generally that which is described in patent EP235752, or else in J. Med. Chem. (1990), 33, (3), 903-905.

 The amount effective for treating the disorders described in the present invention depends on factors such as the effectiveness of Compound A or Compound B, the particular nature of the pharmaceutically acceptable salt or the pharmaceutically acceptable solvate chosen, the nature and severity of the disorders treated and the weight of the mammal. These factors will be appreciated by conventional methods.

 In general, the active compounds are administered in unit dosage form: for example the effective amounts of 3,7-di (cyclopropylmethyl) -9.9 tetramethylene-3, 7-diazabicyclo- (3 .3.1) or a its pharmaceutically acceptable salts, and / or one of its pharmaceutically acceptable solvates or 1 (2- (6-methyl-2-pyridyl) ethyl) -4- (4-methylsulfonyl aminobenzoyl) -piperidine or a its pharmaceutically acceptable salts, and / or one of its pharmaceutically acceptable solvates, are administered in unit dosage forms containing 0.1 to 500 mg, for example 2 to 50 mg, of each of the products.

 Unit doses will normally be administered one or more times a day, for example 2, 3, 4, 5 or 6 times a day, most often 2 to 4 times a day, so that the total daily dose for each compounds is normally understood, for an adult of 70 kg, in the range from 0.1 to 2500 mg, most often from 50 to 2000 mg and for example from 10 to 75 mg; these doses correspond to a dosage of approximately 0.002 to 35 mg / kg / day, most often from 1 to 30 mg / kg / day and for example from 0.15 to 1 mg / kg / day.

 At the dosages indicated above, the compounds which are the subject of the present invention do not produce toxic effects.

 In the treatments according to the present invention, Compounds A and B can be administered by any suitable route of administration, for example, by oral, parenteral or topical route. For this administration, the medicament will normally be used in the form of a pharmaceutical composition in combination with a pharmaceutical carrier, a diluent and / or an excipient for human or veterinary medicament, but the exact form of the composition will naturally depend on the mode of administration.

 The compositions are prepared by mixing and are suitable as appropriate for oral, parenteral or topical administration and for this can be in the form of tablets, capsules, liquid preparations for the oral route, powders, granules, dragees, lozenges, reconstitutable powders, solutions or suspensions for injection or for infusion, suppositories and transdermal devices. Orally administrable compositions are preferred, and especially formulations for oral administration, since they are more convenient to use in general.

 Tablets and capsules for oral administration are generally presented in unit dose and contain the conventional excipients such as binders, fillers, diluents, compression agents, lubricants, disintegrants, colorants, flavors and wetting agents . The tablets can be coated according to methods well known in the state of the art.

 Can be used as fillers in particular cellulose, mannitol, lactose and other similar agents, as disintegrants in particular starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

 These solid compositions for the oral route can be prepared by conventional methods of mixing, filling, compression or the like. In the case where the fillers are in large quantity, it is possible to carry out successive mixing operations in order to distribute the active principle in the compositions. Such operations are of course conventional in the state of the art.

 Liquid preparations for the oral route can be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or can be in the form of a dry product to be reconstituted before use with water or any suitable vehicle. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, an aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, fatty esters such as glycerine, propylene glycol or ethanol esters; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if necessary, conventional flavoring or coloring agents.

 For parenteral administration, the unitary fluid forms are prepared from a compound according to the present invention and from a sterile vehicle. The compound, depending on the vehicle and the concentration, will either be in suspension or in solution. Parenteral solutions are normally prepared by dissolving the compound in a vehicle, then sterilizing filtration before filling with suitable vials or ampoules and sealing. Advantageously, it is possible to also dissolve adjuvants, such as local anesthetics, preservatives and buffering substances, in the vehicle. To increase stability, the composition can be frozen after filling the vials and the water can be removed in vacuo.

 The parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and that the suspension in the sterile vehicle is preceded by sterilization by exposure to ethylene oxide. Advantageously, a surfactant or a wetting agent is included in the composition to facilitate the uniformity of the distribution of the active principle.

If the composition is to be administered topically, it may be in the form of an ointment or a transdermal device allowing systemic absorption; it can be prepared in a conventional manner, for example, as described in reference works such as Dermatological Formulations "BW Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys
Cosmeticology (Leonard Hill Brooks).

 In addition, such compositions may contain other active ingredients such as antihypertensive agents or diuretics.

 As indicated above, the present invention provides that Compounds A and B can be administered simultaneously or one after the other.

It will be noted that the formulations cited in the foregoing can be adapted in a conventional manner to the required methods of administration.

 As a rule in practice, the compositions will usually be accompanied by written or printed instructions explaining their instructions for use for the medical treatment concerned.

 The following pharmacological methods illustrate the present invention without, however, limiting it in any way.

Pharmacological results 1. Compounds tested
3,7-di (cyclopropylmethyl) -9.9 tetramethylene-3,7-diazabicyclo- (3 .3.1) -nonane dihydrochloride (nol test compound) prepared according to the process described in US Pat. No. 4,550,112.

 1- (2- (6-methyl-2-pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) -piperidine dihydrochloride (test compound 2) prepared according to the process described in European patent application publication no. 235752.

 Test compounds 1 and 2 were dissolved in batten. Subsequent dilutions were made in physiological saline. The control groups received an equivalent volume of physiological saline.

2. Methods
Animals and experimental methods.

 The rats were anesthetized with sodium pentobarbital (60 mg / kg IP) and were ventilated, after tracheostomy, by ambient air. The coronary artery was ligated according to the methods described above (Clark et al., 1980). The thorax was opened by left thoracotomy and the heart was externalized. A ligature was placed around the left coronary artery near its origin and the heart was replaced inside the thoracic cavity. The coronary artery was obliterated, at the appropriate time, by making a noose around the artery with a small plastic button in which the ligature was threaded; circulation was restored (reperfusion) by releasing the tension (Kane et al., 1984).

Experimental protocol.

 After placing the ligature around the coronary artery, the rats were left to rest, for stabilization, for 10 minutes before receiving the intravenous treatment. 15 minutes after distribution of the drug, the hemodynamic parameters were recorded and the coronary artery was obliterated.

Regional ischemia was maintained for 5 minutes and then followed by a 10-minute reperfusion period.

In the present study, the duration of ischemia was set at 5 minutes to avoid the onset of ischemia-induced arrhythmias and because it was observed that after 5 minutes of ischemia vulnerability to reperfusion arrhythmias were maximal (Manning and
Hearse, 1984).

Parameters measured and evaluation of rhythm disturbances.

 Ventricular arrhythmias occurring during the reperfusion period have been defined and analyzed according to the Lambeth conventions (Walker et al., 1988). Ventricular extrasystoles were defined as identifiable premature QRS complexes and bursts were defined as 2 or 3 consecutive ventricular extrasystoles. The diagnosis of ventricular fibrillation was made when the morphology of repetitive extrasystoles was completely irregular and it was no longer possible to measure a frequency. Mortality was recorded in each group, animals whose systolic blood pressure remained below 40 mm Hg for a period of 3 minutes were considered dead.

3. Results
A 5-minute ischemia induces a high percentage of reperfusion arrhythmias without inducing ischemia arrhythmias (Manning and Hearse, 1984).

 Test compound 1 and test compound 2 did not reduce the incidence of ventricular tachycardia (Figure 1).

 Test compound 2 did not reduce the incidence of ventricular fibrillation or the mortality occurring after reperfusion. The duration of ventricular fibrillation and the lag time before reperfusion fibrillation were not significantly modified by test compound 2 (table).

 Test compound 1 reduced the incidence of life-threatening reperfusion arrhythmias in a dose-dependent manner (Figure 1). In addition, in animals with reperfusion arrhythmias, test compound 1 reduced the duration of ventricular fibrillation without extending the lag time before ventricular fibrillation (table). At the same time, test compound 1 increased the duration of ventricular tachycardia.

 To define the relative role of the output passenger current and the defective rectifying current in the beneficial effect of test compound n 1, a second series of experiments was carried out in which the anti-fibrillating effect of a combination of test compounds n 1 and 2 has been studied. During these experiments, the test compound No. 1 (1 mg / kg) was associated with the test compound No. 2 (1.0 mg / kg) and the effect of this association was compared with the results obtained in a control group. The reperfusion arrhythmias were markedly reduced by the combination of test compounds 1 and 2.

The incidence of ventricular fibrillation was reduced from 82% in the control group to 8% in the treated group (p <0.05) and mortality was reduced from 58% to 0% (p <0.05) by the association (figure 2).

However, combination therapy did not reduce the incidence of ventricular tachycardia (Figure 2) or the latency before ventricular tachycardia (12.6 + 2.6 seconds and 8.6 + 2.1 seconds in control and treated groups respectively). Likewise, the combination had no effect on the number of extrasystoles or bursts (no figure).

4. Conclusion
The results of the present study suggest that, although product n 2 by itself has little effect on reperfusion arrhythmias in rats, it potentiates the antiarrhythmic action of test product n 1 (acting mainly on Ite). when used in combination with compound 1.

5. References
Bacaner MB, Clay JR, Shrier A, Brochu R. Potassium channel blockade: a mechanism for suppressing ventricular fibrillation. Proc Natl Acad Sci USA 1986 83; 2223-2227.

Carmeliet E, Biermans O, Callevert C, Vercellte J.

Potassium currents in cardiac cells. Experientia 1987 43; 1175-1184.

Clark C, Foreman M, Kane KA, McDonald FM, Parratt JR.

Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size. J Pharmacol Methods 1980; 3; 357-368.

Kane KA, Parratt JR, Williams FM. An investigation into the characteristics of reperfusion-induced arrhythmias in the anesthetized rat and their susceptibility to antiarrhythmic agents. Br J Pharmacol 1984; 82; 349-357
Manning AS, Hearse KJ. Reperfusion-induced arrhythmias mechanisms and prevention. J. Mol Cell Cardiol 1984 16; 497-518.

Walker MJA, Curtis MJ, Hearse DJ et al. The Lambeth conventions: guidelines for the study of arrhythmias in ischaemia, infarction and reperfusion. Cardiovasc Res 1988; 22; 447-455.

 Table: Effects of test compound 1 and test compound 2 on arrhythmias induced by reperfusion in anesthetized rats with transient regional ischemia.

Ventricular tachycardia Ventricular fibrillation
dose N Extrasystoles Bursts n latency durations n latency duration duration
(number) (number) (seconds) (sec) (seconds) (sec)
Witnesses 12 6.7 # 2.1 0.7 # 0.2 11 3.2 # 1.1 10.3 # 3.7 6 18.7 # 3.7 495.9 # 88.2 compound 1 0, 1 mg / kg 12 8.8 # 3.3 0.8 # 0.5 10 13.5 # 3.6 25.0 # 7.8 * 8 30.8 # 11.7 564.7 # 12.6
1.0 mg / kg 12 15.3 # 3.9 4.3 # 1.7 10 4.3 # 1.5 79.8 # 26.2 *** 8 53.1 # 20.3 217.9 # 136.8 ***
3.0 mg / kg 12 12.6 # 2.1 ** 2.6 # 1.9 10 5.5 # 1.4 28.5 # 5.9 ** 1 10.0 3.0 *** compound 2 0.1 mg / kg 12 6.8 # 2.2 1.0 # 0.5 10 7.6 # 1.8 25.4 # 0.1 5 19.1 # 6.6 342.0 # 135.2
1.0 mg / kg 12 19.5 # 10.3 4.1 # 1.4 12 12.2 # 3.9 60.1 # 23.4 3 36.9 # 13.5 368.5 # 86, 3
3.0 mg / kg 12 23.3 # 5.3 * 5.3 # 2.0 11 15.4 # 4.3 31.9 # 10.7 6 21.2 # 10.6 294.2 # 124 , 5 * p <0.05, ** p <0.01, *** p <0.001 compared to the control group. The number of ventricular extrasystoles and bursts was evaluated in all animals during reperfusion, only rats with ventricular tachycardia or ventricular fibrillation during the reperfusion period were used for the analysis, n represents the number of rats who in the origin group
N = 12, presented with ventricular tachycardia or ventricular fibrillation.

Claims (5)

 1. Pharmaceutical product containing a compound which acts by blocking the passing current of cardiac potassium exit ("compound A") and a compound which acts by blocking in a specific way the defective rectifying cardiac potassium channel ("compound B").  2. Product according to claim 1, suitable for the simultaneous or sequential administration of compound A and compound B.  3. Product according to claim 1, suitable for the simultaneous administration of compound A and compound B.  4. Product according to claim 1, characterized in that the compound A represents 3,7-di (cyclopropylmethyl) -9-tetramethylene-3,7-diazabicyclo- (3.3.1) -nonane or a pharmaceutically acceptable salt thereof. derivative and / or a pharmaceutically acceptable solvate of this derivative.  5. Product according to revendicr, characterized in that the compounds represent 1- (2- (6-methyl-2-pyridyl) ethyl) -4- (4-methylsulfonylaminobenzoyl) -piperidine or a pharmaceutically acceptable salt of this derivative and / or a pharmaceutically acceptable solvate of this derivative.