SE461831B - ANTI-RHYTHMIC AND SUPPORTING MEDICINAL PRODUCTS IN MYOCARDIA HYPXI CONTAINING (-) - CIS-2,8 DIMETHYL-2,3,4,4A, 5,9B-HEXAHYDRO-1H-PYRIDO (4,3-B) INDOL - Google Patents

Description

Or salts thereof, preferably the dihydrochloride or dipalmitate, in administrable forms for oral or parenteral use.

To the disadvantages of hitherto used substances, e.g. quinidine, belongs to the property that they cause fibrillation in the heart chambers, hypersensitivity and in large doses directly toxic symptoms.

Procaine can trigger similar reactions of hypersensitivity, in some cases abbreviated prbcaine, heart failure, seizures and the like (Godman L.S., Gilman A .: The Pharmacological Basis of Therapeutics, The Macmillan Comp., London 1970).

In the medicament according to the invention, such similar effects have not been observed.

It exhibits significantly higher antiarrhythmic activity than hitherto used drugs to protect the heart muscle under conditions of low oxygen supply, has unspecified membrane stabilizing action, increases the electrical resistance of cell membranes in smooth muscle and exhibits spasmolytic and GL-adrenolytic action. In addition to the central action (neuroleptic, thymoleptic and hypotensive) previously described in the racemic carbidine (Barkov NK: Pharmacol.Toxicol. Åá, 647 (1971)) and the lower acute toxicity (see Table 1 below), the complexity is of the pharmacological effects of the (-) - cis isomer of the compound of the formula I in a completely unique combination of properties which have not hitherto been present in drugs of this kind. These properties are a prominent prerequisite for curing pathological heart conditions, which are associated with neuroorganic disorders in cardiac function.

The dihydrochloride of the (-) - cis isomer of the compound of formula I in a dose of 0.5 mg.kg-1 shortens after intravenous administration the duration of the cardiac arrhythmias induced by intravenous administration of barium chloride (5 mg. kg_l) in rabbits with a factor of 62.5 compared to the control animals. Quinidine sulphate in a dose of 5 and 10 mg.kg_1 in the same experiment does not give the effect that the (-) - cis isomer of the compound of formula I gives in an amount of 0.5 mg.kg_1. Within the same range of administration, the (+) - cis isomer is ineffective and the racemate (carbidin) is only insignificantly effective.

The duration of the cardiac arrhythmia caused by an intravenous administration of adrenaline to rabbits in an amount of 100 .mu.g.kg / 1.2 .mu.s is a single administration of the (-) - cis isomer of the compound of formula I (dihydrochloride) in doses of 0.5 - 1.5 mg.kg-1.

Quinidine has approximately the same effect in a 2 - 6 times and 9 mg.kg_l). Dihydro-, significantly shortened after intravenous dose (1-3 mg.kg_l chloride of the reverse antipode ((2) -cis isomer) is ineffective within the same range of administration.

In experiments with Starling migratory rats with a 20 ml cardiac preparation of 0.2 mg of the dihydrochloride of the (-) - 'cis isomer of the compound of formula I and with the opposite isomer or racemate with premidicated blood on decreasing saturation in the blood of oxygen from 78 to 52 clinical percent, about 16 - 32 percent higher heart power was achieved than with the control drugs. The saturation point of the blood with oxygen, at which the control preparations effectively cease to function, was significantly higher than with the preparations pre-medicated with the compound of formula I. The use of this substance significantly improves the heart's ability to tolerate the blood's insufficient oxygen supply. This effect has not been observed in any known antiarrhythmic agent used.

The dihydrochloride of the (-) - cis isomer at a dose of 1.5 mg.kg_l moderately reduced cardiac activity in guinea pigs as well as quinidine at a dose of 3 mg.kg_l. The effect was also observed on the cardiopulmonary preparation in walking rats. Despite the cardiac sedative effect on the cardiopulmonary preparation, an increased cardiac effect was achieved after the addition of the dihydrochloride of the (-) - cis isomer of the compound of formula I by 1.3.9%. The association showed a negative chronotropic and positive inotropic effect.

In the guinea pig model for the assessment of andrenaline-induced arrhythmia, the arrhythmic effect of the salts of the (-) - cis isomer of formula I, administered orally in an amount of 72.6 .mu.ml, was tested. Compared to the control model, the compounds showed the following delay of initial extrasystole: the dihydrochloride about 44%, the dipalmitate about 78%, (+) - 0,0'-dibenzoyl tartrate about 19% and quinidine by default about 28%. The extrasystolic period was shortened with the dihydrochloride by 46%, with the dipalmitate 32%, with (+) - 0,0'-dibenzoyl tartrate 78% and with quinidine 55%. The dose dependence was determined for each compound. The results showed that the palmitate was approximately 2 - 2.5 times more effective than the standard sample.

The antiarrhythmic effect, which is evaluated by the elongation of the functional refractory phase by 50% with the tested compound in comparison with the basic method involving measurement of the maximum frequency of electrical rectangular impulses, which is achieved in isolated atria of rabbits, and which expressed by the average dose of ED50 (mol.ml-1), for the dihydrochloride of the (-) - isomer of the formula I was 2,7f1o'7, for mexlethetin to l-lo'7, for gylurhymal to l-10o'8 3-lo'7. and for procainamide to - 30 461 831 The inotropic effect, which was evaluated by the 50% reduction in the amplitude of electrically stimulated contractions in the myocardium of isolated atria of rabbits after application of the tested compound in Control of the amplitude and expressed as the average effective dose of ED50 (mol / ml), the dihydrochloride of the (-) isomer of the compound of formula I was 5.2 to 10. 7 to 5-1o'7 and for gylurhyfmal to 1.5-10 'the effect, which was evaluated by the reduction of the amplitude of the electrically irritated atria of rabbits and for procainamide 8. Anticalcium- was expressed with the average effective dose ED .m1'l), amounted to 5.5-10 'for the dinary arachloride, for verpamine as standard to 3 ° 10_8, the dihydrochloride not affecting the rabbit's breast aorta.

The dihydrochloride of the (-) isomer of the compound of formula I, based on measurements of the activity monitoring of 4 lysozomal enzymes on the mvocardium of migratory rats caused by isoprenaline, contributed to subcutaneous application at doses of 15 mg / kg 30 minutes before and 60 minutes after the application of isoprenaline to return activity of lysozomal enzymes to the control values, i.e. to the persistence of the myocardium at the time of its injury.

The dihydrochloride of the (-) - cis isomer of the compound of formula I and also the motisomer inhibits in doses of 5 and 15 mg.kg_l after intraperitoneal administration the mortality of mice to the same extent as the neuroleptic carbidin (Barkov NK: Pharmacol. Toxicol. Âí 647 (1971)).

The acute toxicity expressed as LD50 is shown in the following Table 1. 461 851 10 15 20 25 30 35 Table 1 LD56 mg.kg-1 (white male mice weighing 18 - 20 g) g compound subcutaneously intravenously orally dihydrochloride of (-) - cis isomer I 560 83 (72-96) 459 (377-539) the dipalmitate of - - 222 (895- (-) - cis isomer I 1599) the dihydrochloride of (+) - cis isomer I 170 - - dihydrochloride of ( i) -isomer (carbidin) 185 - '- The drug with the effective compound of formula I, (-) - cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido ( 4,3- b) indole, preferably present as dihydrochloride or dipalmitate, is prepared by dissolving this compound in physiological solution in other liquids or semi-liquid substrates, optionally in the form of a base in a suitable solvent, preferably ethanol, and further in the form of a solid drug with the addition of conventional aids, ie for liquid forms during the addition of isotonizing additives (eg NaCl and glucose), stabilizing additives (eg phosphate buffer), emulsifiers (eg sorbimacrogel), stabilizers for the suspension or emulsion (eg cellulose ester, aerosil and bentonite) and for solid form with the addition of common auxiliaries (eg starch, lactose, methylcellulose, gelatin, dextran, magnesium stearate, microcrystalline cellulose and the like). Regarding the therapeutic dose of 15 - 150 mg.kg-1 type of drug does not matter. for adults, the active compound of the formula I according to the invention is prepared so that from (I) -cis-2,8-dimethyl-2,3,4,4a, 5,9-hexahydro -1H-pyrido (4,3-b) indole with the aid of the optically active acid, preferably (+) - 0,0'-dibenzoyl-D-tartaric acid, in the presence of an organic solvent, preferably ethanol, prepares the salt of the compound of formula I with this acid and carries out purification by crystallization, after which the compound of formula I is liberated by alkalization and extracted into organic solvent, preferably in ether, and optionally further converted to a salt by neutralization with inorganic or organic acids.

The starting compound (i) -cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole can be prepared by reduction of 2.8 -dimethyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) - moiety with metals in surinyl environment (German Patent 1,952,800) optionally by catalytic hydrogenation, reduction with complex hydrides or with complex amines. diboran.

The optically active acid, preferably (+) - 0,0'-dibenzoyl-D-tartaric acid, which is used in the salt formation to prepare the compound of formula I according to the working example, can be regenerated for maximum utilization u-preped times by acidic decomposition of its salt with the compound of formula I by successive extraction in organic solvent, preferably ether.

Example 1 To a solution of 28.8 g (0.142 mol) of (i) -cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3- b) indole with a melting point of 620 DEG C. and 60 ml of 96% ethanol was added to a solution of 13.4 g (0.0356 mol) of the monohydrate of (+) - 0.0'-dibenzoyl-D-tartaric acid in 60 ml of 96% ethanol. After settling the timber at the edge, the salt formed, if necessary, was washed with ethanol and pentane. The yield was 25.7 g, m.p. 207 DEG-209 DEG C. (decomposition). Crystallization from 50% ethanol (630 ml) extracted 16 g of salt and an additional 3.2 g of the corresponding tartrate salt from the mother liquors. The combined portions were recrystallized from 50% ethanol (600 ml).

The yield of the pure salt was 15.8 g, m.p .: 222 DEG-224 DEG C. (decomposition) c44n50N4O8 (7.2, a) calculated 69.3% (c), 6.60% (H), 7.34% (N) found 69.7% (c), 6.75% (H), 7.77 2 (N).

The compound of formula I was liberated from the recovered salt by shaking, which was shaken in ether, after which the ether layer was washed with water, dried over sodium sulphate and the ether was distilled off. The yield was 8.6 g of compound I, m.p. 82 DEG-830 DEG C., Bi D2 O = -43.10 (c = 0.5, ethanol).

The recovered product (8.6 g) was dissolved in 20 ml of absolute ethanol and, while cooling, 14 ml of ethanolic solution of dry hydrogen kieride (7 ml, 1.1) was added. The dihydrochloride formed was filtered off with suction, washed with absolute ethanol and dried in vacuo.

The yield was 10.8 g. Melting point 270 - 274 ° C (in molten kepillary under decomposition), L ° CIš ° = + 33.9 ° (c = 0.5, water).

Cl 3 H 2 OCl 2 N 2 (275.2), calculated 56.7% (C), 7.33% (H), found 57.1% (C), 7.45% (H) 10.2% (N), 25, 3% (CI) In the same way as the dihydrochloride, from the compound of formula I and other acid in organic solvent could be prepared 11 Dipaimitate with m.p. -5s 56 ° c [u] go -1a, s ° (c = 1.0, ethanol) oxalate "" 196-1980 C (during decomposition).

Example 2 Drugs for intravenous and intramuscular application - form of infection.

To prepare 100 ampoules of 2 ml each, 1.1 g of active substance were dissolved in 220 ml of distilled water, isotonized with 0.99 g of NaCl and worked up in the usual manner. The solution was divided into 2.2 ml doses and dissolved in ampoules. The vials were sterilized by heating in water vapor under a pressure of 98.0 kPa at 120 ° C for 30 minutes. The 2 ml dose was equivalent to 10 mg of active substance.

In a similar manner, the solution was prepared from 220 ml of 2.75 g of active substance. Each ampoule (2 ml) contained 25 mg of active compound.

Example 3 Drugs for oral administration - tablets.

The active compound in an amount of 10 g was mixed with 60 g of lactose and 138 g of starch and moistened with a sufficient amount of strong hydrogel. After adding 2 g of magnesium stearate, the mixture was granulated, homogenized and compressed into tablets weighing 250 mg and diameter 5 ml.

One tablet corresponded to a dose of 10 mg of active substance.

In the same way, tablets with active compound were prepared in a dose of 25 mg by adding to the auxiliaries in the manner indicated 461 851 10 10 the active substance in an amount of 25 g and working up in the same manner. One tablet weighing 250 mg was equivalent to 25 mg of active substance. The compound can be used in all indications of disorders of the heart rhythm, in particular in the disorders associated with neuroorganic disorders in cardiac activity and can be used in conventional application forms such as liquid, semi-liquid and solid forms in doses of 15 - 150 mg per person per day, possibly in doses divided into several smaller portions. The use in veterinary medicine to reduce neurogenic conditioned disorders in the circulatory system of our beneficial animals is not excluded. 10 15 20 25 30 461 831 11 Comparison report The effects of the racemate ('CARBIDINE') were compared with the effects of its optically active enantiomers, ie. 'STOBADINE' ('DH 1011 according to the invention') and 'DH 1111' on different experimental models of arrhythmia to evaluate their activity. It has been shown in various in vitro and in vivo models that 'STOBADINE' is several times more effective than 'CARBODINE' and 'DH 1lll'. Tables 1 and 2 give some examples of the difference in strength between the racemate and its enantioners. Furthermore, toxicological studies showed that 'STOBADINE' has the lowest toxicity of the pyridoindoles studied (Table 3 gives an example). 'STOBADINE' is the (-) cis isomer included in the medicament of the present invention.

Table 1 Effects of pyridoindoles on BaC12-induced arrhythmia 0.5 mg.kg'1 intravenous Control 'CARBIDINE' 'STOBAD1NE' 'DH 1111' Duration of first extrasystolic period (s) 1800¿A73 l000¿389 29¿6 l896¿397 Duration of all extrasystolic periods (s) l954¿380 l697¿35l 959¿345 l975¿340 Table 2 Effects of pyridoindoles on adrenaline-induced arrhythmia 1.5 ng.kg'1 intravenous Control 'CARBIDINE' 'STOBADINE' 'DH llll' Frequency of occurring arrhythmia (S) 100 duration of occurring arrhythmia (5) l06.S¿l1.2 25.3¿l0.4 66.7¿15.7 25.0¿l2.5 100 3.8¿2.7 l29¿12.6 461 85í 12 Table 3 LD50 values for pyridoindoles in mice with confidence intervals (1 mq.kg / l subcutaneous' CARBIDINE 178.95 (149.0-218.9) 'STOBADINE' 483.85 (409.8-576.5 ) 'DH llll' 199,70 (l74.1-231.3) LD50 = mean value of lethal des.

Claims (5)

461 851 13 2. P.ans.nr 8204693-9 25 February 1988 3. Claims Drugs having a particularly antiarrhythmic and supporting effect in myocardial hypoxia, characterized in that it contains as an essential active ingredient the chemical compound (-) - cis-2,8-dimethyl-2,3,4,4a, 5,9b -hexahydro-1H- 5. -pyrido (4,3-b) indole of the formula -4121 CH (I) 1 x 1s H or a salt thereof. preferably the dihydrochloride or the I dipalmitate, together with a carrier in application forms for oral or parenteral use.