CS229067B1 - Medicinal preparation with antiarhythmic and supporting effect applied with hypoxia,and method of preparing active substance thereof - Google Patents

Abstract

The invention relates to (-)-cis-2,8-dimethyl- 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole of the formula I <IMAGE> its salts, its preparation and appropriate pharmaceutical compositions, in particular having antiarrhythmic and subsidiary action in myocardial hypoxia. The compounds according to the invention also have a hypotensive, local anaesthetic, spasmolytic, x-adrenolytic and central sedative action. The compositions can be present in a liquid, semi-liquid and solid administration form. The compounds according to the invention are prepared from (+/-)-cis-2,8-dimethyl- 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole via the salt with an optically active acid, advantageously (+)-O,O'-dibenzoyl-D-tartaric acid, from which the (-)-cis-isomer is liberated by rendering it alkaline and optionally converting it into a pharmaceutically suitable salt, preferably the dihydrochloride (m.p. 270-274 DEG C, with decomposition) or the dipalmitate (m.p. 55-56 DEG C). The active substances according to the invention eliminate cardiac arrhythmias in doses which are lower than the agents used hitherto and at the same time have relatively low acute toxicity and the ability to protect the cardiac muscle during oxygen deficiency. Central effects such as neuroleptic and thymoleptic effects are additionally present.

Description

The invention relates to a medicament 8 for anti-arrhythmic and supportive action in hypoxia and to a process for its preparation.

The medicament according to the invention also has longer effects, such as hypersensitivity, locally-aesthetic, spasmooytic, elephadrenolytic and central sedative. The active substance is (9) -hexyl-1H-pyridyl (4,3b) indole and its salts in liquid, semi-liquid and solid dosage forms.>

The compound of the invention is prepared from (±) - cis-2,8-Methyl-2,3,4,4e, 5,9b-hexahydro-1H-pyrido [4,3-b] indole using an optically active salt. an acid, preferably (+) - O, O-dibenzoyl-Dpvirma, from which the (-) - cis isomer is liberated by alkalization and converted to a pharmaceutically acceptable salt, preferably Uhydrocchloride (tt 270-274). ° C dec.).

It also eliminates cardiac rhythm disturbances at doses lower than those of the drugs used so far in this indication, while at the same time lowering acute toxicity and the ability to protect the heart muscle in the absence of oxygen.

It is further characterized by central effects such as neuroleptic and thymooeptic.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition with entierytrnic supportive action in hypoxia. The medicament also has other effects, such as hypptension, locally anesthetic, spasmo-elective ephedrenolytic and centrally sedative.

A number of drugs are currently used to treat heart rhythm disorders such as chlnidine, procainamide, lidocaine, trimecein, beta-edrenolytics, anti-arrhythmic drugs of the so-called kelci o ·? blockers (Veraparnil, Nifedipine), ajoaline derivatives and other.

Antiarrhythmic activity was observed even karbidnu, i.e., racemic compounds of formula I (i) -iis-2 _d-1 2,3-iiettyl 4,4β, 5,9b-hexehdrro-1H-pyridoi4,3b) indole (STOL S. (Bauer, V. Phys., 26, 253 (1977)), which is used as a neudeptic, in the present. time with unattractive effects compared to similarly active substances (chlorpromazine, amiiriptyline, prothiaden). Kerbidine is the subject of patent protection (U.S. Pat. No. 3,743740, Franc, U.S. Pat. No. 69,36192, U.S. Pat. No. 1,952,002).

A disadvantage of all the substances used hitherto is their limited indication, side effects and lower enthymic rhythmic activity compared to the present substance.

These disadvantages are overcome by the medicament according to the invention, which is based on the fact that it contains as active ingredient. (-) - Ci-2,8-Dimethyl-2,4,4,45,9b9ehexehdro-11H-pyrido (4,3b) indole of Formula I

Or a salt thereof, preferably dihydrochloride, in a dosage form for oral or parenteral use.

The disadvantages of substances used so far, such as quinidine, are that it can cause cardiac ventricular fibriation, hypersensitivity and, at a higher dose, direct toxic symptoms. Similarly, procainamide may induce reactions from hypersensitivity, possibly cross-linked to procain, cardiac insufficiency; convulsions and the like (Goodman L. S., Gilman A .: The Pharmmadogicel Bais of Theerppettcs, The Marnillan Comm., London 1970). Similar to the medicament of the invention. effects were not observed.

It shows a significantly higher enriaryotic activity than the drugs used so far, a protective effect not a cardiac. muscle under reduced oxygen-oxygen conditions, has non-specific specificity · biogenisation effects, increases electrical resistance of smooth muscle cell membranes, and exhibits spasmo0u2 and a4faadicnolytic4 effects. Along with the central effects (neiroleptic, thymoleptic and thymoleptic) previously described with rheumatic kerbidine (Berkov NK: Farmokd. Ttodkol. 34, 647 (1971)) and lower acute toxicity ( see Table 1), the pharmacokinetic complex of (-) - 1-omeas of the compound of formula (I) is a unique property correlation, hitherto for drugs. of this kind will be lost. These properties are excellent. a prerequisite for the treatment of heart conditions associated with neuroorganic disorders of the heart function.

Β1 ^ <1 * ο ^ ¹ ^ 1ογ1 -DS-io ™ © ^ ^^ y in formula ^{1 d} AVCE ^0, 5 mg.kg "^'p o intreiveexiósmím administration shortens the duration of cardiac rhythm disorders chosen intravenous chloride Barnet ^ o ⁽ .mg.kg ⁵ '') in rabbits 62 _F ⁵ Crete, in comparison to the ^{p to} ontro ^O nímizvířaty. ^{Network-wounds} cdddnu the VCE 5 E ¹⁰ m ©. ^ "'In hay potausu netosatouje Taint ^ j-C Doomer area ^la of formula I at a dose of ^0, 5 mg.kg' ^1. In Stenn ^d évkovém extended ^overloading opposite isomer ^{/ (+)} - ^ ^ ilSiioma; ^/ inactive and racemate (kerbidin) only insignificantly effective.

Duration of heart failure. the rhythm caused by intravenous administration of adrenaline to rabbits in a WOug.kg. ²⁰ s''is significantly zfracuje after intravenous ODAN ^{p (-)} - or - lsπileit alkyl ^acrylate of formula ^I ^ ityfrochlorita) in tóvW ^ ^0.5 to ^1.5 mg.kg "'. Cidinidine exhibits the same effect at doses of 2 to 6 or more (1 to 3 and 9 mg / kg, respectively). The opposite antipode DL-hydrochloride ((+) - C 18 isomer) is not effective in the same dose range.

In a Starling rat heart-lung preparation experiment containing 20 ml of blood premedicated with 0.2 mg of the (-) - cis-isomer of the compound of formula I, as well as the opposite isomer or racemate, this was achieved with decreasing oxygen saturation of 78 to 52 clinical percent, 16 to 32% higher cardiac output than the control N blood oxygen saturation, when the control ceased to function efficiently, was significantly higher than the preparations pre-treated with Formula I. The use of this substance greatly improves the ability heart tolerate insufficient supply of oxygen tarvis. This effect has not been observed with any of the antiarrhythmics used hitherto.

(s) -css-isaaer at a dose of 1.5 mg.kg-1 in guinea pigs slightly slows down heart activity, as does quinidine at a dose of 3 mg.kg-1. The effect was confirmed i. Not in the rat heart-lung preparation. Despite the heart-inhibiting effect on the heart-pulmonary preparations, the cardiac output after administration of the dihydroxide (cis-isorner) of the compound of formula I decreased by 13.9%. The substance exhibits a negatively potent and positively instructive effect.

The (-) - cis-iso-isoer of the compound of formula I and the opposite istomer at doses of 5 and 15 mg.kg &quot; after intraperitoneal. filed. it inhibits the mullity of mice as well as non-olefined kerbidine (Berkov, N.K .: Farmma, Tokkikol. Ji, 647 / 1971Z).

The torque torque expressed as LD ^ q is shown in Table 1.

T a b uk uk 'a * 1

Substance LD ^ q, subcutaneous administration m ^ ‘kg’1, mSi The (-) - clisoiser of Formula I 560 (♦ ^ Ιβ ^ μοογ substances of formula I) 170 (i) -cis-derivative (t-nrbidin) 185

Medicinal product with the active ingredient of the formula (I) - (-) - .alpha., 2,8 - .beta., 2,3,4,4a, 5, .beta. ^t <r 1И-ppyidoS4,3b) indolene, with, preferably dihšdrrchlrridem) I Preparation is by dissolving the material in fyzioOogiíkéo solution or other fluids and semi-liquid foundations, optionally in the form of a base in a suitable solvent, preferably ethanol or more in the form of a solid drug formulations with the addition of conventional porn substances, i.e., for liquid forms of isomeric ingredients (e.g., phthalate, glucose), stabilizing ingredients (e.g., phosphate buffering agents, emulsifying agents (e.g., sorbioacers), suspension stabilizers, or emulsions (e.g. cellulose esters - aerosil, bentoidtu) and the solid dosage farm by adding the usual ponoccých agents (e.g. starch, lektáš, meetršcelulózy, gelatin, dextran, steeranu magnesium - oiik ^to oScíyšialicíé. cellulose, etc.).

Due to . expected. therapeutic. . dose ... J5, - up to 150 mg in - adult - - - human - - there is no effect on the - base - pharmaceutical - forms, increased solubility, decomposition, etc.

Process for the preparation of (s) cis-4,8-dimethylene-2,3,4) 4a, 5, -b-hexahydroxy-1Hsp; the salt is carried out by reacting from (1) -cis-2,8-dimethyl-2,3,4,4e, 5,9b-hexahydro-1 H -pyrido [4,3-b] pyridine with an optically active acid, preferably an acid ( In an organic solvent, preferably ethanol, a salt of the compound of formula (I) is prepared with this acid and purified by tarystallization, whereupon the compound of formula (I) is liberated by alkellation and extracted into an organic solvent. and preferably ether, and optionally converted further by neutralization with an inorganic or organic acid to the corresponding salt.

The starting (s) -α-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3b) indole can be prepared by reduction of 2,8-dimethyl-2,3, 4,5-tetrahydro-1H-pyrido (4,3b) indole with metals in an acidic medium (patent NSR 199 2 800), optionally by catalytic hydrogenation, reduction with complex hydrides or emin-diborane complex.

The optically active acid, and preferably (+) - O, O'-dibenzoyl-D-tartaric acid, used in the formation of the aoli for the preparation of the compound of formula I according to an exemplary embodiment is essential for repeated use. followed by shaking into an organic solvent, preferably ether. The following is an example.

Example 1

To a solution of 28.8 g (0.142 nol) of (cis)-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3b) indole, mp 62 ° C in 60 ml of 96% ethanol is added a solution of 13.4 g (0.035 6 mol) of (+) - 0,0 * -dibenzoyl-D-tartaric acid (monohydrate) in 60 ml of 96% ethanol.

After standing at 0 ° C for 5 h, the resulting salt was filtered off with suction, washed with ethanol and pentane. Yield 25.7 g, mp 207 DEG-209 DEG C. (dec.). The crystals melted with 50% ethanol (630 ml) yielded 16 g of salt and from the mother liquors 3.2 g of the corresponding tartrate salt. The combined fractions were recrystallized from 50% aqueous ethanol (600 mL).

Yield of pure salt 15.8 g, mp 222-224 ° C (from decomposition).

^C 44 ^H 50 ^M 4 ° 8 (762.9):

H, 6.60; N, 7.34. found: 69.7% C, 6.75% H, 7.77% N.

The compound of formula I is liberated from the salt obtained by alkalinization, which is shaken into ether, the ether layer is washed with water, dried over sodium sulfate and the ether is distilled off. Yield 8.6 g of the compound of formula I mp 62-83 ° C.

^[A] * ^° -43.1 ° (c 0.5, ethanol).

The product obtained (8.6 g) was dissolved in 20 ml of abs. ethanol, and 14 ml of ethanolic dry hydrogen chloride solution (7 mol / ^l ) are added under cooling. The resulting dihydrochloride is filtered off with suction, washed with absolute ethanol and dried in vacuo.

Yield 10.8 g, mp 270-274 ° C (decomposed in a sealed capillary tube) [α] + 33.9 ° (c 0.5 water).

^С 1 ^ 20 ^С1 2 ^М 2 < ²⁷ 5.2):

calculated: 56.7% C, 7.33% H, 10.2% N; 25.6% Cl; Found: C 57.1%, H 7.45, N 10.2%, Cl 25.3.

In a similar manner to the dihydrochloride, it is possible to prepare from the compound of formula I a the appropriate acid in an organic solvent:

šlavelen mp 168-170 ^β Ο, [ ^α ] D θ · + 14.6 ° (c, 0 * 5 water) fumarate mp 196-196 ° C (decomposition).

Example 2

Medicinal product for intravenous or intramuscular administration - injectable form

For the preparation of 100 pellets of 2 [mu] l, dissolve 1.1 g of the active agent in 220 ml of distilled water, isotonicize 0.99 g of NaCl and work up in the usual way. The vials are sterilized by heating in steam at a pressure of 98.0 kPa at 120 ° C for 30 min. A dose of 2 ml corresponds to 10 mg of the active substance.

Similarly, a solution of 220 ml and 2.75 g of active ingredient is prepared. One vial (2 ml) contains 25 mg of the active substance.

Example 3

Medicinal product for oral administration - tablets

The active ingredient in an amount of 10 g is mixed with 60 g of lactase, 138 g of starch and moistened with the necessary amount of starch hydrogel. The mixture is granulated, homogenized and 2 g of magnesium stearate is added and compressed into tablets of approximately 250 mg, diameter 5 nm. One tablet corresponds to a dose of 10 mg of the active substance.

Similarly, tablets with 25 mg of active ingredient are prepared by adding 25 mg of active ingredient to the excipients at a given rate and then proceeding analogously. One tablet of approximate weight corresponds to 25 ng of the active substance.

The use of the invention is contemplated in all indications of cardiac rhythm disorders, particularly those associated with neuroorgenic heart function disorders, in the usual dosage forms, liquid, semi-liquid and solid at a dose of 15 to 150 mg per person per day, optionally in divided doses. more smaller doses. Use in veterinary medicine for the reduction of neurogenic damage to the circulatory apparatus in livestock is not excluded.

Claims (2)

WHERE TO INVENT THE INVENTION A medicament with antiarrhythmic and supportive effect in hypoxia, characterized in that it contains (-) - cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido ( 4.3b) The indole of formula I (X), or a salt thereof, preferably a hydrochloride, in a dosage form for oral or parenteral use. 2. A process for the preparation of (-) - cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido- (4,3b) indole of formula (I), according to claim 17, characterized in that: team '; from (R) -cis-2,8-dimethyl-2,3,4,4a, 5,9b-hexehydro-1H-pyrido (4,3b) indole using an optically active acid, preferably (♦) - O, O * -dibenzoyl-D-tartaric acid, in an organic solvent, preferably ethanol, prepares a salt of the compound of formula I with this acid and is purified by crystallization, whereupon the compound of formula I is liberated by alkalization; optionally converted further by neutralization with an inorganic or organic acid to the corresponding salt.