LU82975A1 - 5-AMINO- (3,4'-BIPYRIDINE) -6 (1H) -ONE-1'-OXIDE, ITS PREPARATION AND ITS USE AS A CARDIOTONIC AGENT - Google Patents

Description

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This invention relates to a 5-amino-, 4'-bipyridineD -6 (1H) -one N-oxide for use as a cardiotonic agent and its preparation.

5 The U.S. Patent No. 4,072,746 describes inter alia 3-amino- (4-pyridinyl) -2 (1H) -pyridinone, also called 5-amino- [3,4'-bipyridinej-6 (1H) -one, useful as an agent cardiotonic, and its preparation by various means. Also described is the corresponding grouping 3-acetylamino derivative (or 5-acetylamino when it is named in the other way, see above).

The present invention relates to 5-amino ~ | .3,4'-bipyridine3 ~ 6 (1H) -one-1'-oxide or a pharmaceutically acceptable acid addition salt thereof. This compound is useful as a cardiotonic agent, as shown in standard pharmacological test procedures.

5-acetylamino-L3,4'-bipyri-dine] -6 (1H) -one can be reacted with peracetic acid in acetic acid to obtain 5-acetylamino [3,4'-bypiridine3-6 (1H) -20 one-1'-oxide and hydrolyze the latter to obtain 5-amino- [3,4'-bipyridinej-6 (1H) -one-1'-oxide.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable carrier and, as active component, 5-amino-C3,4'-bipyridine ^ -ß (1H) -one-1'-oxide cardiotonic or one of its pharmaceutically acceptable acid addition salts.

Cardiac contractility can be increased in a patient in need of such treatment by administering an effective amount of 5-amino-L3,4'-bipyridine] -6 (1H) -30 one-1'-oxide or a cardiotonic of its pharmaceutically acceptable acid addition salts.

5-amino- [3,4'-bipyridineJ-6 (1H) -one-l'-oxide can be used in the free base form or in the form of its acid addition salts and these two types of form are within the scope of the invention. Acid addition salts are simply a more convenient form for use; and in practice, the use of the salt form inherently corresponds to the use of the base form. The acids 2 which can be used to prepare the acid addition salts preferably include those which, when combined with the free base, give pharmaceutically acceptable salts, i.e. salts of which the anions are relatively harmless towards the animal organism at the pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effects attributed to the anions. In implementing the invention, it is convenient to form the free base form; however, suitable pharmaceutically acceptable salts belonging to the field of the invention are those derived from mineral acids 4.

such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, l cyclohexylsulfonic acid, quinic acid, etc., giving respectively the hydrochloride, the sulfate, the phosphate, the sulfamate, the acetate, the lactate, the citrate, the tartrate, the methanesulfonate, the ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.

The acid addition salts of the basic compound are prepared by dissolving the free base in an aqueous or aqueous-alcoholic solution or in other suitable solvents containing the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Although the pharmaceutically acceptable salts of the basic compound are preferred, all acid addition salts are within the scope of the invention. The acid addition salts can all be used as a source of the free base form even if the particular salt is itself indicated only as an intermediate product, for example when the salt is formed only for the purpose of purification or 4 ”, 3 for identification, or when it is used as an intermediate for the preparation of a pharmaceutically acceptable salt by ion exchange procedures.

5 The molecular structure of 5-amino- | _3,4'-bipyr i-dine] ~ 6 (1H) -one-1'-oxide was assigned on the basis of data provided by the infrared, ultraviolet, resonance spectra nuclear and mass magnetic, and by the correspondence of the calculated values and% 10 found for the elementary analysis.

The manner of making and using this invention will now be described generally to enable those skilled in the art to practice it.

The oxidation of 5-acetylamino- | _3,4'-bipyridine] -15 6 (1H) -one to obtain its oxide is conveniently carried out by heating it with peracetic acid in acetic acid to about 75 - 120 ° C, preferably about 90 to 100 ° C.

Hydrolysis of 5-acetylamino - [_ 3,4'-bipy-20-ridinel-6 (1H) -one-1'-oxide is carried out to obtain the corresponding 5-amino derivative by heating the 5-acetylamino derivative in an acid aqueous mineral, preferably aqueous hydrochloric acid at about 90-100 ° C.

The following examples will illustrate the invention without, however, limiting it.

Example 1 5-acetylamino- [3,4'-bipyridinel-6 (1H) -one-1'-oxide.

To a hot solution containing 16 g of 5-acetylaminator, 4 '-bipyridinel-6 (1H) -one in 150 ml of acetic acid, 24 ml of 40% peracetic acid are added and the resulting mixture is heated over a steam bath for 1 hour, it is cooled and poured over ice. The aqueous mixture is neutralized with ammonium hydroxide and the resulting precipitate is collected, washed with water and dried, giving 12 g of 5-acetylamino - [. 3,4 ' -bipyridinel-6 (1H) -one-1'-oxide, pf ^ 300 ° C.

Example 2 5-amino- [3,4'-bipyridinel-6 (1H) -one-1'-oxide.

A mixture containing 12 g of 5-acetylamino- [3,4'-bypiridine] -6 (1H) -one-l'-oxide and 100 ml of 6N hydrochloric acid is heated on a steam bath for 1 hour. it is cooled and heated under vacuum to expel the liquid.

The residue is made alkaline with ammonium hydroxide and heated again under vacuum to dryness. The remaining substance is recrystallized twice from 50% aqueous methanol and 5 g of 5-amino-L3,4'-bipyridine-6 (1H) -one- are obtained in the form of a pale yellow solid. 1'-oxide monohydrate, * 10 pf 273 - 275 ° C with decomposition.

The acid addition salts of 5-amino [3,4'-bipyridinej-6 (1H) -one-l'-oxide are conveniently prepared by carefully adding to a solution of 2 g of 5-amino- £ 3,4'-bipyridine ~] -6 (1H) -one-1 '-oxide in about 40% aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, cooling the mixture and collecting the precipitated salt, for example methane sulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding equimolar amounts of 5-amino- [3,4 '-bipyridine3 “6 (1H) -one-1 to water, with stirring. '-oxide and suitable acid, for example lactic acid or hydrochloric acid, for preparing the monolactate or the monohydrochloride respectively in aqueous solution.

The usefulness of 5-amino £ 3,4'-bipyridine} -6 (1H) -one-l'-oxide or its salts as cardiotonic agents is demonstrated by its efficacy in pharmacological test procedures conventional, for example by causing a significant increase in the force of contraction of the atria and papillary muscles isolated from cats and by causing a significant increase in the force of cardiac contraction in the anesthetized dog with small or minimal changes in the speed of the heart and blood pressure. These test procedures are described in the following paragraphs.

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Procedure for the atria and papillary muscles isolated from cats.

Cats of both sexes weighing 1.5-5.5 kg are anesthetized with 30 mg / kg intraperitoneally of sodium pentobarbital and exsanguine. One opens the chest of each cat, one excises the heart, one rinses it with physiological saline and one takes by dissection the two auricles and one or two small fine papillary muscles of the right venule. The tissues are then transferred to a Petri dish filled with a cold modified Tyrode solution and bubbled with oxygen. A silver wire is attached to each of two opposite ends of the fabric and one of the wires is hooked to a glass electrode. The preparation is then immediately mounted in a 40 or 50 ml organ bath filled with modified Tyrode solution at 37 ° C. The second wire is attached to a force-displacement transducer and the tension is adjusted to obtain a maximum contraction force (papillary muscle 1.5 - 0.5 g, left atrium 3.0 3.0 - 0.6 g, atrium right 4.5 -0.8 g). The transducer is connected to a Grass polygraph and the force and speed of contraction are continuously recorded. The right atrium beats spontaneously due to the presence of the sinoatrial node while the left atrium and the papillary muscle are stimulated electrically at the rate of two beats per second by a rectangular pulse above the threshold. 0.5 millisecond duration.

The modified Tyrode solution bathing the preparation has the following composition (in millimoles): NaCl 136.87, KC1 30 5.36, NaH2PO4 0.41, CaCl2 1.8, MgCl2.6H20 1.05, NaHCC> 3 11, 9, glucose 5.55 and EDTA 0.04. The solution is balanced with a gas mixture containing 95% O 2 and 5% CC> 2 and the pH is adjusted to 7.4 with a dilute solution of sodium bicarbonate.

The preparation is allowed to equilibrate for 1 hour before administering any test compound and the bath fluid is changed 3 or 4 times during the equilibration period. The 5 * -amino- [j3,4 '-bipyridinej-6 (1H) -one-l'-oxide dissolved in a vehicle (for example, tyrode solution or a solution) is added to the tissue bath. acid addition salt of the compound tested) or else the vehicle is added alone and the total response is recorded. Tissues are washed between doses until the control values are obtained before the rate and force of contraction are administered. 4 to 6 doses are administered to the same preparation over a 4 to 6 hour period.

When tested by the procedure described above, it is found that 5-amino- [3,41 -bipyridine] -6 (1H) -one-1'-oxide, at doses of 100 J * .g / ml, causes a significant increase (i.e. more than 25%) in the strength of the papillary muscle, while causing only a small percentage increase (about 1/3 or less of 15 percentage increase in papillary muscle strength) in the speed of the right atrium.

Procedure using an anesthetized dog.

In this procedure, mongrel dogs of both sexes weighing 9-15 kg are used. Each dog is anesthetized with 30 mg / kg intravenously of sodium pentobarbital. Additional doses of pentobarbital are given if necessary. A cannula is inserted into the trachea and ventilation is performed using a Harvard constant volume displacement pump using room air. A cannula is inserted into the right femoral artery and the cannula is attached to a Statham P23A pressure transducer to measure blood pressure. A cannula is introduced into the right femoral vein for intravenous administration. are compounds to be tested. Pin electrodes are attached to the right front paw, the right rear paw, and the left rear paw, and the lead II electrocardiogram is noted.

A ventro-dorsal incision is made at the third intercostal space, the heart is exposed and a 35 Walton-Brodie strain gauge is sutured on the wall of the right ventricle to measure the force of the cardiac contraction, i.e. -to say cardiac contractility. The aortic and coronary blood flow is measured with a magnetic pulsed field electro- '' '' * 7 catheter (Carolina Medical Electronics) inserted around the blood vessel in question. Aortic blood flow is used as an approximate index of cardiac output and total peripheral resistance is calculated from aortic flow and average blood pressure. The previous measured parameters are all recorded simultaneously on a multi-channel Grass polygraph.

% 10 The test compound is administered intravenously as a single injection of 0.30 to 10 mg / kg.

According to this procedure, it is found that 5-amino - [_ 3,4'-bipyridine J-6 (1H) -one-1'-oxide, administered intravenously as a single injection of 3 or 10 15 mg / kg, causes a significant increase, i.e. greater than 25%, in the heart contraction force or cardiac contractility with only small or minimal changes (less than 25%) in heart speed and blood pressure.

The present invention comprises in its field a cardiotonic composition intended to increase the cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as active component, 5-amino- [3,4'-bipyridine3 ~ 6 (1H) -one -1'-cardiotonic oxide or its pharmaceutically acceptable acid addition salts. The invention also contemplates increasing cardiac contractility in a patient in need of such. treatment by administering to this patient an effective amount of said 5-amino-L3,4'-bipyridine ^ -ô (1H) -one-1'-oxide or one of its acid addition salts pharmaceutically acceptable. In clinical practice, the compound or its salt will normally be administered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, ♦ 8 sucrose or lactose. These compositions can also contain additional substances other than inert diluents, for example lubricating agents, such as magnesium stearate, talc, etc. Liquid compositions for oral administration include emulsions, solutions, Pharmaceutically acceptable suspensions, syrups and elixirs containing the inert diluents commonly used in the art, such as water and liquid paraffin. In addition to these inert diluents, such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfume and preserving agents. According to the invention, the compounds prepared for oral administration also include capsules of absorbable material, such as gelatin, containing the active compound, with or without the addition of diluents or excipients.

Preparations for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or organic suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants.

They can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions, by irradiation or by heating. They can also be produced in the form of sterile solid compositions which can be dissolved in sterile water or any other sterile injectable medium immediately before use.

The percentages of active component in the compositions making it possible to increase the cardiac contractility can vary so as to obtain an appropriate dose. The * 9 dose administered to a particular patient is variable, depending on the judgment of the physician using the following criteria: route of administration, duration of treatment, size and condition of the patient, potency of the active compound and reaction of the patient. An effective dose of active compound can therefore only be determined by the doctor, considering all these criteria and using his best judgment on the behavior of the patient.

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Claims (5)

10 1 en Μ 1. 5-amino - [. 3,4 '-bipyridine3-6 (1H) -one-1'-oxide or one of its acid addition salts. 2. Process for the preparation of a compound according to claim 1, characterized in that the 5-acetyl-amino - [. 3,4'-bipyridine ^ -6 (1H) -one is reacted with the acid peracetic in acetic acid to obtain 5-amino- [3,4'-bipyridine ^ -ö (1H) -one-1'-oxide and the latter is hydrolyzed, and if% 10 desired, transforms the free base obtained into one of its acid addition salts. 3. Method according to claim 2, characterized in that the hydrolysis step is carried out using an aqueous mineral acid, * at about 90 - 100 ° C. 4. Cardiotonic composition for increasing the cardiac con tractility, characterized in that it comprises a pharmaceutically acceptable inert support and, as active component, an effective amount of a compound according to claim 1. 5. A compound according to claim 1, used to increase cardiac contractility in a patient in need of such treatment.