NL8006511A - A NEW BIPYRIDINE COMPOUND AND A PHARMACEUTICAL PREPARATION CONTAINING THIS COMPOUND. - Google Patents

Description

S Ö / 4-201 P & c

Novel bipyridine compound, as well as pharmaceutical composition containing this compound.

The invention relates to an N-oxide of 5-amino- [3,4 * -bipyridin] -6 (1H} -one which is suitable as a cardiotonic agent, and to the preparation of this compound.

U.S. Patent 4,072,746 discloses, inter alia, 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, also referred to as 5-amino- [3,4r-bipyridin] -6 (1H) -one which compound is suitable as a cardiotonic agent, as well as the preparation of this compound by various methods. This US patent also discloses the corresponding 3-acetylamino compound (or 5-acetylamino compound in the above alternative nomenclature).

The invention provides 5-amino- [3,4-bupyridin] -6 (1H) -one-1 "oxide and pharmaceutically acceptable addition salts thereof with acids. The above compound is suitable as a cardiotonic agent, as determined by standard pharmacological tests.

5-Acetylamino- [3,4'-bipyridin] -6 (1H) -one can be converted with peracetic acid to acetic acid to give 5-acetylamino- [3,4'-bipyridin] -6 (1H) -one-1'oxide, and the latter compound hydrolyze to 5-araino [3,4'-bipyridin] -6 (1H) -one-1'-oxide.

The present cardiotonic preparations for increasing the contractile capacity of the heart, contain a pharmaceutically acceptable carrier and as active ingredient the cardiotonic 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide or a pharmaceutically acceptable addition salt thereof with an acid.

Cardiac contraction can be increased in a patient in need of such treatment by providing an effective amount of the cardiotonic 5-amino- [3,4'-bipyridin] -6 (1H) -on-l'- to this patient. oxide or a pharmaceutically acceptable addition salt thereof with an acid.

The 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide is valuable both in the form of the free base and in the form of an addition salt with an acid.

The acid addition salts are simply a more convenient form to be used, and in practice, use of the salt form boils down to use of the base form. The acids which can be used to prepare the addition salts are preferably those which give pharmaceutically acceptable salts when combined with the free base, ie salts of which the anions are relatively harmless to the animal organism when administered pharmaceutical doses of the salts, so that the cardiotonic properties of the free base are not impaired by side effects attributable to the anions. According to the invention, it has been found suitable to prepare the free base form; however, it is also possible to use suitable pharmaceutically acceptable salts, for example those obtained from a mineral acid such as chloro-hydrochloric acid, sulfuric acid, phosphoric acid or sulfamic acid; or an organic acid such as acetic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexyl sulfamic acid, 1,3,4,5-tetrahydrocyclohexanoic acid (quinic acid) and the like; the salts of these acids are the hydrochloride, sulfate, phosphate, sulfamate, acetate, lactate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate ,. p-toluenesulfonate, cyclohexyl sulfanate and 1,3,4,5-tetrahydroxycyclohexane carboxylate.

The addition salts of the basic compound with an acid are prepared by dissolving the free base in water or water-alcohol or another suitable solvent containing the respective acid and isolating the salt by evaporating the solution or by free base and the acid in an organic solvent together, in which case the salt separates directly or can be obtained by concentrating the solution.

Although pharmaceutically acceptable salts of the basic compound are preferred, all addition salts with an acid are within the scope of the invention. All acid addition salts are suitable as a source of the free base form. even if the salt in question is only desirable as an intermediate per se, for example when the salt is only formed for purification or identification purposes or when the salt is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange.

The molecular structure of 5-amino- [3,4'-bipyridin] -6 (1H) -on-1'-oxide was determined based on the infrared spectrum, the ultraviolet spectrum, the nuclear magnetic resonance spectrum and the mass spectrum, and from the similarity between the calculated and found values in the elemental analysis.

The preparation and use of the present compounds is described in more detail below.

The oxidation of 5-acetylamino- [3,4'-bipyridin] -6 (1H) -one to the 1'-oxide is conveniently performed by heating the starting compound with peracetic acid in acetic acid at a temperature of about 75 ° -120 ° C and preferably about 90 ° -100 ° C.

The hydrolysis of 5-acetylamino- [3,4'-bipyridin] -6 (1H) -on-1-oxide 800 6 5 t 1 - 3 - to yield the corresponding 5-amino compound is performed by the 5-acetylamino compound heating in an aqueous mineral acid, preferably aqueous hydrochloric acid, at a temperature of about 90 ° -100 ° C.

The following non-limiting examples further illustrate the invention.

EXAMPLE X

5-Acetylamino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide

To a hot solution of 16 g of 5-acetylamino- [3,4'-bipyridin] -6 (1H) -10 o in 150 ml of acetic acid was added 24 ml of 40% peracetic acid? the resulting mixture was heated on a steam bath for 1 hour, cooled and poured on ice. The aqueous mixture was neutralized with ammonium hydroxide and the resulting precipitate collected, washed with water and dried, yielding 12 g of 5-aceylamino- [3,41-bipyridin] -6 (1H) -15-1'-oxide , melting point> 300 ° C.

EXAMPLE II

5-Amino- [3,4'-bipyridin] -6 (1H) -one-11-oxide

A mixture of 12 g of 5-acetylamino- [3,4'-bipyridin] -6 (1H) -one-1'oxide and 100 ml of 6N hydrochloric acid was heated on a steam bath for 1 hour, cooled and heated under reduced pressure to removal of the liquid. The residue was made basic with ammonium hydroxide and heated again under reduced pressure until a dry material was obtained. The remaining material was recrystallized twice from 50% aqueous methanol to give 5 g of 5-amino- [3,4'-bipyridin] -6 (1H) -one-11oxide monohydrate in the form of a light yellow solid dust, melting point 273 ° -275 ° C (decomposition).

Addition salts of 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'oxide with acids were conveniently prepared by adding to a solution of 2 g 5-amino- [3,4'-bipyridin] - 6 (1H) -one in about 40% aqueous methanol, add the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cool the mixture, and precipitate the salt ( for example the methanesulfonate, sulfate or phosphate). Also, the addition salts with acids can be conveniently prepared in aqueous solution by molar equivalent amounts of 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide and the appropriate acid with stirring in water. for example lactic acid or hydrochloric acid) to obtain the monolactate salt or monohydrochloride salt in aqueous solution.

The suitability of 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide and its salts as cardiotonic agents is demonstrated by their activity at 800 6 5 1 1 - 4 standard pharmacological tests, for example, to achieve a significant increase in the contractile force of the isolated atrial and papillary muscle of cats and a significant increase in the cardiac contraction force in the anesthetized dog test with slight or minimal changes in heart rate and blood pressure. These test methods are discussed in more detail below.

Experiment with isolated atria and papillary muscle of cats Cats of both sexes, weighing 1.5 to 3.5 kg, were anesthetized with 30 mg of sodium pentobarbital per kg of body weight (intra-10 peritoneally) and the cats were allowed to bleed. Each cat's chest was opened. The heart was excised and rinsed with saline; the two atria and one or more small, thin papillary spiers. were isolated from the right ventricle. The tissues were then transferred to a Petri dish filled with cold modified Tyrode's solution and bubbled through. A silver wire was attached to each of two opposite ends of the fabric; one of the wires was connected to a glass electrode.

The preparation was then immediately placed in an organ bath (40 or 50 ml) which was filled slightly with modified Tyrode's solution at 37 ° C. The second wire was connected to a force and displacement sensor; the tension was adjusted to obtain maximum contraction force (papillary muscle 1.5 ± 0.5 g, left atrium 3.0 ± 0.6 g, right atrium 4.5 ± 0.8 g). The sensor was connected to a Grass polygraph with which the force and speed of the contraction were continuously recorded. The right atrium contracted spontaneously due to the presence of the sinus node in the atrium, while the left atrium and the papillary muscle were electrically stimulated (velocity two strokes / second) by means of a rectangle impulse with a resistance of 0, above the threshold value. 5 milliseconds.

The modified Tyrode solution used in the bath had the following composition: NaCl 136.87mmol, KCl 5.36mmol, Ia ^ PO ^ 0.41mmol, CaC ^ 1.8mmol, MgC ^ 10H ^ O 1.05mmol, NaHCO4 11.9mmol, glucose 5.55mmol and EDTA 0.04mmol. The solution was equilibrated with a gas mixture consisting of 95% and 5% CO 2, and the pH was adjusted to 7.4 with a dilute sodium dicarbonate solution.

The preparation was allowed to equilibrate for 1 hour before any compound was administered. The bath liquid was replaced 3 to 4 times during this period. The 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide dissolved in a carrier (e.g. Tyrode's solution or an aqueous 8006511

i V

Solution of an addition salt of the compound to be tested with an acid or the carrier alone was added to the tissue bath and the complete response was recorded. The tissues were washed between the administered doses so that control values for the rate and strength of the contraction were always obtained prior to the administration of the drug, over a period of 4-6 hours, 4-6 doses were administered to the same preparation.

In studies with the above test, 5-amino- [3,4'-bipyridin] -6 (1H) -one-1'-oxide at a dose of 100 µg / ml was found to cause a significant increase in the contractile force of the papillary muscle, more than 25%, while only a slight increase in the contraction rate of the right atrium was achieved (approximately 1/3 or less of the increase in the contraction force of the papillary muscle).

Test with anesthetized dogs In this test, mongrel dogs of both sexes weighing 9-15 kg were used. All dogs were anesthetized with 30 mg sodium pento-barbital per kg body weight (intravenous). If necessary, additional doses of pentobarbital are administered. An intratracheal cannula was applied and ventilated with room air using a Harvard-20 pump with constant volume and defined pressure. a cannula was placed in the right thigh artery, which was connected to a Statham P23A pressure transducer to determine arterial blood pressure. A cannula was placed in the right thigh artery for the intravenous administration of the test compounds. The right front leg, the right back leg and the left back leg were connected with pin electrodes and an electrocardiogram of the configuration II was recorded.

A ventro-dorsal incision was made in the third intercostal space.

The heart was exposed and a Walton-Brodie strain gauge was attached to the wall of the right ventricle to determine the contraction force of the heart. Aortic and coronary blood flow was measured by means of a pulsating electromagnetic flow probe (Carolina Medical Electronics) placed around the affected blood vessel. Aortic blood flow was used as a measure of cardiac performance and total peripheral resistance was calculated from aortic flow and mean arterial pressure. All the above measured parameters were recorded on a multi-channel recording instrument (Grass polygraph).

The investigated compound was administered intravenously as a single "bolus injection of 0.30-10 mg / kg.

In the anesthetized dog experiment described above, 5-amino- [3,4'-8 00 6 5 ff-6-bipyridin] -6 (1H) -one-11-oxide was administered intravenously as a single "bolus" injection of 3-10 mg / kg cause a significant increase in the contraction force of the heart, more than 25%, with only minor or minimal changes (less 25%) in heart rate and blood pressure. The invention also provides a cardiotonic composition for increasing the contractile force of the heart, which composition is a pharmaceutically acceptable carrier and the active ingredient is the cardiotonic 5-amino- [3,4'-bipyridin] -6 (1H) -one- 1'-oxide or a pharmaceutically acceptable addition salt thereof with an acid. The invention also provides a method of increasing cardiac contraction in a patient in need of such treatment, according to which method of providing the patient with an effective amount of 5-amino- [3,4'-bipyridin] - (1H) -one- 1-oxide or a pharmaceutically acceptable addition salt thereof is administered with an acid. In practice, this compound or a salt thereof is normally administered orally or parenterally in a wide variety of dosage forms.

Solid preparations for oral administration include pressed tablets, pills, powders and granules. In these solid preparations, at least one of the active compounds is mixed with at least one inert diluent, such as starch, calcium carbonate, sucrose or lactose. These preparations may also contain materials other than inert diluents, for example, gelling agents such as magnesium stearate, talc and the like.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents such as water and liquid paraffin. In addition to inert diluents, these preparations may also contain auxiliary agents such as wetting and suspending agents, sweetening agents, flavoring and / or flavoring agents, lending agents and preservatives. According to the invention, the orally to be administered compositions also comprise capsules of absorbable material, such as gelatin, which contain the active compound, optionally in combination with a diluent.

Preparations according to the invention to be administered parenterally include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspension media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These preparations may also contain auxiliary agents such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.

The present compositions can be sterilized, for example, 8006511-7 by filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiation or by heating. The formulations can also be prepared in the form of sterile solid materials which can be dissolved in sterile water or other sterile injectable medium immediately before use.

The percentage of active ingredient in the composition and the method of increasing cardiac contraction can be varied to obtain an appropriate dose. The dose administered to a particular patient varies depending on the mode of administration, the duration of the treatment, the size, build and condition of the patient, the efficacy of the active component concerned and the response of the patient.

An effective dose of the active component can thus be determined by the treating physician only on the basis of the above factors.

8006511

Claims (3)

2. Process for preparing a new bipyridine derivative, characterized in that 5-acetyl-amino- [3,4'-bipyridin] -6 (1H) -one is reacted with peracetic acid in acetic acid to obtain 5-acetylamino- [ 3,4'-bipyridin] -6 (1H) -one-1-oxide and the latter compound hydrolyzes, optionally converting the resulting free base to an addition salt thereof with an acid. 3. Process according to claim 2, characterized in that the hydrolysis step is carried out by using an aqueous mineral acid at a temperature of about 90 ° -100 ° C. 4. Cardiotonic composition for increasing the contraction capacity of the heart, comprising a pharmaceutically acceptable inert carrier and an active ingredient, characterized in that the active ingredient composition contains a compound according to claim 1. 8006511