LU83007A1 - (PHENYL SUBSTITUTE) PYRIDINES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Description

* This invention relates to (substituted phenyl) - pyridines, their preparation and their use as cardiotonic agents.

4- (3,4-Dimethoxyphenyl) pyridine, among others, is described in the U.S. Patent. No. 3,575,985 as an intermediate in the preparation of 4- (3-dimethoxyphenyl) -1-methylpyridinium iodide, which is heated with aqueous hydrobromic acid in acetic acid to form a mixture of iodide and 4- (3,4-dihydroxy-10 phenyl) -1-methylpyridinium bromide. The iodide-bromide mixture is treated with freshly prepared silver chloride to obtain 4- (3,4-dihydroxyphenyl) -1-methylpyridinium chloride. It is noted that the pyridinium salts of the U.S. Patent. No. 3,575,985 have "an effect on the cardiovascular and nervous systems, for example having antihypertension activity and can block or stimulate the lymph nodes".

4- (3-Hydroxyphenyl) pyridine is described, among others, by Coates et al. [J. Chem. Soc. 1943, 406].

20 Ginos et al. [J. Med. Chem. 1-8, 1194 (1975)] describe 2- (3,4-dihydroxybenzyl) pyridine as an intermediate.

The invention relates to 4 (or 3) - (3,5-dihydroxy-phenyl) pyridine or its acid addition salts.

The invention also relates to the process which consists in reacting hydrogen bromide or hydrobromic acid with 4 (or 3) - (3,4-dimethoxyphenyl) pyridine to obtain 4 (or 3) - (3,4- dihydroxyphenyl) pyridine.

The invention also relates to a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable pharmaceutical carrier and, as active component, an effective amount of 4 (or 3) -L3,4-di- ( OR) -phenyl] pyridine cardiotonic or a pharmaceutically acceptable acid addition salt thereof wherein R is a hydrogen atom or a methyl group. The preferred embodiments of this aspect of the invention are the compositions comprising, as active component, the compound where 2 R is a hydrogen atom or its salts.

Cardiac contractility may be increased in a patient in need of such treatment, by administration to that patient of an effective amount of the 4 (or 3) [3,4-di-5 (OR) -phenyljpyridine or its salts pharmaceutically acceptable, where R is a hydrogen atom or a methyl group, a preferred use of using the compound where R is a hydrogen atom.

4 (or 3) - [3,4-di- (OR) -phenyl] pyridine can be used in the form of the free base as well as in the form of acid addition salts and both forms are part of the field 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 basic form. The acids which can be used to prepare the acid addition salts preferably include those which produce, when combined with the free base, pharmaceutically acceptable salts, i.e. salts of which the anions are relatively harmless to 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 attributable to the anions. In practicing the invention, it is convenient to form hydrobromide or lactate. However, other suitable pharmaceutically acceptable salts falling within the scope of the invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, acid quinic, etc., giving the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate respectively.

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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 even if the particular salt is itself indicated only as an intermediate, for example when the salt is formed only for the purpose of purification or identification, or when used as an intermediate to prepare a pharmaceutically acceptable salt by ion exchange procedures.

The molecular structure of 4 (or 3) - [3,4-di-20 (OR) -phenylpyridine was assigned on the basis of data provided by the infrared, ultraviolet, nuclear magnetic resonance and mass spectra, by chromatographic mobilities, by the correspondence of the values calculated and found for the elementary analyzes and by the methods making it possible to prepare it.

The manner of making and using the present invention will now be described generally to allow those skilled in the art to make it.

The reaction of 4 (or 3) - (3,4-dimethoxyphenyl) -30 pyridine with a demethylating agent to obtain 4 (or 3) - (3,4-dihydroxyphenyl) pyridine is conveniently carried out by heating the reagents to about 100-126 ° C, preferably using aqueous hydrobromic acid. Other demethylating agents can also be used, for example hydroiodic acid, pyridine hydrochloride, boron tribromide, anhydrous aluminum chloride or bromide, etc.

The intermediate 4 (or 3) - (3,4-dimethoxyphenyl) pyridine 4 is prepared by known or conventional methods, as indicated below.

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

5 EXAMPLE 1

4- (3,4-Dihydroxypheny1) pyridine, also called 4— (4— pyridinyl) -1,2-benzenediol - A mixture containing 10.3 g of 4- (3,4-dimethoxy) is refluxed for 5 hours -phenyl) pyridine and 75 ml 48% hydrobromic acid and then allowed to stand at room temperature over the weekend. The yellow crystalline precipitate is collected, washed with ethanol and dried in an oven at 95 ° C.

to obtain, in the form of yellow needles, 11.8 g of 4- (3,4-dihydroxyphenyl) pyridine hydrobromide, m.p. 214-15 217 0 C.

4- (3,4-dihydroxyphenyl) pyridine is obtained in the form of the free base, by treating an aqueous solution of its hydrobromide with an excess of an aqueous solution of sodium bicarbonate and collecting the free base by filtration, first distilling a little of the excess water if necessary. Other acid addition salts of 4- (3,4-dihydroxyphenyl) pyridine are conveniently prepared by adding, to a mixture of 0.5 g of 4- (3,4-dihvdroxyphenyl) pyridine in about 10 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example methanesulfonate, sulfate or phosphate respectively. The acid addition salt of 4- (3,4-dihydroxyphenyl) pyridine is also conveniently prepared, in aqueous solution, by adding equimolar amounts of 4- (3,4-dihydroxyphenyl) to water. ) pyridine and suitable acid, for example lactic acid or hydrochloric acid, to prepare respectively lactate or 4- (3,4-dihydroxyphenyl) -pyridine hydrochloride in aqueous solution.

The intermediate 4- (3,4-dimethoxyphenyl) - pyridine and the 3- (3,4-dimethoxyphenyl) pyridine and 2- (3,4-dimethoxyphenyl) pyridine isomers are prepared as follows. To a stirred mixture cooled in a salt and ice bath and containing 200 g of 4-aminoveratrole, 400 ml of concentrated hydrochloric acid and 100 ml of water, a solution containing 102 g of sodium nitrite in 180 is added. ml of water in two hours, while maintaining a reaction temperature below 5 ° C during this addition. The reaction mixture is then stirred for an additional 15 minutes and then added slowly, over about two and a half hours, to 2 liters of stirred pyridine preheated to 4 ° C, maintaining. the internal temperature between 45 and 55 ° C. The mixture is then heated on a steam bath for one hour, left to stand at room temperature overnight (about 15 hours) and then the solvent is distilled in vacuo on a steam bath. To the residue is added 400 ml of concentrated hydrochloric acid and 600 ml of water, and the mixture is stirred well. The mixture is extracted with three 600 ml portions of chloroform. The aqueous layer is treated with bleaching charcoal and filtered. The filtrate is made alkaline by adding ammonia and the oily product which separates is extracted with chloroform. The chloroform is distilled in vacuo and 165.7 g of an oily product are obtained, which consists of a mixture of the three 4-, 3- and 2- (3,4-dimethoxy-phenyl) pyridines isomers. These three isomers are separated by chromatography using a column of 2 kilograms of silica gel in a two-liter sintered glass funnel and successively using a 1: 1 mixture by volume of * n-hexane and ether, l ether alone then 2% methanol 30 in ether. Evaporation of the ethereal eluate gives 67.8 g of 2- (3,4-dimethoxyphenyl) pyridine, m.p. 76-78 ° C. Evaporation of the eluate to 2% methanol in ether provides a mixture of isomers 3 and 4, 45.6 g, in the form of a semi-solid which is crystallized from ether to obtain 35 24.8 g of 4- (3,4-dimethoxyphenyl) pyridine, mp 101-103 ° C.

The mother liquor is combined with another fraction which contains a mixture of 30.8 g of isomers 2,3 and 4 in the form of a red oil and the mixture is rechromatographed as above. 15 g of isomer 2 are then obtained and the remaining mixture, essentially isomer 3, is dissolved in 300 ml in 6N HCl and the solution is treated with bleaching charcoal. The filtrate is concentrated on a rotary evaporator to obtain a greenish residue which is recrystallized from isopropyl alcohol to obtain 33 g of 3- (3,4-dimethoxyphenyl) pyridine hydrochloride, m.p. 198-200 ° C.

EXAMPLE 2 3- (3,4-Dihydroxyphenyl) pyridine, also called 4— (3— 10 pyridinyl) -1,2-benzenediol

A solution containing 15 g of 3- (3,4-dimethoxyphenyl) pyridine and 100 ml of 48% hydrobromic acid is heated at reflux for 30 minutes and then left to stand at room temperature overnight. The resulting pale yellow crystalline precipitate is collected, washed with ethanol and dried in an oven at 80 ° C to obtain 14.3 g of 3- (3,4-dimethoxyphenyl) pyridine hydrobromide, m.p. 288-290 ° C. 3- (3,4-dihydroxyphenyl) pyridine is obtained in the form of the free base by treating an aqueous solution of hydrobromide with an excess of an aqueous solution of sodium bicarbonate, collecting the resulting precipitate, washing it with of water and drying it to obtain 3- (3,4-dihydroxy-phenyl) pyridine in the form of the free base.

Other 3- (3,4-dihydroxyphenyl) pyridine acid addition salts are conveniently prepared by adding to a mixture of 1 g of 3- (3,4-dihydroxyphenyl) pyridine in about 20 ml of 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 after partial evaporation and collecting: the salt which precipitated, for example dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to the water, with stirring, an equimolar amount of 3- (3,4-dihydroxyphenyl) pyridine and suitable acid, for example lactic acid or hydrochloric acid, to prepare it, respectively, 3- (3,4-dihydroxyphenyl) pyridine lactate or hydrochloride in aqueous solution.

The following Example 3 is given for comparison. Neither this new 2- (3,4-dihydroxyphenyl) -5 pyridine nor the new corresponding intermediate 2- (3,4-dimethoxyphenyl) pyridine described above in the third paragraph of Example 1 are part of the field of present invention.

EXAMPLE 3 2- (3,4-Dihydroxyphenyl) pyridine is prepared in the form of its hydrobromide, 4.1 g, m.p. 260-262 ° C, according to the procedure described in Example 1, using 4 g of 2- (3,4-dimethoxyphenyl) pyridine, 35 ml of 48% hydrobromic acid and a reflux period of three hours and a half.

The usefulness of 4 (or 3) - [3,4-di- (OR) -phenyl] - pyridine or its salts as a cardiotonic agent is demonstrated by its effectiveness in standard pharmacological test procedures, by 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 little or minimal change in the speed of the heart and blood pressure. These test procedures are described in the U.S. Patent.

No. 4,072,746.

When tested by the procedure previously mentioned on the atrium and isolated papillary muscles of cats, 4 (or 3) -I3,4-di (OR) phenyl] -30 pyridine or its salts in doses of 10, 30 and 100 pg / ml cause a significant increase, i.e. greater than 25%, in the strength of the papillary muscle and a significant increase, i.e. greater than 25%, in the force of the right atrium, while causing only a smaller percentage increase (relative to that of the force of the papillary muscle and the force of the right atrium) of the speed of the right atrium. On the contrary, the 2- (3,4-dihydroxy- "'* 8 phenyl) pyridine hydrobromide isomer (Example 3) is clearly less effective than its isomers 3 and 4 (Examples 1 and 2), in% having only low activity at the highest dose used (100 yg / ml), while the isomers 3 and 5 4 exhibit significant activity at lower doses, that is to say 10 and 30 tg / ml.

When we try them by. the procedure on the anesthetized dog, 4- (3,4-dihydroxyphenyl) pyridine or its salts, administered intravenously in the form of a single injection of 1, 3 and 10 mg / kg, cause a significant increase, that is, greater than 25%, of the cardiac contraction force or cardiac contractility, with less changes per dose in heart rate and blood pressure.

The present invention includes a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as active ingredient, cardiotonic 4 (or 3) - [3,4-di- (OR) -phenylJpyridine or its 20 pharmaceutically acceptable acid addition salts. The invention also includes the use of an effective amount of said 4 (or 3) - [3,4-di- (OR) -phenyl · 'Jpyridine or a pharmaceutically acid addition salt thereof. acceptable to increase cardiac contractility in a patient in need of such treatment. In clinical practice, this compound or its salts will normally be administered orally or parenterally in various »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, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc. Liquid compositions for oral administration

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* i »* 9 include pharmaceutically acceptable emulsions, solutions, 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, fragrance and preservative agents. According to the invention, the compounds prepared for oral administration also include capsules of absorbable material, 4 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, ie uolyethylene. glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may 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 ingredient in the compositions for increasing cardiac contractility can vary so as to obtain an appropriate dose. The 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 "<10 th" doctor by considering all these criteria and using his best judgment on the behavior of the patient.

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Claims (6)

3. Process for the preparation of a compound according to claim 1, characterized in that the 4 (or 3) - (3,4-dimethoxyphenyl) pyridine is reacted with a demethylating agent and, if desired, transforms the free base 10 obtained into one of its acid addition salts. 4. Method according to claim 3, characterized * - in that the demethylating agent is aqueous hydrobromic acid. 5. Method according to either of claims 3 and 4, characterized in that 4 - (3,4 - dihydroxyphenyl) pyridine is produced from 4- (3,4-dimethoxyphenyl) pyridine. 6. Cardiotonic composition for increasing cardiac contractility, characterized in that it comprises an inert pharmaceutically acceptable carrier and, as active ingredient, an effective amount of 4 (or 3) - [3,4-di (OR) - phenyl] pyridine cardiotonic or one of its pharmaceutically acceptable acid addition salts, where R is a hydrogen atom or a methyl group. 7. Compound used to increase cardiac contractility * in a patient in need of such treatment, the compound being 4 (or 3) - [3,4-di- (OR) -phenyl] pyridine or one of its addition salts of pharmaceutically acceptable acids, where R is a hydrogen atom or a methyl group. 8. Composition or compound according to either of Claims 6 and 7, characterized in that the active component is 4- (3,4-dihydroxyphenyl) pyridine or one of its pharmaceutically acceptable salts.