NL8006785A - NEW PHENYLPYRIDINS, METHOD FOR THE PRODUCTION THEREOF, AND PHARMACEUTICAL PREPARATION. - Google Patents

Description

1 S 824-203 * ^

Sterling Drug Inc.

Novel phenylpyridines, process for their preparation, as well as pharmaceutical preparation.

The invention relates to substituted phenylpyridines, their preparation and their use as cardiotonic agents.

U.S. Patent 3,575,985 describes a.o.

4- (3,4-dimethoxyphenyl) pyridine as a starting material for preparing 4- (3,4-dimethoxyphenyl) -1-methylpyridinium iodide, which was heated with aqueous hydrobromic acid in acetic acid to give a mixture of 4- (3, 4-dihydroxyphenyl) -1-methylpyridinium iodide and bromide. The iodide / bromide mixture was treated with freshly prepared silver chloride to give 4- (3,4-dihydroxyphenyl) -1-methylpyridinium chloride. The pyridinium salts of U.S. Pat. No. 3,575,985 have "an effect on the cardiovascular and nervous systems, eg anti-hypertensive activity and the ability to block or stimulate autonomic ganglia11.

In an article by Coates et al., J. Chem. Soc. 1943, 406, a.o. 4- (3-hydroxyphenyl) pyridine is disclosed.

In an article by Ginos et al., J. MecLChem. 18, 1194 (1975), the intermediate product is 2- (3,4-dihydroxybenzyl) pyridine. —_

The invention provides 4 (and 3) - (3,4-dihydroxyphenyl) pyridine and addition salts thereof with acids.

The invention provides a process according to which bromine hydrogen is reacted with 4 (or 3) - (3,4-dimethoxyphenyl) pyridine to give 4 (or 3) - (3,4-dihydroxyphenyl) pyridine.

Furthermore, the invention provides a cardiotonic composition for increasing the contraction capacity of the heart, which composition is a pharmaceutically acceptable slow and active ingredient an effective amount of the cardiotonic 4 (or 3) - [3,4-di- ( OR) -phenyl] pyridine, wherein R is a hydrogen atom or a methyl group, or contains a pharmaceutically acceptable addition salt thereof with an acid. Preferred compositions of the invention contain as active ingredient the compound wherein R 30 is a hydrogen atom or a salt thereof.

Cardiac contraction can be increased in a patient in need of such treatment by providing this patient with an effective amount of cardiac cardiac 4 (or 3) - [3,4-di- (OR) -phenyl] pyridine, wherein R is a hydrogen atom or a methyl group or to administer a pharmaceutically acceptable salt thereof; according to a preferred embodiment, a compound is administered in which R is hydrogen.

4- [3,4-di- (OR) -phenyl] pyridines and 3- [3,4-di- (OR) -phenyl] pyridines 8006785-2 - are both in the free base and in the form of an addition salt with an acid valuable. The addition salts with an acid are simply a more suitable form to be used, and in practice the use of the salt form boils down to the 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, d. i.e. salts the anions of which are relatively harmless to the animal organism when administered in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties of the free base are not impaired by side effects attributable to the anions. According to the invention, it has proved suitable to prepare a hydrobromide or lactate. However, other pharmaceutically acceptable salts are also suitable, e.g., those obtained from mineral acids such as hydrogen chloride, 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, 1,3,4,5-tetrahydroxycyclohexane carboxylic acid (quinic acid) e. d .; the salts of these acids are hydrochlorides, sulfates, phosphates, sulfamates, acetates, citrates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and cyclohexyl sulfamates.

1,3,4,5-tetrahydrocylohexane carboxylates.

The addition salts of the basic compound with an acid are prepared by dissolving the free base in water or water-alcohol or other suitable solvent containing the acid in question 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 concentration of the solution.

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

The molecular structure of the 4 (and 3) - [3,4-di- (OR) -phenyl] pyridines was determined based on the infrared spectrum, the ultraviolet spectrum, the nuclear magnetic resonance spectrum and the mass spectrum, 8006785 * . * t - 3 -; from the chromatographic mobilities, from the correspondence between the calculated and found values in the elemental analysis and on the basis of the preparation method.

The preparation and use of the present compounds 5 is described in more detail below.

The reaction of 4 (or 3) - (3,4-dimethoxyphenyl) pyridine with a demethylating agent to form 4 (or 3) - (3,4-dihydroxyphenyl) pyridine was conveniently performed by the reaction components at about 100 ° -126 ° C, preferably using aqueous hydrogen hydrogen hydrogen. Other demethylating agents may be used instead, e.g. hydrogen iodine, pyridine hydrochloride, boron tribromide, anhydrous aluminum chloride or bromide or the like.

The compound 4 (or 3) - (3,4-dimethoxyphenyl) pyridine can be prepared by known or conventional methods, as explained below.

The following non-limiting examples further illustrate the invention.

Example I

4- (3,4-dihydroxyphenyl) pyridine, also called 4- (4-pyridinyl) -1,2-20 benzenediol. A mixture of 10.3 g of 4- (3,4-dimethoxyphenyl) pyridine and 75 ml of 48% hydrogen bromide was heated under reflux for 5 hours, and the mixture was allowed to stand at room temperature over the weekend. The yellow crystalline precipitate was collected, washed with ethanol and oven dried at 95 ° C, yielding 11.8 g of 4- (3,4-dihydroxyphenyl) pyridine hydrobromide, mp 214 ° -217 ° C, in the form of yellow needles.

4- (3,4-dihydroxyphenyl) pyridine was obtained in the free base form by treating an aqueous solution of its hydrobromide salt with excess aqueous sodium bicarbonate solution and collecting the free base form by filtration, distilling off, if necessary, part of the excess water . Other addition salts of 4- (3,4-dihydroxyphenyl) pyridine with acids were conveniently prepared by adding the appropriate acid, e.g., methanesulfonic acid, to a mixture of 0.5 g of 4- (3,4-dihydroxyphenyl) pyridine in about 10 ml of aqueous methanol. , concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture after partial evaporation and collecting the precipitated salt (the methanesulfate, sulfate or phosphate). Also, the addition salts of 4- (3,4-dihydroxyphenyl) pyridine with acids can be conveniently incorporated

aqueous solution can be prepared by stirring in water molar equiva-O Λ Λ O 7 0 K.

He - 4 - Spring Heovies Add 4- (3,4-dihydroxyphenyl) pyridine and the appropriate acid, e.g. lactic acid or hydrogen chloride, to give the lactate or hydrochloride salt of 4- (3,4-dihydroxyphenyl), respectively. pyridine in aqueous solution.

The 4- (3,4-dimethoxyphenyl) pyridine and the isomeric compounds 3- (3,4-dimethoxyphenyl) pyridine and 2- (3,4-dimethoxyphenyl) pyridine were prepared as follows: cooled in an ice-salt bath mixture of 200 g of 4-aminoveratrol, 400 ml of concentrated hydrochloric acid and 100 ml of water was added with stirring over a period of 2 hours a solution of 102 g of sodium nitrite in 180 ml of water, while this addition was kept the reaction temperature below 5 ° C. The reaction mixture was stirred for an additional 15 minutes and then in. of about 2 hours slowly added to 2 liters of pre-heated pyridine at 4 ° C with stirring, the internal temperature being kept at 45 ° -55 ° C. The mixture was then heated on a steam bath for 1 hour, allowed to stand at room temperature overnight (about 15 hours), and the solvent was then distilled off under a reduced pressure on a steam bath. 400 ml of concentrated hydrochloric acid and 600 ml of water were added to the residue and the mixture was well slurried. on. The mixture was extracted with 3 600 ml portions of chloroform. The aqueous layer was treated with decolorizing charcoal and filtered. The filtrate was made basic by the addition of aqueous ammonia, and the oily product which separated was extracted with chloroform. The chloroform was distilled off under reduced pressure to obtain 165.7 g of an oily product consisting of a mixture of the 3 isomers 4-, 3- and 2- (3,4-dimethoxyphenyl) pyridine.

These 3 isomers were separated chromatographically using a 2 kg silica gel column placed in a 2 L volume sintered glass funnel; n.hexane ether (volume ratio 1: 1), ether alone, and then 2% methanol in ether were used successively. After evaporation of the ether eluate, 67.8 g of 2 (3,4-dimethoxyphenyl) pyridine, melting point 76 ° -78 ° C, were obtained. After evaporation of the eluate of 2% methanol-in-ether, 45.6 was obtained. g of a mixture of the 3-isomer and the 4-isomer, in the form of a semi-solid, which was crystallized from ether to obtain 24.8 (3,4-di-35-methoxyphenyl) pyridine, melting point 101 ° -103 ° C. The mother liquor was combined with another fraction containing a mixture of 30.8 g of the 2 isomer, the 3 isomer and the 4 isomer in the form of a red oil; the resulting mixture was re-chromatographed in the manner described above. 15 g of the 2-isomer were obtained and the residual mixture, 40 which was mainly formed by the 3-isomer, was dissolved in 300 ml of α η η 7 fi 5 - 5 - 6N HCl, after which the solution was treated with decolorizing charcoal. The filtrate was concentrated on a rotary evaporator to obtain a greenish residue, which was recrystallized from isopropanol to obtain 33 g of 3- (3,4-dimethoxyphenyl) pyridine hydrochloride, mp 198 ° -200 ° C.

Example II

3- (3,4-dihydroxyphenyl) pyridine, also called 4- (3pyridinyl) -1,2-benzenediol. A solution of 15 g of 3- (3,4-dimethoxyphenyl) pyridine and 100 ml of 48% hydrogen bromide was heated under reflux for 30 minutes, then the mixture was left overnight at room temperature. The resulting pale yellow crystalline precipitate was collected, washed with ethanol and dried in an oven at 80 ° C, yielding 14.3 g of 3- (3,4-dimethoxyphenyl) pyridine hydrobromide, mp 288 ° -290 ° C. obtained 3- (3,4-dihydroxyphenyl) pyridine in the free base-15 form by treating an aqueous solution of the hydrobromide with an excess of aqueous sodium bicarbonate solution, collecting the precipitate obtained, washing the precipitate with water and then drying it , obtaining 3- (3,4-dihydroxyphenyl) pyridine in the free base form.

Other addition salts of 3- (3,4-dihydroxyphenyl) pyridine with 20 acids were suitably prepared by adding the appropriate acid to a mixture of 1 g of 3- (3,4-dihydroxy-phenyl) pyridine in about 20 ml of aqueous methanol, e.g. add methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cool the mixture after partial evaporation and the precipitated salt, i.e. collecting the dimethane sulfonate, sulfate or phosphate. Also, the addition salts with acids can be conveniently prepared in aqueous solution by adding molar-equivalent amounts of 3- (3,4-dihydroxyphenyl) pyridine and the appropriate acid, e.g., lactic acid or hydrogen chloride, to water with stirring, to give the lactate salt or the hydrochloride salt of 3- (3,4-dihydroxyphenyl) pyridine in aqueous solution, respectively. Example III below is given for comparison. Neither the new 2- (3,4-dihydroxy-phenyl) pyridine nor the corresponding new 2- (3,4-dimethoxyphenyl) pyridine [mentioned in Example I] are included in the invention.

Example III

2- (3,4-dihydroxyphenyl) pyridine was added as the hydrobromide in a. 4.1 g (melting point 260 ° -262 ° C) prepared according to the method described in Example I using 4 g of 2- (3,4-dimethoxyphenyl) pyridine, 35 ml of 48% hydrogen bromide and a reflux time of 3.5 hours.

- 6 -

The suitability of 4- and 3-L 3,4-di- (OR) -phenylpyridines and their salts as cardiotonic agents is evidenced by their effectiveness in standard pharmacological test methods; for example, these compounds cause a significant increase in the contraction force of the isolated atrial and papillary muscles of cats and a significant increase in the cardiac contraction force in the anesthetized dog trial with slight or minimal changes in heart rate and blood pressure. These test methods are described in U.S. Pat. No. 4,072,746.

When tested according to the above test with isolated atria and papillary muscle of cats, the 4- and 3- [3,4-di- (OR) -phenyl] pyridines and their salts were found at doses of 10.30 and 100 µg / ml cause a significant increase, ie more than 25%, in the papillary muscle strength .. and a significant increase, ie more than 25%, in the contraction force of the right atrium, while a smaller increase (than in the contraction force of the papillary muscle and the contraction force of the right atrium) in the contraction rate of the right atrium. In contrast, the isomeric 2- (3,4-dihydroxyphenyl) pyridine hydrobromide (Example III) was significantly less effective than the 3 isomer and the 4 isomer of the compound (Examples I and II); this compound showed only weak activity at the largest dose tested (100 µg / ml), while the 3-isomer and 4-isomer showed significant activity at lower doses, i.e. 1.0 and 30 µg / ml.

Testing in the anesthetic dogs trial showed 4- (3,4-dihydroxyphenyl) pyridine and its salts when administered intravenously as a single "bolus" injection at doses of 1.3 and 10 mg / kg in the contraction force of the heart, more than 25%, with correspondingly smaller changes per dose in heart rate and blood pressure.

30. The invention also provides a cardiotonic composition for increasing the contractile capacity of the heart, which composition is a pharmaceutically acceptable carrier and as active ingredient a cardiotonic 4 (or 3) - [3,4-di (OR) -phenyl] pyridine or pharmaceutically contains 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 said patient with an effective amount of the 4 (or 3) - [3,4-di (OR) -phenyl ] pyridine or pharmaceutically acceptable addition salt thereof is administered with an acid. In practice, the compounds of the invention are 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. In addition to inert ingredients, these preparations may also contain other materials, e.g. lubricants such as magnesium stearate, talc and the like.

Liquid preparations for oral administration include far-10 maceutically 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 adjuvants, such as wetting and suspending agents, sweeteners, flavoring and / or fragrance imparting agents, and preservatives. According to the. Invention, the orally administered compositions also include capsules of absorbable material, such as gelatin, which contain the active compound, whether or not in combination with a diluent,. contain.

Compositions of the invention to be administered parenterally include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending 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, e.g., by filtering through a filter that retains bacteria by incorporating sterilizing agents into the compositions, by irradiation or by heating. The formulations may 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 component 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 treatment, the size, build and condition of the patient, the efficacy of the active component concerned and the response of the patient. Thus, an effective dose of the active component can be determined by the treating physician based on the factors mentioned above. r η n fi 7 «« i

Claims (5)

3. Process for preparing. a new pyridine derivative, characterized in that 4 (ofL 3) - (3,4-dimethoxyphenyl) pyridine is reacted with a demethylating agent and, if desired, converted an obtained free base into an addition salt thereof with an acid. 4. Process according to claim 3, characterized in that as the demethylating agent, aqueous hydrogen bromide is used. Process according to claim 3 or 4, characterized in that 4- (3,4-dihydroxyphenyl) pyridine is prepared from 4- (3,4-dimethoxyphenyl) pyridine. 6. Cardiotonic preparation for increasing the contraction capacity of the heart, containing a pharmaceutically acceptable inert carrier and an active ingredient, characterized in that the active ingredient composition is an effective amount of 4 (or 3) - [3,4-di (OR) -phenyl] pyridine, wherein R is a hydrogen atom or a methyl group, or contains a pharmaceutical addition salt thereof with an acid. 7. A composition according to claim 6, characterized in that the active ingredient. 4- (3,4-dihydroxyphenyl) pyridine or a pharmaceutically acceptable salt thereof. 8 00 6 78 5