FR2496464A1 - 4-(or 3-) 3,4-Di:hydroxyphenyl pyridine and its salts - are cardiotonics which increase cardiac contractility, prepd. by demethylation of 3,4-di:methoxy cpd. with hydrobromic acid - Google Patents

Abstract

4-(or 3)-(3,4-dihydroxy-phenyl) -pyridine, (I), and its acid addn. salts are new. Cardiotonic compsns. for increasing cardiac contractility contg. (I) or 4-(or 3)-(3,4-dimethoxy-phenyl) pyridine (II) or their salts are new. 2-(3,4-dihydroxy or dimethoxy -phenyl)pyridine and its acid addn. salts are described as new cpds., but do not form part of the present invention. (I) is prepd. by demethylation of (II) using aq. hydrobromic acid, pref. at 100-126 deg.C. Other demethylation agents may be used if desired. (II) is described in US3575985 as an intermediate for preparing +, -(3,4-ihydroxy-phenyl)-1-methyl pyridinium cpds. having cardiovascular activity. Cpds. are cardiotonics which increase cardiac contractility and may be administered orally or parenterally using classical formulations. Pharmacological tests are described.

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- (3dimethoxyphenyl) -l-methylpyridinium iodide, which is heated with aqueous hydrobromic acid in acetic acid to form a mixture of iodide and bromide 4- (3,4-dihydroxy phenyl) -1-methylpyridinium. The iodide-bromide mixture is treated with silver chloride freshly prepared to obtain 4- (3,4-dihydroxyphenyl) -1-methylpyridinium chloride. It is stated that the pyridinium salts of the U.S. Patent. NO 3,575,985 have "an effect on the cardiovascular systems; nervous and nervous, by possessing for example an 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, 4061.

 Ginos et al. [J. Med. Chem. 18, 1194 (1975) 1 describe 2- (3,4-dihydroxybenzyl) pyridine as an intermediate.

 The invention relates to 4 (or 3) - (3,4-dihydroxyphenyl) 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 the 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. The preferred embodiments of this aspect of the invention are the compositions comprising, as active component, the compound where
R is a hydrogen atom or its salts.

 Cardiac contractility can be increased in a patient in need of such treatment by administering to that patient an effective amount of the cardiotonic 4 (or 3) [3,4-di (OR) -phenyl] pyridine or its salts 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) -phenyljpyridine 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 base form. The acids which can be used to prepare the acid addition salts preferably include those which produce, when they are combined with the free base, pharmaceutically acceptable salts, that is to say salts whose anions are relatively harmless with respect to the animal body at pharmaceutical doses of the salts, so that the cardiotonic properties benefits inherent in the free base are not tainted by side effects attributable to anions. In carrying out the invention, it is convenient to form hydrobromide or lactate. However, other suitable pharmaceutically acceptable salts which form part of the field 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 quinioue, etc., giving the hydrochloride, the sulfate, the phosphate, the sulfamate, the acetate, the citrate, the tartrate, the methanesulfonate, the ethanesulfonate, the benzenesulfonate, the p-toluenesulfonate, the cyclohexylsulfamate and the quinate respectively.

 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 concentrating the solution.

 Although the pharmaceutically acceptable salts of the basic compound are preferred, all of the 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 indicated in itself 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 (OR) - phenyJl-yridine has been 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 processes 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) pyridine with a demethylating agent to obtain 4 (or 3) - (3,4-dihydroxyphenyl) pyridine is conveniently carried out by heating the reactants to about 100 -1260C, 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 is prepared by known or conventional methods, as indicated below.

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

 EXAMPLE 1 4- (3,4-Dihydroxyphenyl) pyridine, also called 4- (4pyridinyl) -1,2-benzenediol - A mixture containing 10.3 g of 4- (3,4-dimethoxy) is refluxed for 5 hours phenyl) pyridine and 75 ml of hydrobromic acid at 48% then it is left to stand at room temperature for the weekend. The yellow crystalline precipitate is collected, washed with ethanol and dried in an oven at 950C to obtain, in the form of yellow needles, 11.8 g of 4- (3, 4-dihydroxyphenyl) hydrobromide pyridine, pf 2142170C.

 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 distill a little of the excess water if necessary. Conveniently prepare other acid addition salts of 4- (3,4-dihydroxyphenyl) pyridine by adding, to a mixture of 0, 5 g of 4- (3,4-dihydroxyphenyl) pyridine in about 10 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, up to a pH about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, 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 the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the lactate or hydrochloride of 4- (3,4-dihydroxyphenyl) pyridine 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 ml is added. of water in two hours, while maintaining a reaction temperature below 50C during this addition. The reaction mixture is then stirred for an additional 15 minutes and then added slowly, over approximately two and a half hours, to 2 liters of stirred pyridine preheated to 400C, maintaining the internal temperature between 45 and 550C. Then the mixture is heated to a steam bath for one hour, it is 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 under vacuum and 165.7 g of an oily product are obtained, which consists of a mixture of the three 4-, 3- and 2- (3,4-dimethoxyphenyl) pyridines isomers. isomers 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, ether alone then 2 t of methanol in ether. Evaporation of the ethereal eluate gives 67.8 g of 2- (3,4-dimethoxyphenyl) pyridine, m.p. 76-780C. 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 24.8 g of 4- (3,4-dimethoxyphenyl) pyridine, mp 101-1030C.

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 of 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, p. f.

 198-2000C.

EXAMPLE 2 3- (3,4-Dihydroxyphenyl) pyridine, also called 4- (3pyridinyl) -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 precipitate is collected Resulting pale yellow lens, washed with ethanol and dried in an oven at 800C to obtain 14.3 g of 3- (3,4-dihydroxyphenyl) pyridine hydrobromide, mp 288-2900C. 3- (3,4dihydroxyphenyl) 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 water and drying it to obtain 3- (3,4-dihydroxyphenyl) 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-i3,4-dihydroxyphenyl) pyridine in about 20 ml of aqueous methanol. , the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a p 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 is also conveniently prepared in aqueous solution by adding to water, with stirring, an equimolar amount of 3- (3, 4-dihydroxyphenyl) pyridine and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the lactate or hydrochloride of 3 (3,4-dihydroxyphenyl) pyridine in aqueous solution.

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

EXAMPLE 3
2- (3,4-dihydroxyphenyl) pyridine is prepared in the form of its hydrobromide, 4.1 g, mp 260-2620C, according to the procedure described in Example 1, using 4 g of 2- (3, 4-dimethoxyphenyl) pyridine, 35 ml 48% hydrobromic acid and a reflux period of three and a half hours.

 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, 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 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 mentioned above on the auricle and the isolated papillary muscles of cats, 4 (or 3) - [3,4-di (OR) phenylj-pyridine or its salts in doses of 10, 30 and 100 Ug / ml cause a significant increase, that is to say greater than 25%, of the strength of the papillary muscle and a significant increase, that is to say greater than 25%, of the strength of the right atrium, while causing only a smaller percentage increase (compared to that of papillary muscle strength and right atrium strength) in the speed of the right atrium. 2- (3,4-dihydroxy phenyl) pyridine hydrobromide isomer (Example 3) is significantly less effective than its isomers 3 and 4 (Examples 1 and 2), with only weak activity at the highest dose used (100 g / ml), while isomers 3 and 4 show significant activity at lower doses, that is to say 10 and 30 g / ml.

 When tested 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, more than 25%, in the force of heart contraction or cardiac contractility, with less changes per dose in heart rate and blood pressure.

 The present invention comprises a cardiotonic composition intended to increase the cardiac contraetility, said composition comprising a pharmaceutically acceptable carrier and, as active ingredient, 4 (or 3) - [3,4-di- (OR) -phenyljpyridine cardiotonic or its salts of addition of pharmaceutically acceptable acids.

The invention also includes the use of an effective amount of said -4 (or 3) - [3,4-di- (OR) -phenyl] pyridine 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 these 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 can also contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing the inert diluents commonly used in the art, such as water and liquid paraffin. inert, 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, 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> colYethylene 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 filter retaining the bacteria, 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 dose administered to a particular patient is variable, according to the judgment of the doctor using the following criteria: route of administration, duration of treatment, size and condition of the patient, power 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.

Claims (2)

 1. Cardiotonic composition making it possible to increase the cardiac contractility, characterized in that it comprises an inert carrier acceptable on the pharmaceutical level and, as active ingredient, an effective amount of a 4 (ou3) -g3,4-di ( OR) -phenyl / pyridine or a pharmaceutically acceptable acid addition salt thereof, where R is a hydrigen atom or a methyl group.  2. Compound used to increase the cardiac contractility in a patient in need of such treatment, said compound being a 4 (ou3) -L3,4-di (OR) -phenyllpyridine or one of its acid addition salts, where R is a hydrogen atom or a methyl group.