FR2471976A1 - (PHENYL SUBSTITUTE) PYRIDINES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Abstract

4 (OR 3) - (3,4-DIHYDROXYPHENYL) PYRIDINE IS PREPARED BY DEMETHYLATION OF 4 (OR 3) - (3,4-DIMETHOXYPHENYL) PYRIDINE, PREFERABLY BY HEATING WITH AQUEOUS BROMHYDRIC ACID. THE COMPOUND OBTAINED IS A CARDIOTONIC AGENT, AS WELL AS 4 (OR 3) -3,4-DI- (OR-PHENYLPYRIDINE OR R IS A HYDROGEN ATOM OR A METHYL GROUP.

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. N 3,575,985 as

  intermediate in the preparation of 4- (3-

  dimethoxyphenyl) -1l-methylpyridinium, which is heated with aqueous hydrobromic acid in acetic acid to

  form a mixture of 4- (3,4-dihydroxy-) iodide and bromide

  phenyl) -1-methylpyridinium. The iodide-bromide mixture is treated with silver chloride freshly prepared for

  obtain 4- (3,4-dihydroxyphenyl) -1-methyl- chloride

pyridinium. It is noted that the pyridinium salts of the U.S. Patent. N 3,575,985 have "an effect on the cardiovascular and nervous systems, by possessing for example an antihypertension activity and can block or

  stimulate the lymph nodes. "

  4- (3-Hydroxyphenyl) pyridine is described, between

  others, by Coates et al. [J. Chem. Soc. 1943, 406].

Ginos et al. [J. Med. Chem. 18, 1194 (1975)] describe 2- (3,4dihydroxybenzyl) 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) - (3,4dimethoxyphenyl) 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 a component

  active, an effective amount of 4 (or 3) - [3,4-di- (OR) -

phenyl] pyridine cardiotonic or a pharmaceutically acceptable acid addition salt thereof where R is an atom

of hydrogen or a methyl group. The modes of realization

  tion of this aspect of the invention are the compositions comprising, as active component, the compound o

  R is an atom of hydrogen or its salts.

  Cardiac contractility may be increased in a patient in need of such treatment, by administration

to this patient an effective amount of the 4 (or 3) [3,4-di-

  (OR) -phenyl] pyridine cardiotonic or its pharmaceutically acceptable salts, where R is a hydrogen atom

or a methyl group, a preferred use consisting of -

  to use the compound o R is a hydrogen atom.

4 (or 3) - [3,4-di- (OR) -phenyllpyridine 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, when combined with the free base, produce pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal body at 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 carrying out the invention, it is convenient to form the hydrobromide or the 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, the sulfate, the phosphate, the sulfamate, the acetate, the citrate, the tartrate, the methanesulfonate, the ethanesulfonate, the benzenesulfonate, the p-toluenesulfonate,

cyclohexylsulfamate and 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

concentration of 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 are all usable as a source of

  free base even if the particular salt is not indicated in itself

same as as an intermediate, for example when the salt is formed only for the purpose of purification or identification, or when it is used as an intermediate to prepare a pharmaceutically acceptable salt

ion exchange procedures.

  The molecular structure of 4 (or 3) - [3,4-di-

(OR) -phenylpyridine was assigned on the basis of data supplied by infrared, ultraviolet, nuclear magnetic resonance and mass spectra, by chromatographic mobilities, by the correspondence of the values calculated and found for elementary analyzes and by

  the processes for preparing it.

The manner of making and using the present invention will now be described generally for

  allow those skilled in the art to achieve it.

  The reaction of 4 (or 3) - (3,4-dimethoxyphenyl) -

pyridine with a demethylating agent to obtain 4 (or 3) - (3,4dihydroxyphenyl) pyridine is conveniently carried out by heating the reagents to about 100 ° C. to 26 ° 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 internal 4 (or 3) - (3,4-dimethoxyphenyl) pyridine 2471l 976 is prepared by known or conventional methods, such as

indicated below.

The following examples will better illustrate the invention

without however limiting it.

EXAMPLE 1

  4- (3,4-Dihydroxyphen1l) pyridine, also called 4- (4-

pyridinyl) -1,2-benzenediol - Heated at reflux for 5

hours a mixture containing 10.3 g of 4- (3,4-dimethoxy-

  phenyl) pyridine and 75 ml 48% hydrobromic acid and then allowed to stand at room temperature for 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-

2170C.

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 by 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-dihydroxyphenyl) 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 appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the

  4- (3,4-dihydroxyphenyl) lactate or hydrochloride -

pyridine in aqueous solution.

  4- (3,4-dimethoxyphenyl) - is prepared as follows:

  intermediate pyridine and the 3- (3,4-dimethoxyphenyl) pyridine and 2- (3,4-dimethoxyphenyl) pyridine isomers. To a stirred mixture cooled in a salt and ice bath and containing 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 of water is added. 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 approximately two and a half hours, to 2 liters of stirred pyridine preheated to 4 ° C., keeping the internal temperature between 45 and 55 ° C. Then the mixture is heated. mixture on 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-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, ether alone then 2% methanol in ether. Evaporation of the ethereal eluate gives 67.8 g

  of 2- (3,4-dimethoxyphenyl) pyridine, m.p. 76-78 C. L'évapora-

  tion 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, m.p. 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 of 6N HCl 1 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

  3- (3,4-dimethoxyphenyl) pyridine hydrochloride, m.p.

198-200 C.

EXAMPLE 2

  3- (3,4-Dihydroxyphenyl) pyridine, also called 4- (3-

  pyridinyl) -1,2-benzenediol A solution containing 15 g of 3- (3,4-dimnethoxyphenyl) pyridine and 100 ml of 48% hydrobromic acid is refluxed for 30 minutes and then allowed to stand at room temperature. overnight. The resulting pale yellow crystalline precipitate is collected, washed with ethanol and dried in a drying oven.

   C to obtain 14.3 g of 3- (3,4-dimethoxy-) hydrobromide

phenyl) pyridine, m.p. 288-290 C. We obtain the 3- (3,4-

  dihydroxyphenyl) pyridine 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 get 3- (3,4-dihydroxy-

  phenyl) pyridine in the form of the free base.

Other 3- (3,4dihydroxyphenyl) pyridine acid addition salts are conveniently prepared by adding, to a mixture of 1 g of 3- (3,4dihydroxyphenyl) pyridine in about 20 ml of aqueous methanol, the suitable acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of approximately 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has 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 the appropriate acid, e.g. lactic acid or hydrochloric acid, for

prepare 3- lactate or hydrochloride respectively

  (3,4-dihydroxyphenyl) pyridine in aqueous solution.

The following Example 3 is given as

  comparison. Neither this new 2- (3,4-dihydroxyphenyl) -

pyridine nor the corresponding new intermediate 2- (3,4-dimethoxyphenyl) pyridine described above in the third paragraph of Example 1 are not 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, 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 hydrobromic acid

at 48% 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 heart contraction in the anesthetized dog, with little or minimal change in heart speed and blood pressure. These modes

Test procedures are described in the U.S. Patent.

N 4.072.746.

  - When we try them using the procedure mentioned above on the atrium and the muscles

isolated papillaries of cat, 4 (or 3) - [3,4-di (OR) phenyl] -

pyridine or its salts at doses of 10, 30 and 100 pg / ml cause a significant increase, that is to say greater than 25%, in the strength of the papillary muscle and a significant increase, that is to say say greater than 25%, of the strength of the right atrium, while causing only a smaller percentage increase (compared to that of the strength of the papillary muscle and the strength of the right atrium) headset speed

  right. On the contrary, 2- (3,4-dihydroxy- hydrobromide)

  phenyl) pyridine isomer Example 3) is clearly less effective than its isomers 3 and 4 (Examples 1 and 2), exhibiting only weak activity at the highest dose used (100 μg / ml), while the isomers 3 and 4 show significant activity at doses

  lower, i.e. 10 and 30 pg / ml.

When tested by the operating procedure on the anesthetized dog, 4 (3,4-dihydroxyphenyl) pyridine or its salts, administered intravenously as a single injection of 1, 3 and 10 mg / kg, cause significant increase, i.e. greater than 25%, in the force of cardiac contraction or cardiac contractility, with less changes per dose of the

  heart speed and blood pressure.

The present invention comprises a cardiotonic composition intended to increase cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as active ingredient, cardiotonic 4 (or 3) - [3,4-di- (OR) -phenyl] pyridine or his

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] pyridine or a pharmaceutically acceptable acid addition salt thereof. to increase cardiac contractility in a patient in need of such treatment. In clinical practice, this compound or salts will normally be administered orally or parenterally under 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 stlarate, 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. Besides 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

addition of diluents or excipients.

  Preparations for parenteral administration include sterile aqueous, aqueous-organic and organic suspensions and emulsions. Examples of organic solvents or processing media

  organic suspensions 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, agents

  wetting, emulsifying and dispersing agents.

  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

better judgment on patient behavior.

* 2471976

Claims (8)

1. 4 (or 3) - (3,4-Dihydroxyphenyl) pyridine or its acid addition salts.   2. 4- (3,4-Dihydroxyphenyl) pyridine or its acid addition salts. 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 base   free obtained in 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 one or other of the   claims 3 and 4, characterized in that the 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 a pharmaceutically acceptable inert support and, as   active ingredient, an effective amount of the 4 (or 3) -   [3,4-di (OR) -phenyl] cardiotonic pyridine or a pharmaceutically acceptable acid addition salt thereof, where R is a hydrogen atom or a methyl group.   7. Compound used to increase the cardiac contractility in a patient in need of such treatment, the compound being 4 (or 3) - [3,4di- (OR) -phenyl] pyridine or one of its addition salts pharmaceutically acceptable acids, where R is a hydrogen atom or a group methyl.   8. Composition or compound according to one or the other   claims 6 and 7, characterized in that the component   active is 4- (3,4-dihydroxyphenyl) pyridine or one of its   pharmaceutically acceptable salts.