NO803790L - PROCEDURE FOR THE PREPARATION OF SUBSTITUTED PHENYL PYRIDINES - Google Patents

Description

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

4-(3,4-dimethoxyphenyl)pyridine, among others, is disclosed in US Patent No. 3,575,985 as an intermediate in the preparation of 4-(3,4-dimethoxyphenyl)-1-methylpyridinium iodide, which was heated with aqueous hydrogen bromide in acetic acid to form a mixture of 4-(3,4-dihydroxyphenyl)-1-methylpyridinium iodide and bromide. The iodide-bromide mixture was treated with freshly prepared silver chloride to form 4-(3,4-dihydroxyphenyl)-1-methylpyridinium chloride. The pyridinium salts in US patent no. 3,575,985 were stated to have "an effect on the cardiovascular system and the nervous system, for example having antihypertensive activity and being able to block or stimulate autonomic ganglia".

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

Ginos et al. [J. With. Chem. 18, 1194 (1975)] states as an intermediate 2-(3,4-dihydroxybenzyl)pyridine.

The invention relates to 4(or 3)-(3,5-dihydroxyphenyl)pyridine or an acid addition salt thereof.

The invention also relates to a process which comprises reacting hydrogen bromide with 4(or 3)-(3,4-dimethoxyphenyl)pyridine to form 4(or 3)-(3,4-dihydroxyphenyl)pyridine.

Cardiotonic preparations for increasing cardiac contractility are also described, where the preparation comprises a pharmaceutically acceptable pharmaceutical carrier and, as active ingredient therein, an effective amount of the cardiotonically active 4 (or 3)-[3,4-di-(OR) -phenyl]pyridine or pharmaceutically acceptable acid addition salt thereof, where R is hydrogen or methyl. Preferred embodiments of this preparation are those containing active compounds where R is hydrogen or an acid addition salt thereof.

One can increase cardiac contractility in a patient in need of such treatment by administering an effective amount of the cardiotonically active 4(or 3)-

[3,4-di-(OR)-phenyl]pyridine or a pharmaceutically acceptable salt thereof, where R is hydrogen or methyl, it being preferred to use a compound where R is hydrogen.

The 4(or 3)-[3,4-di-(OR)-phenyl]pyridine compound can be used both in the free base form and in the form of acid addition salts, and both forms are covered by the invention. The acid addition ion salts represent a more suitable form of use and in practice it is said that the use of the salt form corresponds to the use of the base form. The acids which can be used for the preparation of the acid addition salts are preferably those which, combined with the free base, give pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal organism in pharmaceutical doses of the salts, so that the useful cardiotonic properties of the free base do not destroyed by side effects caused by the anions. When carrying out the invention, it is appropriate to prepare the hydrobromide or the lactate. However, other suitable pharmaceutically acceptable salts encompassed by 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, quinic acid and the like; which give the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid addition salts of said basic compounds are prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt is excreted directly or can be obtained by concentration of the solution.

Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are encompassed by the invention. All acid addition salts are suitable as sources for the free base form even if the special salt per se is only desired as an intermediate such as e.g. when the salt is formed only for purification or identification purposes, or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange methods.

The molecular structure of 4(or 3)-[3,4-di-(OR)-phenyl]pyridine was determined on the basis of results obtained by infrared, ultraviolet, nuclear magnetic resonance and mass spectra, by chromatographic mobilities, by the equivalence between calculated and found values for the elemental analyses, and by procedures for its preparation.

The present invention will now be described in more detail.

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 carried out by heating the reactants at from about. 100 to 126°C, preferably using aqueous hydrogen bromide. Other demethylating agents can alternatively be used, e.g. hydrogen iodide, pyridine hydrochloride, boron tribromide, anhydrous aluminum chloride or bromide, or the like.

The intermediate 4 (or 3)-(3,4-dimethoxyphenyl)-pyridine is prepared in a known or conventional manner, as shown below.

The following examples further illustrate the invention.

EXAMPLE 1

4 - (3,4-dihydroxyphenyl)pyridine, alternatively designated 4-(4-pyridinyl)-1,2-benzenediol - A mixture containing 10.3 g of 4-(3,4-dimethoxyphenyl)pyridine and 75 ml of 48% hydrogen bromide , was heated under reflux for 5 hours and then set aside at room temperature over the weekend. The yellow crystalline precipitate was collected, washed with ethanol and dried in an oven at 95°C to form yellow needles, of.

11.8 g of 4-(3,4-dihydroxyphenyl)pyridine hydrobromide, m.p. 214-217°C.

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

The intermediate 4-(3,4-dimethoxyphenyl)pyridine

and its isomers 3-(3,4-dimethoxyphenyl)pyridine and 2-(3,4-dimethoxyphenyl)pyridine were prepared as follows. To a stirred mixture cooled in an ice-salt bath and containing 200 g of 4-aminoveratrol, 400 ml of concentrated hydrochloric acid and 100 ml of water, was added a solution containing 102 g of sodium nitrite in 180 ml of water during 2 hours while maintaining a reaction temperature below 5°C during this addition. The reaction mixture was stirred for a further 15 minutes and then added slowly over 2 hours to 2 liters of stirred pyridine preheated to 4°C, the internal temperature being kept between 45-55°C. The mixture was then heated on a steam bath for one hour, left at room temperature overnight (approx. 15 hours) and then the solvent was distilled off in a vacuum 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. The mixture was extracted

with three 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 in vacuo and this gave 165.7 g of an oily product, which consisted of a mixture of the three isomers 4-, 3- and 2-(3,4-dimethoxyphenyl)pyridine. These three isomers were separated by chromatography using a 2 kg silica gel column placed in a 2 liter sintered glass funnel and using successively, calculated by volume, 1:1 n-hexane-ether, ether alone and then 2% methanol in ether. Evaporation of the ether eluate gave 67.8 g of 2-(3,4-dimethoxyphenyl)pyridine, m.p. 76.78°C. Evaporation of the 2% methanol-in-ether eluate gave a mixture of

The 3- and 4-isomers, 45.6 g, as a semi-solid, which was crystallized from ether to give 24.8 g of 4-(3,4-dimethoxyphenyl)pyridine, m.p. 101-103°C. The mother liquor was combined with another fraction containing a mixture of 30.8 g of the 2-, 3- and 4-isomers as a red oil and the mixture was re-chromatographed as above. This gave an additional 15 g of the 2-isomer and the remaining mixture, which consisted mainly of the 3-isomer, was dissolved in 6N HCl, 300 ml, and the solution treated with decolorizing charcoal. The filtrate was concentrated in a rotary evaporator and this gave a greenish residue which was recrystallized from isopropyl alcohol to give 33 g of 3-(3,4-dimethoxy-phenyl)pyridine hydrochloride, m.p. 198-200°C.

EXAMPLE 2

3-(3,4-dihydroxyphenyl)pyridine, alternatively designated 4-(3-pyridinyl)-1,2-benzenediol - A solution containing 15 g of 3-(3,4-dimethoxyphenyl)pyridine and 100 ml of 48% hydrogen bromide was heated under reflux for 30 minutes and then set aside at room temperature overnight. The resulting pale yellow crystalline precipitate was collected, washed with ethanol and dried in an oven at 80°C to give 14.3 g of 3-(3,4-dimethoxyphenyl)pyridine hydrobromide, m.p. 288-290°C. 3-(3,4-dihydroxyphenyl)pyridine in free base form

is obtained by treating an aqueous solution of the hydrobromide with an excess aqueous sodium bicarbonate solution, collecting the resulting precipitate, washing it with water and drying to form 3-(3,4-dihydroxyphenyl)-pyridine in free base form.

Other acid addition salts of 3-(3,4-dihydroxyphenyl)-pyridine are conveniently prepared by adding to a mixture of 1 g of 3-(3,4-dihydroxyphenyl)pyridine in approx. 20 ml aqueous methanol, of the appropriate acid, e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH value of approx. 2-3, cooling the mixture after partial evaporation and collecting the precipitated salt, e.g. the dimethanesulfonate, the sulfate, the phosphate, respectively. The acid addition salt can also conveniently be prepared in aqueous solution by adding to water with stirring molar equivalent amounts each of 3-(3,4-dihydroxyphenyl)-pyridine and the appropriate acid, e.g. lactic acid or hydrochloric acid, respectively, to prepare the lactate or the hydrochloride salt of 3-(3,4-dihydroxyphenyl)pyridine in aqueous solution.

Example 3 below is a comparison example. Neither this new 2-(3,4-dihydroxyphenyl)pyridine compound nor the new corresponding intermediate 2-(3,4-dimethoxy-phenyl)pyridine shown above in the third paragraph in example 1 is covered by the present invention.

EXAMPLE 3

2-(3,4-dihydroxyphenyl)pyridine in the form of its hydrobromide, 4.1 g, m.p. 260-262°C, was prepared by following the method described in example 1 using 4 g of 2-(3,4-dimethoxyphenyl)pyridine, 35 ml of 48% hydrogen bromide and refluxing for 3% hours.

The utility of 4(or 3)-[3,4-di-(OR)-phenyl]-pyridine or a salt thereof as a cardiotonic agent is demonstrated by the compound's effectiveness in standard pharmacological test methods, e.g. by causing a significant increase in the contractile force in isolated cat cardiac atria and papillary muscle and by causing a significant increase in the cardiac contractile force in anesthetized dogs with small or minimal changes in heart rate and blood pressure. These test methods are described in US patent no. 4,072,746.

When examined using the method described above with isolated cat heart atria and papillary muscle, it was found that 4 (or 3)-[3,4-di-(OR)-phenyl pyridine or a salt thereof in doses of 10 . for papillary muscle force and right atrial force) in right atrial velocity. In contrast, the isomeric compound 2-(3,4-dihydroxyphenyl)-pyridine hydrobromide (Example 3) was significantly less effective than its 3- and 4-isomers (Examples 1 and 2), showing only weak activity at only the highest dose tested (100 yg/ml), whereas, on the other hand, the 3- and 4-isomers showed significant activity at lower doses, i.e. 10 and 30 yg/ml.

When examining the aforementioned method with anesthetized dogs, 4-(3,4-dihydroxyphenyl)pyridine or a salt thereof when administered intravenously as a single bolus injection of 1, 3 and 10 mg/kg caused a significant increase, i.e. over 25 %, in the cardiac contractile force or cardiac contractility with correspondingly smaller changes per dose in heart rate and blood pressure.

The invention comprises a cardiotonic preparation for increasing cardiac contractility, and this preparation comprises a pharmaceutically acceptable carrier, and as an active component therein, the cardiotonically active 4-(or 3)-[3,4-di-(OR)-phenyl ]pyridine compound or a pharmaceutically acceptable acid addition salt thereof. The invention also includes a method for increasing cardiac contractility in a patient in need of such treatment, whereby one administers an effective amount of said 4 (or 3)-[3,4-di-(OR)-phenyl]pyridine or a pharmaceutically acceptable acid addition salt thereof. In clinical practice, said compound or salt thereof will normally be administered orally or parenterally in a number of different dosage forms.

Solid preparations for oral administration include compressed tablets, pills, powders and granules.

In such 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 additional substances other than inert diluents, e.g. lubricants, such as magnesium stearate, talc and the like.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art,

such as water and liquid paraffin. In addition to inert diluents, such preparations may also contain auxiliaries, such as wetting and suspending agents, and sweeteners, flavourings, perfuming and preserving agents. The compositions for oral administration also include capsules

of absorbable material such as gelatin, containing said active component with or without the addition of the diluent or excipients.

Preparations for parenteral administration 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 substances such as stabilising, preserving, wetting, emulsifying and dispersing agents.

They can be sterilized, e.g. by filtering through a bacteria-retaining filter, by incorporating sterilizing agents into the preparations, by irradiation or by heating. They can also be produced in the form of sterile, solid preparations that can be dissolved in sterile water or another sterile injectable medium immediately before use.

The percentages of active component in said preparation and the method for increasing cardiac contractility can be varied so that a suitable dose is obtained. The dose administered to a particular patient can be varied depending on the physician's judgment using as criteria: route of administration, duration of treatment, patient's size and condition, the effect of the active component and the patient's reaction to it. An effective dosage amount of active component can thus only be determined by the doctor in consideration of all criteria.

Claims (3)

1. Process for the preparation of a 4(or 3)-(3,4-dihydroxyphenyl)pyridine compound or an acid addition salt thereof, characterized by reacting 4(or 3)-(3,4-dimethoxyphenyl)pyridine with a demethylating agent and, if desired, converts an obtained free base into an acid addition salt thereof. 2. Process according to claim 1, characterized in that aqueous hydrogen bromide is used as demethylating agent. 3. Method according to claim 1 or 2, characterized in that 4-(3,4-dihydroxy- o phenyl)pyridine is prepared from 4-(3,4-dimethoxyphenyl)pyridine.