NO146599B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-CHLORO-2- (1`-PIPERAZINYL) -PYRAZINE AND SALTS THEREOF - Google Patents

Description

The present invention relates to analogous methods for the production of 6-chloro-2-(1'-piperazinyl)-pyrazine with anorexic activity.

Obesity is a relatively common condition and a potentially serious

lig one in light of the connection between the occurrence of various diseases and the degree to which a person is overweight. For example, obese people succumb to cardiovascular renal disease statistically more often than people of normal weight do.

Obesity also leads to higher rates of death from diabetes, nephritis, pneumonia, cirrhosis, appendicitis and post-operative complications. As obesity often occurs simply as a result of excessive intake of calories, good treatment of the condition in these cases can be achieved by limiting calorie intake.

Often, however, the patient finds it difficult to start creating

maintain dietary restrictions, which makes it necessary to use anorexic drugs as aids to therapy.

It is therefore an aim of the present invention to produce the new 6-chloro-2-(1'-piperazinyl)-pyrazine which is an effective, strong and non-toxic anorexic agent.

The piperazinyl-pyrazine compound produced according to the invention has the formula:

This compound is prepared according to the invention by reacting a 2-X-pyrazine of formula I with piperazine.

The reaction is as follows:

The reaction takes place at temperatures varying from room temperature to 90°C, preferably under an inert atmosphere, e.g. nitrogen, helium or argon, until a considerable amount of the desired adduct of formula III is formed, typically in a period of from 0.5 to 6 hours, preferably from 1 to 4 hours.

Other methods by which 6-chloro-2-(1*-piperazinyl)-pyrazine can be prepared according to the invention are as follows: ;I. Removal of nitrogen protecting groups ;;where R 1 is 6-chloro-2-pyrazinyl; formyl or cyano. ;Removal of these groups is effected by hydrolysis in polar solvents in the presence of acid or base or by catalytic hydrogenolysis in non-polar or polar solvents such as water or alcohols in the presence of catalysts such as Pt, Pd, Ru and their oxides at from 25°C to the reflux temperature . II. Chlorination ;;The method is carried out by passing chlorine gas through a solution of the piperazinyl pyrazine in a solvent such as glacial acetic acid or the like, at a temperature from 0° to 100°C. Other solvents that can be used are aqueous hydrochloric acid, dimethylformamide and acetonitrile. III. Reduction of N-oxyd-intermediate gr ;;Suitable reducing agents are tin, zinc, iron or sulfur dioxide in inorganic or organic acids; triphenylphosphine, sodium arsenite, ammonium sulfide, sodium dithionite, ferrooxalate-granulated lead; and catalytic hydrogenation over palladium-on-carbon, Råney nickel and the like. Suitable solvents include polar solvents such as water, acetic acid, lower alcohols and the like. The reduction is carried out at from 0° to 150°C. IV. Formation of the piperazine ring ;;where X is halogen. In general, the above process is carried out by heating the reactants at from 0° to 250°C in a polar solvent such as water, dimethylformamide, alcohols and the like, in the presence of a base. B. Suitable catalysts are Raney nickel, copper chromium oxide, platinum, palladium and oxides thereof in a polar solvent such as aqueous acid, alcohol and the like, or hydrides such as borane, lithium aluminum hydride in a non-polar solvent such as tetrahydrofuran or ethyl ether. The reactions are carried out at a temperature from -70°C to 300°C and at a pressure from 1.0 to 300 atm. ;V. Removal of eri carboxyl group ;;The removal takes place by heating without solvent or in solvents such as hydrocarbons such as tetralin, aromatic hydrocarbons, and substituted aromatic solvents such as chlorobenzene, nitrobenzene and the like, at a temperature from 100° to 300°C. ;WE. Introduction of chlorine by substitution or rearrangement ;;Y is lower alkoxy, and the chlorinating agent is BCl^r POCl^, PC15 or PC13>;The chlorinating agent can also be the solvent. The reaction temperatures are from 25°C to the reflux temperature for the solvent. Mixtures of the above reagents can also be used. Chlorination with phosphorus oxychloride. VII. Reduction of amides and imides ;;Z = H,j or O , with at least one Z being 0. ;Suitable reducing agents include hydrides such as borane or lithium aluminum hydride and the like; or catalysts such as molybdenum sulphide, copper-chromium oxide, ruthenium, platinum oxide and the like. Suitable solvents for catalytic hydrogenation include polar solvents such as water, alcohols, glymes, dioxane and the like. However, reduction with hydrides is carried out in aprotic solvents, such as ethyl ether, tetrahydrofuran and the like. JThe reaction temperature is from -70°C to 250°C at a pressure from 1.0 to 300 atm. ;The method compound may be administered as an anorexic agent to mammalian species, e.g. rats and mice, in amounts varying from 0.01 to 20 mg per kg body weight, preferably from 0.1 to 10 mg per kg body weight in a single dose or in 2 to 4 divided doses. ;Procedure The compound in the indicated doses may be administered orally, but other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be used. With regard to pharmaceutically acceptable salts, those that come within the scope of the invention include the pharmaceutically acceptable acid addition salts. Acids useful for the production of these acid addition salts include e.g. inorganic acids such as the hydrogen halide acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, 2-acetoxybenzoic acid, salicylic acid, succinic acid, theophylline, 8~chloro- theophylline, p-aminobenzoic acid, p-acetamidobenzoic acid or methanesulfonic acid. The method compound shows increased efficiency and less toxicity than known anorexic agents. The 6-chloro-2-(1'-piperazinyl)-pyrazine compound is e.g. 10 times as effective as fenfluramine in cats when administered orally. Besides the anorexic activity described above, the new compound produced according to the invention pharmacologically affects the serotonin level in a way that suggests that it is also useful as an antidepressant, antihypertensive, analgesic and sleep-inducing agent. For these purposes, the same administration methods and pharmaceutical preparations as described above are used. The following examples further illustrate the present method. ;Example 1 ;6-chloro-2- ((1'-piperazinyl)-pyrazine hydrochloride ;0.10 mol of 2,6-dichloropyrazine is added to 20 g of piperazine in 200 ml of acetonitrile, and the mixture is refluxed for 1.5 hours under nitrogen. The mixture is evaporated in vacuo, and the residue is distributed between 1N aqueous sodium hydroxide and benzene. ;The combined benzene extracts are washed with 1N aqueous sodium hydroxide, dried over magnesium sulfate, filtered and evaporated in vacuo to a yellow oil which is dissolved in 200 ml of absolute ethanol containing 10 ml of cold, saturated, anhydrous ethanolic hydrogen chloride. The precipitated hydrogen chloride is recrystallized from 95% ethanol, whereby faint yellow needles with m.p. 350°C during decomposition. ;Example 2 ;From N,N'-bis-(6-chloro-2-pyrazinyl)-piperazine ;(a) A mixture of-15.0 g (0.10 mol) 2,6-dichloropyrazine, ;4, 3 g (0.050 mol) of anhydrous piperazine and 20.4 g (0.20 mol) of triethylamine in 200 ml of n-butanol are heated under reflux for 3 hours. The mixture is evaporated under reduced pressure, and the residue is distributed between IN aqueous sodium hydroxide solution and benzene. The combined benzene extracts are washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to N,N•-bis-(6-chloro-2-pyrazinyl)-piperazine. (b) The N,N'-bis-(6-chloro-2-pyrazinyl)-piperazine from the previous step is stirred under reflux for 8 hours in 500 ml of concentrated hydrochloric acid. After evaporation to dryness under reduced pressure, the residue is recrystallized from 95% ethanol, whereby 6-chloro-2-(1<*->piperazinyl)-pyrazine hydrochloride is obtained.

Example 3

From 2-chloro-6-(4-formyl-1-piperazinyl)-pyrazine

(a) 7.5 g (0.050 mol) of 2,6-dichloropyrazine is added to 10 g of N-formylpiperazine in 100 ml of acetonitrile, and the mixture is heated under reflux for 2 hours. After evaporation under reduced pressure, the residue is distributed between 2N sodium carbonate solution and benzene. The benzene layer is removed, washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is essentially pure 2-chloro-6-(4-formyl-1-piperazinyl)-pyrazine. (b) 2.0 g (8>82 mmol) of the N-formyl derivative is added to 100 ml of concentrated hydrochloric acid and stirred under reflux for 10 hours. The solution is evaporated to a small volume, diluted with water and cooled, whereby 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 4

From 6-chloro-2-(4-methyl-1-piperazinyl)-pyrazine

(a) A mixture of 30 g (0.20 mol) of 2,6-dichloropyrazine and

40 g (0.40 mol) of N-methylpiperazine in 200 ml of n-butanol are stirred under reflux for 6 hours. The reaction mixture is evaporated under reduced pressure. After adding 200 ml of saturated sodium carbonate solution to the residue, the product is extracted in benzene. The benzene extract is washed with water, dried (magnesium sulfate), filtered and evaporated, whereby 6-chloro-2-(4-methyl-1-piperazinyl)-pyrazine is obtained.

(b) The 4-methylpiperazine derivative from the previous step is treated with 0.2 mol of cyanogen bromide in toluene at 0°C, and the resulting mixture is heated for 4 hours under reflux and cooled. The mixture is evaporated in vacuo and treated with 100 ml

6N aqueous hydrochloric acid for 18 hours under reflux and cool. The precipitated product is further recrystallized from 95% ethanol, whereby 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 5

A stream of chlorine gas is bubbled through a well-stirred solution of 1.0 mol of 2-(1-piperazinyl)-pyrazine hydrochloride in 1 liter of glacial acetic acid at 100°C until the reaction is complete. After evaporation under reduced pressure, the residue is dissolved in 600 ml of 0.5N aqueous hydrochloric acid, inoculated with an authentic sample of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride, evaporated and cooled. The precipitated solid is further recrystallized from 95% ethanol, whereby pure 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 6

21.5 g (0.100 mol) 1- or 4-N-oxide of 6-chloro-2-(1-piperazinyl)-pyrazine are dissolved in 200 ml of glacial acetic acid. The solution is heated to 85°C, saturated with anhydrous hydrogen chloride gas and treated with a stream of sulfur dioxide at this temperature for 1 hour. The acetic acid is removed under reduced pressure, and the residue is recrystallized from 95% ethanol, whereby 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 7

A mixture of 5.8 g (0.045 mol) 2-amino-6-chloropyrazine, 4.68 g (0.015 mol) bis-(2-bromomethyl)amine hydrobromide and 25 ml 2-butanone is heated under reflux for 10 hours . After cooling at 0°C for 15 hours, the mixture of hydrobromide salts is removed by filtration and dissolved in 25 ml of water. The aqueous solution is made alkaline to pH 10 with 10% sodium hydroxide solution. The crude product is extracted in 100 ml of benzene and washed with 2 x 25 ml of water. The benzene extract is dried over anhydrous magnesium sulfate, filtered and evaporated, whereby the free base of 6-chloro-2-(1-piperazinyl)-pyrazine is obtained. Transfer to the hydrochloride salt with anhydrous ethanolic hydrogen chloride and recrystallization from 95% ethanol gives 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.

Example 8

(a) A mixture of 15.0 g (0.10 mol) of 2,6-dichloropyrazine and 19.0 g (0.20 mol) of iminodiacetonitrile in 200 ml of 2-butanol is heated under reflux for 6 hours. After evaporation under reduced pressure at 55°C, the residue is distributed between 200 ml of 2N sodium carbonate solution and 200 ml of benzene. The water layer is extracted again with 100 ml of benzene. The combined benzene extract is dried (sodium sulfate), filtered and evaporated under reduced pressure at 45°C, whereby 6-chloro-2-(bis-cyanomethylamino)-pyrazine is obtained. (b) To a solution of 2.5 g (0.012 mol) of 6-chloro-2-(bis-cyanomethylamino)-pyrazine in 500 ml of tetrahydrofuran is added 0.048 mol of borane in tetrahydrofuran at 0°C. The mixture is heated to 25°C for 3 hours and then refluxed for 1 hour and cooled to 0°C. 0.072 mol of glacial acetic acid is added at 0°C, and the mixture is stirred at 0-28°C until hydrogen evolution ceases. The solvent is removed under vacuum, and the residue is distributed between chloroform and 2N aqueous sodium hydroxide. After drying the organic phase over anhydrous sodium sulfate, filtering and evaporation, the residue is transferred to the hydrochloride salt with anhydrous ethanolic hydrogen chloride. Recrystallization from 95% ethanol gives 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.

Example 9

(a) A suspension of 18.7 g (0.10 mol) of 5-amino-3-chloro-2-carbomethoxypyrazine in a mixture of 114 ml of 48% hydrobromic acid and 30 ml of acetic acid is cooled to 0°C, stirred and treated with a solution of 15 ml of bromine in 30 ml of acetic acid for 45 minutes. A solution of 17.4 g (0.10 mol) of sodium nitrite in 40 ml of water is added while maintaining a reaction temperature of 0°C. Stirring is continued for 30 minutes, and excess bromine is destroyed by the dropwise addition of 150 ml of a 30% aqueous solution of sodium bisulphite. The product is removed by filtration, washed with water and recrystallized from an ethyl acetate-hexane mixture, whereby 5-bromo-3-chloro-2-carbomethoxypyrazine is obtained. (b) A mixture of 10.0 g (0.040 mol) of 5-bromo-3-chloro-2-carbomethoxypyrazine, 6.9 g (0.080 mol) of anhydrous piperazine and 100 ml of acetonitrile is heated under reflux for 2 hours. The mixture is evaporated under reduced pressure, and the residue is distributed between 2N sodium carbonate solution and benzene. The benzene extract is washed with water, dried (anhydrous magnesium sulphate), filtered and evaporated under reduced pressure. The residue is transferred to the hydrochloride salt with ethanolic hydrogen chloride solution and recrystallized from ethanol-ethyl acetate, whereby 2-carbomethoxy-3-chloro-5-(1-piperazinyl)-pyrazine hydrochloride is obtained. (c) A solution of 5.8 g (0.023 mol) of the methyl ester in 50 ml of 1N hydrochloric acid is heated under reflux for 5 hours. After evaporation to a small volume under reduced pressure, the residue is further dried by azeotropic distillation with ethanol. The solid 2-carboxy-3-chloro-5-(1-piperazinyl)-pyrazine hydrochloride is removed by filtration and dried. (d) A suspension of 5.0 g (0.018 mol) of the hydrochloride of 2-carboxy-3-chloro-5-(1-piperazinyl)-pyrazine hydrochloride in 50 ml of tetralin is stirred under reflux for approx. 1 hour until the evolution of carbon dioxide is complete. The hot mixture is extracted with 2 x 50 ml of 0.5N aqueous hydrochloric acid. The aqueous extracts are combined, evaporated and cooled. The precipitated 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is removed by filtration and dried.

Example IQ

38.8 g (0.20 mol) of solid 6-methoxy-2-(1-piperazinyl)-pyrazine dihydrochloride are added in portions over the course of 1 hour to 300 ml of rapidly stirred phosphorus oxychloride at ZfO - 50°C. After the addition is finished, the mixture is stirred under reflux for 1 hour, cooled and evaporated to dryness under reduced pressure. The residue is first recrystallized from a small volume of water, then from 95% ethanol, whereby 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 11

(a) A mixture of 100 g (0.77 mol) of 2-chloro-pyrazine-1-oxide and 17.2 g (2.0 mol) of anhydrous piperazine in 1 liter of 2-butanol is heated under reflux for 6 hours. After evaporation under reduced pressure, the residue is dissolved in a mixture of 1 liter of 2N sodium carbonate solution and 1 liter of chloroform. The aqueous layer is re-extracted twice with fresh chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate, filtered and

is evaporated. The residue is treated with an excess of ethanolic hydrogen chloride and recrystallized from 95% ethanol, whereby 2-(1-piperazinyl)-pyrazine-1-oxide hydrochloride is obtained. (b) To 300 ml of cold redistilled phosphorus oxychloride, 21.7 g (0.10 mol) 2-(1-piperazinyl)-pyrazine-1-oxyd-hydrochloride are added in several portions. The mixture is heated, and after a vigorous reaction has subsided, it is stirred under reflux for a further 1 hour. Excess phosphorus oxychloride is removed under reduced pressure. The residue is carefully poured onto 200 g of crushed ice. The solution is neutralized with cold 5N sodium hydroxide solution and extracted with chloroform. The combined chloroform extract is dried over anhydrous sodium sulfate, filtered and evaporated. The remaining oil is transferred to the hydrochloride salt with ethanolic hydrogen chloride and recrystallized from 95% ethanol, whereby 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is obtained.

Example 12

To a solution of 21.3 g (0.10 mol) of 6-chloro-2-(3-oxo-1-piperazinyl)-pyrazine in 200 ml of tetrahydrofuran is added 0.12 mol of borane in tetrahydrofuran at 0°C. The mixture is heated to 25°C for 3 hours and then refluxed for 1 hour and cooled to 0°C. 0.6 mol of glacial acetic acid is added at 0°C, and the mixture is stirred at 0-25°C until hydrogen evolution ceases. The solvent is removed under vacuum, and the residue is distributed between chloroform and 2N aqueous sodium hydroxide. After drying the organic phase over anhydrous sodium sulfate, filtering and evaporation, the residue is transferred to the hydrochloride salt with anhydrous ethanolic hydrogen chloride. Recrystallization from 95% ethanol gives 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.

Attempt

On the day before the experimental day (control day), the intake is measured for groups from 7 to 10 rats who are allowed access to food for only 2 hours per day. day. On the next day (test day) the rats are injected i.p. with different dose levels of the test compound 3 minutes before the beginning of the 2-hour feeding period. The intake on the experimental day is then measured and compared (paired t-test) with the intake on the control day. The results are shown in the following table.

<a>Standard deviation.

Claims (1)

Analogous procedure for the preparation of therapeutically active 6-chloro-2-(1'-piperazinyl)-pyrazine with the formula: or a pharmaceutically acceptable salt thereof, characterized in that: (a) a compound of the formula: where X is halogen, is reacted with piperazine, or (b) a compound of the formula: where R a is 6-chloro-2-pyrazinyl, formyl or cyano, is hydrolysed, or (c) a compound of the formula: is chlorinated, or (d) a compound of the formula: is reduced, or (e) a compound of the formula: where X is halogen, is ring-closed, or (f) a compound of the formula: is reduced, or (g) a compound of the formula: is heated, or (h) a compound of the formula: where Y is lower alkoxy, is chlorinated with phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or boron trichloride, or (i) a compound of the formula: is chlorinated with phosphorus oxychloride, or (j) a compound of the formula: where at least one Z is 0 and the others are H9, is reduced, and that a base obtained is optionally transferred to an acid addition salt thereof.