FI62666C - FORM OF THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVE 6-CHLORO-2- (1'-PIPERAZINYL) PYRAZINE AND SALTER DAERAV - Google Patents

Description

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Patent · ech ragutantyralaan '' Autetun uttagd och «Ukrtfun pubikwrtd ^, JU, U £: (32) (33) (31) Claim claimed — Begird priorittt 21.01.75 USA (US) 570052 (71) Merck & Co., Inc. ·, 126 E. Lincoln Avenue, Rahway, New Jersey, USA (72) Walfred Spencer Island, Lansdale, Pennsylvania, William Carl Lumma, Jr., Lansdale, Pennsylvania, USA (Jk) Oy Kolster Ab ( 5l) Process for the preparation of therapeutically active 6-chloro-2- (1'-piperazinyl) -pyrazine and its salts - For the preparation of therapeutically active 6-chloro-2- (1'-piperazinyl) pyrazine and its salts

The invention relates to the preparation of a novel appetite suppressant 6-chloro-2- (11-piperazinyl) pyrazine and its pharmaceutically acceptable acid addition salts.

Obesity is relatively common and potentially dangerous when it comes to the correlation between the incidence of various diseases and the amount of overweight in a person. For example, statistically, it has been found that overweight people die more often from cardiovascular disease than normal weight people. Being overweight also leads to higher mortality due to diabetes, kidney disease, pneumonia, cirrhosis of the liver, colitis, and postoperative diseases.

Because overweight is often simply due to too much food, good management of the conditions in these cases 62 6 6 6 can be achieved by reducing the amount of food consumed. Often, however, the patient has difficulty initiating and maintaining a diet, so it is mandatory to use appetite suppressants as therapeutic adjuvants.

The piperazinylpyrazine compound of the invention has the following structural formula:

C1A

The process according to the invention is characterized in that a) a compound of the formula ci ^ x in which X is halogen is reacted with piperazine, or b) a compound of the formula f ΛΛ s ci / Nä / \ _ / 01 5 is reacted with 6 -chloro-2-pyrazinyl, formyl or cyano, is hydrolysed, or c) the compound of formula / is chlorinated, or d) of formula 3 6 2 6 6 6 of or. / \

J-N NH Jk J - N NH

c1 ^ n / \ / \ /

O

the compound of formula r is reduced with SO 2 / HCl, or e)

At". JJ NH NH

/ -

X

a compound of formula wherein X is halogen is cyclized, or f) of formula

_CN

ci \ - CN

the compound of formula Vn / \

S N NH

Or a compound of formula N wherein Y is lower alkoxy is chlorinated with phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or boron trichloride, or 4 6 2 6 6 6 i) a compound of formula I ΑΛ

1¾. „J-N NH

4 W

O

the compound of formula ataan is chlorinated with phosphorus oxychloride, or j) the formula ka Γ Ή *

.L · J-N NH

“M

wherein Z is H 2 or O, and at least one Z is O, is reduced, and the resulting base is converted, if desired, to an acid addition salt.

The reaction of process variant a) is carried out at temperatures ranging from about room temperature to about 90 ° C, preferably under a protective gas such as He or Ar, until a significant amount of the desired addition compound is obtained, typically 0.5 to 6 hours, preferably one to 4: n hours.

In process variant b), the deprotection of the nitrogen atom takes place by hydrolysis in a polar solvent in the presence of an acid or a base, preferably under reflux.

The chlorination according to process variant c) is carried out by allowing the CO 2 gas to flow through the piperazinylpyrazine / glacial acetic acid solution at a temperature of 0 to 100 ° C. Other useful solvents include hydrochloric acid, dimethylformamide and acetonitrile.

Suitable reducing agents for use in process variant d) are tin, zinc, iron and sulfur dioxide with an inorganic or organic acid, triphenylphosphine, sodium arsenite, ammonium sulphide, sodium dithionite, ferrooxalate granular lead. Catalytic hydrogenation can also be used in the presence of palladium on carbon, Raney nickel or other catalyst. Suitable solvents include polar solvents such as water, acetic acid, lower alcohols and the like. The reduction occurs at about 0-150 ° C, 62666

The cyclization according to process variant e) takes place by heating the starting material at about 0-250 ° C in a polar solvent such as a base in water, dimethylformamide or alcohol.

In process variant f) the reduction can be carried out with the aid of hydrogen and a suitable catalyst, e.g. using Raney nickel, copper chromium oxide, platinum, palladium or Pt or Pd oxide in a polar solvent such as an acidic aqueous solution or an alcohol. Hydrides such as borane or lithium aluminum hydride in a non-polar solvent such as tetrahydrofuran or ethyl ether may also be used. The reactions are performed at temperatures from about -70 ° C to about 300 ° C and at a pressure of about 1-300 atm.

In process variant g) the removal of the carboxyl group takes place by heating at about 100-300 ° C without solvent or in the presence of a solvent such as a hydrocarbon, e.g. tetralin, an aromatic hydrocarbon or a substituted aromatic solvent such as chlorobenzene or nitrobenzene.

In process variant h) the lower alkoxy group Y is replaced by chlorine. The chlorinating agent is BC1, POCl2, PCI,. or PCI3.

The reaction temperature is from 25 ° C to the reflux temperature of the solution. Mixtures of the above chlorinating agents can also be used.

The chlorination according to process variant i) is carried out using POCl 3 and.

The reaction conditions are the same as those mentioned in h).

Suitable reducing agents for use in the reduction according to process variant j) are hydrides such as borane or lithium aluminum hydride. Hydrogen and a catalyst such as molybdenum sulfide, copper chromium oxide, ruthenium or platinum oxide can also be used. Suitable solvents for catalytic hydrogenation are polar solvents such as water, lower alcohols, glyme or dioxane. However, the reduction with the hydride takes place in an aprotic solvent such as ethyl ethers or tetrahydrofuran. The reaction temperature is from about -70 ° C to about 250 ° C at a pressure of about 1 to about 300 atmospheres.

The compound of the invention can be used as an appetite suppressant in mammals. The dosage is about 0.01 to 20 mg / kg, preferably about 0.1 to 10 mg / kg as a single dose or 2 to 4 sub-doses.

6 2. 6 6 6 6 The drug may be administered orally at the above dose, however, other uses such as intraperitoneal, subcutaneous, intramuscular or intravenous are possible.

The pharmaceutically acceptable salts of the invention may be salts of inorganic acids such as hydrochloric acids (e.g. HCl and HBr), sulfuric acid, nitric acid or phosphoric acid, or organic acids such as maleic, fumaric, tartaric, citric, acetic or , benzoic, 2-acetoxy-benzoic, salicylic, succinic acid salts, or salts of theophylline, 8-chloro-theophylline, p-aminobenzoic acid, p-acetamidobenzoic acid or methanesulfonic acid.

6-Chloro-2- (11-piperazinyl) pyrazine has better potency and lower toxicity than known appetite suppressants. For example, it is 10 times more effective in oral dosing than fenfluramine (1- (3-trifluoromethylphenyl) -2-ethylaminopropane) in experiments in cats.

Appetite suppressant effect in rats

On the day before the day of the experiment (control day), food consumption was measured in groups of 7-10 rats, which were allowed to eat for only 2 hours a day. The next day (the day of the experiment), the rats were injected intraperitoneally with various doses of the test compound three minutes before the two-hour meal period. Food consumption on the test day was measured and compared (even t-test) to food consumption on the control day. The results are shown in the following table.

Dosage mg / kg Abdominal Grams fed cont- Grams fed internally __________ on roll day ___ test day 1.5 14.2 + 2.5a 7.5 - 2.0a a is the standard deviation of the mean.

The following examples illustrate the invention. Unless otherwise stated, all temperatures are expressed in degrees Celsius.

Example 1 6-Chloro-2- (11-piperazinyl) pyrazine hydrochloride 2,6-Dichloropyrazine (0.10 mol) is added to 20 g of piperazine in 200 ml of acetonitrile and the mixture is refluxed for 1.5 h. The mixture is concentrated in vacuo and the residue is partitioned between 1N NaOH and benzene. The combined benzene fractions were washed with 1N NaOH, dried over MgSO 4, filtered and concentrated in vacuo to a yellow oil which was dissolved in 200 mL of abs. ethanol with 10 ml of cold, saturated anhydrous ethanolic HCl. The precipitated hydrochloride is recrystallized from 95% ethanol to give slightly yellow needles, m.p. 350 ° (decompose).

6 2 6 6 6 7

Example 2 6-Chloro-2- (11-piperazinyl) -pyratine A. 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 triethylaraine in 200 ml of n-butanol are heated under reflux for 3 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between 1N NaOH and benzene. The combined benzene extracts are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to N, N 1-bis (6-chloro-2-pyrazinyl) piperazine.

(b) N, N1-Bis (6-chloro-2-pyrazinyl) -piperazine from the previous preparation is stirred at 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 to give 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride.

B. From 2-chloro-6- (4-formyl-1-piperazinyl) pyrazine (a) 2,6-Dichloropyrazine, 7.5 g (0.050 mol), is added to 10 g of N-formylpiperazine in 100 ml of acetonitrile. and the mixture is heated to reflux for 2 hours. After evaporation to dryness under reduced pressure, the residue is partitioned between 2N Na 2 CO 3 and benzene. The benzene layer is separated, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is essentially pure 2-chloro-6- (4-formyl-1-piperazinyl) -pyrazine.

(b) N-Formyl derivative, 2.0 g (8.82 mmol) are added to 100 ml of concentrated hydrochloric acid and stirred at reflux for 10 hours. The solution is concentrated to a small volume, diluted with water, and cooled to give 6-chloro-2- (1'-piperazinyl) pyrazine hydrochloride.

C. From 6-chloro-2- (4-methyl-1-piperazinyl) -pyrazine (a) A mixture of 30 g (0.20 moles) of 2,6-dichloropyrazine and 40 g (0.40 moles) of N- methylpiperazine in 200 ml of n-butanol is stirred at reflux for 6 hours. The reaction mixture is concentrated under reduced pressure. After the addition of 200 ml of saturated sodium carbonate solution added to the residue, the product is extracted into benzene. The benzene extract is washed with water, dried (magnesium sulfate), filtered and concentrated to give 6-chloro-2- (4-methyl-1-piperazinyl) pyrazine.

8 6 2 6 6 6 (b) The 4-methylpiperazine derivative from the previous preparation step is treated with 0.2 mol of bromocyanide in toluene at 0 °, and the resulting mixture is heated under reflux for 4 hours and cooled. The mixture is concentrated in vacuo and treated with 100 ml of 6N hydrochloric acid for 18 hours under reflux and cooled. The precipitated product is recrystallized from 25% ethanol to give 6-chloro-2- (1'-piperazinyl) pyrazine hydrochloride.

Example 3 6-Chloro-2- (11-piperazinyl) -pyrazine hydrochloride

Chlorine gas is bubbled through a well-stirred solution of (1.0 mole) of 2- (1'-piperazinyl) -pyrazine hydrochloride in 1 L of glacial acetic acid at 100 ° C until the reaction is complete. After concentration under reduced pressure, the residue is dissolved in 600 ml of 0.5 N hydrochloric acid, inoculated with 6-chloro-2- (1-piperazinyl) -pyrazine hydrochloride, concentrated and cooled. The precipitated solid is recrystallized from 95% ethanol to give pure 6-chloro-2- (1'-piperazinyl) pyrazine hydrochloride.

Example 4 6-Chloro-2- (11-piperazinyl) -pyrazine hydrochloride (a) 6-Chloro-2- (1'-piperazinyl) pyrazine-1-oxide 2-Chloropyrazine (0.1 mol) is added to a solution of 0 .3 moles of trifluoroperacetic acid in CH 2 Cl 2 (300 mL) at 0 °.

The mixture is stirred for 4 hours at 0 °, 4 hours at 25 ° and finally refluxed for 4 hours. The resulting solution is washed with saturated aqueous NaCl and then saturated aqueous Na 2 CO 3 and concentrated in vacuo to give crude 2-chloropyrazine-1,4-dioxide.

Crude 2-chloropyrazine-1,4-dioxide, 20 g, is stirred for 4 hours in 50 ml of benzenesulfonyl chloride at 50 ° under N 2 and the mixture is poured into a mixture of ice, pyridine and saturated NaCl solution. The precipitated 2,6-dichloropyrazine-1-oxide is collected by filtration and converted to the title compound by reaction with piperazine as in Example 1.

(b) 6-Chloro-2- (1'-piperazinyl) -pyrazine-4-oxide

As in Example 4 (a), 2,6-dichloropyrazine is converted to the 4-oxide with 1.8 molar equivalents of trifluoroperacetic acid. The crude 2,6-dichloropyrazine-4-oxide is converted to the title compound by reaction with piperazine as in Example 1.

9 6? 6 h f ((c) 1- or 4-N-oxide from 6-chloro-2- (1'-piperazinyl) -pyrazine, 21.5 g (0.100 mol), dissolved in 200 any glacial acetic acid. The solution is heated to 85 ° C, saturated with hydrogen 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 to give 6-chloro-2- (1'-piperazinyl) pyrazine hydrochloride.

Example 5 6-Chloro-2- (1'-piperazinyl) -pyrazine hydrochloride A. A mixture of 5.8 g (0.045 moles) of 2-amino-6-chloropyrazine 4.68 g (0.015 moles) of bis- ( 2-Bromoethyl) -amine hydrobromide and 25 ml of 2-butanone are heated at reflux for 10 hours. After cooling at 0 ° C for 15 hours, the hydrogen bromide salts are removed by filtration and dissolved in 25 ml of water. The aqueous solution is basified to pH 10 with 10% sodium hydroxide solution. The crude product is extracted into 100 ml of benzene and washed with two 25 ml portions of water. The benzene extract is dried over magnesium sulfate, filtered and concentrated to give the free base 6-chloro-2- (1'-piperazinyl) pyrazine. Conversion to the hydrochloride salt with anhydrous ethanol-hydrogen chloride solution and recrystallization from 95% ethanol gives 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride.

B. (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 concentration under reduced pressure at 55 ° C, the residue is partitioned between 200 ml of 2N sodium carbonate solution and 200 ml of benzene. The aqueous layer is repeatedly extracted with 100 ml of benzene. The combined benzene extracts are dried (sodium sulfate), filtered and concentrated under reduced pressure at 45 ° C to give 6-chloro-2- (bis-cyanomethylamino) pyrazine.

(b) To a solution of 2.5 g (0.012 mol) of 6-chloro-2- (bisyanomethylamino) pyrazine in 500 ml of tetrahydrofuran is added 0.048 mol of borane in tetrahydrofuran at 0 ° C. The mixture is warmed to 25 ° C for three hours and then refluxed for 1 hour and cooled to 0 ° C. Glacial acetic acid (0.072 mol) is added at 0 ° and the mixture is stirred at 0-28 ° until hydrogen evolution ceases. The solvent is removed in vacuo and the residue is partitioned between CHCl 3 and 2N sodium hydroxide solution. After the organic 6 2 6 6 6 10 phase is dried over anhydrous sodium sulfate, filtered and concentrated, the residue is converted into the hydrochloride salt with anhydrous ethanol-hydrogen chloride. Recrystallization from 95% ethanol gives 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride.

Example 6 6-Chloro-2- (1'-piperazinyl) -pyrazine hydrochloride a) A suspension of 18.7 g (0.10 mol) of 5-amino-3-chloro-2-carbomethoxypyrazine in a mixture of 114 ml 48 % hydrobromic acid and 30 ml of acetic acid are 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 (0.10 moles) of sodium nitrite in 40 ml of water is then added keeping the reaction temperature at 0 ° C. Stirring is continued for 30 minutes and the excess bromine is discarded by dropwise addition of 350 ml of 30% aqueous sodium bisulfite solution. The product is filtered off, washed with water and recrystallized from ethyl acetate-hexane to give 5-bromo-3-chloro-2-carbomethoxypyrazine.

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 concentrated under reduced pressure and the residue is partitioned between 2N sodium carbonate solution and benzene. The benzene extract is washed with water, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The residue is converted into the hydrochloride salt with chloro-hydrogen-ethanol solution and recrystallized from ethanol-ethyl acetate to give 2-carbomethoxy-3-chloro-5- (1'-piperazinyl) -pyrazine hydrochloride.

c) A solution of 5.8 g (0.023 mol) of methyl ester in 50 ml of 1N hydrochloric acid is heated under reflux for 5 hours. After evaporation to a small space under reduced pressure, the residue is dried by ethanol-acetotropic distillation. The solid 2-carboxy-3-chloro-5- (1'-piperazinyl) -pyrazine hydrochloride is filtered off and dried.

d) A suspension of 5.0 g (0.018 mol) of 2-carboxy-3-chloro-5- (1'-piperazinyl) pyrazine hydrochloride in 50 ml of tetralin hydrochloride is stirred and refluxed for about 1 hour until the evolution of carbon dioxide ceases. . The hot solution is extracted with two 50 ml portions of 0.5N hydrochloric acid. The aqueous extracts are combined, r 11 6? 6 6 6 concentrated and cooled. The precipitated 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride is removed by filtration and dried.

Example 7 6-Chloro-2- (1'-piperazinyl) -pyrazine hydrochloride A. Solid 6-methoxy-2- (1'-piperazinyl) -pyrazine dihydrochloride, 38.8 g (0.20 mol) is added in small portions 1 to 300 ml of vigorously stirred phosphorus oxychloride at 40-50 ° C. After the addition is complete, the mixture is stirred at reflux for 1 hour, cooled and evaporated to dryness under reduced pressure. The residue is recrystallized first from a small volume of water, then from 95% ethanol to give 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride.

B. (a) A mixture of 100 g (0.77 moles) of 2-chloropyrazine-1-oxide and 17.2 g (2.0 moles / anhydrous piperazine in 1 l of 2-butanol) is heated under reflux for 6 hours. After concentration 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 repeatedly extracted twice with fresh chloroform. From 95% ethanol to give 2- (1'-piperazinyl) -pyrazine-1-oxide hydrochloride.

(b) To 300 ml of cold freshly distilled phosphorus oxychloride, 21.7 g (0.10 mol) of 2- (1'-piperazinyl) -pyrazine-1-oxide hydrochloride are added in several portions. The mixture is heated and when the vigorous reaction has ceased the mixture is stirred and refluxed for a further hour. Excess phosphorus oxychloride is removed under reduced pressure. Carefully pour the residue over 200 g of ice cubes. The solution is neutralized with cold 5N sodium hydroxide solution and extracted with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil is converted to the hydrochloride salt with a mixture of hydrogen chloride and ethanol and recrystallized from 95% ethanol to give 6-chloro-2- (1'-piperazinyl) pyrazine hydrochloride.

Example 8 6-Chloro-2- (11-piperazinyl) -pyrazine hydrochloride

To a solution of 21.3 g (0.10 mol) of 6-chloro-2- (3'-oxy-1'-piperazinyl) -pyrazine in 200 ml of tetrahydrofuran is added 12 r, s, 6? 6 b b 0.12 moles of borane in tetrahydrofuran at 0 ° C. The mixture is warmed to 25 ° C for 3 hours and then refluxed for 1 hour and cooled to 0 ° C. Glacial acetic acid (0.6 mol) is added at 0 ° C and the mixture is stirred at 0-25 ° C until hydrogen evolution ceases. The solvent is removed in vacuo and the residue is partitioned between CHCl 3 and 2N sodium hydroxide solution. After the organic phase is dried over anhydrous sodium sulfate, the filtered and concentrated residue is converted into the hydrochloride salt with an anhydrous ethanol-hydrogen mixture. Recrystallization from 95% ethanol gives 6-chloro-2- (1'-piperazinyl) -pyrazine hydrochloride.

Claims (2)

A process for the preparation of 6-chloro-2- (1'-piperazinyl) pyrazine of the therapeutically active formula (VI), or a pharmaceutically acceptable salt thereof, characterized in that a) a compound of the formula wherein X is halogen , is reacted with piperazine, or b) the compound of formula J, K 1 and R 3 having 6-chloro-2-pyrazinyl, formyl or cyano is hydrolysed, or c) a compound of formula k · '\ / The compound of formula is chlorinated, or d) of the formula ΓΛ or I / \ ciAn ^ -Wh 62 66 6 is reduced with SO 2 / HCl, or e) a compound of formula ΙΠ> 5 ^ J-NH NH / / “X, wherein X is halogen, is cyclized, or f) the compound of formula j-CN N_CN is reduced, or g) the formula HOOC ^ .. N. the compound of formula ci / Sr 2 -V_ / H is heated, or h) the compound of formula, wherein Y is lower alkoxy, is chlorinated with phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or with boron trichloride, or i) the compound of formula ^ s .., iK \ hl v_ / o is chlorinated with phosphorus oxychloride, or ό 2 6 6 6 15 j) the compound of formula ZH / Z ci A Α ~ λ) H ΓΛ zz, where Z is H 1 or 0, and at least one Z is 0, is reduced, and the resulting base is converted, if desired, into an acid addition salt, 16 62666 A process for the preparation of therapeutically active 6-chloro-2- (1H-piperazinyl) pyrazine or a pharmaceutical formulation according to the formula "") ^ X JN NH V_ / kännetecknat därav, att a) X is halogen, with piperazine, or b) hydrolysers with formulations N f 1 / \ 5 L I - N NR (V Cl ^ N ^ \ _ / * 5 color with 6-chloro-2-pyrazinyl, formyl or cyan , or c) chlorinated with form N. 1 / "Λ ^ or d) reducing with S02 / HC1 formed with form 0 ΐ or I /" A f / \ / 1¾¾. J-N MH -L. JN NH Cl v_y o eller 17 6 2 6 6 6 e) cyclic derivatives with formulas R / H / color X with halogen, or f) reducing derivatives with formulas ^ —— CN / N-JN Cl · ^ ^ 18Γ \ x-CN or g) upphettar föreningen med formeln HOOC. .NT n eller (h) chlorinated with phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or boron trichloride for formulations I ΑΛ, Λη ^ »NH wo eller