IE42979B1 - Pyrazinyl piperazine derivatives - Google Patents

Abstract

Novel piperazinylpyrazines of the formula in which the substituents are defined in Claim 1, and their N-oxides are prepared. These compounds are obtained by reacting an appropriate pyrazine or its N-oxide, which contains an easily removable group in the 2-position, which is defined in Claim 1, with an appropriate piperazine. The compounds III are also prepared as acid addition salts. The compounds obtained can be used in pharmaceutical compositions having anorexic action.

Description

Obesity is a fairly common condition and a potentially srious one in view of the correlation between incidence of arious diseases and the degree to which a person is overweight, ar example, obese persons succumb statistically more frequently 3 cardiovascular renal disease than, do persons of normal weight, sesity likewise results in higher death rates from diabetes, sphritis, pneumonia, cirrhosis, appendicitis and postoperative 3mplieations. Since obesity often occurs simply as a consequence f excessive intake of calories, good management of the condition i these cases can be achieved by restricting the caloric intake. ?equently, however, the patient has difficulty in initiating and ixtttaining dietary restrictions, making it necessary to use lorexigenic drugs as adjuvants to therapy.

The piperazinylpyrazine compounds useful in the novel method : treatment of the present invention have the structural formula: ι which R1 is hydrogen, halogen (F, Cl, Br or l), haloalkyl, C, , alkoxy, amino, C. _ alkylthio, phenylthio carbamoyl, (C . 1—4 I—/ i—4 alkyl)carbamoyl, (CJ alkoxy) carbonyl, c2-6 dialkylamino, phenyl, or phenyl substituted by halogen (F,C1, Br, or T), by alkyl or by alkoxy; R is hydrogen, halogen (F, Cl, Br or l), alkyl of from 1 to carbon atoms, cyano, amino (C^ alkoxy) carbonyl, carbamoyl, alkoxy of from 1 to 4 carbon atoms, haloalkyl of from 1 to 3 carbon atoms, phenyl or substituted phenyl wherein the substituent is halogen (F,Cl, Br or I); is hydrogen, halogen (F, Cl, Br, or I), alkanoylamino of from 1 to 3 carbon atoms, carbamoyl, phenyl or phenyl substituted by halogen (F, Cl, Br or I), by alkyl of from 1 to 4 carbon atoms or by alkoxy from 1 to 3 carbon atoms; is hydrogen, alkyl of from 1 to 3 carbon atom, carboxyl or (C^ j alkoxy) carbonyl; c R is hydrogen or alkanoyl of from 1 to 3 carbon atoms; and the N-oxides and the acid addition salts of the foregoing compounds. 3 Preferably, R and R are as defined above and R is hydrogen, 2 particularly when one of R and R is also hydrogen.

The novel compounds of the present invention have the structural formula: ci or pharmaceutically acceptable salt thereof, where R is hydrogen, halogen, especially chlorim·, alkoxy, such as methoxy, tri2 fluoromethyl, dialkylamino or phenylthio; R is hydrogen, halogen, especially chlorim·, or phenyl, with the proviso that R - 3 9 79 < I R& are not both hydrogen.

The compounds useful in the novel method of treatment of the ssent invention, which have formula XIX, or are N-bxides or acidLition salts of such compounds, are prepared by reaction of a 2-X•azine of formula X or an N-oxide or acid-addition salt of such a ipound with piperazine or a substituted piperazine of formula II tere and R3 are as defined above). The novel compounds of ; present invention can of course be made by this reaction by lice of suitable values of the variable radicals. For example :hloro-2-piperazinylpyrazine may be prepared by reaction of a ipound of formula: Cl :re X is as defined below, with piperazine at a temperature in i range IS to 90°C· The reaction sequence, showing the free base forms of compounds md III rather than the N-oxide or a salt, is as follows: R2. _ N R3 R1/^ X is halogen, C _ alkylsulfonyl, phenolsulfonyl, C _ alkylsulfinyl, pnefiylsulfinyl The reaction takes place at temperatures ranging from 15°C to C., preferably under an inert atmosphere, e.g. Ng, He or Ar, until ubstantial amount of desired adduct of formula III is obtained, ically for a period of from 0.5 to 6 hours, preferably from 1 to - 4 429 79 hours. c Where R is to be a alkanoyl radical, the compound may be prepared by alkanoylating in known manner the corresponding compound in which R is hydrogen.

If a compound in which R^ is carboxy is desired, it may be obtained by acid hydrolysis of the corresponding compound in which R^ is alkoxycarbonyl.

Other processes by which 6~chloro-2~(l’-piperazinyl)pyrazine, a particularly preferred compound of this invention, can be prepared are as follows: I. Removal of Nitrogen Protective groups where R'’ is a heterocycle such as 0-chloro-2-pyrazinyl;alkanoyl such a as formyl or acetyl; aroyl such as benzoyl or p-methoxybenzoyl; alkoxycarbonyl, alkenoxycarbonyl, aralkoxycarbonyl or aryloxyCarbonyl such as benzyloxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl, vinyloxycarbonyl; cyano; carbamoyl, N-alkyl carbamoyl, or N-arylcarbamoyl; aralkyl such as benzyl; or alkyl such as methyl.

Removal of these groups (except aralkyl and alkyl) is effected by hydrolysis in polar solvents in the presence of acid or base.

The alkyl groups and aralkyl groups can be removed by reaction with cyanogen bromide, an aikoxycarbonyl halide, or an aryloxyCarbonyl halide to give compounds in which R^=cyano, alkoxycarbonyl, or aryloxycarbonyl, respectively, and subsequently removing these groups as above or below.

Removal of aralkyl or aralkoxycarbonyl can alternatively be effected by catalytic hydrogenolysis. This may be carried out in nonpolar or polar solvents such as water or alcohols in the presence - 5 379 ? catalysts such as Pt, Pd, Ru and oxides thereof at from 25°C. to le reflux temperature. l. Chlorination e process is conveniently effected by passing Cl^ gas through solution of the piperazinyl-pyrazine in a solvent such as glacial etic acid at a temperature of from 0- to 100°C. Other solvents ich can be used are aqueous hydrochloric acid, dimethylformamide, d acetonitrile.

I. Reduction of N-hydroxy and N-oxide Intermediates 0 .table reducing agents, are tin, zinc, iron, or sulfur-dioxide in irganic or organic acids; triphenylphosphine, sodium arsenite, ionium sulfide, sodium dithionite, and ferrous-oxalate-granulated d; or the reduction may be effected by catalytic hydrogenation, > over palladium on carbon or Raney nickel. Suitable solvents lude polar solvents such as water, acetic acid and alcohols. reduction is preferably conducted at from 0 to 150°.

Formation of the Piperazine Ring - 6 A.

X'CH2CH2^ X'CH2CH2 NH Cl'xli -N NH wherein X' is a displaceable group or atom such as halogen, tosyloxy, mesyloxy, hydroxy, amino, and trialkylammonium. Usually, the above process is effected by heating the reactants at from 0 to 25O°C in a polar solvent such as water, dimethylformamide or alcohols in the presence of base.

B. where X1 and process condiiions are as described in IVA. above Cl' hydride or catalyst, H., ,-'χ. Cl N NH Suitable catalysts are Raney nickel, copper-chromium oxide, platinum, palladium and oxides thereof in a polar solvent such as aqueous acid or alcohol. Suitable hydrides are borane and lithium aluminium hydride in a nonpolar solvent such as tetrahydrofuran or diethyl ether. The reactions are preferably carried out at a - 7 7 9 lerature of from -70°C. to 300°C. and a .pressure of from 1.0 100 atmospheres, ; ·' ‘ Removal of carboxy or esterified carboxy groups Λ or 2; R°—H, alkyl or aralkyl.

The removal is effected by hydrolysis and/or heating. 'olysis may be effected in the presence of acid or base in a ir solvent such as water, alcohols or glymes at a temperature 'rom 0 to 150°C; heating may take place without solvent or in rents such as hydrocarbons such as tetrahydronaphthalene, latic hydrocarbons, and substituted aromatic solvents such as jrobenzene or nitrobenzene at a temperature of from 100 to 300°C.

Introduction of Chlorine by displacement or rearrangement vhich Y is hydroxy or alkoxy. The chlorinating agent is Ferably BClg, POCi^, or PCl^ and it may also serve as solvent. Reaction temperatures are preferably from 25°C. to reflux perature of the solvent. Mixtures of the above reagents may also used: N ction conditions are the same as those given above, 0 2 9 7 3 Benzenesulfonyl chloride is usually used for this reaction under the same conditions as described above.

VII. Reduction of Amides and Imides z=H2 or at least one beinS °· Suitable reducing agents include hydrides such as borane or lithium aluminum hydride, or catalysts such as molybdenum sulfide, copper chromium oxide, ruthenium and platinum oxide. Suitable solvents for catalytic hydrogenation include polar solvents Such as water, lower alcohols, glymes and dioxane. Reduction with hydrides, however, is conducted in aprotic solvents, such as diethyl ether and tetrahydrofuran. The reaction temperature is in the range -70°C. to 25O°C. at a pressure of from 1.0 to 300 atmospheres.

The compounds of the present invention may be administered as anorexic agents to mammalian species, e.g. rats and mice, in amounts ranging from 0.01 to 20 rag. per kg. of body weight, preferably from 0.1 to 10 mg. per kg. of body weight in a single dose or in 2 to 4 divided doses.

The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously,intramuscularly, or intravenously may be used.

The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directl; with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with ex< ipients and used in the form of tablets, - 9 7 » •oches, pills, capsules, elixirs, suspension^, syrups,, waters > chewing gum. The amount of active compound in s,uch therapeut:ally useful'compositions or preparations is such that a suitable isage will be obtained.' The tablets,, troches, pills or capsules, may also contain the illowing; a binder such as gum tragaeanth, acacia, corn starch or ilatin; an excipient such as dicalcium phosphate; a disintegrating ;ettt such as corn starch, potato starch or alginic acid; a lub.cant such as magnesium stearate; a sweetening agent such as icrose, lactose or saccharin; or a flavoring agent such as ippermint, Oil of Wintergreen, or cherry flavoring. When the >sage unit form is a capsule, it may contain in addition to iterials of the above type a liquid carrier such as a fatty oil. irious other materials may be present as coatings or to otherwise idify the physical form of the dosage unit, for instance, tablets, .Ils, or capsules may be coated with shellac, sugar, or both. A τιιρ or elixir may contain the active compounds, sucrose as a reetening agent, methyl and propyl parabens as preservatives, a dye id a flavoring such as cherry or orange flavor. Of course, any iterials used in preparing any dosage unit form should be pharmacitically pure ,and substantially non-toxic in the amounts used.

As to the pharmaceutically acceptable salts, those coming thin the purview of this invention include the pharmaceutically ceptable acid-addition salts. Acids useful for preparing these :id-addition salts include, inter alia, inorganic acids, such as ie hydrohalic acids (e.g. hydrochloric and hydrobromic acid), ilfuric acid, nitric acid, and phosphoric acid, and organic acids ich as maleic, fumaric, tartaric, citric, acetic, benzoic, 2etoxybenzoic, salicylic and succinic acids, theophylline, 8lorotheophylline and p-aminobenzoic, p-acetamidobenzoic, or thanesulfonic acids. - 10 4 2979 The compounds of the present invention show enhanced effectiveness and less toxicity than known anorexic agents. The 6-chloro-2-(l'-piperazinylJpyrazine compound, for example, is 10 times as effective as fenfluramine in the cat following oral administration.

In addition to the anorexic activity described above, the novel compounds of this invention pharmacologically influence serotonin levels in a manner that suggests that they are also useful as antidepressant, anti-hypertensive, analgesic and sleep-inducing agents. For these purposes, the same routes of administration, and pharmaceutical formulations as described above would be used.

The following examples illustrate the present invention.

Unless otherwise indicated, all temperatures are expressed in degrees Celsius, percentages are on a volume basis where they refer only to liquids and on a weight basis otherwise, and mesh and screen sizes are U.S. standards.

EXAMPLE 1. 6-Chloro-2(l'-piperazinylJpyrazine hydrochloride 2,6-Dichloropyrazine (0.10 mole) is added to 20 g. piperazine in 200 ml. acetonitrile and the mixture is refluxed for 1.5 nr. under . The mixture is concentrated in vacuo and the residue partitioned between IN aqueous NaOH and benzene. The combined benzene extracts are washed with IN aqueous ia0H, dried over MgSO^, filtered and concentrated in vacuo to a vellow oil which is dissolved in 200 ml. absolute ethanol containing 10 ml. of cold, saturated anhydrous ethanolic HC1. The precipi1ated hydrochloride is recrystallized from 95% ethanol to give faintly yellow needles, m.p. 350° dec.

EXAMPLE 2 6-Chloro-2-(41-acetyl-1'-piperazinyl)-pyrazine 6-Chloro-2-(l'-piperazinyl)-pyrazine hydrochloride (0.004 mole) from Example 1 is dissolved in 250 ml. ice water containing 20 g. sodium acetate trihydrate and the rapidly stirred solution treated th 15 ml. acetic anhydride. After 3 hours the mixture is :tracted with benzene, the benzene dried and filtered, and the Ivent replaced by n-butylchloride. Crystallization gives the tie compound, m.p. 106-107,5° EXAMPLE 3 - Chloro-2-(l '-piperazinyl)-pyrazine hydrochloride The title compound, m.p. 301-302°, is prepared similarly to . :ample 1 by substituting 2,5-dichloropyrazine for 2,6-dichloropyr;ine.

EXAMPLE 4. 6- Trifluoromethyl-2-(l’-piperazinyl)-pyrazine hydrochloride 2-Pyrazinoic acid (25 g, 0.20 mole) is converted to 2-triuoromethylpyrazine by heating with sulfur tetrafluoride (54 g. ) an initial pressure of l60 psi and l50°in a stainless steel toclave for 6 hours. After quenching the reaction mixture on e and adding Sufficient NaOH to adjust the pH to 6, the crude oduct is extracted into methylene chloride. Distillation gives trifluoromethylpyrazine, b.p. 118°. The freshly distilled 2-triuoromethylpyrazine .(15,9 g, ) is converted to the 4-N-oxide with ml. glacial acetic acid and 20 ml. 30$ aqueous hydrogen peroxide r 48 hours at 7θ°· After quenching the reaction mixture on ice, e product is extracted into benzene. The benzene extracts are shed with aqueous sodium carbonate, dried (NagSO^) and concentrated vacuo to give the crystalline 4-N-oxide, m.p. 57°-59°. The Nide (3.28 g. ) is rearranged nearly exclusively to 2-chloro-6ifluoromethylpyrazine, b.p. 115° (25 in. Hg.) by heating with 5 . benzenesulfonylchloride, for 4 hours at 100° and distilling e reaction mixture.

The title compound, m.p. 292-294°, is prepared similarly to ample 1, starting from the 2-chloro-6-trifluoromethylpyrazine epared as described above. 39 7 9 EXAMPLE 5. 6-Methoxy-2-(l'-piperazinyl)-pyrazine dihydrochloride 2,6-Dichloropyrazine (0.067 mole) is treated with a solution of sodium methoxide (0.067 mole) in 100 ml. dry methanol for 1 hour at °. The solvent is removed in vacuo and the residue is extracted with boiling hexane extract. 2-Chloro-6-methoxypyrazine crystallizes from the hexane extract. Another recrystallization from isopropanol at -70° gives 2-chloro-6-methoxypyrazine as an oil at room temperature.

The title compound, m.p. 189-191°, is prepared similarly to Example 1, using the 2-chloro-6-methoxypyrazine prepared as described above in place of 2,6-di.chloropyrazi ne.

EXAMPLE 6.

O-Chloro-2-(1’-piperazinyl)-pyrazine-1-oxide 2-Chloropyrazine (0.1 mole) is added to a solution of 0.3 mole trifluoroperacetic acid in CHgClgOOO ml.) at 0°C. The mixture is stirred for 4 hours at 0°, 4 hours at 25° and finally at reflux for 4 hours. The resulting solution is washed with saturated aqueous NaCl solution and then saturated aqueous Na2COg solution and concentrated in vacuo to give crude 2-chloropyrazine-l,4-dioxide.

The crude 2-chloropyrazlne-1,4-dioxide, 20 g., is stirred for hours with 50 ml. benzenesulfonyl chloride at 50° under Ng and quenched on a mixture of ice, pyridine and saturated NaCl solution.

The precipitated 2,6-di-chlc.iopyrazine~ 1-oxide is collected by filtration and converted to the title compound by reaction with piperazine as in Example 1.

EXAMPLE 7. 6-Chloro-2-(11-piperazinyl)-pyrazine-4-oxide In a similar manner to that of Example 6, 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 •s nverted to the title compound by reaction with piperazine as Example 1.

EXAMPLES 8-23 Following the procedure of Example 1, the following substituted lopyrazines are reacted with piperazine in acetonitrile to give e corresponding 2—(1'-piperazinyl)-pyrazine derivatives.

Example Starting Material Product 8 2,3-Dibromopyrazine 3-Bromo-2-(l'-piperazinyl)pyrazine hydrochloride 9 .2,6-Dibromopyrazine 6-Bromo-2-(1'-piperazinyl)pyrazine hydrochloride 10 2-Chloro-3}5-diphenylpyrazine 3 , 5-Diphenyl-2-(1'-piperazinyl) pyrazine hydrochloride 11 2-Chloro-3 j6-diphenylpyrazine 3 , 6—Diphenyl—2-(1'-piperazinyl) pyrazine hydrochloride 12 2-Chloro-S,6-diphenylpyr azine 5,6-Diphenyl-2-(l'-piperazinyl) pyrazine hydrochloride 13 6-Carbamoyl-2- chloropyrazine 6-Carbamoyl-2-(1'-piperazinyl)pyrazine hydrochloride 14 2-Chloro-6~d Lethylcarbamoylpyrazine 6-Diethylcarbamoyl-2-(1'piperazinyl)—pyrazine-hydrochloride 15 6-Methoxycarbonyl-2chloropyrazine 6-Methoxycarbonyl-2-(l'piperazinyl)_pyrazine hydrochloride 16 5-Carbamoyl-2chloropyrazine 5-Carbamoyl-2-(l'-piperazinyl)pyrazine hydrochloride 17 2-Chloro-5-methoxy pyrazine S-Methoxy-2-(l'-piperazinyl)pyrazine hydrochloride 18 2-Chloro-5-trichloromethylpyrazine 5-Prichloromethyl-2-'1'piperazinyl)-pyrazine hydrochloride 19 2-chloro-S-phenyl- pyrazine S-phenyl-2-(l'-piperazinyl)pyrazine hydrochloride, m.p. 304-308° (dec) 20 2-chloro-6-phenylthio- pyrazine 6-phenylthio-2-(l'-piperazinyl) pyrazine hydrochloride, m.p. 221-222°C. - 14 42979 Example Starting Material Product 21 2-Chloro-5-cyanopyrazine 5-Cyano-2-(l'-piperazinyl)pyrazine hydrochloride 22 5 2-Chloro-5-(p-chlorophenyl)-pyrazine 5-(p-chlorophenyl)-2-(l'piperazinyl)-pyrazine hydrochloride 23 5-Amino-2-chloropyrazine 5-Amino-2-(l'-piperazinyl)pyrazine hydrochloride EXAMPLE 24. 6-Dimethylamino-2-(l'-piperazinyl)-pyrazine. millimoles (3.14 g) of 64N,N-dimethylamino)-2-chloropyrazine and 3 g. of piperazine are fused under nitrogen at 135° for 6 hours. The mixture is digested with water and,after being filtered to remove insoluble material, Is made alkaline with ION sodium hydroxide and extracted with chloroform. The combined chloroform extracts are washed with 2N sodium hydroxide, dried (anhydrous sodium sulfate), filtered and concentrated to an oil under reduced pressure. The product is isolated as the dihydrochloride salt, M.P. 249-250°C, from isopropanol, EXAMPLES 25-32.

The 2-hydroxypyrazine derivatives (0.10 mole) listed below are converted to the corresponding substituted 2-chloropyrazines by reaction with 0.4θ mole pho .phorus oxychloride and 10 ml, N,Ndimethylformamide at reflux for 1-4 hours. After quenching the reaction mixture on ice, the substituted 2-chloro-pyrazine is isolated by extraction into diethyl ether or benzene or by crystallization of the separated product. The 2-chloropyrazine derivatives m turn are converted to the corresponding 2-(l'-piperazinyi)-pyrazine derivatives by reaction with piperazine following the procedure of Example 1. 7 9 imple Starting Material Product 3,6-Di-(4-bromophenyl)pyr'azinol 3,6-Di-(4-butylphenyl)pyrazinol 3,6-Diy(4-methoxyphenyl) pyrazinol 3-Acetamidopyrazinol 3-HydroxypyTazincarboxamide 3-Hydroxy-6-methylpyrazincarboxaniide j 6-Diphenyl-3-hydroxypyrazincarboxamide 3-Methyl-5-phenylpyrazinol 3.6- DiC4-bromophenyl)-2(l'-piperazinyl)-pyrazine hydrochloride 3.6- Di-(4-butylphenyl )2-(1’-piperazinyl)-pyrazine hydrochloride •3,6-Di-(4-methoxyphenyl)2- (1 '-piperazinyl)-pyrazine hydrochloride 3- Acetamido-2-(l’-piperazinyl) pyrazine hydrochloride· 3-Carbamoyl-2-(l’-piperazinyl) pyrazine hydrochloride 3-Carbamoyl-5-methyl-2-(l*piperazinyl)-pyrazine hydrochloride 3-Carbamoyl-S,6-diphenyl2- (1'-piperazinyl)-pyrazine hydrochloride 3- Methyl-5-phenyl-2-(l piperazinyl)-pyrazine hydrochloride EXAMPLE 33. 2-(3'-Carbethoxy-1-’-piperazinyl)-pyrazine hydrochloride.

The title compound is prepared similarly to Example 1 by stituting 2-chloropyrazine for 2,6-dichloropyrazine and 2bethoxypiperazine for piperazine EXAMPLE 34. 2-(3’-Carboxy-1’-piperazinyl)-pyrazine hydrochloride A solution of 5 g. of 2-(3'-carbethoxy-1’-piperazinyl)-pyrazine rochloride in 50 ml. of IN hydrochloric is stirred at reflux for hours. After concentration under reduced pressure at 50°, olute ethanol is added to the residue and the solution is recentrated. The addition of ethanol and concentration are eated two more times. The residue is recrystallized from a ture of methanol and ethyl acetate to give 2-(3'-carboxy-1 - 16 42979 piperazinyl)-pyrazine hydrochloride, EXAMPLE 356-Methylthio-2-(l’-piperazinyl)-pyrazine hydrochloride A mixture of 0.13 mole of sodium methylmercaptide (prepared from 3.12 g. sodium hydride and an excess of methyl mercaptan), g. (0.13 mole) of 2,6-dichloropyrazine and 200 ml. benzene is heated at reflux for 24 hours, cooled and washed twice with 50 ml. water. The benzene layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue gives 2-chloro-6-methylthhpyrazine.

To a solution of 10 g. piperazine in 150 ml. of 2-butanol is added 8.03 g (0.050 mole) of 2-chloro-6-methylth±pyrazine. After heating at reflux under nitrogen for 6 hours, solvent is removed under reduced pressure and the residue partitioned between dilute sodium hydroxide solution and benzene. The benzene extract is washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in ethanol and acidified with anhydrous ethanolic-hydrogen chloride solution. The precipitated salt is recrystallised from a methanolethyl acetate mixture to give 6- methylthio-2-(l’-piperazinyl)pyrazine hydrochloride.

The following examples describe alternative synthetic routes for the preparation of 6-chloro-2-(1-piperazinylJpyrazine hydrochloride.

EXAMPLE 36.

A. From N,N'-bis-(6-chloro-2-pyrazinyl)-piperazine (a) A mixture of 15.0 g. (0.10 mole) of 2,6-dichloropyrazine, 4.3 g. (0.050 mole) of anhydrous piperazine, and 20.4 S (0.20 mole) of triethylamine in 200 ml. n-butanol is heated at reflux for 3 hours. The mixture is concentrated under reduced pressure and the residue partitioned between 1 N aqueous sodium hydroxide solution and benzene. The combined benzene extracts are washed with water, dried 9 ϊγ anhydrous sodium sulfate, filtered and concentrated to N,N's*. (6—chloro—2—pyrazinyl)—piperazine. (b) The N,N,-bis('6-chloro-2.-Byrazinyl)-piperazine from the seeding step is stirred at reflux for 8 hours in 500 ml. of icentrated hydrochloric acid. After concentrating to dryness ler reduced pressure, the residue is recrystallized from 95% lanol to give 6-chloro-2-(1-piperazinyl)- pyrazine hydrochloride.

B. From 2-chloro-6-(4-formyl-l-piperazinyl)-pyrazine (a) 2,6-Dichloropyrazine, 7-5 g. (0.050 mole) is added to 10 g.

N-formyl-piperazine in 100 ml. of acetonitrile and the mixture ι ited at reflux for 2 hours. After concentrating under reduced issure, the residue is partitioned between 2 N sodium carbonate sol .on and benzene. The benzene layer is removed,washed with water, .ed over anhydrous magnesium sulfate, filtered and concentrated. : residue is essentially pure 2-chloro-O-(4-formyl-l-piperazinyl)azine. (b) The N-formyl derivative, 2.0 g. (8.82 mmole) is added to • ml. concentrated hydrochloric acid and stirred at reflux for hours. The solution is concentrated to a small volume, diluted ;h water, and cooled to give 6-chloro-2-(1-piperazinyl)pyrazine rochloride.

C. From 6-chloro-2-(4-methyl-l-piperazinyl)-pyrazine (a) A mixture of 30 g. (0.20 mole) of 2,6-dichloropyrazine and g. (0.40 mole) of N-methylpiperazine in 200 ml. of n-butanol is rred at reflux for 6 hours. The reaction mixture is concentrated er reduced pressure. After addition of 200 ml. of saturated ium carbonate solution to the residue, the product is extracted o benzene. The benzene extract is washed with water, dried gnesium sulfate), filtered and concentrated to give 6-chloro-2methyl-1-piperazinyl)-pyrazine. 4 2979 (b) The 4-methylpiper«zine derivative from the previous step is treated with 0.2 mol of cyanogen bromide in toluene at 0° and the resulting mixture heated 4 hours at reflux and cooled. The mixture is concentrated in vacuo and treated with 100 ml. of 6 N aqueous hydrochloric acid for l8 hours at reflux and cooled.

The precipitated product is recrystallized further from 95$ ethanol to give 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.

EXAMPLE 37.

A stream of chlorine gas is bubbled through a well stirred solution of (l.O mol) of 2~(l—piperazinyl)—pyrazine hydrochloride in J.) of glacial acetic acid at 100°C. until reaction is complete. After concentrating under reduced pressure, the residue' is dissolved in 600 ml. of 0.5 N aqueous hydrochloric acid, seeded with an authentic sample of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride, IS concentrated and cooled. The precipitated solid is recrystallized further from 95$ ethanol to give pure 6-chloro-2-(l-piperazinyl) pyrazine hydrochloride.

EXAMPLE 38.

The 1- or 4-N-oxide of 6-chloro-2-(l-piperazinyl)-pyrazine, 21.5 g. (0.100 mole), is dissolved in 200 ml. of glacial acetic acid.

The solution is warmed to 85C., saturated with anhydrous hydrogen chloride gas and treated witi a stream of sulfur dioxide at this temperature for 1 hour. The acetic acid is removed under reduced pressure and the residue reci vstallized from 95$ ethanol to give 6-chloro-2-(1-piperazinyl)-p; razine hydrochloride.

EXAMPLE 39.

A. A mixture of 5.8 g. (0.()45 mole) of 2-amino-6-chloropyrazine 4.68 g (0,015 mole) of bis-(z-bromoethyl)-ainine hydrobromide and 25 ml. of 2-butanone is heated at 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. water. The aqueous solution is made basic to pH 10 with 10$ sodium hydroxide solution. The crude 979 ?oduct is extracted into 100 ml. benzene and washed with two j- ml. portions of water. The benzene extract is dried over ihydrous magnesium sulfate, filtered and concentrated to give le free base of 6-chloro-2-(l-piperazinyl)-pyrazine. Conversion > the hydrochloride salt with anhydrous ethanolic hydrogen chloride id recrystallization from 95% ethanol gives 6-chloro-2-(l-piper:inyl)-pyrazine hydrochloride. (a) A mixture of 15.0 g. (0.10 mole) of 2,6-dichloropyrazine id 19.0 g (0.20 mole) of iminodiacetonitrile in 200 ml. of 2itanol is heated, at reflux for 6 hours. After concentrating under sduced pressure at’55°C., the residue is partitioned between 200 .. of 2 N sodium carbonate solution and 200 ml. of benzene. The [ueous layer is re-extracted with 100 ml. benzene. The combined mzene extracts are dried (sodium sulfate), filtered and concenated under reduced pressure at 45°C. to give 6-chloro-2-(bis•anome thyl amino)-pyrazine. (b) To a solution of 2.5 g. (0.01 mole) of 6-chloro-2-(bisanomethyl amino) -pyrazine in 5θ0 ml. tetrahydrofuran is added 048 mole of borane in tetrahydrofuran at 0°C. The mixture is rmed to 25°C. for 3 hours and then to reflux for 1 hour and oled to 0°C. Glacial acetic acid (0.072 mol) is added at 0° d the mixture stirred at 0-28° until hydrogen evolution ceases, e solvent is removed in vactio and the residue partitioned between Clg and 2 N aqueous sodium hydroxide. After drying the organic ase over anhydrous sodium sulfate, filtering and concentrating, e residue is converted to the hydrochloride salt with anhydrous hanolic hydrogen chloride. Recrystallization from 95% ethanol ves 6-chloro-2-(l-piperazlnyl)-pyrazine hydrochloride.

EXAMPLE 40.

A. A suspension of 18.7 g. (0.10 mole) of 5 -amino-3-chlorocarbomethoxy-pyrazine in a mixture of 114 ml. 48% hydrobromic id and 30 ml. acetic acid is cooled to 0°C., stirred and treated 2979 with a solution of 15 mi. bromine in 30 ml. acetic acid over a period of 45 minutes. A solution of 17-4 g. (0.10 mole) of sodium nitrite in 40 ml. water is then 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 bisulfite. The product is removed by filtration, washed with water and recrystallized from an ethyl acetate-hexane mixture to give 5-bromo-3-chloro-2carbomethoxypyrazine.

B. A mixture of 10.0 g (0.040 mole) of 5-bromo-3-chloro-2carbomethoxy-pyrazine, 6.9 g. (0.080 mole) of anhydrous piperazine and 100 ml. acetonitrile is heated at reflux for 2 hours. The mixture is concentrated under reduced pressure and the residue 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 to the hydrochloride salt with ethanolic hydrogen chloride solution and recrystallized from ethanol-ethyl acetate to give 2-carbomethoxy-3-chloro-5-(l-piperazinyl)-pyrazine hydrochloride.

C. A solution of 5.8 g. (0.023 mole) of the methyl ester in ml. of IN hydrochloric acid is heated at reflux for 5 hours. After concentrating to a small volume under reduced pressure, the residue is dried further by azeotroping with ethanol. The solid 2-carboxy-3-chloro-5-(1-pipt ι-azinyl )-pyrazine hydrochloride is removed by filtration and dr.

B. A suspension of 5·θ g. '0.018 mole) of the hydrochloride of 2-carboxy-3-chloro-5-(1-pipe azinyl)-pyrazine hydrochloride in 50 ml. of tetralin is stirred a1 reflux for about 1 hour until evolution of carbon dioxide 1s complete. The hot mixture is itracted with two 50 ml. portions of 0.5 N aqueous hydrochloric :id. The aqueous extracts are combined, concentrated id cooled. The precipitated 6-chloro-2-(l-piperazinyl)-pyrazine -drochloride is removed by filtration and dried.

EXAMPLE 41.

Solid 6-methoxy-2-(l-piperazinyl)-pyrazine dihydrochloride, 1,8 g. (0.20 mole) is added in portions over 1 hour to 300 ml. ' rapidly stirred phosphorus oxychloride at 4O-5O°C. After tdition is complete, the mixture is stirred at reflux for 1 hour, loled and concentrated to dryness under reduced pressure. The ssidue is recrystallized first from a small volume of water,. ien from 95% ethanol to give 6-chloro-2-(l-piperazinyl)-pyrazine rdrochloride. (a) A mixture of 100 g. (0.77 mole)of 2-chloro'-pyrazine-l:ide and 17.2 g. (2.0 mole) of anhydrous piperazine in 1 liter ' 2-butanol is heated at reflux for 6 hours. After concentrating ider reduced pressure, the residue is dissolved in a mixture of liter of 2 N sodium carbonate solution and 1 liter of chl'oroirm. The aqueous layer is re-extracted two times with fresh iloroform. The combined-chloroform extracts are dried over ihydrous sodium sulfate, filtered and concentrated. The residue > treated with excess of ethanolic hydrogen chloride and recry;allized from 95% ethanol to give 2-(l-piperazinyl)-pyrazine-l:ide hydrochloride. (b) To 300 ml. of cold redistilled phosphorus oxychloride, .7 (0.10 mole) of 2-(l-piperazinyl)-pyrazine-l-oxide hydrochlorle is added in several portions. The mixture is warmed and ;ter a vigorous reaction has subsided i.s stirred at reflux for ι additional hour. Excess of phosphorus oxychloride is removed ider reduced pressure. The residue is poured cautiously onto )0 g. crushed ice. The solution is neutralized with cold 5N >dium hydroxide solution and extracted with chloroform. The 2979 combined chloroform extracts are dried over anhydrous sodium sulfate, filtered and concentrated. The residual oil is converted to the hydrochloride salt with ethanolic hydrogen chloride and recrystallized from 95$ ethanol to give 6-chloro2-(l-piperazinyl)-pyrazine hydrochloride.

EXAMPLE 42.

To a solution of 21.3 g- (0.10 mole) of 6-chloro-2-(3-oxo1-piperazinyl)-pyrazine in 200 ml. tetrahydrofuran is added 0.12 mole of borane in tetrahydrofuran at 0°C. The mixture is warmed to 25°C. for 3 hours and then to reflux for 1 hour and cooled to 0°C. Glacial acetic acid(0.6 mole) 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 partitioned between CHCl^ and 2 N aqueous sodium hydroxide. After drying the organic phase over anhydrous sodium sulfate, filtering and concentrating, the residue is converted to the hydrochloride salt with anhydrous ethanolic hydrogen chloride. Recrystallization from 95$ ethanol gives 6-chloro-2-(l-piperazinyl)-pyrazine hydrochloride.

EXAMPLE 43.

PREPARATION OF CAPSULE FORMULATION ingredient Milligrams per Tablet 6-Chloro-2-(l'-piperazinyl)pyrazine hydrochloride 6 Starch S7 Magnesium stearate 7 The active ingredient, starch and magnesium stearate are blended together, The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 100 milligrams per capsule. 79 I EXAMPLE 44.

PREPARATION OF TABLET FORMULATION Ingredient Milligrams ; -Chloro-2- (4 ’ -acetyl-1·'piperazinyl)-pyrazine 12 actose 200 arn starch (for mix) so □rn starch (for paste) 50 agnesium stearate 6 The active ingredient, lactose and corn starch (for mix) ?e blended together, The corn starch (for paste) is suspended i water at a ratio of 10 grams of corn starch per 80 milliliters : water and heated with stirring to form a paste. This paste 3 then used to granulate the mixed powders. The wet granules •e passed through a No. 8 screen and dried at 120°F. The dry •anules are passed through a No. 16 screen. The mixture is ibricated with magnesium stearate and compressed into tablets ι a suitable tableting machine. Each tablet contains 12 milliams of active ingredient.

EXAMPLE 45.

PREPARATION OF ORAL SYRUP FORMULATION Ingredient Amount Chloro-2-(l'-piperazinyl)- pyrazine 25 mg. rbitol solution (70% N.F.) 40 ml. dium benzoate 150 mg. .caryl 90 mg. ccharin 10 mg. d Dye (F.D. & Co. No. 2) 10 mg. erry Flavor 50 mg. stilled water qs to 100 ml. - 24 4 2979 The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacant.h, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers Preservatives may include the parabens or sorbic acid and other flavors and dyes may be used in place of those listed above.

EXAMPLE 46.

On the day immediately preceding the test day (control day) the food consumption is measured for groups of from 7 bo 10 rats allowed access to food for only 2 hours per day. On the next day (test day) the rats are injected i.p. with different dose levels of the test compound 3 minutes prior to commencement of the 2-hour feeding period. Food consumption on the test day is then measured and compared (paired t-test) with consumption on the control day. The resu·ts using representative compounds of the present invention are <-t forth in the following table.

Compound of Dose mg/ Example kg i.p.

Grams Eaten on Control Day Grams Eaten on Test Day 1.5 14.2 J. 2.53 7-5- I >.oa 12.0 19.3 + 2.2 14.1 ί 2.2 6.0 15.9 + 2.9 5.5 ί 2.2 3.0 14.0 + 2.3 8.3 ΐ 2.1 6.0 12.3 i 4.6 3.1 i 0.9 Standard Deviation, - 25 79 ILA3MS ir pharmaceutically acceptable salt or ϊί-oxide thereof, where R/ is hydrogen, halogen, trifluoromethyl, alkoxy, dialkylamino or phenylthio, and iv is hydrogen, halogen, or phenyl, with the proviso that a 2 L and R are not both hydrogen.

Claims (3)

1. A compound according to claim 1 wherein R^ is chlorine andis hydrogen. a , ,. A method of preparing’a compound of claim 1 which comprises eacting a pyrazine- of the formula: R 2 , s R l N-'X a here X is halogen, alkylsulfonyl, phenylsulfonyl, lkylsulfinyl or phenylsulfinyl, with piperazine at a temperature f from 15°C. to 90°C. until a substantial amount of compound f claim 1 is obtained. . A method according, to claim 3 in which the reaction takes lace under inert atmosphere for from 0.5 to 6 hours. . A method of preparing 6-chloro-2-(l'-piperazinyl)pyrazine, hat comprises treating a compound of formula: Cl/^N-^X here X is halogen, alkylsulfonyl, phenylsulfonyl, lkylsulfinyl or phenylsulfinyl with piperazine at a temperature - 26 4 2979 in the range 15 to 90 C. ό. A method of preparing 6-chloro-2~(l'-piperazinylJpyrazine, that comprises hydrolysing a compound of formula: I il r~\ cr ' nwhere R^ is a heterocycle, alkanoyl, aroyl, alkoxycarbonyl, a alkenoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, cyano, carbamoyl, N-alkylcarbamoyl, or N-arylcarbamoyl. 7. A method of preparing 6-chloro-2-(l'-piperazinylJpyrazine, that comprises catalytically hydrogenolysing a compound of formula: where R^ is carboaralkoxy, ur aralkyl. 8. A method of preparing O-chioro-2-(l^piperazinylJpyrazine, that comprises chlorinating a compound of formula: :N NH 9. A method of preparing O-chloro-2-(l'-piperazinylJpyrazine, that comprises reducing a compound of formula: ,N 10. NH, Cl NH, or L / Λ N-OH A method of preparing 0-chloro-2-(1'-piperazinylJpyrazine, 20 that comprises cyclizing a compound of formula / / Nil Nil Cl - 27 579 n which X' is a displaceable group or' atom. 1. A method of preparing 6-chloro-2-(i'-piperazinyl)pyrazine, hat comprises reducing the compound of formula: y catalytic hydrogenation or the use of a hydride reducing agent;.

2. A method of preparing 6-chloro-2-(l'-piperazinyl)pyrazine, hat comprises hydrolysing and/or heating a compound of formula: N (CO ? R 6 )n · · · iere n is 1 or 2 and R is hydrogen, alkyl or aralkyl.

3. A method of preparing 6-chloro-2-(l'-piperazinyl)pyrazine, lat comprises chlorinating a compound of formula: iere Y is hydroxy or alkoxy. I·. A method of preparing 6-chloro-2-(l'-piperazinyl)pyrazine, lat comprises chlorinating a compound of formula: A method of preparing 6-chloro-2-(l'-piperazinyl)pyrazine, at comprises reducing a compound of formula: -.28 42979 where Z Is Hg 01 θ’ at l east - otle Z being 0, by catalytic hydrogenation or by means of a hydride reducing agent. 16. A method of preparing a compound as claimed in Claim 1, substantially as hereinbefore described in any one of Examples 1, 3 to 7? 9, 19, 20, 24 and 36 to 42. 17. A compound as claimed in Claim 1, when prepared by a method as claimed in any one of Claims 3 to 10. 18. A method of decreasing food intake in a mammalian species which comprises administering to a host animal an effective amount of a compound of formula: J 4- ,K ΎτΎ < N-- It in which R? is hydrogen, halogen (F, Cl, Br or I), haloalkyl, Cj alkoxy, amino, ? alkylthio, phenylthio, carbamoyl, (C^ alkyl)carbamoyl, (C^ $ alkoxy)carbonyl, g dialkylamino, phenyl, or phenyl substituted by halogen (F, Cl, Br or I), by alkyl or by C !_g alkoxy; R is hydrogen, halogen, C* alkyl, cyano, amino (C^ alkoxy)carbonyl, carbamoyl, alkoxy, C^_ghaloalkyl, phenyl, or phenyl substituted by halogen; •3 R is hydrogen, halogen, C, alkanoylamino, carbamoyl, phenyl or phenyl substitute! by halogen, by C* alkyl or by alkoxy; ,4 R 4 is hydrogen, C alkyl, carboxyl or (C. . alkoxy)carbonyl; 1-3 1 -J and R^ is hydrogen or alkanoyl; or an N—oxide or acid—addition salt of such a compound. 19. A pharmaceutical composition in the form of tablets, troches, pills, capsules, elixirs, suspensions, syrups, wafers or chewing 3 79 gum, comprising a compound as defined in Claim l8 in combination with a pharmaceutically acceptable carrier. 20. A food containing as an ad’ded ingredient a compound as iefined in Claim 18. 21. A composition containing as active ingredient a non-toxic carrier and a compound as claimed in Claim 1, 2 or 17. 22. A composition as claimed in Claim 21 in a pharmaceutical >rally administrable form. 23· A composition as claimed in Claim 22 in the form of tablets, ;ro.ches, pills, capsules, elixirs, suspensions, syrups, wafers >r chewing gum. 14. A composition as claimed in Claim 21, in which the carrier .s a food. 15. A composition as claimed in Claim 19, substantially as tereinbefore described in Example 43, 44 or 45.