Note: Descriptions are shown in the official language in which they were submitted.
15742Y
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BACKGROUND OF THE INVENTION
This invention relates to a new compound having
anorexic activity, to methods of preparing the new compounds,
to pharmaceutical formulations containing the new compounds,
and to methods of administering the anorexic agents to a host
animal. c
Obesity is a fairly common condition and a poten-
tially serious one in view of the correlation between inci-
dence of various diseases and the degree to which a person is -
10 overweight. For example, obese persons succumb statistically
more frequently to cardiovascular renal disease than do
persons of normal weight. Obesity likewise results in higher
death rates from diabetes, nephritis, pneumonia, cirrhosis, --~
appendicitis and postoperative complications. Since obesity
often occurs simply as a consequence of excessive intake of
calories, good management of the condition in these cases can
be achieved by restricting the caloric intake. Frequently,
however, the patient has difficulty in initiating and main- -
taining dietary restrictions, making it necessary to employ
20 anorexigenic drugs as adjuvants to therapy.
Accordingly, it is an object of the present
invention to provide the novel 6-chloro-2-(1'-piperazinyl)-
'
.: ,, , ~ ,
1574~Y
1059~28
1 pyrazine which is an effective, potent and nontoxic
2 anorexic agent. Another object is to provide pharma-
3 ceutical formulations for administration of the anorexic
4 agent. Further objects are to provide methods for pre-
paring the novel compound and for administering the
6 anorexic agent of the present invention to a mammalian
7 host ani~al. `
8 DETAILED DESCRIPTION
9 The piperazinylpyrazine compound of the present
invention has the structural formula:
Cl ~ H
11 The compound of the present invention is pre-
12 pared by reaction of a 2-X-pyrazine of formula I with
13 piperazine.
14 The reaction sequence is as follows:
Cl N X
I 1 II ~ -
X is halogen, Cl_5-
alkylsulfonyl, N ~l ~
phenylsulfonyl, ~ NH
C1_5 alk~lsulfinyl, `'"
phenylsulfinyl III
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1059128
1 The reaction takes place at temperatures
2 rangin~ from about ambient to about 90C., preferably
3 under an inert atmosphere, e.g. N2, He or Ar, until a
4 substantial amount of desired adduct of formula III is
obtained, typically for a period of from about 0.5 to
6 about 6 hours, preferably from about 1 to about 4 hours.
7 Other processes by which 6-chloro-2-(1'-
8 piperazinyl)pyrazine of this invention can be prepared
g are as follows:
I. Removal of Nitrogen Protective groups
Cl ~ N ~ ~ NR5 ______~ Cl ~ N ~ N NH
11 wherein ~ -~
12 Ra is a heterocycle such as 6-chloro-2-pyrazinyl;
13 alkanoyl such as formyl, acetyl; aroyl such as benzoyl or
14 p-methoxybenzoyl; carboalkoxy or carboaryloxy, such as
carbobenzyloxy, carbo-t-butoxy, carbophenoxy, carbovinyl-
16 oxy, cyano; carbamyl, N-alkyl carbamyl, or N-arylcarbamyl;
17 aralkyl such as benzyl; or alkyl such as methyl.
18 Removal of these groups is effected by hydrolysis~
19 in polar solvents in the presence of acid or base or by --
catalytic hydrogenolysis in nonpolar,or polar solvents
21 such as water or alcohols in the presence of catalysts
22 such as Pt, Pd, Ru and oxides thereof at from about 25C. ~`
23 to the reflux temperature.
24 The alkyl groups and aralkyl groups can be
removed by reaction with cyanogen bromide, a carboalkoxy
157~2 ~
1059128
l halide, or a carboaryloxyhalide to give R5 = cyano, carbo-
2 alkoxy, or carboaryloxy, respectively, and subsequent re-
3 moval of these groups as above.
4 II. Chlorination
(~ ~L /~H .HCl 2 ~ L N NH .HCl
The process is effected by passing C12 gas through a solu-
6 tion of the piperazinyl-pyrazine in a solvent such as
7 ~lacial acetic acid or the like at a temperature of from
8 about 0 to about 100C. Other solvents which can be
9 used are aqueous hydrochloric acid, dimethylformamide,
and acetonitrile.
ll III. Reduction of N-hydroxy and N-oxide Intermediates
O
Cl~[~N~L ~NH ~(~LN~NH
O ' ~':'' .
Cl ~ N~L N~OH 1~ N3--N NH
--4--
~ 15742 Y
1059128
1 Suitable reducing agents are tin, zinc, iron, or sulfur-
2 dioxide in inorganic or organic acids; triphenylphosphine,
3 sodium arsenite, ammonium sulfide, sodium dithionite,
4 ferrous oxalate-granulated lead; and catalytic hydrogena-
tion over palladium on carbon, Raney nickel and the like.
6 Suitable solvents include polar solvents such as water,
7 acetic acid, lower alcohols, and the like. The reduction
8 is conducted at from about 0 to about 150C.
9 IV. Formation of the Piperazine Ring
A- ~ ~ XCH2CH
x
~ N ~
Cl N~ NH
wherein X is a displaceable group such as halogen, tosyloxy
11 mesyloxy, hydroxy, amino, and trialkylammonium. In general, ~ -
12 the above process is effected by heating the reactants at .
3 from about 0 to about 250C. in a polar solvent such as
14 water, dimethylformamide, alcohols, and the like in the
presence of base.
B. :~
Cl ~ 2 CH2CH2 ~ ~ N ~
X : - .
C 1~ 3~ N~_~H ' ~
16 wherein X and process conditions are as described in
17 IV A. above
~ 15742 Y
~059lZ8
C.
~ CN hydride or ~ N
Cl ~ N ~ catalyst, H2 ~ N ~ N ~ H
1 Suitable catalysts are Raney nickel, copper-
2 chromium oxide, platinum, palladium and oxides thereof in :~
3 a polar solvent such as a~ueous acid, alcohol and the like
4 or hydrides such as borane, lithium aluminum hydride in a
nonpolar solvent such as tetrahydrofuran or ethyl ether.
6 The reactions are run at a temperature of from about -70C.
7 to about 300C. and a pressure of from about 1.0 to 300
8 atmospheres.
9 V. Removal of Other Groups
(CO2R )n
N ~ N~ NH Cl ~ N N\__J H
n = 1-2; R6 = H, alkyl, aralkyl.
The removal is effected by hydrolysis in the
11 presence of acid or base in a polar solvent such as water,
12 lower alcohols, glymes, and the like, at a temperature of
13 from about 0 to about 150C.; and/or by heating without sol-
14 vent or in solvents such as hydrocarbons such as tetralin,
aromatic hydrocarbons, and substituted aromatic solvents
16 such as chlorobenzene, nitrobenzene, and the like, at a
17 temperature of from about 100 to about 300C.
8 Vl. ment duction of Chlorine by Displacement or Rearrange-
A- N Chlorinating ~ ~
~ ~ 3 agent
Y is hydro~y or alkoxy, and the chlorinating agent
21 is BCl, POC13, PC15, or PC13
--6--
-~ 15742 Y
1059128
1 The chlorinating agent may be also the solvent.
2 Reaction temperatures are from 25C. to reflux temperature
3 of the solvent. Mixtures of the above reagents may also
4 be used.
B.
(~N~I~NI~ N~N}I
Reaction conditions are the same as those given above.
C. O
~ Cl~ N ~ N 3 H
6 Benzenesulfonyl chloride is usually used for this reaction
7 under the same conditions as described above.
8 VII. ~eduction of Amides and Imides
Z Z
hydride or ~ N ~
H2, catalyst N NH
Z ',' -:
Z = H2 or 0 ~ -
g Suitable reducing agents include hydrides such as borane
10 or lithium aluminum hydride and the like; or catalysts `
11 such as molybdenum sulfide, copper chromium oxide,
12 ruthenium, platinum oxide, and the like. Suitable sol-
13 vent8 for catalytic hydrogenation include polar solvents -~
14 such as water, lower alcohols, glymes, dioxane, and the
like. Reduction with hydrides, however, is conducted in
16 aprotic solvents, such as ethyl ether, tetrahydrofuran,
17 and the like. The reaction temperature is from about -70C.
18 to about 250C. at a pressure of from about 1.0 to about
19 300 atmospheres.
,
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1 The compound of the present invention may be
2 administered as an anorexic agent to mammalian species, - -
3 e.g. rats and mice, in amounts ranging of from about 0.01
4 to about 20 mg per kg. of body weight, preferably from
about 0.1 to about 10 mg. per kg. of body weight in a
6 single dose or in 2 to 4 divided doses.
7 The compound of the present invention in the
8 described dosages may be administered orally; however,
9 other routes such as intraperitoneally, subcutaneously,
intramuscularly, or intravenously may be employed.
11 The active compound of the present invention is
12 orally administered, for example, with an inert diluent or -
13 with an assimilable edible carrier, or it may be enclosed
14 in hard or soft gelatin capsules, or it may be compressed
into tablets, or it may be incorporated directly with the
16 food of the diet. For oral therapeutic administration,
17 the active compound of this invention may be incorporated
18 with excipients and used in the form of tablets, troches,
19 capsules, elixirs, suspensions, syrups, wafers, chewing
gum, and the like. The amount of active compound in such
21 therapeutically useful compositions or preparations is
22 such that a suitable dosage will be obtained.
23 The tablets, troches, pills, capsules, and the
24 like, may also contain the following: a binder such as
gum tragacanth, acacia, corn starch or gelatin; an ex-
26 cipient such as dicalcium phosphate; a disintegrating agent
27 such as corn starch, potato starch, alginic acid and the
28 like; a lubricant such as magnesium stearate, and a `
29 sweetening agent such as sucrose, lactose or saccharin may
--8--
` ~ 15742 Y
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1 may be added or a flavoring agent such as peppermint, oil
2 of wintergreen, or cherry flavoring. When the dosage
3 unit form is a capsule, it may contain in addition to
4 materials of the above type a liquid carrier such as a
fatty oil. Various other materials may be present as
6 coatings or to otherwise modify the physical form of the
7 dosage unit, for instance, tablets, pills, or capsules
8 may be coated with shellac, sugar, or both. A syrup or
9 elixir may contain the active compound, sucrose as a
sweetening agent, methyl and propyl parabens as preserva-
11 tives, a dye and a flavoring such as cherry or orange
12 flavor. Of course, any material used in preparing any
13 dosage unit form should be pharmaceutically pure and sub-
14 stantially non-toxic in the amounts employed.
As to the pharmaceutically acceptable salts,
16 those coming within the purview of this invention include
17 the pharmaceutically acceptable acid~addition salts. Acids
18 useful for preparing these acid-addition salts include,
19 inter alia, inorganic acids, such as the hydrohalic acids
(e.g., hydrochloric and hydrobromic acid), sulfuric acid,
21 nitric acid, and phosphoric acid, and organic acids such
22 as maleic, fumarlc, tartaric, citric, acetic, benzoic, 2- ~-
23 acetoxybenzoic, salicylic, succinic acid, theophylline,
24 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic,
or methanesulfonic.
26 The compound of the present invention show
27 enhanced effectiveness and less toxicity than known
28 anorexic agents. The 6-chloro-2-(1'-piperazinyl)pyrazine
29 compound, for examp~e, is 10 times as effective as fen-
fluramine in the cat following oral administration.
15742 ~
lOS91Z8
1 In addition to the anorexic activity described
2 above, the novel compound of this invention pharmaco-
3 logically influences serotonin levels in a manner that
4 suggests it is also useful as an antidepressant, anti-
hypertensive, analgesic and sleep inducing agent. For
6 these purposes, the same routes of administration, and
7 pharmaceutical formulations as described above would be
8 employed.
9 The following examples illustrate the present
invention without, however, limiting the same thereto.
11 Unless otherwise indicated, all temperatures are expressed
12 in degrees Celsius.
13 EXAMPLE 1
14 6-Chloro-2(1'-piperazinyl)pyrazine hydrochloride
2,6-Dichloropyrazine (0.10 mole) is added to
16 20 g. piperazine in 200 ml. acetonitrile and the mixture
17 refluxed 1.5 hr. under N2. The mixture is concentrated in
18 vacuo and the residue partitioned between lN aqueous NaOH
19 and benzene. The combined benzene extracts are washed with
lN aqueous NaOH, dried over MgSO4, filtered and concen-
21 trated _ vacuo to a yellow oil which is dissolved in
22 200 ml. absolute ethanol containing 10 ml. of cold, satur-
23 ated anhydrous ethanolic HCl. The precipitated hydrochlor-
24 ide is recrystallized from 95% ethanol to give faintly
yellow needles, m.p. 350 dec.
26 ExAMæLE 2
27 6-Chloro-2-(1'-piperazinyl)-pyrazine_l_oxide
28 2-Chloropyrazine (0.1 mole) is added to a
29 solution of 0.3 mole trifluoroperacetic acid in CH2C12
--10--
\
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1059128
1 (300 ml.) at 0. The mixture is stirred 4 hours at 0,
2 4 hours at 25 and finally at reflux for 4 hours. The
3 resulting solution is washed with saturated aqueous NaCl
4 solution and then saturated aqueous Na2CO3 solution and
concentrated in vacuo to give crude 2-chloropyrazine-1,4-
6 dioxide.
7 The crude 2-chloropyrazine-1,4-dioxide, 20 g.,
8 is stirred 4 hours with 50 ml. benzenesulfonyl chloride
9 at 50 under N2 and quenched on a mixture of ice, pyridine
and saturated NaCl solution. The precipitated 2,6-di-
11 chloropyrazine-l-oxide is collected by filtration and ~ --
12 converted to the title compound by reaction with piper-
13 azine as in Example 1.
14 EXAMPLE 3
.. .:
6-Chloro-2-(1'-piperazinyl)-pyrazine-4-oxide
16 Similarly to Example 2, 2,6-dichloropyrazine
17 is converted to the 4-oxide with 1.8 molar equivalents of
18 trifluoroperacetic acid. The crude 2,6-dichloropyrazine- -
19 4-oxide is converted to the title compound by reaction
20 with piperazine as in Example 1. ;
'.~ '
21 The following examples describe alternate syn-
22 thetic routes for the preparation of 6-chloro-2-(1- -
23 piperazinyl)pyrazine hydrochloride.
24 EXAMPLE 4
P.. From N,N'-bis-(6-chloro-2-pyrazinyl)-piperaZine
26 (a) A mixture of 15.0 g. (0.10 mole) of 2,6-
27 dichloropyrazine, 4.3 g. (0.050 mole) of anhydrous pipera-
28 zine, and 20.4 g. (0.20 mole) of triethylamine in 200 ml.
--11--
15742 ~
105~1~8
1 n-butanol is heated at reflux for 3 hours. The mixture
2 is concentrated under reduced pressure and the residue
3 partitioned between 1 N aqueous sodium hydroxide solution
4 and benzene. The combined benzene extracts are washed
with water, dried over anhydrous sodium sulfate, filtered
6 and concentrated to N,N'-bis-(6-chloro-2-pyrazinyl)-
7 piperazine.
8 (b) The N,N'-bis-(6-chloro-2-pyrazinyl)-pipera-
9 zine from the preceding step is stirred at reflux for 8
hours in 500 ml. of concentrated hydrochloric acid. After
11 concentrating to dryness under reduced pressure, the residue
12 is recrystallized from 95~ ethanol to give 6-chloro-2-(1-
13 piperazinyl)-pyrazine hydrochloride.
/ /
/
/
/
-12- r
~ ~ 15742 Y
105~28
1 B. _om 2-chloro-6-(4-form~-1-piperazinyl)-pyrazine
2 (a) 2,6-Dichloropyrazine, 7.5 g. (0.050 mole),
3 is added to 10 g. of N-formylpiperazine in 100 ml. of
4 acetonitrile and the mixture heated at reflux for 2 hours. -
After concentrating under reduced pressure, the residue is
6 partitioned between 2 N sodium carbonate solution and
7 benzene. The benzene layer is removed, washed with water,
8 dried over anhydrous magnesium sulfate, filtered and con-
9 centrated. The residue is essentially pure 2-chloro-6- ~ -
(4-formyl-1-piperazinyl)-pyrazine.
11 (b) The N-formyl derivative, 2.0 g. (8.82 mmole)
12 is added to 100 ml. concentrated hydrochloric acid and
13 stirred at reflux for 10 hours. The solution is concen-
14 trated to a small volume, diluted with water, and cooled
to give 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride.
16 C. From 6-c~loro-2-( ~
17 (a) A mixture of 30 g. (0.20 mole) of 2,6- ;
18 dichloropyrazine and 40 g. (0.40 mole) of N-methylpipera-
19 zine in 200 ml. of n-butanol is stirred at reflux for 6
hours. The reaction mixture is concentrated under reduced
21 pressure. After adding 200 ml. of saturated sodium car- -~
22 bonate solution to the residue, product is extracted into
23 benzene. The benzene extract is washed with water, dried
24 (magnesium sulfate), filtered and concentrated to give
25 6-chloro-2-(4-methyl-1-piperazinyl)-pyrazine. ~-~
26 (b) The 4-methylpiperazine derivative from the
27 previous step is treated with 0.2 mol of cyanogen bromide
28 in toluene at 0 and the resulting mixture heated 4 hours
29 at reflux and cooled. The mixture is concentrated in vacuo
and treated with 100 ml. of 6 N aqueous hydrochloric acid
-13-
1 5 / ~ ~ Y
1059~8
1 for 18 hours at reflux and cooled. The precipitated
2 product is recrystallized further from 95% ethanol to give
3 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.
4 EXAMPLE 5
A stream of chlorine gas is bubbled through a
6 well stirred solution of (1.0 mole) of 2-(1-piperazinyl)-
7 pyrazine hydrochloride in 1 1. of glacial acetic acid at
8 100C. until reaction is complete. After concentrating
9 under reduced pressure, the residue is dissolved in 600 ml.
of 0.5 N aqueous hydrochloric acid, seeded with an
11 authentic sample of 6-chloro-2-(1-piperazinyl)-pyrazine
12 hydrochloride, concentrated and cooled. The precipitated
13 solid is recrystallized further from 95% ethanol to give
14 pure 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride.
EXAMPLE 6
16 The 1- or 4-N-oxide of 6-chloro-2-(1-pipera-
17 zinyl)-pyrazine, 21.5 g. (0.100 mole), is dissolved in
18 200 ml. of glacial acetic acid. The solution is warmed to
19 85C., saturated with anhydrous hydrogen chloride gas and
20 treated with a stream of sulfur dioxide at this tempera- ~-
21 ture for 1 hour. The acetic acid is removed under reduced
22 presssure and the residue recrystallized from 95% ethanol
23 to give 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.
24 EXAMPLE 7
A. A mixture of 5.8 g. (0.045 mole) of 2-amino-6-
26 chloropyrazine, 4.68 g. (0.015 mole) of bis-(2-bromoethyl)-
27 amine hydrobromide and 25 ml. of 2-butanone is heated at
28 reflux for 10 hours. After cooling at 0C. for 15 hours,
29 the mixture of hydrobromide salts is removed by filtration
and dissolved in 25 ml. water. The aqueous solution is
s / ~ y
10591~8
1 made basic to pH 10 with 10% sodium hydroxide solution.
2 The crude product is extracted into 100 ml. benzene and
3 washed with two 25 ml. portions of water. The benzene
4 extract is dried over anhydrous magnesium sulfate, filtered
and concentrated to give the free base of 6-chloro-2-(1-
6 piperazinyl)-pyrazine. Conversion to the hydrochloride
7 salt with anhydrous ethanolic hydrogen chloride and re-
8 crystallization from 95% ethanol gives 6-chloro-2-(1-
9 piperazinyl)-pyrazine hydrochloride.
B. (a) A mixture of 15.0 g. (0.10 mole) of 2,6-
11 dichloropyrazine and 19.0 g. (0.20 mole) of iminodiaceto-
12 nitrile in 200 ml. of 2-butanol is heated at reflux for
13 6 hours. After concentrating under reduced pressure at
14 55C., the residue is partitioned between 200 ml. of 2 N
sodium carbonate solution and 200 ml. of benzene. The
16 aqueous layer is re-extracted with 100 ml. benzene. The
17 combined benzene extracts are dried (sodium sulfate),
18 filtered and concentrated under reduced pressure at 45C.
19 to give 6-chloro-2-(biscyanomethylamino)-pyrazine.
(b) To a solution of 2.5 g. (0.012 mole) of 6-
21 chloro-2-(biscyanomethylamino)-pyrazine in 500 ml. tetra-
22 hydrofuran is added 0.048 mole of borane in tetrahydro-
23 furan at 0C. The mixture is warmed to 25C. for 3 hours
24 and then to reflux for 1 hour and cooled to 0C. Glacial
acetic acid (0.072 mol) is added at 0 and the mixture
26 stirred at 0-28 until hydrogen evolution ceases. The
27 solvent is removed in vacuo and the residue partitioned
28 between CHC13 and 2 N aqueous sodium hydroxide. After
29 drying the organic phase over anhydrous sodium sulfate,
filtering and concentrating, the residue is converted to
` 15742 Y
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1~59128
1 the hydrochloride salt with anhydrous ethanolic hydrogen
2 chloride. Recrystallization from 95% ethanol gives 6-
3 chloro-2-(1-piperazinyl)-pyrazine hydrochloride.
4 EXAMPLE_8
A. A suspension of 18.7 g. (0.10 mole) of 5-amino-
6 3-chloro-2-carbomethoxypyrazine in a mixture of 114 ml.
7 48% hydrobromic acid and 30 ml. acetic acid is cooled to
8 0C., stirred and treated with a solution of 15 ml. bromine
9 in 30 ml. acetic acid over a period of 45 minutes. A
solution of 17.4 g. (0.10 mole) of sodium nitrite in
11 40 ml. water is then added while maintaining a reaction
12 temperature of 0C. Stirring is continued for 30 minutes
13 and excess bromine is destroyed by the dropwise addition of
14 150 ml. of a 30% aqueous solution of sodium bisulfite.
The product is removed by filtration, washed with water
16 and recrystallized from an ethyl acetate-hexane mixture to
17 give 5-bromo-3-chloro-2-carbomethoxypyrazine.
18 B. A mixture of 10.0 g. (0.040 mole) of 5-bromo-3-
19 chloro-2-carbomethoxypyrazine, 6.9 g. (0.080 mole) of an-
hydrous piperazine and 100 ml. acetonitrile is heated at
21 reflux for 2 hours. The mixture is concentrated under
22 reduced pressure and the residue partitioned between 2 N
23 sodium carbonate solution and benzene. The benzene ex- ~ i
24 tract is washed with water, dried (anhydrous magnesium
sulfate), filtered and concentrated under reduced pressure.
26 The residue is converted to the hydrochloride salt with
27 ethanolic hydrogen chloride solution and recrystallized
28 from ethanol-ethyl acetate to give 2-carbomethoxy-3-chloro-
29 5-(1-piperazinyl)-pyrazine hydrochloride.
C. A solution of 5.8 g. (0.023 mole) of the methyl
31 ester in 50 ml. of 1 N hydrochloric acid is heated at
-16-
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1 reflux for 5 hours. After concentrating to a small
2 volume under reduced pressure, the residue is dried
3 further by azeotroping with ethanol. The solid 2-carboxy-
4 3-chloro-5-(1-piperazinyl)-pyrazine hydrochloride is re-
moved by filtration and dried.
6 D. A suspension of 5.0 g. (0.018 mole) of the hydro-
7 chloride of 2-carboxy-3-chloro-5-(1-piperazinyl)-pyrazine
8 hydrochloride in 50 ml. of tetralin is stirred at reflux
9 for about 1 hour until evolution of carbon dioxide is com-
plete. The hot mixture is extracted with two 50 ml. por-
11 tions of 0.5 N aqueous hydrochloric acid, The aqueous
12 extracts are combined, concentrated and cooled. The pre-
13 cipitated 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride
14 is removed by filtration and dried.
EXAMPLE 9
16 A. Solid 6-methoxy-2-(1-piperazinyl)-pyrazine di- ~--
17 hydrochloride, 38.8 g. (0.20 mole) is added in portions
18 over 1 hour to 300 ml. of rapidly stirring phosphorous
19 oxychloride at 40-50C. After addition is complete, the
mixture is stirred at reflux for 1 hour, cooled and con-
21 centrated to dryness under reduced pressure. The residue
22 is recrystallized first from a small volume of water, then
23 from 95% ethanol to give 6-chloro-2-(1-piperazinyl)-
24 pyrazine hydrochloride. ~
25 B. (a) A mixture of 100 g. (0.77 mole) of 2-chloro- ~ -
26 pyrazine-l-oxide and 17.2 g. (2.0 mole) of anhydrous
27 piperazine in 1 liter of 2-butanol is heated at reflux
28 for 6 hours. After concentrating under reduced pressure,
29 the re6idue is dissolved in a mixture of 1 liter of 2 N
sodium carbonate solution and 1 liter of chloroform.
-17-
,', ' . : , . . :
..
` 15742 y
l~S9~Z8
1 The aqueous layer is re-extracted two times with fresh
2 chloroform. ~he combined chloroform extracts are dried
3 over anhydrous sodium sulfate, filtered and concentrated.
4 The residue is treated with excess ethanolic hydrogen
chloride and recrystallized from 95~ ethanol to give 2-
6 (l-piperazinyl)-pyrazine-l-oxide hydrochloride.
7 (b) To 300 ml. of cold redistilled phosphorous
8 oxychloride, 21.7 g. (0.10 mole) of 2-(1-piperazinyl)-
9 pyrazine-l-oxide hydrochloride is added in several portions.
The mixture is warmed and after a vigorous reaction has
11 subsided is stirred at reflux for an additional hour.
12 Excess phosphorous oxychloride is removed under reduced
13 pressure. The residue is poured cautiously onto 200 g.
14 crushed ice. The solution is neutralized with cold 5 N
sodium hydroxide solution and extracted with chloroform.
16 The combined chloroform extracts are dried over anhydrous
17 sodium sulfate, filtered and concentrated. The residual
18 oil is converted to the hydrochloride salt with ethanolic
19 hydrogen chloride and recrystallized from 95% ethanol to
give 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride.
21 EXAMPLE 10
. _ :
22 To a solution of 21.3 g. (0.10 mole) of 6- -
23 chloro-2-(3-oxo-1-piperazinyl)-pyrazine in 200 ml. tetra-
24 hydrofuran is added 0.12 mole of borane in tetrahydrofuran
at 0C. The mixture is warmed to 25C. for 3 hours and
26 then to reflux for 1 hour and cooled to 0C. Glacial
27 acetic acid (0.6 mole) is added at 0C. and the mixture is
28 stirred at 0-25C. until hydrogen evolution ceases. The
29 solvent is removed in vacuo and the residue partitioned
30 between CHC13 and 2 N aqueous sodium hydroxide. After '~
18_ :
J ~
"--~
1~59128
1 drying the organic phase over anhydrous sodium sulfate,
2 filtering and concentrating, the residue is converted to
3 the hydrochloride salt with anhydrous ethanolic hydrogen
4 chloride. Recrystallization from 9596 ethanol gives 6-
chloro-2-(1-piperazinyl)-pyrazine hydrochloride.
6 EXAMPLE 11:
7 PREPARATION OF CAPSULE FORMULATION
. . .
8 Milligrams per
9 Ingr d ent Tablet
10 6-Chloro-2~(1'-piperazinyl)-
11 pyrazine hydrochloride 6
12 Starch 87
13 Magnesium stearate 7
14 The active ingredient, starch and magnesium
15 stearate are blended together. The mixture is used to
16 fill hard shell capsules of a suitable size at a fill
17 weight of 100 milligra~s per capsule.
18 E~MPLE 12
19 PREPAR?TION OF TABLET FORMULATION
Milligrams per
21 _gredient _ Tablet
22 6-Chloro-2-(l'- 12
23 piperazinyl)-pyrazine
24 Lactose 200 -
25 Corn starch (for mix) 50
26 Corn starch (for paste) 50
27 Magnesium stearate 6 -
--19--
1059128
The active ingredient, lactose and corn
2 starch (for mix) are blended together. The corn starch
3 (for paste) is suspended in water at a ratio of 10
4 grams of corn starch per 80 milliliters of water and
5 heated with stirring toform a paste. This paste is then
6 used to granulate the mixed powders. The wet granules are
7 passed through a No. 8 screen and dried at 120F. The
8 dry granules are passed through a No. 16 screen. The
9 mixture is lubricated with magnesium stearate and com-
10 pressed into tablets in `a suitable tableting machine.
11 Each tablet contains 12 milligrams of active ingredient.
12 EXAMPLE 13
13 PREPARATION OF ORAL SYRUP FORMULATION
_
14 In~redient Amount
6-Chloro-2-(l~-piperazinyl)- t
16 pyrazine 25 mg.
17 Sorbitol solution (70% N.F.)40 ml.
18 Sodium benzoate 150 mg.
19 Sucaryl 90 mg.
Saccharin 10 mg.
21 Red Dye (F.D. & Co. No. 2)10 mg.
22 Cherry Flavor 50 mg.
23 Distilled water qs to 100 ml.
24 The sorbitol solution is added to 40 milliliters
25 of distilled water and the active ingredient is suspended
26 therein. The sucaryl, saccharin, sodium benzoate, flavor
27 and dye are added and dissolved in the above solution.
28 The volume i9 adjusted to 100 milliliters with distilled
29 water.
Other ingredients may replace those listed in
31 the above formulation. For example, a suspending agent
--20--
1 5 / 4 ~ Y
10591;~8
1 such as bentonite magma, tragacanth, carboxymethyl-
2 cellulose, or methylcellulose may be used. Phosphates,
3 citrates or tartrates may be added as buffers. Pre-
4 servatives may include the parabens, sorbic acid and the
like and other flavors and dyes may be used in place of
6 those listed above.
7 EXAMPLE 14
8 On the day immediately preceding the test day
9 (control day) the food consumption is measured for groups
of from 7 to 10 rats allowed access to food for only 2
11 hours per day. On the next day (test day) the rats are
12 injected i.p. with different dose levels of the test com-
13 pound 3 minutes prior to commencement of the 2-hour feeding
14 period. Food consumption on the test day is then measured
and compared (paired t-test) with consumption on the
16 control day. The results are set forth in the following
17 table.
Grams Grams
18 Dose mg./ Eaten on Eaten On
19 kg. i.p. Control Day Test Day
20 1.5 14.2 + 2.5a 7.5 + 2.0a
21 a Standard Deviation.
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