BE824005A - PROCESS FOR THE PRODUCTION OF A PYRAZINE DERIVATIVE - Google Patents

Description

       

   <EMI ID = 1.1>

  
 <EMI ID = 2.1>

  
new pyrazine derivative and more particularly a process for preparing a new pyrazine derivative represented by formula III -

  

 <EMI ID = 3.1>


  
wherein R <1> and R2 which may be similar or different each represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a phenyl-lower alkoxy group, a phenoxy group, a mercapto group , a lower alkyl group, a phenyl-lower alkylthio group, a phenylthio group, an amino group, a substituted amino group, a group

  
 <EMI ID = 4.1>

  
R represents a lower alkoxy group, R, R and R, which may be the same or different, each represents a

  
hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl-lower alkyl group or a phenyl group and A represents a lower alkylene group; said R4 and A, said

  
 <EMI ID = 5.1>

  
5- or 6-membered nitrogen-containing heterocyclic ring which may additionally contain a hetero atom together with the nitrogen atom and their pharmaceutically acceptable non-toxic salts.

  
Since the compound of the present invention has an activity

  
 <EMI ID = 6.1>

  
sand as an excellent medicament as an anti-emetic agent and as an agent for treating chronic or acute gastric disorders.

  
In the compound of the present invention represented by

  
 <EMI ID = 7.1>

  
hydrogen; a halogen atom such as a chlorine atom, a bromine atom, etc; a hydroxy group; a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc; a phenyl-lower-alkoxy group such as <EMI ID = 8.1>

  
lower alkylthio group such as methylthio group, ethylthio group, butylthio group, etc; a phenyl-lower alkylthio group such as a benzylthio group, etc; a phenylthio group;

  
 <EMI ID = 9.1>

  
amino, an acetylamino group, a benzylamino group, a benzoylamino group, a pyrrolidino group, a piperidino group, a

  
 <EMI ID = 10.1>

  
zino, etc; a lower alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a

  
 <EMI ID = 11.1>

  
likewise R <3> is typically an inferior alkoxy group.

  
 <EMI ID = 12.1>

  
bites a hydrogen atom; a lower alkyl group, such as a methyl group, an ethyl group, an isopropyl group, a butyl group, etc; a cycloalkyl group, such as a cyclopentyl group, a cyclohexyl group, etc; a phenyl-lower-alkyl group such

  
 <EMI ID = 13.1>

  
phenyl. A typically represents a lower alkylene group, such as a methylene group, an ethylene group, a group.

  
 <EMI ID = 14.1>

  
ethylene, an ethyl-2-ethylene group, etc. In the compound of the present invention represented by the general formula (III), the lower alkyl group, the phenyl-lower alkyl group, and the phenyl group, may each be further substituted by a hydroxy group, an ipercapto group, a group amino or the like.

  
 <EMI ID = 15.1>

  
forming a 5 or 6 membered nitrogen-containing heterocyclic ring which may additionally contain a heteroatom such as a nitrogen atom, an oxygen atom together with the nitrogen atom and as such heterocyclic rings containing nitrogen, mention may be made of a pyrrolidine nucleus, a pireridine nucleus, a piperazi- nucleus

  
 <EMI ID = 16.1>

  
as a group represented by:

  

 <EMI ID = 17.1>


  
there may be mentioned the diethylamino-3-pyrrolidino group, the group

  
 <EMI ID = 18.1>

  
piperidino, diethylamino-4-piperidino group, diethylamino-3-morpholino group, (ethyl-1-pyrrolidinyl-2-

  
 <EMI ID = 19.1>

  
pyrrolidinyl-2-methyl) amino, the group (benzyl-1-pyrrolidinyl-2-

  
 <EMI ID = 20.1>

  
amino.

  
In the preferred pyrazine derivatives which are the subject of the present invention, R is an amino group or a substituted amino group; R2 is a halogen atom, R3 is a lower alkoxy group; R 'is a hydrogen atom or a lower alkyl group, R5 and R6 which may be the same or different each represent a lower alkyl group, a cycloalkl group, a phenyl-lower alkyl group or a phenyl group; A is a group

  
 <EMI ID = 21.1>

  
can form a 5 or 6 membered heterocyclic ring containing nitrogen which may additionally contain a hetero atom together with the nitrogen atom.

  
Typical examples of the compounds of the present invention are given below:

  
 <EMI ID = 22.1> <EMI ID = 23.1>

  
methoxy-3-pyrazine-carboxylic-2;

  
 <EMI ID = 24.1> <EMI ID = 25.1> <EMI ID = 26.1>

  
is particularly preferable.

  
As non-toxic pharmaceutically acceptable salts of the compound of the present invention represented by formula III, mention may be made of its acid addition salts with a mineral acid such as

  
 <EMI ID = 27.1>

  
nitric acid, phosphoric acid, etc. and with an organic acid such as citric acid, acetic acid, lactic acid

  
 <EMI ID = 28.1>

  
damage to the digestive organs (eg feeling of heavy stomach, anorexia, postponement, nausea, vomiting, etc.) caused by gastritis, gastroatonia, etc.

  
 <EMI ID = 29.1>

  
gastric activity and further, as the compound has greater antiemetic activity than chloropromazine which has been widely used as an antiemetic agent, this compound was <EMI ID = 30.1>

  
 <EMI ID = 31.1>

  
As a result of various investigations starting from this technical level, it has been found that the compounds of the present invention represented by the general formula III have a gastric activity stimulating effect completely free of catalepsy and a potent antiemetic activity compared to to that of metoclopramide.

  
That is, since the coirposés of the present invention have a more potent anti-emetic activity than metoclopramide and do not exhibit catalepsy, which is a defect

  
 <EMI ID = 32.1>

  
tive and strong. In addition, since the compounds of the present invention have a stimulating effect of gastric activity, they can suppress the unpleasant symptoms of the digestive organs (for example the feeling of heavy stomach, anorexia, postponement, nausea , vomiting etc.) caused by gastritis, gastroatonia, etc. In addition, the compounds of the present invention

  
 <EMI ID = 33.1>

  
medicines to treat acute or chronic stomach problems. In addition, as the compounds of the present invention also block a conditioned cancellation response to an activity.

  
 <EMI ID = 34.1>

  
or thicbenzamide represented by the formula:

  

 <EMI ID = 35.1>


  
in which R represents a cycloalkyl group, a group

  
 <EMI ID = 36.1>

  
 <EMI ID = 37.1>

  
senses halogen atom, lower alkyl group or lower alkoxy group, nitro group, nonoalkyllamino group, <EMI ID = 38.1>

  
sulfur atom and n represents 0-3, has anti-emetic activity exhibiting low cataleptic activity, i.e. acting selectively, but the patent does not disclose whether the compound has an activity stimulating effect gastric.

  
It is heretofore known that compounds having a benzene ring such as metoclopramide and the aforementioned compound have anti-eriotic activity, but with regard to compounds having a pyrazine ring, it is known that they only have diuretic activity ( as described in the United States patent

  
 <EMI ID = 39.1>

  
It is the unexpected fact that the compounds of the present invention comprising a pyrazine nucleus have a strong anti-emetic activity which has just been discovered.

  
In Experiment I described below, the activity was tested.

  
 <EMI ID = 40.1>

  
invention and metoclopramide and the safety margins of these were discussed.

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
Each of the samples tested was administered to a dog by subcutaneous injection, then 0.1 mg / kg of apomorphine was administered to the dog by subcutaneous injection after 30 minutes and the frequency of vomiting was then measured for 30 minutes. minutes (each dog was used only once). It was calculated from the frequency of vomiting, the inhibition ratio and from the relationship between the amount of sample

  
 <EMI ID = 43.1>

  
mined. The activity of the drug was assessed according to the values

  
 <EMI ID = 44.1> b) Acute toxicity:

  
Each of the samples tested was injected into a mouse by intravenous tail injection at a rate of 0.1 ml /
10 g / 10 seconds by increasing and decreasing method. The <EMI ID = 45.1>

  
The results are shown in Table I.

  

 <EMI ID = 46.1>


  
From the results given in Table I, it will be assumed that the compounds of the present invention have an activity

  
 <EMI ID = 47.1>

  
In Experiment II described below, the antiemetic activity and the cataleptic activity of the compounds of the present invention and of metoclopramide were tested and the selection

  
 <EMI ID = 48.1>

  
compared with each other.

  
 <EMI ID = 49.1>

  
1) Subcutaneous administration: similar to experience

  
(I-a)

  
2) Oral administration:

  
Each of the samples tested was mixed with lake-

  
 <EMI ID = 50.1>

  
Orally to a dog, 0.1 ng / kg of apomorphine was administered to the dog by subcutaneous injection after 90 minutes and then the frequency of vomiting was measured during the next 30 minutes. (each dog was used only once).

  
 <EMI ID = 51.1>

  
manner as described in experiment I-a.

  
b) Cataleptic activity:

  
According to the Courvoisier method (Courvoisier, S. DURCOT, R. & Jolou, L, (1957), Psychotropic drugs (Ed. Garattini, S and Ghetti, V.) p. 373, Else vier Company, Amsterdam, London, NewYork , Princeton) the four limbs of a rat were placed on four rubber stoppers and when the rat could hold

  
 <EMI ID = 52.1>

  
positive. Catalepsy was measured every 30 minutes until
240 minutes after subcutaneous administration of the sample. The sample which produced a positive response in the rat at least once was considered known to be positive in the cataleptic test.

  
From the relation between the positive response and the

  
 <EMI ID = 53.1>

  
results are given in Table II.

  

 <EMI ID = 54.1>


  
The symbol * means that catalepsy was not observed at all for 100 mg / kg and a higher amount of sample

  
 <EMI ID = 55.1>

  
From the results shown in Table II, it will be understood that the compounds of the present invention have

  
 <EMI ID = 56.1>

  
and that they exhibit no cataleptic activity, the compounds have a selective and strong anti-emetic activity. Also, we

  
 <EMI ID = 57.1>

  
2 of the compounds of the present invention show excellent activity efficiency of 2.0 and 2.3 respectively and show good absorption coefficient when administered orally.

  
In the following Experiment III, the compounds of the present invention will be compared with metoclopramide with regard to the effect of stimulating gastric motility.

  
 <EMI ID = 58.1>

  
After anesthetizing a dog put on the diet overnight by an intravenous injection of 30 rg / kg of pentobarbital, each of the samples tested was injected intravenously and the spontaneous activity of the estcrac was then recorded.

  
 <EMI ID = 59.1>

  
(1966)). The results are given in Table III. More,

  
 <EMI ID = 60.1>

  
that the stimulated motility of the stomach continued for more than 20 minutes.

  

 <EMI ID = 61.1>


  
From the results shown in Table III it will be understood that the compounds of the present invention have an effect

  
 <EMI ID = 62.1>

  
The compound of the present invention represented by formula III can be prepared by reacting a pyrazinecarboxylic acid represented by formula 1:

  

 <EMI ID = 63.1>
 

  
 <EMI ID = 64.1>

  
fcrr.ule III where reactive derivatives thereof with a derivative

  
 <EMI ID = 65.1>

  

 <EMI ID = 66.1>


  
 <EMI ID = 67.1>

  
in formula III.

  
 <EMI ID = 68.1>

  
shown by formula I, there may be mentioned an acid halide such as an acid chloride, an acid bromide, etc; an acid azide, an ester such as methyl ester, ethyl ester, p-nitrophenyl ester, p-chlorophenyl ester, etc; a symmetrical acid anhydride; a mixed acid anhydride such as an alkyl carbonate mixed with an acid anhydride prepared by reacting a haloalkyl carbonate (e.g. chloro carbonate

  
 <EMI ID = 69.1>

  
 <EMI ID = 70.1>

  
acid mixture prepared by reacting an acid (eg an alkylphosphoric acid, an alkylphosphoric acid and sulfuric acid) or reactive derivatives thereof and pyrazinecarboxylic acid of formula I; and an active amide such as imidazoli-

  
 <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
reacting an acid hydrazide of pyrazinecarboxylic acid of formula I and acetylacetone.

  
For the practical production of the compound of the present invention, the pyrazinecarboxylic acid of the formula I or the reactive derivative thereof can be reacted with an equimolar amount or a slightly molar excess amount of the amine derivative of the formula II. .

  
When the pyrazinecarboxylic acid represented by the for-

  
 <EMI ID = 73.1>

  
that of formula I can be reacted with the amine derivative of formula II at room temperature or under heating in an inert solvent in the presence of a condensing agent such as <EMI ID = 74.1>

  
furthermore, the amino derivative of formula II can be reacted beforehand with a phosphorus halide such as trichloru-

  
 <EMI ID = 75.1>

  
phite, o-phenylenechlorophosphite, ethyldichlorophosphite, etc. in an inert solvent and then reacted with pyrazine acid-

  
 <EMI ID = 76.1>

  
 <EMI ID = 77.1>

  
re of phosphorus is phosphorus trichloride the amine derivative first reacts with about 1/2 mole of phosphorus trichloride in an inert solvent in the presence of a tertiary base

  
 <EMI ID = 78.1>

  
etc under cooling or at room temperature and reacts

  
 <EMI ID = 79.1>

  
ambient temperature or under heating, preferably under heating

  
at reflux in an inert solvent.

  
When an acid halide is used as the reactive derivative of pyrazinecarboxylic acid of formula I, the reaction is usually carried out in water, under cooling or at room temperature, in the presence of an alkali such as hydroxide. sodium, potassium hydroxide, etc. or alternatively it is usually carried out in an inert solvent under cooling or at room temperature in the presence of a ter-

  
 <EMI ID = 80.1>

  
 <EMI ID = 81.1>

  
Usually carried out in water under cooling or at room temperature in the presence of an alkali such as sodium hydroxide, potassium hydroxide, etc. When an ester is used as the reactive derivative of pyrazinecarboxylic acid of formula I, the reaction is usually carried out in an inert solvent at room temperature or with heating, preferably under heating under reflux. In addition, when a symmetrical acid anhydride or a mixed acid anhydride is used as the reactive derivative of pyrazinecarboxylic acid of formula I, the reaction is usually carried out in an inert solvent, at room temperature or with heating, in presence of, depending on the case, a tertiary base such as triethylamine, pyridine, N, N-dimethylamine, etc.

   In addition, when an active amide is used as a reactive derivative of pyrazinecarboxylic acid of the formula <EMI ID = 82.1>

  
at room temperature or under heating. In addition, the reactive derivatives of pyrazinecarboxylic acid of formula I can be reacted with the amino derivative of formula II without being isolated from the reaction mixture thereof.

  
The inert solvent used in the reaction of the present invention is an inert organic solvent which does not participate in the reaction and preferred examples of such solvents are benzene, toluene, methanol, ethanol, isopropyl alcohol.

  
 <EMI ID = 83.1>

  
depending on the nature of the reactive derivative used.

  
The compound of the present invention represented by Formula III thus prepared is isolated or purified by a usual chemical operation such as extraction, recrystallization, column chromatography and the like.

  
In addition, the compound of the present invention shown

  
 <EMI ID = 84.1>

  
can be converted into the compound of formula III, wherein

  
 <EMI ID = 85.1>

  
In this case, if the compound has a group which can be reduced,

  
 <EMI ID = 86.1>

  
tick in the presence of a catalyst such as carbon-palladium, etc.

  
In addition, the compound of the present invention, such as,

  
 <EMI ID = 87.1>

  
mercaptan.

  
The compound of the present invention represented by formula III can be administered orally, for example under <EMI ID = 88.1>

  
rale, for example by intravenous injection or intramuscular injection. The dosage of the compound of the present invention is about 1-300 mg / day, preferably about 5-50 mg / day.

  
The production of the compounds of the present invention and also the raw materials for producing the compounds of the present invention will now be described with reference to the following Examples and Reference Examples.

  
Reference Example 1: Production of 5,6-dichloro

  
 <EMI ID = 89.1>

  
was added to the solution while the solution was maintained at 50-60 [deg.] C. In this case, after the exothermic reaction was terminated, the chlorine gas was further passed through the reaction mixture for 6 hours under heating at 70-80 [deg.] C to terminate the reaction.

  
After cooling, the reaction mixture was dispersed

  
 <EMI ID = 90.1>

  
The lilies were filtered off, washed with ice water and dried to give 2.4 g (85.0% yield) of methyl dichloro-5,6-nethoxy-3-pyrazinecarboxylate-2.

  
 <EMI ID = 91.1>

  
gaseous moniac was introduced into the solution keeping the solution at 65-70 [deg.] C. After further passing gaseous ammonia for 1.5 hours while cooling the reaction system to 10 [deg.] C, the reaction mixture was dispersed in 50 ml of ice-water and the precipitated crystals were collected. by filtration, washed with ice-water and dried to provide 1.9 g (yield

  
 <EMI ID = 92.1>

  

 <EMI ID = 93.1>
 

  
 <EMI ID = 94.1>

  
of aniline and after heating the solution under reflux for 5 hours, the reaction mixture was dispersed in 100 ml of ice-water. The precipitated crystals were collected by filtration, washed with water and dried to provide 2.5 g of anilino-5-chloro-6-.

  
 <EMI ID = 95.1>

  
sion of 167 [deg.] C.

  

 <EMI ID = 96.1>


  
 <EMI ID = 97.1>

  
 <EMI ID = 98.1>

  
heated at reflux for 17 hours. After cooling, the

  
 <EMI ID = 99.1>

  
diluted, the extract was washed with chloroform and basified with aqueous sodium hydroxide solution, whereby an oily material was formed. The oily material was extracted with

  
 <EMI ID = 100.1>

  
 <EMI ID = 101.1>

  
to provide crystals. When the crystals were recrystallized from 10 µl of toluene, 1.2 g of crystals were obtained.

  
 <EMI ID = 102.1>

  

 <EMI ID = 103.1>


  
EXAMPLE 2

  
 <EMI ID = 104.1>

  
N, N-diethylethylenediamine and the mixture was heated under reflux for 5 hours. After cooling, the reaction mixture has <EMI ID = 105.1>

  
washed with chloroform and then alkalized with aqueous sodium hydroxide solution, whereby an oily material has

  
 <EMI ID = 106.1>

  
and the extract was washed with water and dried over anhydrous magnesium sulfate. When the solvent has been distilled off

  
of the extract, crystals were obtained which were recrystallized from 7 ml of toluene to provide 1.16 g (yield 55.8%)

  
 <EMI ID = 107.1>

  

 <EMI ID = 108.1>


  
EXAMPLE 3

  
 <EMI ID = 109.1>

  
distilled off and the residue was dissolved in acid

  
 <EMI ID = 110.1>

  
and basified with an aqueous solution of sodium hydroxide, whereby an oily material was formed. The oily material was extracted with chloroform, the extract was washed with water and dried, and the solvent was distilled off to provide 1.7 g of an oily material which was dissolved in water. absolute ethanol. Then, after introducing dry hydrochloric gas into the solution, ethanol was distilled off and the residue was recrystallized from acetone to provide 1.7 g.

  
 <EMI ID = 111.1>

  

 <EMI ID = 112.1>


  
EXAMPLE 4

  
In 20 ml of methanol were dissolved 2.0 g of anilino-5-

  
 <EMI ID = 113.1>

  
N, N-diethylethylenediamine and the solution was heated to reflux <EMI ID = 114.1>

  
tion and the residue was dissolved in dilute hydrochloric acid. The solution was washed with chloroform and then basified with aqueous sodium hydroxide solution, whereby the crystals were precipitated. The crystals were extracted with

  
chloroform and after washing with water and drying the extract, the solvent was distilled off from the extract and the resulting crystals were recrystallized from toluene to provide

  
 <EMI ID = 115.1>

  

 <EMI ID = 116.1>


  
EXAMPLE 5

  
 <EMI ID = 117.1>

  
10 ml of toluene was heated under reflux for 3.5 hours. After cooling, the reaction mixture was extracted with dilute hydrochloric acid and the extract was washed with chloroform and basified with an aqueous hydroxide solution.

  
sodium, whereby an oily material was formed. The oily material was extracted with chloroform and the extract was washed with water, dried and the solvent was then distilled off to provide an oily residue. A small amount of n-hexane was added to the residue and the crystals formed were collected by filtration and recrystallized from n-hexane to provide 0.8 g of chloro-6- (diethyl amino - 2-ethylamino) - 5-

  
 <EMI ID = 118.1>

  
106 [deg.] C.

  
The mother liquor of n-hexane was evaporated under reduced pressure to dryness and the oily residue was triturated with a small amount of petroleum ether, whereby crystals were formed. When the crystals have been recrystallized from

  
 <EMI ID = 119.1> <EMI ID = 120.1>

  
was heated at reflux for one hour. After the completion of the reaction, the solvent was distilled off from the reaction mixture and the solid residue obtained was washed with 100 ml of water.

  
 <EMI ID = 121.1>

  
 <EMI ID = 122.1>

  
were recrystallized from benzene, yellow prismatic crystals were obtained thereof having a melting point of
128 [deg.] C.

  
 <EMI ID = 123.1>

  

 <EMI ID = 124.1>


  
Reference Example 5: Production of 6-chloro-nethoxy-3-

  
 <EMI ID = 125.1>

  
was heated at reflux for 1 hour. After completion of the reaction, the solvent was removed by pressure distillation.

  
 <EMI ID = 126.1>

  
residue obtained, which gave a suspension. The suspension was

  
 <EMI ID = 127.1>

  
were combined and washed with water, dried and the solvent was distilled off under reduced pressure to provide

  
 <EMI ID = 128.1>

  
Methyl pyrazine-2-carboxylate. The light yellow needle crystals obtained by recrystallization of the product from benzene had a melting point of 147 [deg.] C.

  
 <EMI ID = 129.1>

  
Reference Example 6: Production of n-butylamino-5- <EMI ID = 130.1>

  
solvent was distilled off under reduced pressure from the reaction mixture and the residue obtained was washed with 50 ml of water and dried to provide 2.56 g of light yellow crystals of n-butyl-

  
 <EMI ID = 131.1>

  
light yellow needle crystals obtained by recrystallization of

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  

 <EMI ID = 134.1>


  
Reference Example 7: Production of amino-5-chloro-6-

  
 <EMI ID = 135.1>

  
(a) During reflux heating of an ethylate solution <EMI ID = 136.1>

  
drop to the solution over 10 minutes and the mixture was then heated to reflux for 90 minutes. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was mixed with 50 ml of water while shaking well and the mixture was then extracted 3 times, each time with 30 ml of dichloromethane. The extracts were combined, washed with water, dried and the solvent was then removed by distillation under reduced pressure to provide 3.5 g of light yellow oily material of ethyl 3-ethoxy-2-ethylcarboxylate-2.

  
 <EMI ID = 137.1> the solution for 1 hour and then, while maintaining the solution at 70-75 [deg.] C, chlorine gas was further passed through the solution for 3 hours. After cooling, the reaction mixture was dispersed in 200 ml of ice water and the crystals <EMI ID = 138.1>

  
with water and dry. The crystals were then extracted with
200 ml of hot n-hexane. By distilling off the solvent

  
 <EMI ID = 139.1>

  
Ethyl dichloro-5,6-ethoxy-3-pyrazine-carboxylate-2. The colorless needle crystals obtained by recrystallizing the product from n-hexane had a melting point of 56-
57 [deg.] C.

  
 <EMI ID = 140.1>
 <EMI ID = 141.1>
(c) While maintaining at 65-70 [deg.] C, the solution obtained by dissolving 2.0 g of dichloro-5,6-ethoxy-3-pyrazine-carboxylate-2 <EMI ID = 142.1>

  
passed through the solution for 40 minutes. Then, after allowing the reaction mixture to stand for 1 hour at room temperature, it was dispersed in 30 ml of ice-water, and the yellow needle-like crystals formed were collected by

  
 <EMI ID = 143.1>

  
ethyl 2-carboxylate. The light yellow needle crystals obtained by recrystallizing the product from a mixture of

  
 <EMI ID = 144.1>

  

 <EMI ID = 145.1>


  
EXAMPLE 6

  
In 14 ml of isopropyl alcohol, 1.4 g of

  
 <EMI ID = 146.1>

  
reflux for 4 days. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture, and the obtained residue was subjected to silica gel column chromatography. The column was then developed using a mixture of ether and n-hexane in a 1: 1 volume ratio as the eluting solution. 0.7 g of ethylamino-5-chloro-6-methoxy-3-pyrazine- <EMI ID = 147.1> was recovered from the first fraction.

  
 <EMI ID = 148.1>

  
mixture of benzene and n-hexane had a melting point of
142 [deg.] C.

  
 <EMI ID = 149.1>

  

 <EMI ID = 150.1>


  
EXAMPLE 7

  
In 5 ml of ethanol, 1.3 g of methoxy-3-pyrazine- was dissolved

  
 <EMI ID = 151.1>

  
the solution was heated at reflux for 4 hours. The solution was then left to stand overnight at room temperature. After completion of the reaction, the ethanol was distilled off under reduced pressure from the reaction mixture and the residue formed was dissolved in 5 ml of chloroform and

  
 <EMI ID = 152.1>

  
After acidifying the solution with hydrochloric acid, the solution was then extracted three times each time with 5 ml of water. The extracts were combined and after alkanizing the

  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>

  
washed with water, dried and the chloroform was then removed by distillation under reduced pressure to provide 1.6 g of

  
 <EMI ID = 155.1>

  
pale yellow.

  
 <EMI ID = 156.1>

  
EXAMPLE 8

  
In 35 ml of isopropyl alcohol was dissolved 3.5 g of

  
 <EMI ID = 157.1>

  
fairy at reflux for 1 day. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture and the residue formed was dissolved in 50 ml of chloroform. After washing the solution twice, each time with 30 ml of water, the solution was acidified with acid <EMI ID = 158.1>

  
of water. (The chloroform layer was washed with water, dried and evaporated to dryness, whereby 2.4 g of

  
 <EMI ID = 159.1>

  
used as starting material). The aqueous extracts were combined, neutralized with ammonia, diluted and then extracted three times, each time with 30 ml of chloroform. The extracts were combined, washed with water, dried and then the chloroform was removed by distillation under reduced pressure.

  
 <EMI ID = 160.1>

  
obtained by recrystallization of the product from benzene exhibited a melting point of 157 [deg.] C.

  
 <EMI ID = 161.1>

  

 <EMI ID = 162.1>


  
EXAMPLE 9

  
In 30 ml of isopropyl alcohol, 3.0 g of

  
 <EMI ID = 163.1>

  
fairy reflux for a day. After completion of the reaction, the

  
 <EMI ID = 164.1>

  
 <EMI ID = 165.1>

  
form. After washing the solution twice, each time with
30 ml of water, the solution was acidified with hydrochloric acid and extracted three times, each time with 20 ml of water. (The chloroform layer was washed with water, dried and then evaporated to dryness to give 0.9 g of n-butylamino-5chloro-6-metthoxy-3-pyrazine-carboxylate-2 methyl used as starting material). The aqueous extracts were combined, neutralized with ammonia, diluted and then extracted three times, each time with 30 ml of chloroform. The extracts were combined, washed with water, dried and the chloroform was then removed by distillation under reduced pressure to provide 1.0 g of.

  
 <EMI ID = 166.1>

  
carboxamide-2. The colorless flat crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane had a melting point of 127 [deg.] C.

  
 <EMI ID = 167.1>

  

 <EMI ID = 168.1>


  
EXAMPLE 10

  
 <EMI ID = 169.1>

  
ethyl-1-piperidine and the solution was refluxed for
30 hours. After cooling, the reaction mixture was extracted 3 times, each time with 5 ml of dilute hydrochloric acid and the confined extract was washed three times, each time with 5 ml of chloroform. (The organic layer was combined with the products of the chloroform wash and the mixture was washed with water, dried and the solvent was then removed by distillation.

  
 <EMI ID = 170.1>

  
starting material). The extract was basified with an aqueous solution of sodium hydroxide and the oily material formed was extracted twice, each time with 2 ml of chloroform. The extracts were combined, washed with water, dried and the chloroform was removed by distillation under reduced pressure to provide an oily residue. The residue was triturated with a small amount of petroleum ether, whereby crystals were formed. The crystals were collected by filtration and recrystallized from toluene to provide 90 mg of N- (ethyl-1-

  
 <EMI ID = 171.1>

  

 <EMI ID = 172.1>


  
EXAMPLE 11

  
In 20 ml of methanol, 2.0 g of chloro-6- was dissolved

  
 <EMI ID = 173.1>

  
aminoethyl-2-ethyl-1-pyrrolidine and the solution was heated at reflux for 24 hours. After cooling, the solvent was distilled off under reduced pressure from the reaction mixture to provide an oily residue. The residue was dissolved in <EMI ID = 174.1>

  
solution was washed three times each time with 10 ml of chloroform. (The chloroform washes were washed with water, dried, and the solvent was then distilled off under reduced pressure, whereby 1.5 g of was collected.

  
 <EMI ID = 175.1>

  
nized with 3N aqueous sodium hydroxide solution and the oily material formed was extracted with 30 ml of chloroform. The extract was washed with water, dried, the solvent was distilled off under reduced pressure and the oily residue formed was left to stand, whereby the oily residue was removed.

  
 <EMI ID = 176.1>

  

 <EMI ID = 177.1>


  
EXAMPLE 12

  
To 8 ml of toluene was added 0.8 g of amino-S-chloro-6-

  
 <EMI ID = 178.1>

  
hours. After completion of the reaction, the reaction mixture

  
was cooled to room temperature and then extracted with
20 ml of an aqueous solution of IN hydrochloric acid. The extract was neutralized with dilute ammonia under cooling.

  
 <EMI ID = 179.1>

  
of chloroform. The extracts were combined, washed with water, dried and the solvent was then removed by distillation.

  
under reduced pressure. By washing the residue obtained with 30 ml of n-hexane, 0.53 g of colorless crystals of N- (diethyl-

  
 <EMI ID = 180.1>

  
The colorless needle crystals obtained by recrystallization of the product from a mixture of benzene and n-hexane showed a melting point of 147-148 [deg.] C.

  
 <EMI ID = 181.1>

  

 <EMI ID = 182.1>


  
Example refer to ce 8: Production of chloro-6-cyclohexyl-

  
 <EMI ID = 183.1>

  
cyclohexylamine and 1.1 g of triethylamine and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture and the obtained residue was washed with 100 ml of water and dried to give 2.5 g of colorless crystals of 6-chloro.

  
 <EMI ID = 184.1>

  
Colorless prismatic crystals obtained by recrystallization of the product exhibited a melting point of 100 [deg.] C.

  
 <EMI ID = 185.1>

  

 <EMI ID = 186.1>


  
Reference Example 9: Production of 6-chloro-diethyl-

  
 <EMI ID = 187.1>

  
 <EMI ID = 188.1>

  
The reaction mixture was distilled off under reduced pressure and the oily residue obtained was left to stand overnight, whereby the oily residue crystallized. The crystals were washed twice, each time with 50 ml of water and dried to provide 2.4 g of pink chloro-6- crystals.

  
 <EMI ID = 189.1>

  
Colorless prismatic crystals obtained by recrystallizing the product from n-hexane exhibited a melting point of 60 [deg.] C.

  
 <EMI ID = 190.1>
 <EMI ID = 191.1>
  <EMI ID = 192.1>

  
within 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture and the obtained residue was added to 30 ml of water, mixed well and the mixture was extracted twice, each time with 30 ml. of

  
 <EMI ID = 193.1>

  
dried and the solvent was removed by pressure distillation

  
 <EMI ID = 194.1>

  
 <EMI ID = 195.1>

  
methyl. The colorless needle crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane exhibited a melting point of 110 [deg.] C.

  
 <EMI ID = 196.1>

  

 <EMI ID = 197.1>


  
EXAMPLE 13

  
In 24 ml of isopropyl alcohol, 2.4 g of

  
 <EMI ID = 198.1>

  
was heated at reflux for 2 days. After the reaction was completed, the solvent was distilled off from the reaction mixture under reduced pressure, and then 50 ml of ether was added to the oily residue obtained, whereby crystals were formed. The crystals were collected by filtration and washed twice, each time with 50 µl of ether to provide 2.5 g of crystals.

  
 <EMI ID = 199.1>

  
by recrystallization of the product from toluene exhibited a melting point of 140 [deg.] C.

  
 <EMI ID = 200.1>

  

 <EMI ID = 201.1>
 

  
 <EMI ID = 202.1>

  
was heated under reflux for 3 days. After the completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture and the obtained residue was dissolved in 50 ml of chloroform. The solution was washed twice, each time with 30 ml of water, acidified with hydrochloric acid

  
 <EMI ID = 203.1>

  
 <EMI ID = 204.1>

  
diluted niac, they were extracted three times, each time with
30 ml of chloroform. The extracts were combined washed with water, dried and the chloroform was then removed by distillation.

  
 <EMI ID = 205.1>

  
 <EMI ID = 206.1>

  
mixture of chloroform and methanol in a volume ratio 9: 1

  
 <EMI ID = 207.1>

  
 <EMI ID = 208.1>

  

 <EMI ID = 209.1>


  
EXAMPLE 15

  
To 5 ml of isopropyl alcohol was added 390 mg of chloro-

  
 <EMI ID = 210.1>

  
methyl and 350 mg of N, N-diethylethylenediamine and the mixture was heated under reflux for 7 days. After the completion of the reaction, the solvent was distilled off under reduced pressure from the reaction mixture and the residue obtained was dissolved in

  
 <EMI ID = 211.1>

  
hydrochloric acid and extracted with 20 ml of water. The extracts were basified with ammonia and then extracted three times, each time with 20 ml of chloroform. The extracts were combined, washed with water, dried and the chloroform was then removed by distillation under reduced pressure. The oily material <EMI ID = 212.1>

  
yolks obtained by recrystallization of the product from

  
 <EMI ID = 213.1>

  
 <EMI ID = 214.1>

  

 <EMI ID = 215.1>


  
Reference Example 11: Production of Chloro-6- Acid

  
 <EMI ID = 216.1>

  
stirred for 15 hours at room temperature to give a homogeneous solution. The solution was acidified with 80 ml of an 18% aqueous hydrochloric acid solution and then allowed to

  
 <EMI ID = 217.1>

  
collected by filtration, washed with water and dried over anhydrous phosphorus pentoxide under reduced pressure to give

  
 <EMI ID = 218.1>

  
that-2. Melting point 166.5-166 [deg.] C (recrystallized from chloroform).

  
 <EMI ID = 219.1>

  

 <EMI ID = 220.1>


  
Reference Example 12: Production of Chloro-6- Acid

  
 <EMI ID = 221.1>

  
methyl 2-carboxylate, 15 ml of a 20% aqueous solution of sodium methanethiolate and 30 ml of ethanol was stirred for

  
2 hours at 70-80 [deg.] C. After cooling the mixture to room temperature and adding 80 ml of water, the mixture was acidified with concentrated hydrochloric acid, whereby crystals were formed. The crystals were collected by filtration, washed with water and dried to provide 2.55 g of acid crystals.

  
 <EMI ID = 222.1>

  
pyrazine-carboxylic-2 having a melting point of 206-207 [deg.] C.

  
 <EMI ID = 223.1>

  

 <EMI ID = 224.1>


  
Reference Example 13: Production of Benzylamino5-chloro-6-methoxy-3-pyrazine-carboxylic-2 acid.

  
a) To 30 ml of isopropyl alcohol, 2.37 g of methyl dichloro-5,6-methoxy-3-pyrazine-carboxylate-2, 1.2 g of benzylamine and 1.4 ml of triethylamine were added and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure and the resulting residue was washed three times, each time with 30 ml of water and dried to provide 2.95 g of benzylamino. -5-chloro-6-methoxy-3-pyrazine-carboxylate-2 <EMI ID = 225.1>

  
 <EMI ID = 226.1>
 <EMI ID = 227.1>
 b) To a mixture of 13 ml of an aqueous solution of 0.5 N sodium hydroxide and 0.5 ml of methanol was added 2.0 g of <EMI ID = 228.1>

  
and the mixture was heated to 90 [deg.] C for 10 minutes. The reaction mixture was cooled to room temperature and neutralized with hydrochloric acid, whereby crystals were formed. The crystals were collected by filtration, washed with water and dried to give 1.85 g benzylamino-5-chloro- acid

  
 <EMI ID = 229.1>

  
 <EMI ID = 230.1>

  
 <EMI ID = 231.1>

  

 <EMI ID = 232.1>


  
 <EMI ID = 233.1>

  
 <EMI ID = 234.1>

  
a) To 30 ml of isopropyl alcohol were added 2.37 g of methyl dichloro-5,6-methoxy-3-pyrazine-carboxylate-2, 0.8 ml <EMI ID = 235.1> <EMI ID = 236.1 >

  
di at room temperature and the solvent was removed by distillation under reduced pressure from the reaction mixture. The residue obtained was washed three times, each time with 30 ml of water and dried to give 2.35 g of colorless prismatic crystals.

  
 <EMI ID = 237.1>

  
 <EMI ID = 238.1>

  
 <EMI ID = 239.1>
 <EMI ID = 240.1>
 b) To 17 ml of an aqueous solution of sodium hydroxide <EMI ID = 241.1>

  
methyl pyrazine-2-carboxylate and the mixture was heated to
80 [deg.] C for 10 minutes. The reaction mixture was cooled to room temperature and acidified with hydrochloric acid.

  
 <EMI ID = 242.1>

  
pyrazine-carboxylic-2 having a melting point of 125-126 [deg.] C
(decomposition).

  
 <EMI ID = 243.1>

  

 <EMI ID = 244.1>


  
Reference Example 15: Production of chloro-6- acid

  
 <EMI ID = 245.1>

  
 <EMI ID = 246.1> In isopropyl alcohol 1.24 g of o-methoxyphenol was added under ice-cooling and the mixture was stirred at room temperature for 30 minutes. A solution of 2.37 g of methyl dichloro-5,6-methoxy-3-pyrazine-carboxylate-2 in 15 ml of isopropyl alcohol was added dropwise to the solution, at 10-20 [deg.] C, over a period of 30 minutes. The mixture was then heated at reflux for 30 minutes and dispersed in 10 ml of ice-water, whereby crystals were formed. The crystals were collected by filtration to provide chloro-6-methoxy-3-

  
 <EMI ID = 247.1>

  
melting point 94-95 [deg.] C.

  
 <EMI ID = 248.1>
 <EMI ID = 249.1>
 b) To 50 ml of an aqueous solution of sodium hydroxide <EMI ID = 250.1>

  
at 80 [deg.] C for 30 minutes. The reaction mixture was cooled

  
at room temperature and acidified with concentrated hydrochloric acid, whereby crystals were formed. The crystals were collected by filtration, washed with water and dried.

  
 <EMI ID = 251.1>

  
5-pyrazine-carboxylic-2 having a melting point of 165 [deg.] C. (recrystallized from isopropyl alcohol).

  
 <EMI ID = 252.1>

  

 <EMI ID = 253.1>


  
 <EMI ID = 254.1>

  
 <EMI ID = 255.1> of magnesium and 5.1 g of 5% carbon-palladium and the mixture has

  
 <EMI ID = 256.1>

  
rique. After absorption of a theoretical amount (900 ml) of hydrogen, the insoluble materials were collected by filtration and extracted with 200 ml of a hot mixture of isopropyl alcohol and water in a volume ratio of 1: 1 . The extracts were combined with the filtrate obtained above, and the mixture was concentrated to 100 ml under reduced pressure and cooled with ice, whereby crystals were formed. The crystals were collected by filtration to provide 5.0 g of flat crystals.

  
 <EMI ID = 257.1>

  
having a melting point of 225-226 [deg.] C (decomposition).

  
 <EMI ID = 258.1>
 <EMI ID = 259.1>
 <EMI ID = 260.1> <EMI ID = 261.1>

  
Acetic acid containing 0.56 ml of bromine was added dropwise to the mixture at 50 ° C. over a period of 10 minutes. The mixture was then stirred for 10 minutes at 25-30 [deg.] C and cooled to
12 [deg.] C whereby crystals were formed. The crystals were collected by filtration and recrystallized from isopropyl alcohol to give 1.85 g of yellow prismatic crystals.

  
 <EMI ID = 262.1>

  
a melting point of 151-152 [deg.] C;

  
 <EMI ID = 263.1>
 <EMI ID = 264.1>
 c) To 10 ml of an aqueous solution of sodium hydroxide <EMI ID = 265.1>

  
methyl 2-carboxylate and the mixture was heated to 80 [deg.] C during

  
 <EMI ID = 266.1>

  
rature and acidified with hydrochloric acid, whereby crystals were formed. The crystals were collected

  
 <EMI ID = 267.1>

  
 <EMI ID = 268.1>

  
(decomposition).

  
 <EMI ID = 269.1>

  

 <EMI ID = 270.1>


  
Reference Example 17: Production of Chloro-6- Acid

  
 <EMI ID = 271.1>

  
In 25 ml of methanol, 7.1 g of methyl dichloro-5,6methoxy-3-pyrazine-carboxylate-2 were dissolved and after adding

  
to solution a solution of 0.9 g of metallic sodium in 25 ml of methanol, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature

  
and the methanol was removed by distillation under reduced pressure. To the obtained residue was added 60 ml of a 0.5N aqueous sodium hydroxide solution and the mixture was stirred for 10 minutes.

  
 <EMI ID = 272.1>

  
ambient and acidified with hydrochloric acid, whereby ...--. crystals were formed. The crystals were collected by filtration, washed with water and dried to provide 5.5 g <EMI ID = 273.1>

  
195-196 [deg.] C fusion belt (recrystallized from a relaunch of isopropyl alcohol and water).

  
 <EMI ID = 274.1>

  

 <EMI ID = 275.1>


  
EXAMPLE 16

  
In 400 ml of dichloroethane, it was suspended

  
 <EMI ID = 276.1>

  
que-2 and then 22.8 g of triethylamine was added to the suspension to form a solution. After cooling the solution to a temperature from -35 [deg.] C to -40 [deg.] C, 21.4 g of ethyl chlorocarbonate was added to the solution and the mixture was stirred for

  
 <EMI ID = 277.1>

  
 <EMI ID = 278.1>

  
 <EMI ID = 279.1>

  
reaction mixture was then extracted successively with

  
 <EMI ID = 280.1>

  
 <EMI ID = 281.1>

  
and then 2.5 g of activated carbon was added thereto and filtration was carried out. The pH of the filtrate was adjusted to 12 with 30% aqueous sodium hydroxide solution, whereby crystals were formed. The crystals were collected by filtration, washed with water and a small amount of acetone and dried to

  
 <EMI ID = 282.1>

  
Levels obtained by recrystallization of the product from isopropyl alcohol exhibited a melting point of 167.2 [deg.] C.

  
The infrared absorption spectrum of the product coincided with that of the product obtained in Example II.

  
In 10 ml of benzene, 1.7 g of the product was suspended and after addition to the suspension of 1 g of methyl iodide, the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the residue obtained was recrystallized from a mixture of ethanol and water <EMI ID = 283.1>

  

 <EMI ID = 284.1>


  
EXAMPLE 17

  
Has a mixture of 1.5 g of benzylmercaptan, 0.5 g of hydride

  
 <EMI ID = 285.1>

  
12 hours at room temperature. The reaction mixture was then dispersed in 100 ml of ice-water and extracted three times, with

  
 <EMI ID = 286.1>

  
combined, dried over anhydrous potassium carbonate and the solvent was removed by distillation under reduced pressure. The residue obtained was subjected to chromatography on an alumina column.

  
 <EMI ID = 287.1>

  
 <EMI ID = 288.1>

  
The product from a mixture of benzene and n-hexane showed a melting point of 95-97 [deg.] C.

  
 <EMI ID = 289.1>

  

 <EMI ID = 290.1>


  
EXAMPLE 18

  
In 30 ml of methanol, 1.7 g of N- (ethyl-1-

  
 <EMI ID = 291.1>

  
5% palladium, the hydrogenation was carried out at normal temperature and under normal pressure. After a theoretical amount of hydrogen (120 ml) was absorbed, insoluble matters were removed by filtration and the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was dissolved in 10 ml of water and the solution was made alkaline with 20% aqueous sodium hydroxide solution, whereby cris- <EMI ID = 292.1>

  

 <EMI ID = 293.1>


  
EXAMPLE 19

  
To 30 ml of toluene was added 3.0 g of chloro-6-ethyl-

  
 <EMI ID = 294.1>

  
at reflux for 4 days. The reaction mixture was acidified with hydrochloric acid at room temperature and then extracted twice, each time with 30 ml of water. From the toluene layer, 0.9 g of 6-chloro-5-ethylamino was collected.

  
 <EMI ID = 295.1>

  
starting point. The extracts were combined, alkalized with

  
 <EMI ID = 296.1>

  
chloroform. The extracts were combined and evaporated to

  
 <EMI ID = 297.1>

  
 <EMI ID = 298.1>

  
Colorless films obtained by recrystallization of the product from a mixture of benzene and n-hexane exhibited a melting point of 126-127 [deg.] C.

  
 <EMI ID = 299.1>

  

 <EMI ID = 300.1>


  
The following pyrazine derivatives of formula III were produced by the following process:

  
Method A:

  
0.01 was suspended in 30 ml of dichloromethane.

  
 <EMI ID = 301.1>

  
 <EMI ID = 302.1>

  
to form a solution. After cooling the solution to a temperature between -20 [deg.] C and -40 [deg.] C, 0.01 mole of chloro-
 <EMI ID = 303.1>
  <EMI ID = 304.1>

  

 <EMI ID = 305.1>


  
 <EMI ID = 306.1>

  
 <EMI ID = 307.1>

  
 <EMI ID = 308.1>

  

 <EMI ID = 309.1>


  
 <EMI ID = 310.1>

  

 <EMI ID = 311.1>


  
EXAMPLE 24

  
 <EMI ID = 312.1>

  
having a melting point of 153-154 [deg.] C (recrystallized from a mixture of isopropyl alcohol and n-hexane). from 0.95 g

  
 <EMI ID = 313.1>

  
0.52 g of aminomethyl-2-ethyl-1-pyrrolidine.

  
 <EMI ID = 314.1>

  

 <EMI ID = 315.1>
 

  
 <EMI ID = 316.1>

  
pyrrolidine.

  
 <EMI ID = 317.1>

  

 <EMI ID = 318.1>


  
EXAMPLE 26

  
By Method A, 1.0 g of (4-methyl) piperazide was obtained

  
 <EMI ID = 319.1>

  
having a melting point of 127-128 [deg.] C (recrystallized from a mixture of benzene and n-hexane) from 1.09 g of chloro-

  
 <EMI ID = 320.1>

  

 <EMI ID = 321.1>


  
EXAMPLE 27

  
 <EMI ID = 322.1>

  
 <EMI ID = 323.1>

  
3 - pyrazine-carboxylic-2 and 0.8 g of N, N-diethyl-N'-methylethylenediamine.

  
 <EMI ID = 324.1>

  

 <EMI ID = 325.1>


  
EXAMPLE 28

  
By Method A, 2.2 g of N- (diethylamino-3-

  
 <EMI ID = 326.1>

  
having a melting point of 92-94 [deg.] C (recrystallized from a mixture of benzene and n-hexane) from 2.2 g of acid

  
 <EMI ID = 327.1> <EMI ID = 328.1>

  

 <EMI ID = 329.1>


  
EXAMPLE 29

  
By Method A, 2.5 g of N- (piperidino-2-ethyl) - were obtained.

  
 <EMI ID = 330.1>

  
melting point 137-139 [deg.] C (recrystallized from a mixture

  
 <EMI ID = 331.1>

  
 <EMI ID = 332.1>

  

 <EMI ID = 333.1>


  
EXAMPLE 30

  
 <EMI ID = 334.1>

  
carboxamide-2 having a melting point of 138-140 [deg.] C (recrystallized

  
 <EMI ID = 335.1>

  
 <EMI ID = 336.1>

  

 <EMI ID = 337.1>


  
EXAMPLE 31

  
 <EMI ID = 338.1>

  
melting point 119-120 [deg.] C (recrystallized from a mixture of benzene and n-hexane) from 1.43 g of chloro-6- acid

  
 <EMI ID = 339.1>

  

 <EMI ID = 340.1>
 

  
 <EMI ID = 341.1>

  

 <EMI ID = 342.1>


  
EXAMPLE 33

  
 <EMI ID = 343.1>

  
1-pyrrolidine.

  
 <EMI ID = 344.1>

  

 <EMI ID = 345.1>


  
EXAMPLE 34

  
 <EMI ID = 346.1>

  
que-2 having a melting point of 78-83 [deg.] C (recrystallized from a mixture of benzene and n-hexane) from 2.55 g of acid

  
 <EMI ID = 347.1>

  
1.55 g of dimethylamino-3-piperidine.

  
 <EMI ID = 348.1>

  

 <EMI ID = 349.1>


  
EXAMPLE 35

  
 <EMI ID = 350.1>

  
2 having a melting point of 119-120 [deg.] C (recrystallized from a mixture of benzene and n-hexane from 2.3 g of acid <EMI ID = 351.1>

  

 <EMI ID = 352.1>


  
EXAMPLE 36

  
 <EMI ID = 353.1>

  
 <EMI ID = 354.1>

  
at 5%, the hydrogenation was carried out at room temperature

  
and under atmospheric pressure. After absorption of 2 equivalents of hydrogen, the insoluble materials were removed by filtration and the filtrate was distilled under reduced pressure to remove the solvent. The residue obtained was recrystallized from a mixture of ether and ethanol to give 1.2 g of hydrochloride.

  
 <EMI ID = 355.1>

  

 <EMI ID = 356.1>


  
EXAMPLE 37

  
 <EMI ID = 357.1>

  
containing 2.7 g of aminomethyl-2-ethyl-1-pyrrolidine at -20 [deg.] C, 7 ml of a pyridine solution containing 0.7 g of phosphorus trichloride were added dropwise to the mixture. solution and the mixture was stirred at room temperature for 1 hour. 2.32 g

  
 <EMI ID = 358.1>

  
was then added to the mixture and the resulting mixture was heated at 80 [deg.] C for 4 hours. After completion of the reaction, the pyridine was distilled off under reduced pressure from the reaction mixture and the oily residue obtained was dissolved in 50 ml of water. Activated carbon was added to the solution and the mixture was then filtered. The filtrate was then basified with 1.29 g of baking soda, the solution was concentrated

  
 <EMI ID = 359.1>

  
adding 20% aqueous sodium hydroxide solution and the <EMI ID = 360.1> concentrate was then cooled with ice water. The crystals formed were collected by filtration to provide 2.46 g.

  
 <EMI ID = 361.1>

  
fusion of 155-160 [deg.] C. The filtrate was extracted twice, each time with 20 ml of dichloromethane. The extracts were combined, dried over anhydrous potassium carbonate, the solvent was removed by distillation under reduced pressure and the crystals formed.

  
 <EMI ID = 362.1>

  
 <EMI ID = 363.1>

  
5-methoxy-3-pyrazine-carboxamide-2. The crystals obtained, recrystallized from isopropyl alcohol, exhibited a melting point of 167.2 [deg.] C. The infrared absorption spectrum and the nuclear magnetic resonance spectrum of the product were identical to those of the product obtained in Example 11.

  
EXAMPLE 38

  
In the same way as in Exerrple 37, we obtained 2.92 g

  
 <EMI ID = 364.1>

  
The crystals obtained by recrystallization of the product from a mixture of benzene and n-hexane exhibited a melting point of 142 [deg.] C. The infrared absorption spectrum and nuclear magnetic resonane spectrum of the product were identical to those of the product obtained in Example 6.

  
 <EMI ID = 365.1> hydrochloric acid was introduced into the suspension for 2 hours

  
 <EMI ID = 366.1>

  
 <EMI ID = 367.1>

  
crystals were formed. The crystals were collected by filtration and dried to provide 3.0 g of hydroxy-3-dimethyl-5,6-.

  
 <EMI ID = 368.1>

  
Needles obtained by recrystallizing the product from methanol had a melting point of 156-157 [deg.] C.

  
 <EMI ID = 369.1>
 <EMI ID = 370.1>
 b) To 8 ml of phosphorus oxychloride containing one drop of concentrated sulfuric acid was added 2.4 g of methyl 2-hydroxy-3-dimethyl-5,6-pyrazine-carboxylate and the mixture was heated to reflux for 7 hours. The excess phosphorus oxychloride was distilled off under reduced pressure from the reaction mixture and the residue obtained was dispersed in 20 ml of ice-water and the mixture was extracted three times, each time with
20 ml of ethyl acetate. The extracts were combined, dried

  
over anhydrous magnesium sulfate and the solvent was then distilled off to provide 1.9 g of methyl 2-chloro-3-dimethyl-5,6pyrazine-carboxylate-2. The colorless needle-shaped crystals obtained by recrystallization from n-hexane had a melting point of 50-51 [deg.] C.

  
 <EMI ID = 371.1>
 <EMI ID = 372.1>
 c) To 20 ml of a solution of 0.1 g of metallic sodium in methanol, 0.3 g of methyl 3-chloro-dimethyl-5,6pyrazine-carboxylate-2 was added and the mixture was heated at reflux for one hour. Methanol was distilled off from the reaction mixture and the obtained residue was added to 20 ml of water and the mixture was extracted three times, each time with 20 ml <EMI ID = 373.1>

  
Anhydrous magnesium sulfate and the dichloromethane was then removed by distillation to provide 0.2 g of methyl 3-methoxy-dimethyl5,6-pyrazine-carboxylate-2. The prismatic yellow crystals obtained by recrystallization from n-hexane had a melting point of 80-81 [deg.] C.

  
 <EMI ID = 374.1>
 <EMI ID = 375.1>
  <EMI ID = 376.1> Methyl 5,6-pyrazine-carboxylate-2 and 1.5 g of aminomethyl-2ethyl-1-pyrrolidine and the mixture was heated under reflux for
30 hours. The methanol was distilled off under reduced pressure from the reaction mixture and the obtained residue was added.

  
to a mixture of 20 ml of water and 20 ml of dichloromethane and

  
well mixed. The separated organic layer was acidified with aqueous hydrochloric acid and extracted three times, each time with 20 ml of water. The aqueous extracts were combined, basified with 2N aqueous sodium hydroxide and extracted three times, each time with 20 ml of dichloromethane. The dichloromethane extracts were combined, dried over anhydrous magnesium sulfate and the solvent was then removed by distillation. The residue obtained was subjected to column chromatography on

  
silica gel and then developed using a mixture of chloroform and methanol in a volume ratio of 1: 1 as the eluting solution, whereby 0.8 g of N- (ethyl-1-

  
 <EMI ID = 377.1>

  
2 oily light yellow.

  
 <EMI ID = 378.1>

  

 <EMI ID = 379.1>


  
EXAMPLE 40 (Tablets)

  

 <EMI ID = 380.1>


  
The above mixture was molded in a die having

  
 <EMI ID = 381.1>

  
tablets. If necessary, the tablets can be coated with sugar by the usual method.

  
EXAMPLE 41 'Injection)

  

 <EMI ID = 382.1>


  
The above mixture was dissolved in distilled water for injection and used to fill closed ampoules and
10 sterilized.


    

Claims (1)

<EMI ID = 383.1> 1.- A process for preparing a pyrazine derivative represented by the formula: <EMI ID = 384.1> wherein R <1> and R2 which may be the same or different each represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group, a phenoxy group, a group mercapto, a lower alkylthio group, a phenyl-lower alkylthio group, a phenylthio group, an amino group, a substituted amino group, an <EMI ID = 385.1> may be identical or different, each representing a hydrogen atom, a lower alkyl group or a cycloalkyl group, a phenyl-lower-alkyl group or a phenyl group and A represents <EMI ID = 386.1> <EMI ID = 387.1> a 5- or 6-membered heterocyclic ring containing nitrogen which <EMI ID = 388.1> the latter pharmaceutically acceptable characterized in that one reacts a pyrazinecarboxylic acid represented by the formula: <EMI ID = 389.1> <EMI ID = 390.1> above formula. or a reactive derivative thereof and an amine derivative represented by the formula <EMI ID = 391.1> <EMI ID = 392.1> above. 2.- A process according to claim 1 characterized in that R <1> is an aminoethyl group, R <2> is a chlorine atom, R <EMI ID = 393.1> <EMI ID = 394.1> 3.- A method according to claim 1 characterized in that <EMI ID = 395.1> methoxy group, R 4 is a hydrogen atom, A and R 5 together with the nitrogen atom form a pyrrolidinyl-2-methyl group and <EMI ID = 396.1> 4.- A method according to claim 1 characterized in that <EMI ID = 397.1> <EMI ID = 398.1> ethyl groups and A is an ethylene group. 5.- A method according to claim 1 characterized in that <EMI ID = 399.1> <EMI ID = 400.1> ble with the nitrogen atom, a piperidinyl-3 group and R is an ethyl group.