JPH0524906B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides 3,5-diamino-1H-1,2,
The present invention relates to a novel method for producing 4-triazole derivatives and salts thereof.

According to the invention, the general formula () (In the formula, R ₁ and R ₂ each represent a group selected from the group consisting of hydrogen, an alkyl group, an alkenyl group, an aralkyl group, and a cycloalkyl group, and R ₁ and R ₂ represent a group to which these are bonded. can form a heterocycle with adjacent nitrogen atoms.
R ₃ represents hydrogen or an alkyl group. ) 3,5-diamino-1H-1,2,4
-Processes for making triazole derivatives and pharmaceutically usable acid addition salts thereof are provided.

(Prior Art) The compound represented by the general formula () is a known histamine _H2 -blocker with a long-lasting effect.
These compounds can neutralize the effect of histamine on enhancing gastric acid secretion, and are useful for anti-ulcer treatment.

There are several known methods for producing the compound represented by the general formula ().

According to Belgian Patent No. 875846, the general formula () (In the formula, R ₁ and R ₂ are the same as the groups described above.) An amine represented by the general formula () (In the formula, R ₄ and R ₅ represent an alkylthio group or an alkoxy group.) It is reacted with a cyanoimino derivative represented by the following formula.

The general formula obtained in this way () (In the formula, R ₁ and R ₂ are the same as the above-mentioned groups.) The isoyuria or isothiourea derivative represented by the general formula () R ₃ -NH-N=Z () (in the formula, R ₃ is , which is the same as the group described above, and Z represents two hydrogen atoms).

During the reaction, general formula (), and general formula () A mixture of isomeric compounds of the formula (wherein R ₁ , R ₂ and R ₃ are the same as the groups described above) is obtained. The compound represented by the general formula () is separated from the mixture by crystallization.

A significant drawback of this method is that the isomers of the general formulas () and (), which differ from each other in the position of the R ₃ substituent, are formed only in the final stage of the synthesis;
Therefore, only a small amount of the desired isomer represented by the general formula () can be obtained. Since such large losses occur at the final stage of a long synthesis process consisting of several steps, this method results in very high production costs.

In order to eliminate the production of isomeric compounds represented by the general formula (), according to another method described in the Belgian patent specification, isothiourea represented by the general formula () is converted into isothiourea represented by the general formula () (in which R ₃ is the same as the group described above, and Z represents a protecting group.)
React with a protected hydrazine derivative represented by

The general formula obtained in this way () (In the formula, R ₁ , R ₂ , R ₃ and Z are the same as the groups described above.) When the protecting group is removed from the protected cyanoguanidine derivative represented by the formula (XI), (In the formula, R ₁ , R ₂ and R ₃ are the same as the above-mentioned groups.) The cyanoguanidine derivative represented by this formula is spontaneously cyclized to become a compound represented by the general formula ().

According to the Belgian patent, the key intermediate represented by the general formula () can also be prepared by reacting the protected hydrazine derivative represented by the general formula () with the cyanoimino derivative represented by the general formula (). General formula () (In the formula, R ₃ and R ₄ are the same as the above-mentioned groups, and Z represents a protecting group.) The protected cyanoguanidine derivative represented by the formula (2) is bonded to the amine represented by the general formula (), The desired intermediate represented by the general formula () is produced.

All of the above methods have a common drawback that in the step of closing the triazole ring, a protecting group must be used to aid in the elimination of the triazole isomeric derivative represented by the general formula ().
That is, the literature [J.Org.Chem. 39 , page 1522,
1974], dimethyl-
N-cyanoimino-dithiocarbamate and N
A similar reaction of -methyl-hydrazine would produce isomers as shown in the general formulas () and ().

According to yet another reaction disclosed in the aforementioned Belgian patent specification, the general formula () (In the formula, R ₁ and R ₂ are the same as the groups described above, and R ₈ represents a C _1-10 alkyl group.) The isothiourea derivative represented by the general formula (
) (In the formula, Y represents a group selected from the group consisting of -NH-, oxygen, and sulfur, and R ₃ is
It is the same as the group mentioned above. ) is reacted with semicarbazide or thiosemicarbazide of aminoguanidine.

The general formula obtained in this way () (In the formula, R ₁ , R ₂ , R ₃ and Y are the same as the above-mentioned groups, and Q represents an -NH- group.)
It is now being replaced with triazole derivatives shown in

Furthermore, according to the method disclosed in the Belgian patent specification, the general formula () (In the formula, R ₁ and R ₂ are the same as the above-mentioned groups, and P is oxygen or sulfur.) An isocyanate represented by the general formula ()
(In the formula, R ₃ is the same as the group described above, and Y
represents an -NH- group. ) When an addition reaction is carried out with the compound represented by the general formula (), the compound represented by the general formula () is cyclized,
A desired triazole derivative represented by the general formula () is obtained.

All of the above-mentioned methods have the common drawback that the preparation of the reactants is complex and the final condensation step requires a long and laborious time with modest yields.

According to another reaction disclosed in the Belgian patent specification, isothiourea represented by the general formula () is reacted with a protected hydrazine represented by the general formula () to remove the protecting group. ing.

General formula () (In the formula, R ₁ , R ₂ and R ₃ are the same as the above-mentioned groups.) When the aminoguanidine derivative represented by the following is reacted with liquefied carbamoyl, the desired compound represented by the general formula () is produced. can get.

In this method, in order to eliminate the generation of unnecessary isomers represented by the general formula (),
Z represents a protecting group. ) The disadvantages of using protected hydrazine derivatives are that the preparation of the reactants is complicated and that the final condensation step of the synthesis requires a long and laborious time.

According to another reaction disclosed in said Belgian patent specification, instead of an amino compound of the general formula (), an amino compound of the general formula () (In the formula, R ₁ and R ₂ are the same as the groups described above.) An acid amide represented by the formula () or the general formula () (In the formula, R ₆ represents an alkyl group. That is,
The (R ₆ O) ₂ CH− group represents a cyclic acetal. ) This reaction is different from the reaction explained above in that it uses a cyclic acetal. The final step of this synthesis is to synthesize compounds of general formula () and (XI) obtained by known methods used to synthesize compounds of general formula (). (In the formula, R ₁ , R ₂ , R ₃ and R ₆ are the same as the groups described above.) From the intermediate represented by the general formula R ₁ R ₂ N-CH ₂ -
It is designed to generate the group shown in .

Furthermore, according to the method disclosed in the Belgian patent specification, general formula (XII) (In the formula, R ₃ is the same as the above-mentioned group, and X represents a halogen.) The key intermediate represented by the formula R ₁ R ₂ NH (wherein R ₁ and R ₂ are , are the same as the groups mentioned above.)
It is condensed with the amine shown in

According to European Patent Application No. 29303, a compound represented by the general formula () is a compound represented by the general formula () (In the formula, R ₃ is the same as the group described above.) An aldehyde represented by the general formula R ₁ R ₂ NH (In the formula, R ₁ and R ₂ are the same as the group described above.)
It is made by aminating the amine shown under reducing conditions.

Furthermore, according to the reaction described in the European patent application specification, the general formula () (In the formula, R _{2 and} R ₃ are the same as the groups described above _. ) _The secondary amine represented by
The CH ₂ - group is a R ₁ group) or is reductively condensed with an aldehyde of the general formula R _7
-CH2 -X (wherein _R7 - _CH2- is as described above and X represents a halogen) is used as a starting material to be alkylated with a compound of the general formula ( ) is making the desired compound.

In the last four reaction types, the same reaction steps are carried out using already known methods, only the order is changed. Therefore, the four operations mentioned above are subject to exactly the same drawbacks as the methods already described.

According to the method disclosed in the Belgian patent specification, a narrower subgroup of compounds of the general formula () (In the formula, R ₃ is the same as the group described above.) A phenoxyalkyl derivative represented by the formula () (CH ₃ ) ₂ N = CH ₂ Cl () It is now made by reacting.

In this way, a compound represented by the general formula () is obtained. In that case, R ₁ and R ₂ are both methyl groups.

The above-mentioned method has the disadvantage that it can only be applied to the production of a narrow group of compounds, and the production and reaction itself of the compound represented by the general formula () are complicated and time-consuming.

Further, according to the method disclosed in the Belgian patent specification, general formula () (in which R ₃
are the same as the aforementioned groups, and Y represents imino. ), the aminoguanidine represented by the general formula () (In the formula, R ₈ and R ₉ represent appropriate protecting groups.) (In the formula, R ₃ , R ₈ and R ₉ are the same as the groups described above.) 3,5-diamino-1H-1,2,4
- The triazole derivative is expressed by the general formula () (In the formula, R ₁ and R ₂ are the same as the groups described above.) General formula () obtained by reacting with an aldehyde represented by (In the formula, R ₁ , R ₂ , R ₃ , R ₈ and R ₉ are the same as the groups described above.) After reducing the Schiff base represented by There is.

According to a modification of the above method, an aminotriazole represented by the general formula () is converted into the aminotriazole represented by the general formula (
XI) (In the formula, R ₁ and R ₂ are the same as the groups described above, and A represents a group selected from the group consisting of halogen, hydroxy, alkoxy, and acyloxy.) General formula (XII) obtained by reacting with (In the formula, R ₁ , R ₂ , R ₃ , R ₈ , and R ₉ are the same as the groups described above.) If the acid amide represented by the formula () is reduced, the general formula ()
This results in the desired compound represented by

Also, according to a modification of the above method, the general formula (
), the aminotriazole represented by the general formula () (In the formula, R ₁ and R ₂ are the same as the above-mentioned groups, and B represents a mesyloxy group or a toxyloxy group.) Creating compounds.

The above method has the problems of having to use the complicated method described above to generate the triazole ring, and the proper selection and removal of the protecting groups R ₈ and R ₉ . Moreover, it is inevitable that inconveniences will occur.

(Object of the invention) The object of the present invention is to solve the above-mentioned problems associated with conventional methods by providing an economical and simple method for producing the compound represented by the general formula (). That's true.

(Means for Solving the Problems) According to the present invention, the general formula () (wherein R ₁ and R ₂ are each a group consisting of hydrogen, an alkyl group, an alkenyl group, an aralkyl group, and a cycloalkyl group) and R ₁ and R ₂ can form a heterocycle together with the adjacent nitrogen atom to which they are bonded. R ₃ represents hydrogen or an alkyl group.) and its pharmaceutically usable acid addition salts, (a) General formula () (In the formula, R ₃ is the same as the group described above.) A hydroxy compound represented by the general formula () (In the formula, R ₃ is the same as the group described above,
and X represents halogen. ), and the compound thus obtained is converted into a halogen compound represented by the general formula (). (In the formula, R ₁ and R ₂ are the same as the groups described above.) or (b) react with a salt of an alkali metal or alkaline earth metal of a phenol derivative represented by the general formula (). Halogen compounds,
A step of reacting the phenol derivative represented by the general formula () with an alkali metal or alkaline earth metal salt, and, if necessary, the step of reacting the compound represented by the general formula () obtained in the above manner in a pharmaceutical manner. converting the compound into a usable acid addition salt thereof.

The hydroxy compound represented by the general formula () is
It can be converted into a halogen derivative represented by the general formula () by a known method. Preferably, the compound of general formula () is reacted with a suitable halogenating agent (eg, particularly preferably a thionyl halide, such as thionyl chloride) in an inert solvent. The excess thionyl halide acts as a reaction medium. For example, benzene, toluene,
Alternatively, aromatic hydrocarbons such as xylene can also be used as reaction media. The reaction is carried out at room temperature or under heated conditions, for example in the range of 20°C to 80°C.

Next, the halogen derivative represented by the general formula () is added to the alkali metal (such as potassium, sodium, etc.) of the phenol compound represented by the general formula ().
or lithium) or alkaline earth metal (e.g. calcium or magnesium) salts. This reaction is carried out in a dipolar aprotic solvent such as, for example, dimethylformamide.

The alkali metal or alkaline earth metal salt of the compound represented by the general formula () can be prepared in a dipolar aprotic solvent (e.g. dimethylformamide).
The phenol derivative represented by the general formula () is formed in the reaction mixture by reacting with the corresponding alkali metal or alkaline earth metal hydride or alcoholate (e.g., sodium hydride, calcium hydride, or tert-butylpotassium). It will be done.

The compound represented by the general formula () thus obtained is separated by a known method.

The salt is prepared by adding the compound represented by the general formula () obtained in an organic solvent as described above to a corresponding inorganic or organic acid (e.g., hydrochloric acid, hydrobromic acid,
It is produced by reacting with sulfuric acid, maleic acid, fumaric acid, lactic acid, etc.) in a conventional manner.

The starting materials represented by general formulas () and () are known compounds and are easily available.

The compound represented by the general formula () is completely new and has never existed in the prior art.

The term "alkyl group" means a linear or branched aliphatic saturated hydrocarbon group having 1 to 5 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, etc.) do.

The term "alkenyl group" refers to a straight chain or branched olefinic hydrocarbon group having 2 to 5 carbon atoms (eg, allyl group, propenyl group, etc.).

The term "aralkyl group" refers to an alkyl group substituted with an aryl group (eg, benzyl group, β-phenylethyl group, etc.).

The term "cycloalkyl group" refers to an aliphatic saturated cyclic hydrocarbon group having 3 to 8 carbon atoms (e.g., cyclobutyl group, cyclopentyl group,
cyclohexyl group, etc.).

The term "halogen" includes fluorine, chlorine, bromine,
and iodine, preferably chlorine or bromine, particularly preferably chlorine.

The "heterocyclic group" formed by R ₁ and R ₂ and the adjacent nitrogen atom is a 5-membered ring or a 6-membered ring.
It has a membered ring, contains one or two nitrogen, oxygen and/or sulfur atoms, and is selectively substituted. Suitable heterocyclic groups are pyrrolidinyl, piperidinyl, morpholnyl, and piperazinyl groups.

Preferably R ₁ and R ₂ represent a methyl group and preferably together with the adjacent nitrogen atom,
Creates a pyrrolidino group or a piperidino group. Preferably R ₃ represents a methyl group.

The method according to the invention comprises 1-thymel-N ⁵ -{3-
(3-(1-piperidinyl)-methyl)-phenoxy-propyl}-1H-1,2,4-triazole-
Suitable for making 3,5-diamines and their salts.

Next, we summarize the advantages of the method according to the invention.

(a) It can be carried out industrially with simple operations.

(b) does not require special equipment or tooling;

(c) Starting materials are also readily available in large quantities.

(d) There is no generation of isomeric compounds represented by the general formula (), and the synthesis of the desired compound represented by the general formula () is not stepwise and produces two key intermediates of approximately the same size. Since the total yield of the compound is far superior to that of conventional methods.

(Example) Hereinafter, preferred examples according to the present invention will be described. However, the present invention is not limited to these protection scopes.

Example 1 ^N5- (3-chloropropyl)-1H-1,2,4
-triazole-3,5-diamine hydrochloride 5 g (0.032 mol) of N ⁵ -(3-hydroxypropyl)-1H-1,2,4-triazole-3,
Dissolve the 5-diamine in 15 ml of benzene. To this solution, 4.2 g (0.035 mol) of thionyl chloride are added while cooling to 10° C. and stirring. The reaction mixture is gradually warmed to room temperature. The reaction mixture is stirred for 30 minutes. The precipitated crystals are filtered and washed with benzene. In this way, 6.3 g of the desired compound were obtained. Yield is 92.8%. A white crystalline substance with high hygroscopicity was obtained. It liquefies on contact with air. Melting point 130-132℃.

Example 2 ^N5- (3-chloropropyl)-1H-1,2,4
-Triazole-3,5-diamine hydrochloride The same procedure as in Example 1 is carried out, except that benzene is not used and 10.6 ml (0.15 mol) of thionyl chloride is added. Excess thionyl chloride serves as reaction medium. In this way, 6.8 g of the desired compound were obtained. Yield is 94.4%. The product was consistent with the compound made based on the method of Example 1.

Example 3 1-Methyl- ^N5- (3-chloropropyl)-1H
-1,2,4-triazole-diamine hydrochloride As starting material, 8.6 g (0.05 mol) of 1-methyl- ^N5- (3-hydroxypropyl)-1H-
The same procedure as in Example 2 is carried out, except that 1,2,4-triazole-3,5-diamine is used and the reaction mixture is heated to 60 DEG C. and stirred at this temperature for 15 minutes. In this way, 10.7 g of the desired compound were obtained. Yield: 94.7%, melting point: 170-172°C (decomposition).

Example 4 1-Thymel- ^N5- {3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-triazole-3,5-diamine 1.0 g (0.033 mol) of 80% sodium hydride,
5.7 g (0.03 mol) of 3-(1-piperidinylmethyl)-phenol are slowly added to the oily solution suspended in 20 ml of anhydrous dimethylformamide and the mixture is stirred at room temperature for 30 minutes.

Using a separate flask, 8.1 g (0.036 mol) of 1
-Methyl- ^N5- (3-chloropropyl)-1H-
3.04 g (0.03 mol) of triethylamine was added to 15 ml of anhydrous dimethylformamide solution containing 1,2,4-triazole-3,5-diamine hydrochloride.
Add while stirring at room temperature. The precipitated triethylamine hydrochloride is filtered and washed with an appropriate amount of anhydrous dimethylformamide.

The solution thus obtained was added to the previously prepared dimethylformamide solution of phenolate.
Add while stirring at room temperature. The reaction mixture is
Stir at room temperature for 72 hours, add 30 ml of water and then extract three times with 20 ml of chloroform each time.

The combined organic phases are extracted three times with 20 ml of water each time, the chloroform phase is dried over anhydrous magnesium sulfate and the chloroform is distilled off in vacuo. The remaining brown oil (9.6 g) gradually crystallized when left to stand, and was mixed with ethyl acetate and cyclohexane in a ratio of 1:4.
The mixture is used for recrystallization. In this way, 5.6 g of the desired compound were obtained. The yield is
54.4%, melting point 93-94°C.

Example 5 1-Thymel- ^N5- {3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-Triazole-3,5-diamine-fumarate The oily crude product prepared by the procedure of Example 4 was dissolved in 30 ml of ethanol, heated to 50°C, and 3.5 g ( 0.03 mol) of fumaric acid. After dissolution, the reaction mixture is cooled and kept in the refrigerator overnight. Filter the precipitated crystals and wash with an appropriate amount of ethanol. In this way, 7.8 g of the desired compound were obtained. Yield: 56.4%, melting point: 142~
145℃.

Example 6 1-Thymel- ^N5- {3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-triazole-3,5-diamine 10.2 g (0.045 mol) of 1-methyl-N ⁵ -(3-
The same procedure as in Example 4 is carried out, except that chloropropyl)-1H-1,2,4-triazole-3,5-diamine hydrochloride is used. In this way,
5.3 g of the desired compound were obtained. Yield is 51.4%. The product was consistent with the compound made based on the method of Example 4.

Example 7 1-Thymel- _N5- {3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-triazole-3,5-diamine As starting material, 6.8 g (0.03 mol) of 1-methyl- ^N5- (3-chloropropyl)-1H-1,
The same procedure as in Example 4 is carried out, except that 2,4-triazole-3,5-diamine hydrochloride is used.
In this way, 4.9 g of the desired compound were obtained.
Yield is 47.6%. The product was consistent with the compound made based on the method of Example 4.

Example 8 1-Thymel- ^N5- {3-[3-[(1-pyrrolidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-triazole-3,5-diamine The same procedure as in Example 4 is carried out, except that 1.4 g (0.033 mol) of calcium hydride is used instead of sodium hydride. In this way, 5.1g
The desired compound was obtained. Yield is 49.5%. The product was consistent with the compound made based on the method of Example 4.

Example 9 1-Thymel- ^N5- {3-[3-[(1-pyrrolidinyl)-methyl]-phenoxy]-propyl}-
1H-1,2,4-triazole-3,5-diamine fumarate The same procedure as in Example 5 is carried out, except that the compound prepared according to the method of Example 9 is used as starting material. In this way, 7.2 g of the desired compound were obtained. Yield: 53.7%, melting point: 140-142°C.

Example 11 1-Thymel- ^N5- {3-[3-[(dimethylamino)-methyl]-phenoxy]-propyl}-1H
-1,2,4-triazole-3,5-diamine The same procedure as in Example 4 is carried out, except that 4.5 g (0.03 mol) of 3-dimethylaminomethyl-phenol are used as starting material. In this way, 4.1 g of the desired compound were obtained. Yield is 44.9%,
Melting point 95-96℃.

Example 12 N ⁵ -{3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-1H-1,2,
4-Triazole-3,5-diamine As starting material, 7.6 g (0.036 mol) of N ⁵ −
The same procedure as in Example 4 is carried out, except that (3-chloropropyl)-1H-1,2,4-triazole-3,5-diamine hydrochloride is used. In this way, 4.7 g of the desired compound were obtained. Yield is 47.4%,
Melting point 100-101℃.

Example 13 N ⁵ -{3-[3-[(dimethylamino)-methyl]
-phenoxy]-propyl}-1H-1,2,4
-triazole-3,5-diamine As starting materials, 4.5 g (0.03 mol) of 3-dimethylaminomethyl-phenol and 7.6 g (0.036
mol) of N ⁵ -(3-chloropropyl)-1H-1,
The same procedure as in Example 4 is carried out except that 2,4-triazole-3,5-diaminohydrochloride is used. In this way, 4.2 g of the desired compound were obtained. Yield: 48.2%, melting point: 91-93°C.

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ and R ₂ each represent a group selected from the group consisting of hydrogen, an alkyl group, an alkenyl group, an aralkyl group, and a cycloalkyl group, and R ₁ and R ₂ represent a group to which these are bonded. can form a heterocycle with adjacent nitrogen atoms.
R ₃ represents hydrogen or an alkyl group. ) 3,5-diamino-1H-1,2,4
- A method for producing a triazole derivative and a pharmaceutically usable acid addition salt thereof, the method comprising: (a) general formula () (In the formula, R ₃ is the same as the group described above.) A hydroxy compound represented by the general formula () (In the formula, R ₃ is the same as the group described above,
and X represents halogen. ), and the compound thus obtained is converted into a halogen compound represented by the general formula (). (In the formula, R ₁ and R ₂ are the same as the groups described above.) or (b) react with a salt of an alkali metal or alkaline earth metal of a phenol derivative represented by the general formula (). Halogen compounds,
A step of reacting the phenol derivative represented by the general formula () with an alkali metal or alkaline earth metal salt, and, if necessary, using the compound represented by the general formula () thus obtained for pharmaceutical purposes. 3,5-diamino-
Method for producing 1H-1,2,4-triazole derivatives and acid addition salts thereof. 2. The 3,5-diamino-1H-1,2, A method for producing a 4-triazole derivative and an acid addition salt thereof. 3. 3,5-diamino-1H-1,2,4- according to claim 2, characterized in that the reaction is carried out using an excess of thionyl halide or an inert organic solvent. A method for producing a triazole derivative and its acid addition salt. 4 As a solvent, an aromatic hydrocarbon, preferably,
The method for producing 3,5-diamino-1H-1,2,4-triazole derivatives and acid addition salts thereof according to claim 3, characterized in that toluene, benzene, or xylene is used. 5. 3 according to claim 1, characterized in that the sodium salt, potassium salt, calcium salt or magnesium salt of the compound represented by the general formula (), preferably the sodium salt, is used.
A method for producing a 5-diamino-1H-1,2,4-triazole derivative and an acid addition salt thereof. 6. 3,5-diamino- as claimed in claim 1 or 5, characterized in that an alkali or alkaline earth metal salt of the compound represented by the general formula () is prepared in the reaction mixture. 1H−1,
A method for producing a 2,4-triazole derivative and an acid addition salt thereof. 7. Claim 5, characterized in that the reaction is carried out in an inert dipolar aprotic organic solvent.
A method for producing a 3,5-diamino-1H-1,2,4-triazole derivative and an acid addition salt thereof according to any one of items 6 to 6. 8. The method for producing a 3,5-diamino-1H-1,2,4-triazole derivative and its acid addition salt according to claim 7, characterized in that dimethylformamide is used as the solvent. 9 1-Methyl-N ⁵ -{3-[3-[(1-piperidinyl)-methyl]-phenoxy]-propyl}-
To prepare 1H-1,2,4-triazole-3,5-diamine and its pharmaceutically available acid addition salts, starting materials of the general formulas () and (), where R ₁ and R ₂ forms a piperidine ring with the adjacent nitrogen atom, and R ₃ is
Represents a methyl group. ) Claims 1 to 8 are characterized in that the compounds shown in
3,5-diamino-1H- according to any of paragraphs
A method for producing a 1,2,4-triazole derivative and an acid addition salt thereof. 10 The method for producing 3,5-diamino-1H-1,2,4-triazole derivatives and acid addition salts thereof according to claim 9, characterized in that thionyl chloride is used as the halogenating agent. .