Derivative 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole, method thereof, pharmaceutical composition and the intermediate connection

 

(57) Abstract:

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, in which R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl) amino and di(C1-4alkyl)amino group; or a group of formula (a) Z means a hydrogen atom or a C1-4alkoxygroup, R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, one of R2and R3is amino and the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula - SR. Compounds affect the heart and Central nervous system. It also describes the way the th. 4 c. and 14 C.p. f-crystals, 4 PL.

< / BR>

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole, method for their production and pharmaceutical compositions containing these compounds as active ingredient. These new compounds have an effect on the circulatory system and heart, and Central nervous system.

More specifically, the invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula

< / BR>
where R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl)amino and di(C1-4alkyl)amino group; or a group of the formula

< / BR>
where Z means a hydrogen atom or a C1-4alkoxygroup,

R0means a group of the formula Alk-NR4R5< / BR>
where Alk is alkalinous group having a straight or branched C1-6chain,

R4and R5signify, independently from each other, a hydrogen atom, a C2-6alkenylphenol group1-8alkyl group which may be substituted replace the group, phenyl groups - the latter may be substituted by 1 to 3 C1-4alkoxygroup(groups) - and 5 - or 6-membered saturated heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, or

R4and R5form together with the adjacent nitrogen atom and possibly one or more atom(atoms) of nitrogen and/or oxygen and/or sulfur from 5 to 10-membered saturated heterocyclic group which may be substituted WITH1-4alkyl group or phenyl group, the latter can be replaced WITH1-4alkoxygroup,

one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen and/or sulfur, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR,

where R is lilina group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

and their pharmaceutically acceptable salts accession acids.

Derivatives of 1,3,4-thiadiazole, substituted in position 2 substituted morpholino group described in the application for the European patent 123473. These known compounds have antitumor activity. 2-amino-1,3,4-thiadiazole, substituted aminoalkyl group in position 5, is known from WO 92/22541. 2-amino-1,3,4-thiadiazole, replaced by aminoalkylation in position 5, as described in WO 92/22542. These known thiadiazole derivatives are suitable for treating diseases of the Central nervous system and hypertension.

The synthesis of derivatives of 2-(3-methylthio-5-amino-1,2,4-triazole-1-yl)-1,3,4-thiadiazole, substituted with mercaptopropyl in thiadiazoline ring, described in J. Het. Chem., 30, 333-343 (1993) without any indications of their potential biological effects.

The purpose of the present invention was to obtain new derivatives of 1,3,4-thiadiazole with cardiotoxin action and/or the new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I.

In the description and the claims in the notation of deputies under the halogen atom should be understood first and foremost atom of fluorine, chlorine, bromine or iodine, preferably fluorine atom, chlorine or bromine.

WITH1-4an alkyl group is methyl, ethyl, n-sawn, ISO-propyl, n-butilkoi, second-butilkoi, tert-butilkoi or isobutylene group. Preferably, if C1-4an alkyl group is methyl, ethyl or isopropyl group.

WITH1-6the alkyl group can be in addition to the above alkyl groups, n-Pintilei, 2-methylbutyl, n-hexylene, 2,2-dimethylbutyl or 2,3-dimethylbutyl group, etc.

In addition to the above alkyl groups, C1-8the alkyl group can be, for example, n-heptylene, 2-methylhexane, n-octiles or 2,2-di-methylhexane group, etc.

WITH2-6Alchemilla group can be, for example, vinyl, allyl, 3-butene-1-ilen, 2-butene-1-ilen, 3-penten-2-ilen, 4-penten-2-ilen, 3-HEXEN-1-ilen, 4-HEXEN-1-ilen, 5-HEXEN-1-ilen, 2-HEXEN-1-ilen group, etc. are Preferred, WITH2-6Alchemilla group is an allyl group.

WITH2-6ilen, 3-penten-1-ilen, 4-pentyn-1-ilen, 3-hexyne-1-ilen, or 5-hexyne-1-ilen group, etc. is Preferable, if a2-6Alchemilla group is a propargyl group.

C1-4alkoxygroup is, first and foremost, methoxy, ethoxy - n-propoxy or n-butoxypropyl, preferably, a methoxy group.

Under from 5 to 10-membered saturated heterocyclic group mean heterocyclic group containing one or more heteroatoms, where the heteroatoms (heteroatoms) may be an atom(s) of nitrogen and/or oxygen and/or sulphur, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinilnom, imidazolidinyl, pyrimidinyl, pyrazolidinone, hexamethylenimine-1-ilen, heptamethylnonane-1-ilen group, etc. are Preferred, specified heterocyclic group is piperidinyl, piperazinilnom or morpholine-1-ilen group.

Under a 5-or 6-membered saturated heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom imply preferable pyrrolidinyloxy, piperidinyloxy, piperazinilnom or morpholinyl group.

Under pharmaceutically priemlite a suitable inorganic acid, such as hydrochloric, sulphuric, phosphoric, etc., or pharmaceutically suitable organic acids such as acetic, fumaric, lactic, malic, tartaric acid, etc.

The invention encompasses any tautomeric forms of the compounds of formula I and mixtures thereof.

The sub-group of novel compounds of formula I consists of derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole and their pharmaceutically acceptable salts accession acid,

where R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl)amino and di(C1-4alkyl)amino group,

one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen and/or sulfur, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR, the PU, moreover, the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group.

Another sub-group of new compounds of formula I consists of derivatives of 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula

< / BR>
where R0means a group of the formula Alk-NR4R5< / BR>
where Alk is alkalinous group having a straight or branched C1-6chain,

R4and R5signify, independently from each other, C1-6alkyl group or a C2-6alkenylphenol group, or

R4and R5form together with the adjacent nitrogen atom and possibly with one or more atom(atoms) of nitrogen and/or oxygen and/or sulfur from 5 to 10-membered saturated heterocyclic group which may be substituted WITH1-4alkyl group or phenyl group, the latter can be substituted C1-4alkoxygroup,

Z means a hydrogen atom or a C1-4alkoxygroup,

one of R21-4alkyl group, phenyl group or kalogeropoulou group

or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)groups

and their pharmaceutically acceptable salts accession acids.

Another sub-group of novel compounds of formula I consists of derivatives of 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula

< / BR>
where one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/IET be substituted C1-4alkyl group, phenyl group or kalogeropoulou group

or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group and halogenarenes(C1-4alkyl)group,

Alk is C1-6alkalinous group

R4and R5denote, independently of one another, hydrogen or C1-8alkyl group which may be substituted by the Deputy selected from the group consisting of hydroxy-group, (C1-4alkyl)amino, di-(C1-4alkyl)amino group, phenyl group - the latter may be substituted by 1 to 3 C1-4alkoxygroup(groups) - and 5 - or 6-membered saturated heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom, and attached via its nitrogen atom, and the criminal code is acceptable salts accession acids.

Preferred new compounds of formula I are derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole,

where R1means a hydrogen atom, a methyl, ethyl or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, metoxygroup and dimethylaminopropyl,

R2means an amino group which may be substituted halogenosilanes group

R3means piperidine-1-ilen, piperazine-1-ilen, morpholine-1-ilen, or 4-methylpiperazin-1-ilen group or a group of the formula-SR, where R is a methyl group,

and their pharmaceutically acceptable salts accession acids.

Among the new compounds of the formula Ia are preferred derivatives of 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole,

where R0means a group of the formula Alk-NR4R5,

where Alk is ethylene or propylene group,

R4and R5signify, independently from each other, C1-3alkyl group, or

R4and R5together with the adjacent nitrogen atom form pyrrolidinyloxy group

R2is an amino group,

R3is aminopropanol, or a group of the formula-SR,

where R is C1-3alkyl group,

and the amino group may be substituted by two metal groups or two allyl groups,

Z means a hydrogen atom,

and their pharmaceutically acceptable salts accession acids.

Among the new compounds of the formula Ib are preferred derivatives of 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole,

where R4means a hydrogen atom or a C1-2alkyl group,

R5means ethyl group substituted by a Deputy selected from the group consisting of hydroxy-group, dimethoxyphenyl group and morpholino group,

R2is an amino group,

R3is piperidino group or a group of the formula-SR,

where R is C1-3alkyl group,

Alk is C2-3alkalinous group

and their pharmaceutically acceptable salts accession acids.

Particularly preferred compounds of formula I are the following:

1. 2-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-5-(2,6-dichlorophenyl)-1,3,4-thiadiazole,

2. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

3. 2-(5-amino-3-Dima is-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole,

5. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

6 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(2-dimethylaminoethoxy)phenyl/-1,3,4-thiadiazole,

7. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-pyrrolidinyloxy)phenyl/-1,3,4-thiadiazole,

8. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-di(2-methylethyl)aminopropoxy/-phenyl]-1,3,4-thiadiazole,

9. 2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/4-(3-dimethylamino-propoxy)phenyl/-1,3,4-thiadiazole,

10. 2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

11. 2-(5-amino-3-pyrrolidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

12. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{2-[2-/2-ethyl-2-(2-hydroxyethyl)-amino/ethoxy]phenyl}-1,3,4-thiadiazole,

13. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-(2-morpholinoethyl)amino/-ethoxy]phenyl-1,3,4-thiadiazole,

14. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

15. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{2-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

16. 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxy is ethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

18. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 4-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy] phenyl}-1,3,4-thiadiazole, and their pharmaceutically acceptable salts accession acids.

Derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole according to the present invention will receive:

a) cyclization of the hydrazone thiocarbonic acid formula

< / BR>
where R1, R2and R3such as described above, an oxidizing agent; or

b) reaction of the hydrazide thiocarbonic acid formula

< / BR>
where R2and R3such as described above with orthoevra formula

< / BR>
where R1as mentioned above, R11means tsepliaeva group; or

C) reaction of a phenol of the formula

< / BR>
where R2, R3and Z such as described above with aminoalkylsilane formula

< / BR>
where Alk, R4and R5such as specified in the description of R1Hal means a halogen atom, to obtain the compounds of formula I, where R1means a group of formula a, R2, R3, R0and Z such as specified in paragraph 1 of the claims; or

d) reaction of a halide of the formula

< / BR>
where R2, R3and Z such as described above, Alk as mentioned in the description of R1Hal means the atom hallucine the compounds of formula I, where R1means a group of formula a, R2, R3, R0and Z such as specified in paragraph 1 of the claims;

and, if necessary, turn the thus obtained compound of formula I, its pharmaceutically acceptable salt accession acid, or select a compound of formula I from its salts.

In method a) use inorganic or organic oxidizing agent.

As the inorganic oxidizing agent is used, the halide of a heavy metal, such as iron chloride(III) chloride mercury(II) chloride lead(VI), pentachloride antimony chloride thallium(III), preferably a chloride of iron(III).

As an organic oxidizing agent used benzoquinone derivative such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzoquinone (p-chloranil), 2,3-dichloro-1,4-dihydroxyanthraquinone, 6,7-dichloro-1,4-dihydroxyanthraquinone or 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone, preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

Oxidation of hydrazones thiocarbonic acid of the formula II inorganic oxidizing agent is carried out in polar solvent such as water, acetic acid, methanol, acetonitrile or dimethylformamide, preferably at a CME>
With over 0.05 to 12 hours, preferably from 0.25 to 2 hours.

The reaction of the closing ring using organic oxidizing agent is carried out in a solvent which is inert to the components of the reaction mixture, preferably in tetrahydrofuran, at temperatures from 0oWith up to 80oC, preferably from 15oWith up to 20oWith, for 0.25 to 4 hours, preferably from 1 to 1.5 hours.

For separation of the reaction product from the reaction mixture using known methods. So, if the product crystallizes from the reaction mixture, the crystals are filtered. If the product is not deposited mainly due to the fact that the solvent was taken in excess, the solution is concentrated and the precipitated product is filtered. Purify the product, usually by recrystallization from a suitable solvent.

In method (b) reaction of the hydrazide thiocarbonic acid of formula III with orthoevra formula IV is carried out in a polar solvent, such as alcohols, preferably methanol boiling under reflux, however, the reaction can also be carried out in excess of artefiera formula IV. In this case, the excess orthoevra plays the role of the solvent. is ode reactions. If R11means alkyl group, e.g. ethyl, he, together with the adjacent oxygen atom and a hydrogen atom, otdalennym from hydrazide thiocarbonic acid of the formula III, forms in the reaction ethanol.

Preferably R11means1-4alkyl tsepliaeva group.

For separation of the reaction product from the reaction mixture using known methods. So, if the product crystallizes from the reaction mixture, the crystals are filtered. If the product is not deposited mainly due to the fact that the solvent was taken in excess, the solution is evaporated to dryness and the remaining product was then purified by recrystallization from a suitable solvent.

In method (C) reaction of a phenol of formula V with aminoalkylsilane formula VI is carried out in the presence of an organic or inorganic base in a solvent which is inert to the components of the reaction mixture.

As inorganic bases are used, for example, a hydroxide of alkali or alkaline earth metal, preferably potassium hydroxide or sodium, as an organic base is used, as a rule, of tetraalkylammonium hydroxide, prefer and in a small excess, for example, 0.1 to 0.5 molar excess. Based on the phenol of formula V, aminoalkylsilane formula VI taken in equimolar amounts or in 0.1 to 0.5 molar excess.

If you use an organic base, it is convenient to first obtain the appropriate of tetraalkylammonium hydroxide, and then perform the reaction with aminoalkylsilane formula VI.

In this reaction the solvent can be used alcohols, preferably methanol or ethanol, ketones, preferably acetone or methyl ethyl ketone, acetonitrile, dimethylformamide, dimethylsulfoxide, halogenated solvents, preferably 1,2-dichloroethane or chlorobenzene.

For separation of the reaction product from the reaction mixture using known methods. So, if you use a solvent from which the product crystallized, the crystals filtered off and purified by recrystallization. If the product is not precipitated when the use is not miscible with water solvent, the reaction mixture is diluted with water, the phases are separated, the organic phase is evaporated, the remaining product was then purified by simple recrystallization. When using miscible with water solvent, the product is precipitated with water, filtered or races of the memory is separated, is evaporated, the residue is recrystallized.

In method (d) reaction of a halide of formula VII with an amine of formula VIII is carried out in an excess of amine, however, the reaction can be carried out in a solvent which is inert to the components of the reaction mixture.

As the inert solvent can be used alcohols, preferably methanol or ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, halogenated solvents, preferably 1,2-dichloroethane or chlorobenzene.

The product isolated from the reaction mixture using any of the methods described above.

If the reaction mixture is evaporated, the residue can be mixed with water and does not mix with water solvent, to bring the reaction mixture to alkaline, split phase and after evaporation of the organic phase to clean up the remaining base recrystallization.

If the compound of the formula I is converted into the salt of the accession acid, the basis of the formula I are dissolved in a suitable solvent, add the appropriate acid and after cooling is filtered off the crystals of salt.

The hydrazones thiocarbonic acid of the formula II are known from the literature (description Hungarian is th shown in the examples.

The hydrazides thiocarbonic acid of the formula III are known from the literature (described in the Hungarian patent 206095).

Compounds of formulae IV, VI and VIII are commercially available.

The phenol of formula V are obtained from the corresponding hydrazone thiocarbonic acid, where R1is a hydrogen atom, by reaction of the closing ring under the conditions described in method (a).

The invention also includes a new intermediate products of the formula

< / BR>
where R7means a group of formula-Alk-L

where Alk denotes a straight or branched C1-6alkylenes chain,

L means a halogen atom or a hydroxy-group,

Z means a hydrogen atom or a C1-4alkoxygroup,

one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen and/or sulfur, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6iroppoi or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

and their salts accession acids.

The compounds of formula IX include halides of formula VII.

Intermediates of formula IX is obtained by cyclization of the hydrazone thiocarbonic acid formula

< / BR>
where R2, R3, R7and Z such as described above, with an oxidizing agent. The reaction is carried out analogously to method a).

The compounds of formula IX, where L is a halogen atom, R2, R3, Z and Alk are, as indicated above, can also be obtained by reaction of a phenol of formula V with dihalogenoalkane formula

Hal - Alk - Hal XI

where Hal is a halogen atom, Alk as mentioned above. The reaction is carried out in a polar solvent such as an alcohol, preferably methanol, in the presence of inorganic or organic bases. Also as a solvent, you can use the excess dihalogenoalkane formula XI.

The basis taken in equimolar amounts or a slight excess (from 0.1 to 0.5 m is cinselligi metal, better hydroxide of potassium or sodium, as an organic base can be used, for example, Quaternary amine or hydroxide of tetraalkylammonium, namely, triethylamine, dimethylaniline, hydroxide or tetrabutylammonium hydroxide designed.

The reaction is carried out in the temperature range from room temperature up to the boiling temperature of the reaction mixture, preferably from 40oWith up to 80oC.

The compounds of formula IX, where L is a halogen atom, can also be obtained by reaction of hydroxycodone formula

< / BR>
where R2, R3, Z and Alk are, as indicated above, with a halogenation agent. The reaction is carried out using a suitable halogenation agent in an inert solvent. As the reaction medium can be used aromatic hydrocarbons, preferably benzene or toluene, or halogenated hydrocarbons, such as chlorobenzene, chloroform, dichloromethane or carbon tetrachloride.

As the halogenation agent, you can use the halides of elements of the 5th or 6th groups of the periodic system, for example, trichloride phosphorus, pentachloride phosphorus, phosphorus oxychloride, thionyl chloride, preferably phosphorus oxychloride or mperature boiling point of the reaction mixture, preferable from the 40oWith up to 70oC.

Gidroksosoedinenii formula XII can be obtained by reaction of a phenol of formula V with hydroxyalkylated formula

Hal - Alk - OH XIII

where Hal means a halogen atom, Alk has the values listed above. The reaction is carried out in a manner analogous to the method described in connection with the reaction of the phenol of formula V with dihalogenoalkane formula XI.

If necessary, the intermediate product of formula IX is transformed into salt accession acid in a known manner or separated from salt accession acid in a known manner.

Biological effects of derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the present invention were studied in the following experiments.

1. Measurement of the effect of relaxation of the blood vessels of the isolated thoracic aorta of the rat, contrastirovanii in potash.

The experiments were performed on the thoracic aorta obtained from male SPRD rats weighing 250-300 g of the Thoracic aorta, cut in rats, dead by decapitate and bleeding, were cleaned of fat and connective tissue, then immediately placed in a solution turbogenerating of TIRED. The composition of a normal solution of TYRODE was as follows (in mmol): NaCl To 114.7, KCl 3,7, CaClo. The aortic strips were placed vertically between two cotton threads in chambers with a volume of 10 ml, the lower threads were attached to the cameras, and the upper bound with isometric torque sensors. Strips were incubated with residual tension of 1 g at 37oC for 120 minutes, after which it was registered residual vascular tone. Then the strips were contractionary with a solution of TYRODE containing 20 mmol KCl. The composition of the solution of TYRODE with a high content of potassium was as follows (in mmol): NaCl 94,7, KCl 20, CaCl23,6, MgCl20,49, NaHCO319,9, NaH2PO40,32, glucose 5,1.

When was sustained vascular tone in the bath were added increasing the dose of the control substance. The effect of each dose of the control substance was measured at least three tissue preparations obtained from different animals. The decrease of vascular tone caused by the control substances was expressed as change percentage, and the IC50for each drug, tissue was determined by fitting a sigmoidal curve (in some cases - direct). The values of the IC50for each test substance were averaged and are given in table.I shall original)-2H-1-benzopyran-6-carbonitrile.

For additional comparison was used diltiazem, i.e., (2S)-CIS-3-atomic charges-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-he.

Diltiazem is a blocker of calcium channels, so its effect was tested on vessels, contractorowned with a solution of TYRODE with a content of 40 mmol of potassium chloride. The testing procedure was in all respects identical to that described above, except that strips of isolated thoracic aorta of the rat was contractibility using a modified solution TYRODE containing 40 mmol of potassium chloride. The composition of the solution of TYRODE with a high content of potassium was as follows (in mmol): NaCl 74,7, KCl 40, CaCl23,6, MgCl20,49, NaHCO319,9, NaH2PO40,32, glucose 5,1.

Some of the tested compounds, such as derivatives, specified in examples 29, 30 and 101, led to a relaxation of the isolated thoracic aorta in rats more effectively than the reference substance, opening the channel K+and blocking the channel CA2+. Has been very favorable, other derivatives, providing cardiotoxin and/or antiarrhythmic effect, did not cause relaxation of blood vessels.

2. Measurement Of The Sabbath.

Effective refractory period (ETA) is considered as the shortest time interval between two identical electrical stimuli, both of which lead to the reduction of the papillary muscles. The second irritation is applied before the ETA is not effective. Connection extending ETA may have antiarrhythmic effects. This method is useful primarily when the trials of antiarrhythmic agents of class III according to the classification of Vaughan Williams (Vaughan Williams; Bexton, R. S. and Camm. A., J. Pharmacol. Ther., 17, 315 (1982)).

The experiments were conducted in the system of baths type Schuler with 4 channels. Male Guinea pigs weighing 450-750 g were killed by a blow on the head and exsanguinated. The heart was quickly cut, and papillary muscles of a suitable size (less than 1 mm in diameter) were separated from the right ventricle. The preparations were placed vertically in a chamber with a volume of 20 ml with Krebs solution, barbotirovany carbon-containing gas (consisting of 95% O2and 5% CO2and the temperature of the 35oC. the Upper ends of the muscles were connected using cotton threads with a torque sensor connected to the data logger for the measurement of isometric tension by using amplifiers constant that is a, which were also used as the stimulating electrode. The other electrode was immersed in the bath and had no direct contact with the drug. The composition of the Krebs solution was as follows (in mm): NaCl 118, KCl 4,8, Panso327,2, glucose of 11.1, MgSO41,2, KH2PO41, l22,6, pH 7.4.

The drugs were brought into equilibrium within 120 minutes at a residual tension of 1 g. During the equilibration they were subjected to irritation of the electric current with a frequency of 2 Hz rectangular pulses of 1 MS, which is 10% above the diastolic threshold voltage. ETA was determined using standard technologies extrastimulation. Extrastimulation (S2) was made between normal stimuli (S1) so that the interval S1-S2was initially less refractory period of the tissue. Then the interval S1-S2gradually increased to 1 msec until extrastimuli (S2) did not cause contraction of the papillary muscles. The strength reduction caused by the S2that was more of strength reduction due to normal stimuli (S1) (postextrasystolic gain). The shortest interval S1-S2when CSU devices. This interval is equivalent to the ETA.

The Protocol was the following:

Two test measurements ETA was carried out with an interval of 20 minutes, then was added the appropriate amount of test substance required to get in the bath solution concentration of 10-4mol. After 30 minutes of incubation with the test substance at intervals of 30 minutes were carried out two measurements of ETA.

When the test substance increased ETA at 10-4mol 40 msec or more, the impact on the ETA was also tested at 10-5the mole.

The effect of the tested substance was characterized by the difference between the first and second control measurements. Data obtained by at least 4 different drugs were averaged. The obtained average values are presented in table. II. As a reference substance was used sotalol, i.e. N-[4-/1-hydroxy-2-(1-methylethylamine)ethyl/phenyl]methanesulfonamide.

As can be seen from the table.II, many new compounds of this invention significantly prolong ETA at 10-4mol with greater efficiency than the reference substance sotalol. Moreover, the effect of the compound of example 32 was also significant at the 10-5the mole.

If blood flow to part of the heart muscle is interrupted (for example, during a myocardial infarction), the concentration of intracellular calcium begins to grow and eventually reaches the pathophysiological levels. Contraction of the heart muscle is regulated by calcium, so a high concentration of intracellular calcium leads to involuntary spastic contraction of the heart muscle. In isolated hearts of rats involuntary spastic contraction develops in about 10 minutes after the onset of total ischemia, and this period is called the time to contracture (VDK). Any substance that can inhibit the increase in the concentration of intracellular calcium and the development of contractures caused by high concentration of calcium during ischemia protects the myocardium from damage, i.e. has cardiotoxicity effect. In the experiment cardiotoxicity effect of drugs is manifested in their ability to extend VDK. Cardiotoxicity effect of chemical compounds of this invention was studied by measuring VDK on the hearts of rats (drug Langendorf), completely amazed ischemia (Longman, S. D. and Hamilton, T. S., Medicinal Research Reviews, 12, 73-148 (1992)).

Males Victorovich rats weighing 300-350 g were made inje what rutala sodium (sodium salt of 5-ethyl-5-(1-methylbutyl)-2,4,6-(1H, 3H, 5H)-pyrimidinetrione) in an amount of 60 mg/kg intraperitoneally. The heart was quickly excised and attached to the apparatus Langendorf through the aorta. Heart, at constant pressure (60 mm Hg) and temperature (37oC), were subjected to perfusion with a modified Krebs solution-Henseleit (Krebs-Henseleit), through which was passed a gas containing 95% O2and 5% CO2. The composition of the modified Krebs solution-Henseleit was as follows (in mm): NaCl 118, KCl 4.7 In, CaCl22,5, NaHCO3ARE 24.88, KH2PO41,18, MgSO41,6, EDTA 0.5, and glucose 11. The partial pressure of O2and CO2and pH were measured and maintained within normal limits (Rho2=64000-77000 PA, RNO2= 3800-4500 PA, pH of 7.3 was 7.45). In the wall of the left atrium, a hole was made, and then to measure the left ventricular pressure in the left ventricle via the left atrium was introduced water-filled plastic container, connected to the metal cannula. End-diastolic pressure was set to approximately 645 PA, and then was maintained for a period of equilibration, but not later.

After a 20-minute period of equilibration heart for 10 minutes was subjected to perfusion of the test substance with concentric the freight flow perfusion solution and carbohydate for 25 minutes. During ischemia was measured period of time from the beginning of ischemia before the rise of diastolic pressure to 645 PA at the end of the left ventricle (VDK).

There were three experiences with the tested substances each concentration were simultaneously measured parameters 3 hearts, solvent-treated.

Individual values VDK were averaged, the effect of the test substances was expressed in percentage changes VDK compared with the group that was treated with solvent. Connection extending VDK are cardiotoxicity. The results obtained are presented in table.III. As a reference substance was used by imaclim, i.e., (3S)-TRANS-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-6-carbonitrile.

Some new compounds of this invention caused a greater extension VDK than the reference substance of imaclim.

According to the data presented in table.I and III, substances, extending VDK, did not cause muscle relaxation, in contrast to lemnalia, which not only prolongs VDK, but also causes a significant relaxation of the isolated thoracic aorta of rats. Thus, these new derivatives of 1,3,4-thiadiazole demonstrated villages is adavale, lowering blood pressure is favorable, because for most patients, low blood pressure caused cardiostim connection can be regarded as an unwanted side effect.

Some of the new compounds, for example, the compound from example 26, extending not only VDK, but the ETA. These results reveal the presence of double - cardiotoxins and antiarrhythmic - efficacy of some new compounds. This profile increases the possibility of extremely favorable therapeutic applications because, by assigning a single drug, it is possible to achieve as cardiotoxins effect and prevent arrhythmias are frequently observed in patients with heart failure. This connection is superior to both the standard drug, each of which is suitable for only one therapeutic targets.

In short, the data obtained in the pharmacological studies of derivatives of 1,3,4-thiadiazole of the present invention, proved that some of these compounds have the desired effect on the blood vessels and myocardium. The effectiveness of some derivatives of 1,3,4-thiadiazole surpassed the effectiveness of therapeutically probe have a significant effect relaxation of blood vessels, therefore, such derivatives can be useful for the treatment of hypertension and for vasodilator therapy for peripheral vascular diseases. From the latest therapeutic indications should mention coronary heart disease, and vasospasm brain (stroke). Its effects on the heart, other compounds of this invention useful for treatment of ventricular fibrillation and to prevent myocardial damage caused by insufficient coronary blood flow, resulting in ischemic heart disease or during cardiac operations, i.e., to protect the heart from the effects of the inevitable ischemic stroke attack.

4. Study of the binding of the receptors 5-HT2Aand 5-HT2C< / BR>
Assessment of binding of the receptors 5-HT2Aand 5-HT2Cwas carried out according to the method described by Lasanum (Leysen), and other (Mol. Pharmacol., 21, 301 (1981)) and Passam (Pazos) and other (Eur. J. Pharmacol., 106, 539 (1985)), respectively. Assessment of binding of the receptor 5-HT2Awas conducted on the preparation of the membrane cortex is the anterior part of the brain of the rat using titiraupenga ketanserina (3-(2-(4-perbenzoic)-1-piperidinyl(ethyl-2,4-(1H, 3H)-chineselanguage) (60-90 CI/mmol) as the ligand. Assessment of binding of the receptor is eat titiraupenga mesulergine /N'/(8)-1,6-dimethylarginine-8-yl/-N,N-dimethylsulfide (70-85 CI/mmol) as the ligand. Nonspecific binding to receptors 5-HT2Aand 5-HT2Cwas determined in the presence of 10 µmol ciprogeptadina (4-(5H-dibenzo (a,d) cyclohepten-5-ilidene)-1-methylpiperidin) and 1 µmol mianserin (1,2,3,4,10,14 b-hexahydro-2-methyldibenzo (c, f) - pyrazino/1,2-a/ azepine), respectively. The final volume of incubation was 250 and 1000 ál. The samples were subjected to incubation for 15 and 30 minutes at 37oC. Incubation was stopped by adding to the reaction mixture of 9 ml of ice-cold Tris(hydroxymethyl)-aminomethylpyrrolidine (pH of 7.7) with a concentration of 50 mmol. The samples were rapidly filtered through a filter Paper (Whatman) GF/B glass fiber under reduced pressure. Before using the filters were immersed in a 0.05% solution of polyethylenimine from 2 to 3 hours. The radioactivity of the filters was determined by scintillation spectrometer.

The results obtained are presented in table.IV.

From table.IV shows that the new compounds of this invention have significant affinity for the receptors 5-HT2Cwith moderate or high degree of selectivity compared with receptors 5-HT2A. Thus, these compounds can be used for the treatment of disorders resulting from pathologies who was tarawali their affinity primarily to the subtypes of serotonergic receptor 5-HT2C. In the literature that this receptor plays a major role in pathomechanism phobias, schizophrenia and headaches. Agonist of the receptor 5-HT2Cm-chlorophenylpiperazine (Conn et al., Proc. Natl. Acad. Sci USA, 83, 4086 (1986)) causes a feeling of fear in rats (Kennett et al., Eur. J. Pharmacol., 164, 455 (1989)), and people (Kahn and Weltzer, Biol. Psychiat., 30, 1139 (1991)). On the basis of studies conducted on rats, the effects of m-chlorophenylpiperazine causing an alarm condition can be explained by the activation of receptors 5-HT2C(Kennett et al., Eur. J. Pharmacol., 164, 455 (1989)). In experiments on animals shows that the compounds exerting an antagonistic effect on the receptors 5-HT2A/2Chave a calming effect (Kennett, Psychopharmacol., 107, 379 (1992)). It is proved that the connection ritanserin (6-[2-(4-bis(4-forfinal)-methylene)-1-piperidinylmethyl] -7-methyl-5H-thiazolo(3,2-a)pyrimidine-5-Oh), which has an antagonistic effect on the receptor 5-HT2A/2Cis effective in the treatment of various forms of phobias in humans (Ceulemans et al., Pharmacopsychiat., 18, 303 (1985). It should be emphasized that the compounds selectively bind to the receptors 5-HT2Cmay have advantages compared to compounds with affinity for the receptor subtypes 5-HT2Aand 5-HT2C.

2C(Sleight et al., in Serotonin Receptor Subtypes: Basic and Clinical Aspects, ed. Peroutka, S. J., pp.211, Wiley-Liss Inc., 1991).

Thus, some new compounds of this invention can be used in particular for the treatment of heart failure and/or arrhythmia, while the other compounds of this invention useful for treatment of diseases of the Central nervous system.

As the results of the experiments described above, the new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I and their pharmaceutically acceptable salts accession acids can be used as active ingredients of pharmaceutical compositions. The pharmaceutical compositions of this invention contain a therapeutically active amount of the compound of formula I or its pharmaceutically acceptable salt accession acid and one or more traditional media.

The pharmaceutical compositions of the present invention is convenient for oral, parenteral or rectal, and topical treatments, and can be applied in the form of solid or liquid preparations.

Solid pharmaceutical compositions, convenient for oral administration, can be used in the form of powders, capsules, tablets, tableprovider and so on; fillers such as lactose, glucose, starch, calcium phosphate, and so on; excipients for the manufacture of tablets, for example, magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.; moisturizers, for example, sodium lauryl sulfate, etc. as carriers.

Liquid pharmaceutical compositions, convenient for oral administration, can be used in the form of solutions, suspensions or emulsions, and may include, for example, suspendresume agents, such as gelatin, carboxymethyl cellulose, etc.; emulsifying agents, for example, servicemanuals and so on; solvents such as water, oil, glycerine, propylene glycol, ethanol and so on; preservatives, for example methyl-p-hydroxybenzoate etc. as carriers.

Pharmaceutical compositions, convenient for parenteral use, usually consist of sterile solutions of the active ingredient.

The above dosage forms, as well as other dosage forms, known per se, see, for example. Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions of this invention contain as a rule 0.1 to 95,0 wt.% the compounds of formula I or its pharmaceutically acceptable salt accession acceptable salt accession acid daily. This dose can be taken in one or several stages. The actual dose depends on many factors and is determined by the doctor.

The pharmaceutical compositions of the present invention is obtained by mixing the compounds of formula I or its pharmaceutically acceptable salts accession acids with one or more carrier (s) and converting the mixture into a pharmaceutical composition by known methods. These methods known from the literature, for example, Remington''s Pharmaceutical Sciences.

Subgroup of pharmaceutical compositions of the present invention contains as an active ingredient a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I,

where R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl)amino and di(C1-4alkyl)amino group,

one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen, and/or 1-4 alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

or its pharmaceutically acceptable salt accession acid.

Another subgroup of pharmaceutical compositions of the present invention contains as an active ingredient derived 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ia,

where R0means a group of the formula Alk-NR4R5,

where Alk is alkalinous group having a straight or branched C1-6chain,

R4and R5signify, independently from each other, C1-6alkyl group or a C2-6alkenylphenol group, or

R4and R5form together with the adjacent ATA is nnow saturated heterocyclic group, which may be substituted WITH1-4alkyl group or phenyl group, the latter can be replaced WITH1-4alkoxygroup,

Z means a hydrogen atom or a C1-4alkoxygroup,

one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen and/or sulfur, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl) group,

or its pharmaceutically acceptable salt accession Ki the th active ingredient derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ib,

where one of R2and R3is amino and the other is an amino group or a 5-to 10-membered saturated heterocyclic group containing one or more atom(s) of nitrogen and/or oxygen and/or sulfur, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR,

where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group

and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

Alk is C1-6alkalinous group

R4and R5signify, independently from each other, a hydrogen atom, a C1-8alkyl group which may be substituted by the Deputy selected from the group consisting of hydroxy-group, (C1-4alkyl)amino-4 alkoxygroup(groups) - and 5 - or 6-membered saturated heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group,

or its pharmaceutically acceptable salt accession acid.

Preferred pharmaceutical composition of the present invention contains as an active ingredient a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I,

where R1means a hydrogen atom, a methyl, ethyl or fenloe group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, metoxygroup and dimethylaminopropyl,

R2means an amino group which may be substituted halogenosilanes group

R3means piperidine-1-ilen, piperazine-1-ilen, morpholine-1-ilen, or 4-methylpiperazin-1-ilen group or a group of the formula-SR, where R is a methyl group,

or its pharmaceutically acceptable salt accession acid.

Accordingly, the pharmaceutical composition of nastoiashaia Ia

where R0means a group of the formula Alk-NR4R5,

where

Alk is ethylene or propylene group,

R4and R5signify, independently from each other, C1-3alkyl group, or

R4and R5together with the adjacent nitrogen atom form pyrrolidinyloxy group, R2is an amino group,

R3is an amino group or piperidinyl, or 4-methylpiperidino group, and these groups are attached through the nitrogen atom, or a group of the formula-SR, where R is a C1-3alkyl group,

and the amino group may be substituted by two methyl groups or two allyl groups,

Z means a hydrogen atom,

or its pharmaceutically acceptable salt accession acid.

Another preferred pharmaceutical composition of the present invention contains as an active ingredient derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ib,

where R4means a hydrogen atom or a C1-2alkyl group,

R5means ethyl group substituted by a Deputy selected from the group consisting of hydroxy-group, dimethoxyphenyl group and Mohali formula-SR,

where R is a C1-3alkyl group,

Alk is C2-3alkalinous group

or its pharmaceutically acceptable salt accession acid.

A particularly preferred pharmaceutical composition of the present invention contains as an active ingredient any one of the following connections:

1. 2-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-5-(2,6-dichlorophenyl)-1,3,4-thiadiazole,

2. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

3. 2-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

4. 2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole,

5. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

6. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(2-dimethylaminoethoxy)phenyl/-1,3,4-thiadiazole,

7. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-pyrrolidinyloxy)phenyl/-1,3,4-thiadiazole,

8. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-di(2-methylethyl)aminopropoxy/-phenyl]-1,3,4-thiadiazole,

9. 2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/4-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

10. 2-(5-amino is about-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

12. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{2-[2-/2-ethyl-2-(2-hydroxyethyl)-amino/ethoxy]phenyl}-1,3,4-thiadiazole,

13. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-(2-morpholinoethyl)amino/-ethoxy]phenyl-1,3,4-thiadiazole,

14. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

15. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

16. 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]-phenyl}-1,3,4-thiadiazole,

17. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 3-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

18. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 4-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole,

or its pharmaceutically acceptable salt accession acid.

In addition, the invention relates to a method for the treatment of pharmaceutical preparations, which comprises the administration to a patient suffering from a disease of the heart and/or circulatory system or the Central nervous system, a therapeutically effective non-toxic amount of a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiad the e is illustrated in detail by the following examples.

Getting starting compounds of formula II

1) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

2,72 ml (0,026 mol) of salicylic aldehyde is added to the suspension 4.83 g (0.02 mol) of 1-(5-amino-3-piperidino-1,2,4-triazole-1-yl)thiohydrazide in 20 ml of methanol; the reaction mixture is stirred for 4 days. The crystals are filtered, washed with some methanol, chloroform, and then the tetrahydrofuran.

So get 5,94 g (86,1%) connection specified item with the melting temperature of 170-175oC.

2) 1-(5-amino-3-methylthio,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

of 2.3 ml (0,022 mol) of salicylic aldehyde is added to the suspension 4,08 g (0.02 mol) of 1-(5-amino-3-methylthio-1,2,4-triazole-1-yl)thiohydrazide in 20 ml of methanol; the reaction mixture is stirred for 16 hours. The crystals are filtered and washed with some methanol.

So get of 5.48 g (88,8%) of the named compound with a melting point 180-183oC.

3) 1-(5-amino-3-propylthio--1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

2,69 g (0,022 mol) of salicylic aldehyde is added to the suspension with 4.65 g (0.02 mol) of 1-(5-amino-3-propylthio-1,2,4-triazole-kristalli filter, washed with some methanol.

So get of 6.65 g (98,8%) of the named compound with a melting point 178-181oC.

4) 1-(5-amino-3-allylthio,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

1.10 g (0.09 mol) of salicylic aldehyde is added to a suspension of 1.84 g (0.08 mol) of 1-(5-amino-3-allylthio-1,2,4-triazole-1-yl)thiohydrazide in 15 ml of methanol; the reaction mixture is stirred at room temperature for 4 hours. The crystals are filtered, washed with some methanol.

So get 2,53 g (94,5%) of the named compound with a melting point 171-174oC.

5) 1-(5-amino-3-benzylthio,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

of 1.34 g (to 0.011 mol) of salicylic aldehyde is added to a suspension of 2.8 g (0.01 mol) of 1-(5-amino-3-benzylthio-1,2,4-triazole-1-yl)thiohydrazide in 10 ml of methanol; the reaction mixture is stirred at room temperature for 24 hours. The crystals are filtered, washed with some methanol.

So get to 3.34 g (87,0%) of the named compound with a melting point 164-167oC.

6) 1-(5-amino-3-morpholino,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbothioamides

Thus obtained 3.2 g (92.2 per cent) of these compounds with a melting point 183-186oC.

7) 1-/5-amino-3-(4-methylpiperazine)1,2,4-triazole-1-yl/-N'-(2-hydroxybenzylidene)carbothioamides

of 2.68 g (0,022 mol) of salicylic aldehyde is added to the suspension to 5.13 g (0.02 mol) 1-/5-amino-3-(4-methylpiperazine)-1,2,4-triazole-1-yl/thiohydrazide in 40 ml of methanol; the reaction mixture is stirred at room temperature for 24 hours. The crystals are filtered, washed with some methanol.

So get 6,35 g (88,0%) of the named compound with a melting point 176-179oC.

8) 1-(5-amino-3-propylthio,2,4-triazole-1-yl)-N' -(2-hydroxybenzylidene)carbothioamides

of 1.34 g (to 0.011 mol) of salicylic aldehyde is added to a suspension of 2.28 g (0.01 mol) of 1-(5-amino-3-propylthio-1,2,4-triazole-1-yl)thiohydrazide in 10 ml of methanol; the reaction mixture is stirred at room temperature for 24 hours. The crystals are filtered, washed with some methanol.

So get 3,14 g (94,6%) of the named compound with ten)carbothioamides

of 0.77 g (0,006 mol) of salicylic aldehyde is added to a suspension of 1.37 g (0,005 mol) 1-/(5-amino-3-(n-hexylthio)-1,2,4-triazole-1-yl/thiohydrazide in 10 ml of methanol; the reaction mixture is stirred at room temperature for 20 hours. The crystals are filtered, washed with some methanol.

So get 1,76 g (93.1%) are named compound with a melting point 158-160oC.

10) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/4-(2-bromoethoxy)benzyliden/carbothioamides

to 2.41 g (0,0105 mol) of 4-(2-bromoethoxy)of benzaldehyde are added to a solution to 2.41 g (0.01 mol) of (5-amino-3-piperidino-1,2,4-triazole-1-yl)carbodiimide 13.5 ml of chloroform and 1.5 ml of methanol. The reaction mixture was stirred at room temperature for 22 hours, filtered, the product on the filter is washed with chloroform. The filtrate is evaporated to dryness under reduced pressure and dry the residue is subjected to chromatography on a column of Kieselgel 60 H. The fractions containing the desired product are evaporated.

So get of 2.92 g (64,6%) of the named compound with a melting point 158-161oWith decomposition, after recrystallization from acetonitrile).

11) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(3-bromopropane)bensulide the Ino-3-piperidino-1-1,2,4-triazole-1-yl) carbodiimide in 100 ml of methanol; the reaction mixture was stirred at room temperature for 22 hours. Precipitated precipitated crystals are filtered, washed with methanol or ether.

So get to 11.8 g (96,2%) of the named compound with a melting point 167-168oC.

12) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(2-bromoethoxy)benzyliden/carbothioamides

24,05 g (0,105 mol) of 2-(2-bromoethoxy) of benzaldehyde are added to a solution and 24.1 g (0.1 mol) of (5-amino-3-piperidino,2,4-triazole-1-yl)carbodiimide in 150 ml of methanol; the reaction mixture is stirred at room temperature for 27 hours. Precipitated precipitated crystals are filtered, washed with methanol and tetrahydrofuran.

So get 30,2 g (66,8%) of the named compound with a melting temperature of 150-160oWith decomposition, after recrystallization from acetonitrile).

13) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/3-(2-bromoethoxy)benzyliden/carbothioamides

24,1 g (0,105 mol) of 3-(2-bromoethoxy)of benzaldehyde are added to a solution 24,13 g (0.1 mol) of (5-amino-3-piperidino,2,4-triazole-1-yl)carbodiimide in 150 ml of ethanol; the reaction mixture is stirred at room temperature for 17 hours. Precipitated precipitated crystals are filtered, washed uroy melting 173-176oWith decomposition, after recrystallization from acetonitrile).

14) 1-(5-amino-3-piperidino)1,2,4-triazole-1-yl)-N'-/2-(4-bromobutoxy)benzyliden/carbothioamides

14,01 g (0,0545 mol) of 2-(4-bromobutoxy)of benzaldehyde are added to a solution 12,07 g (0.05 mol) of (5-amino-3-piperidino,2,4-triazole-1-yl)carbodiimide in 72 ml of chloroform and 8 ml of methanol. The reaction mixture was stirred at room temperature for 18 hours, then evaporated to dryness. The dry residue is subjected to chromatography on a column of Kieselgel 60 H. The fractions containing the desired product are evaporated.

So get 11.5g (47.9 per cent) of these compounds with a melting point 130-133oC (decomposition).

15) 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(3-bromopropane-3-methoxy)benzylidene/carbothioamides

9,83 g (being 0.036 mol) of 2-(3-bromopropane)-3-methoxybenzaldehyde added to a solution of 7.24 g (0.03 mol) of (5-amino-3-piperidino,2,4-triazole-1-yl)carbodiimide in 60 ml of methanol. The reaction mixture was stirred at room temperature for 48 hours. Precipitated precipitated crystals are filtered, washed with methanol and ether.

So get 13,87 g (93.1%) are named compound with a melting point of 149 to 152oC.

Thus obtained 4.0 g (93.1%) are named compound with a melting point 157-159oC (decomposition).

17) 1-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/2-(3-bromopropane)benzyliden/carbothioamides

30,6 g (0.125 mol) of 2-(3-bromopropane)of benzaldehyde are added to a solution of 23.2 g (0.1 mol) /5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/carbothioamides in 30 ml of methanol. The reaction mixture was stirred at room temperature for 2.5 hours. Precipitated precipitated crystals are filtered, washed with methanol and ether.

So get of 38.4 g (84,0%) of the named compound with a melting point 136-139oC.

18) 1-(5-amino-3-methylthio,2,4-triazole-1-yl)-N'-/3-(3-bromopropane)benzyliden/carbothioamides

35,8 g (0.147 mol) of 3-(3-bromopropane)of benzaldehyde are added to a solution of 20.4 g (0.1 mol) of (5-amino-3-methylthio,2,4-triazole-1-yl)carbodiimide in 500 ml of methanol. The reaction mixture was stirred at room temperature for 16 hours. Precipitated precipitated crystals are filtered, washed with methanol and ether.

So obratiti,2,4-triazole-1-yl)-N'-/4-(3-bromopropane)benzyliden/carbothioamides

35,8 g (0.147 mol) of 4-(3-bromopropane)of benzaldehyde are added to a solution of 20.4 g (0.1 mol) of (5-amino-3-methylthio,2,4-triazole-1-yl)carbodiimide in 500 ml of methanol. The reaction mixture was stirred at room temperature for 16 hours. Precipitated precipitated crystals are filtered, washed with methanol and ether.

So get 42,0 g (97.8 per cent) of these compounds with a melting point of 135-137oC.

20) 1-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/3-(3-bromopropane)benzyliden/carbothioamides

15.3 g (0,067 mol) of 3-(3-bromopropane)of benzaldehyde are added to a solution of 11.6 g (0.05 mol) /5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/carbothioamides in 180 ml of methanol. The reaction mixture was stirred at room temperature for 2.5 hours. Precipitated precipitated crystals are filtered, washed with methanol and ether.

Thus obtain 20.6 g (90,0%) of the named compound with a melting point 136-139oC.

21) 1-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/4-(3-bromopropane)benzyliden/carbothioamides

15.3 g (0,067 mol) of 4-(3-bromopropane)of benzaldehyde are added to a solution of 11.6 g (0.05 mol) /5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/carbothioamides in 180 ml of methanol. Reaction cosmetolog and ether.

Thus obtain 20.7 g (90,5%) of the named compound with a melting point 132-135oC.

22) 1-/5-benzylamino-3-(2-mediately)1,2,4-triazole-1-yl/-N-/2-(3-bromopropane)benzyliden/carbothioamides

2,80 g (0.012 mol) of 2-(3-bromopropane)of benzaldehyde are added to a solution 3,22 g (0.01 mol) /5-benzylamino-3-(2-metalicity)1,2,4-triazole-1-yl/carbothioamides in 25 ml of methanol. The reaction mixture was stirred at room temperature for 2 hours. Precipitated precipitated crystals are filtered, washed with methanol and cyclohexane.

So get to 4.01 g (73.4%) of the named compound with a melting point 110-112oC.

23) 1-/5-(4-chlorobenzylamino)-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/2-(3-bromopropane)benzyliden/carbothioamides

2,80 g (0.012 mol) of 2-(3-bromopropane)of benzaldehyde are added to a solution of 3.57 g (0.01 mol) /5-(4-chlorobenzylamino)-3-(2-metalicity)1,2,4-triazole-1-yl/carbothioamides in 25 ml of methanol. The reaction mixture was stirred at room temperature for 3 hours. Precipitated precipitated crystals are filtered, washed with methanol and cyclohexane.

So get 4,70 g (81,1%) of the named compound with a melting point 109-111oC.

Policenet

To a suspension 2,71 g (0,006 mol) of 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/4-(2-bromoethoxy)benzyliden/carbodiimide in 20 ml of tetrahydrofuran with stirring and cooling to 25oWith add 1.5 g (of 0.066 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get of 2.56 g (94.7 percent) of these compounds. After chromatography on a column of Kieselgel 60 H and recrystallization from acetonitrile, the product melts at a temperature 229-235oC (decomposition).

25) 2-(5-amino-3-piperidino,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 11.5 g (0,0246 mol) of 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(3-bromopropane)benzyliden/carbothioamides in 75 ml of tetrahydrofuran with stirring and cooling to 25oTo add to 6.43 g (0,028 mol) DDQ, after which the suspension is stirred at room temperature for another 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get 9,36 g (81.9 percent) of these compounds. After chromatography on a column of Kieselgel 60 H and recrystallization from acetonitrile, the product melts at 192-195 (in Russian)oC.

26) 2-(5-amino-3-piperidino,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazol

To a suspension 3,62 g (0,008 mol) of 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(2-bromoethoxy)benzyliden/carbothioamides in 25 ml of tetrahydrofuran with stirring and cooling to 25oTo add 2,04 g (0,009 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get 3.25 g (90.2 per cent) of these compounds. The product was then purified using chromatography on a column of Kieselg(5-amino-3-piperidino,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazol

To a suspension of 40.7 g (0.09 mol) of 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/3-(2-bromoethoxy)benzyliden/carbothioamides in 400 ml of tetrahydrofuran with stirring and cooling to 25oTo add to 22.7 g (0.01 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 30 ml of 5% aqueous sodium hydroxide solution. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get of 38.6 g (94,8%) of the named compound. The product was then purified using chromatography on a column of Kieselgel 60 H and recrystallization from a mixture of chloroform and methanol in the ratio of 2:1. The melting point is 175-178oC (decomposition).

28) 2-(5-amino-3-piperidino,2,4-triazole-1-yl)-5-/2-(4-bromobutoxy)phenyl/-1,3,4-thiadiazole

To a suspension 11,53 g (0,024 mol) of 1-(5-amino-3-piperidino,2,4-triazole-1-yl)-N'-/2-(4-bromobutoxy)benzyliden/carbodiimide in 50 ml of tetrahydrofuran with stirring and cooling to 25oWith the type of 5.99 g (0,264 mol) DDQ, after which the suspension is stirred at room temperature even in those who make 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

Thus obtain 10.3 g (89,7%) of the named compound. The product was then purified using chromatography on a column of Kieselgel 60 H and recrystallization from a mixture of acetonitrile and tetrahydrofuran in the ratio of 1:1. The melting point is 209-212oC.

29) 2-(5-amino-3-piperidino,2,4-triazole-1-yl)-5-/2-(3-bromopropane)-3-methoxyphenyl/-1,3,4-thiadiazole

To a suspension of 13.4 g (or 0.027 mol) of 1-(5-amino-3-piperidino,2,7-triazole-1-yl)-N'-/2-(3-bromopropane)-3-methoxybenzylidene/carbothioamides in 70 ml of tetrahydrofuran with stirring and cooling to 25oWith add for 6.81 g (0.03 mol) DDQ, after which the suspension is stirred at room temperature for 20 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get to 13.1 g (98%) Natasha the desired product, the suspension of solids in acetonitrile, filtration and recrystallization from tetrahydrofuran. The melting point is 199-205oC (decomposition).

30) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 7.3 g (of 0.017 mol) of 1-(5-amino-3-methylthio,2,4-triazole-1-yl)-N'-/2-(3-bromopropane)benzyliden/carbodiimide in 50 ml of tetrahydrofuran with stirring and cooling to 25oTo add 4,36 g (0.019 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get 6,37 g (87.6 per cent) of these compounds. The product was then purified using chromatography on a column of Kieselgel 60 H and recrystallization from acetonitrile. The melting point is 209-212oC.

31) 2-/5-amino-3-(metalicity)1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension 37,38 g (0,0817 mol) of 1-(5-amino-3-IU is eshiwani and cooled to 25oTo add to 21.6 g (0,095 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 100 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get 29,15 g (78,3%) of the named compound with a melting point of 183-185oC.

32) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/3-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension 35,8 g (0,0834 mol) of 1-(5-amino-3-methylthio,2,4-triazole-1-yl)-N'-/3-(3-bromopropane)benzyliden/carbothioamides in 350 ml of tetrahydrofuran with stirring and cooling to 25oTo add to 21.4 g (0,094 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 100 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous hydroxide solution nogo connection with a melting point 174-176oC.

33) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/4-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 41.5 g (0,0967 mol) of 1-(5-amino-3-methylthio,2,4-triazole-1-yl)-N'-/4-(3-bromopropane)benzyliden/carbothioamides in 300 ml of tetrahydrofuran under stirring and cooling to 25oTo add to 25.5 g (0,112 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 150 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get of 35.2 g (82,47%) of the named compound. After recrystallization from a mixture of dimethylformamide and acetonitrile, melting point is 219-222oC.

34) 2-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-5-/3-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 20.0 g (0,0437 mol) 1-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/3-(3-bromopropane)benzyliden/carbothioamides in 115 ml of tetrahydrofuran with stirring and cooling to 25oTo add 11,59 g (0N is removed from the reaction mixture under reduced pressure. To the dry residue add 100 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

So get to 14.4 g (72,4%) of the named compound with a melting point 177-179oC.

35) 2-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-5-/4-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 20.0 g (0,0437 mol) 1-/5-amino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/4-(3-bromopropane)benzyliden/carbothioamides in 115 ml of tetrahydrofuran with stirring and cooling to 25oTo add 11,59 g (0,051 mol) DDQ, after which the suspension is stirred at room temperature for 2 hours. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 100 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed first with 5% aqueous sodium hydroxide solution and then several times with water until neutral.

Thus obtained 11.9 g (59,8%) of the named compound with a melting point 190-191oC.

Amino-3-methylthio,2,4-triazole-1-yl)-N'-/5-(2-hydroxyphenyl)-1,3,4-thiadiazole in 10 ml of methanol is added first, 0.1 g (0.002 mol) of solid sodium methylate, and then 0,81 g (0,004 mol) of 1,3-dibromopropane. The suspension is boiled for 24 hours, then cooled. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

Thus obtain 0.39 g (91.3 percent) of these compounds. After recrystallization from a mixture of dimethylformamide and acetonitrile, melting point is 218 to 221oC.

37) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 14.0 g (0.045 mol) of 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-(2 hydroxyphenyl)-1,3,4-thiadiazole in 500 ml of methanol is added 4.0 g (0.1 mol) of sodium hydroxide and 13.9 g (0.05 mol) of tetrabutylammonium chloride. The resulting solution is evaporated to dryness. The remaining crystalline substance suspended in water, filtered, washed with water and ether.

So get of 22.8 g (92,5%) tetrabutylammonium salt of 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole with a melting point 194-196oC.

To 0.55 g (0.001 mol) of this salt add 5 ml of acetonitrile and 0.81 g (0,004 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 24 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and afroalpine and acetonitrile, the product melts at 219-221oC.

38) 2-/5-amino-3-(n-hexylthio)1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

0.4 g (0.01 mol) of sodium hydroxide dissolved in 5 ml of water, then add a solution of 0.68 g (0.002 mol) of tetrabutylammonium sulfate in 5 ml of water. To the reaction mixture is added 15 ml of chloroform and of 0.60 g (0,0016 mol) 2-/5-amino-3-(n-hexylthio)1,2,4-triazole-1-yl/-5-(2-hydroxyphenyl)-1,3,4-thiadiazole.

The reaction mixture was intensively stirred for 5 minutes. The phases are separated, the aqueous layer was extracted with 10 ml of chloroform. The combined organic solution is extracted with water, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining crystalline substance is suspended in ether, filtered and washed with ether.

So get 0,76 g (76,9%) tetrabutylammonium salt 2-/5-amino-3-(n-hexylthio)1,2,4-triazole-1-yl/-5-(2-hydroxyphenyl)-1,3,4-thiadiazole melting temperature of 150-160oC.

To 0,62 g (0.001 mol) tetrabutylammonium salt 2-/5-amino-3-(n-hexylthio)1,2,4-triazole-1-yl/-5-(2-hydroxyphenyl)-1,3,4-thiadiazole add 5 ml of acetonitrile and 0.81 g (0,004 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 24 hours. Precipitated precipitated crystals filtrol recrystallization from a mixture of dimethylformamide and acetonitrile, the product melts at 180-186oC.

39) 2-/5-benzylamino-3-(2-metalicity)1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a freshly prepared suspension of 0.55 g (0.001 mol) 1-/5-benzylamino-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/2-(3-bromopropane)benzyliden/-carbothioamides in 3 ml of tetrahydrofuran with stirring and cooling to 25oWith added 0.27 g (0.001 mol) of DDQ. The suspension is stirred at room temperature for 30 minutes. The tetrahydrofuran is removed from the reaction mixture under reduced pressure. To the dry residue add 5 ml of isopropanol, the mixture was thoroughly stirred, filtered, washed several times with isopropanol and ether.

So get 0,46 g (84.3 percent) of these compounds with a melting point 148-150oC.

40) 2-/5-(4-chlorobenzylamino)-3-(2-metalicity)1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 0.58 g (0.001 mol) 1-/5-(4-chlorobenzylamino)-3-(2-metalicity)1,2,4-triazole-1-yl/-N-/2-(3-bromopropane)benzyliden/carbothioamides in 3 ml of tetrahydrofuran with stirring and cooling to 25oWith added 0.27 g (0.001 mol) of DDQ. The suspension is stirred at room temperature for 30 minutes. The tetrahydrofuran is removed from the reaction mixture at mA and cyclohexane with a gradient of increasing polarity. The fractions containing the desired compound is evaporated. The dry residue is dissolved in 5 ml of hot isopropanol and give yet to crystallize. Precipitated precipitated crystals are filtered, washed with isopropanol and ether.

Thus obtain 0.40 g (70.2 per cent) of these compounds with a melting point 123-124oC.

41) 2-(5-amino-3-propylthio,2,4-triazole-1-yl)-

5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole.

To a suspension of 1.98 g (0,006 mol) of 2-(5-amino-3-propylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole in 25 ml of chloroform, add a solution of 0.84 g (0,021 mol) of sodium hydroxide in 10 ml of water, then add a solution of 2.38 g (0,0072 mol) of tetrabutylammonium chloride in 10 ml of water. The reaction mixture is thoroughly stirred for 20 minutes. The crystalline product is filtered, washed with water and ether.

So get 2,84 g (83%) of 2-(5-amino-3-propylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole of tetrabutylammonium with a melting point 165-170oC.

To to 2.29 g (0,004 mol) of this salt add 2 ml of acetonitrile and 4.04 g (0.02 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 24 hours. Precipitated precipitated crystals are filtered, ProMat from a mixture of dimethylformamide and acetonitrile.

42) 2-(5-amino-3-allylthio,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 1.66 g (0,005 mol) of 2-(5-amino-3-allylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole in 20 ml of chloroform, add a solution of 0.84 g (0,021 mol) of sodium hydroxide in 10 ml of water, and then the solution 2,04 g (0,006 mol) of tetrabutylammonium chloride in 10 ml of water. The reaction mixture is thoroughly stirred for 20 minutes. The crystalline product is filtered, washed with water and ether.

So get 2,04 g (74,8%) of 2-(5-amino-3-allylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole of tetrabutylammonium with a melting point 180-183oC.

To 2,01 g (0,0035 mol) of this salt add 20 ml of acetonitrile and 3.03 g (0.15 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 24 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

So get 1,33 g (84.2 per cent) of these compounds. After recrystallization from a mixture of dimethylformamide and acetonitrile gain of 1.33 g of the desired product with a melting point 178-180oC.

43) 2-(5-amino-3-propylthio,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 1.34 g (0,004 mol) 2,015 mol) of sodium hydroxide in 10 ml of water, and then a solution of 1.70 g (0.05 mol) of tetrabutylammonium chloride in 10 ml of water. The reaction mixture was intensively stirred for 20 minutes. The crystalline product is filtered, washed with water and ether.

So get of 1.30 g (56,5%) of 2-(5-amino-3-propylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole of tetrabutylammonium with a melting point 195-198oC.

To 1,15 g (0.002 mol) of this salt added 15 ml of acetonitrile and 2.02 g (0.01 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 24 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

So get 0,78 g (85.7 percent) of these compounds. After recrystallization from a mixture of dimethylformamide and acetonitrile, the product melts at 178-180oC.

44) 2-(5-amino-3-benzylthio,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To a suspension of 1.61 g (0,0042 mol) of 2-(5-amino-3-benzylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole in 20 ml of chloroform, add a solution of 0.48 g (0.012 mol) of sodium hydroxide in 10 ml of water, and then a solution of 1.70 g (0,005 mol) of tetrabutylammonium chloride in 10 ml of water. The reaction mixture is thoroughly stirred for 20 minutes. Cree is about-3-benzylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole of tetrabutylammonium with a melting point 170-174oC.

To 1,87 g (of 0.003 mol) of this salt add 20 ml of acetonitrile and 2,42 g (0.012 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 44 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

So get to 1.37 g (90.7 percent) of these compounds with a melting point 175-180oC.

45) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazol

To 4,60 g (0.015 mol) of 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole add 20 ml of methanol and a solution of 1.08 g (0.002 mol) of sodium methylate in 10 ml of methanol. The reaction mixture is stirred for 10 minutes, then evaporated to dryness. To the dry residue add 35 ml of dimethylformamide and 12,27 g (0.06 mol) of 1,2-dibromethane. The suspension is stirred at 80oC for 18 hours, then cooled. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

Thus obtain 2.16 g (34,9%) of the named compound with a melting point 227-229oC.

46) 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazol

To of 4.38 g (0,008 mol) tetrabutylammonium salt of 2-(5-amino-3-methylthio,2,4-triazole-1-yl)-5-(2-up at room temperature for 64 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

So get to 3.02 g (90,9%) of the named compound with a melting point 227-228oC.

47) 2-(5-amino-3-morpholino,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole

To 2.64 g (0,0045 mol) tetrabutylammonium salt of 2-(5-amino-3-morpholino,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole add 20 ml of acetonitrile and 3,63 g (0.018 mol) of 1,3-dibromopropane. The suspension is stirred at room temperature for 26 hours. Precipitated precipitated crystals are filtered, washed with cold methanol and ether.

Thus obtain 1.85 g (88.1 per cent) of these compounds. After recrystallization from a mixture of dimethylformamide and acetonitrile, melting point 210-214oC.

Obtaining compounds of formula I

Example 1

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole

To a solution of 17.2 g (0.045 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(3,4,5-trimethoxybenzamide)-carbodiimide in 110 ml of acetic acid is added a solution of 67.5 g of iron chloride(III) in 75 ml of water under stirring and cooling to 20oC. the Reaction mixture was stirred at room temperature precipitated product is filtered.

Thus obtain 15.9 g (92,8%) of the named product. Melting point (after recrystallization from ethanol): 234-236oC.

Example 2

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-phenyl-1,3,4-thiadiazole

To a solution of 0.88 g (of 0.003 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-benzylidene-carbothioamides 7.5 ml acetic acid is added a solution of 4.5 g of iron chloride(III) in 5 ml of water under stirring and cooling to 20oC. the Reaction mixture was stirred at room temperature for 2 hours, then diluted with 60 ml of water, stirred for further 5 hours and left overnight. The next day, the precipitated product filtered.

So get to 0.47 g (54%) of the named product. Melting point (after recrystallization from isopropanol): 220-222oC.

Example 3

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-phenyl-1,3,4-thiadiazole

To a solution 2,04 g (0.01 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-carbodiimide in 50 ml of methanol is added 3.4 ml (0.015 mol) of triethylorthoformate and boil for 4 hours. The next day, the precipitated crystals are filtered and washed with a small amount of methanol.

Thus obtain 0.95 g (32.8 per cent) of these compounds. T the Mino-3-morpholino-1H-1,2,4-triazole-1-yl)-1,3,4-thiadiazol

To a solution of 14,58 g (0.06 mol) of 1-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-carbodiimide in 300 ml of methanol, add 30 ml of triethylorthoformate and boiled for 8 hours. The precipitated crystals are filtered from the hot mixture and washed with a small amount of methanol.

Thus obtained 10.4 g (68,4%) of the named compound. Melting point (after recrystallization from methanol): 203-205oC.

Example 5

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-1,3,4-thiadiazole

To a suspension of 10.2 g (0.05 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-carbodiimide in 250 ml of methanol, add 25 ml of triethylorthoformate and boil for 4 hours. After cooling, the precipitated crystals are filtered and washed with a small amount of methanol.

Thus obtain 8.8 g (82,1%) of pure titled compound. Melting point: 202-203oC.

Example 6

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-methyl-1,3,4-thiadiazole

To a suspension 2,04 g (0.01 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-carbodiimide in 50 ml of methanol add 5.7 ml of triethylorthoformate and boiled for 8 hours. After cooling, the precipitated crystals are filtered and washed with a small amount of methanol.

oC.

Example 7

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-ethyl-1,3,4-thiadiazole

To a suspension of 14.28 g (0.07 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-carbodiimide in 200 ml of methanol, add 80 ml of triethylorthoformate and boiled for 8 hours. After cooling, the precipitated crystals are filtered and washed with a small amount of methanol.

So get 9,42 g (55,5%) of pure titled compound. Melting point: 166-168oC.

Example 8

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(4-dimethylaminophenyl)-1,3,4-thiadiazole

To a suspension of 10.05 g (0.03 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(4-dimethylaminobenzylidene)carbodiimide 32.5 ml acetic acid is added a solution of 19.5 g of iron chloride(III) in 22 ml of water under stirring and cooling to 20oTo the Reaction mixture was stirred at room temperature for 2 hours, then diluted with 100 ml of water, stirred for further 1 hour and left overnight. The next day, the precipitated product is filtered and washed with a small amount of ethanol.

So get a 8.9 g (89%) of the named product. Melting point (after recrystallization from dimethylformamide): 292-294oC.

ü) 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(4-chlorobenzylidene)carbodiimide in 25 ml acetic acid is added a solution of 15 g of iron chloride(III) in 17 ml of water with stirring. The reaction mixture is boiled for 15 minutes, then diluted with 100 ml of water, stirred for further 1 hour, the precipitated product is filtered and washed with a small amount of ethanol.

So get a 2.71 g (83.4% of said product. Melting point (after recrystallization from dimethylformamide): 269-271oC.

Example 10

2-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-5-(2,6-dichlorophenyl)-1,3,4-thiadiazole hydrochloride monohydrate

To a suspension 2,07 g (0,005 mol) 1-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-N'-(2,6-dichlorobenzamide)carbodiimide 12.5 ml of acetic acid is added a solution of 7.5 g of iron chloride(III) in 8.5 ml of water with stirring. The reaction mixture is boiled for 1 hour, then diluted with 100 ml of water, stirred for further 1 hour, the precipitated product is filtered and washed with a small amount of water and then with isopropanol.

So get 2,12 g (91,0%) of the named product. Melting point (after recrystallization from methanol): 281-284oC.

Example 11

2-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2,4-triazole-1-yl/-1,3,4-thiadiazole

To a suspension of 1.0 g (of 0.003 mol) 1-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2,4-triazole-1-yl/-carbodiimide in 20 ml of methanol d is t and washed with a small amount of methanol.

Thus obtained 0.5 g (49.2 percent) of these compounds. Melting point (after recrystallization from methanol): 140-141oC.

Example 12

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(4-nitrophenyl)-1,3,4-thiadiazole

To a suspension 3,37 g (0.01 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(4-nitrobenzylidene)carbodiimide in 25 ml acetic acid is added a solution of 15 g of iron chloride(III) in 17 ml of water with stirring. The reaction mixture is boiled for 2 hours, then diluted with 200 ml of water, stirred for further 1 hour, the precipitated product is filtered and washed with a small amount of ethanol.

So get 2,44 g (72,8%) of the named product. Melting point (after recrystallization from dimethylformamide): 301-303oC.

Example 13

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(4-forfinal)-1,3,4-thiadiazole

To a suspension of 0.93 g (of 0.003 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(4-formanilide)carbodiimide 7.5 ml acetic acid is added a solution of 4.5 g of iron chloride(III) in 5.2 ml of water under stirring and cooling to 20oC. the Reaction mixture is stirred for 2 hours, then diluted with 50 ml of water, stirred for further 1 hour and left overnight. Next give 0.75 g (81,0%) of the named product. Melting point (after recrystallization from dimethylformamide): 246-247oC.

Example 14

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To the suspension is 5.18 g (0.015 mol) of 1-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 30 ml of tetrahydrofuran added 3.75 g (0,0165 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1 hour, the precipitated product filtered and washed with tetrahydrofuran.

So get totaling 3.04 g (59,7%) of pure titled product. Melting point: 268-272oC.

Example 15

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension of 6.78 g (0,022 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 50 ml of tetrahydrofuran, add 5.49 g (0,0242 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1.5 hours, the precipitated product filtered and washed with tetrahydrofuran.

So get of 6.17 g (of 91.6%) of pure titled product. Melting point: 304-306oC.

Note the s) 1-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 20 ml of tetrahydrofuran, add 2,95 g (0,013 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1 hour, the precipitated product filtered and washed with tetrahydrofuran.

So get 1,82 g (45,3%) of pure titled product. Melting point: 224-227oC. the mother liquor is evaporated to dryness, the residue suspended in isopropanol to obtain more of 1.05 g (26,2%) of product, which is identical to the above connection. Melting point: 221-225oC.

Example 17

2-(5-amino-3-allylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension of 2.34 g (to 0.007 mol) of 1-(5-amino-3-allylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 20 ml of tetrahydrofuran, add 1,82 g (0,008 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1 hour, the precipitated product filtered and washed with tetrahydrofuran and ether.

Thus obtained 1.8 g (77,3%) of pure titled product. Melting point: 222-224oC. the mother liquor is evaporated to dryness, the residue suspended in isopropanol to obtain 0.28 g (12,0%) of product, which is identical to the above connection. Melting point: 222-223oC.

Example 18(5-amino-3-benzylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 15 ml of tetrahydrofuran, add 2,04 g (0,009 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1 hour, the precipitated product filtered and washed with tetrahydrofuran.

Thus obtain 1.12 g (36,6%) of pure titled product. Melting point: 200-202oC. the mother liquor is evaporated to dryness, the residue suspended in isopropanol to obtain 1.0 g (32,7%) of product, which is identical to the above connection. Melting point: 198-201oC.

Example 19

2-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension of 1.95 g (0,0085 mol) of 1-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 30 ml of tetrahydrofuran added 2.16 g (0,0095 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 1 hour, the precipitated product filtered and washed with tetrahydrofuran.

Thereby obtaining 2.4 g (81,9%) of pure titled product. Melting point: 265-270oC.

Example 20

2-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension 5,95 g (0,0165 mol) 1-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-N'-(2-hydroxybenzylidene)carbamazepine stirred at room temperature for another 1 hour, the precipitated product filtered and washed with tetrahydrofuran.

Example 21

2-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension of 2.83 g (0,0085 mol) of 1-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 30 ml of tetrahydrofuran, add a 2.13 g (0,0094 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 2 hours, the precipitated product filtered and washed with tetrahydrofuran.

So get of 1.81 g (64,6%) of pure titled product. Melting point: 236-240oC.

Example 22

2-(5-amino-3-n-hexylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole

To a suspension of 1.59 g (0,0042 mol) of 1-(5-amino-3-n-hexylthio-1H-1,2,4-triazole-1-yl)-N'-(2-hydroxybenzylidene)carbodiimide in 10 ml of tetrahydrofuran added 1.07 g (0,0047 mol) DDQ under stirring and cooling to 20oC. the Suspension is stirred at room temperature for a further 2 hours, the precipitated product filtered and washed with tetrahydrofuran.

Thus obtained 1.01 g (63,9%) of pure titled product. Melting point: 212-214oC.

Example 23

2-(5 the hydrate

of 14.7 g (being 0.036 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylamino-2-methylpropoxy)benzyliden/-carbodiimide dissolved in 40 ml of acetic acid at room temperature. To the solution add 15 ml of methanol and the mixture add a solution of 43.2 g of iron chloride(III) in 40 ml of water at 25oWith stirring and cooling. The reaction mixture is stirred for 2 hours at room temperature. The next day the reaction mixture is evaporated to dryness under reduced pressure, to the precipitate add 200 ml of ethanol, and the precipitated product filtered and washed carefully twice with methanol.

So get 12,65 g (70.7 percent) of the named product. Melting point (after recrystallization from water): 244-246oC.

Example 24

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole hydrochloride

To a solution of 17,95 g (0,0455 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)-benzyliden/carbodiimide in 50 ml acetic acid is added a solution of 35 g (0,216 mol) of ferric chloride(III) in 35 ml of water at 35oWith under stirring. The reaction mixture is stirred for 2 hours at room temperature. The thick reaction smfilter. Thus obtain 15.2 g (78,0%) of the named product. Melting point (after recrystallization from water): 250-252oC.

Example 25

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 13.6 g (0,0345 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 100 ml of tetrahydrofuran, add at 9.53 g (0,042 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 6 hours at room temperature. To the reaction mixture is added 300 ml of 5% aqueous sodium hydroxide solution and stirred for another 0.5 hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 12,65 g (93.5 per cent) of these compounds. Melting point (after recrystallization from a mixture of 19 volumes of ethanol and 1 volume of water): 179-180oC.

Example 26

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole hydrochloride

To a suspension of 13.0 g (0,033 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/3-(3-dimethylaminopropoxy)-benzilic the 45 ml of water at 25oWith under stirring. Then the reaction mixture is boiled for 0.5 hour. The next day the reaction mixture is evaporated to dryness under reduced pressure. To the precipitate add 200 ml of ethanol, the precipitated product is filtered and thoroughly washed.

Thus obtain 10.8 g (74,5%) of the named product. Melting point (after recrystallization from water): 242-244oC.

Example 27

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylamino-2-methylpropoxy)phenyl/-1,3,4-thiadiazole hydrochloride

To a suspension 20,37 g (0.05 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/4-(3-dimethylamino-2-methylpropoxy)-benzyliden/carbodiimide in 100 ml acetic acid is added a solution of 54 g (0.09 mol) of ferric chloride(III) of uranyl in 300 ml of water at 25oWith under stirring. Then the reaction mixture was stirred at room temperature for 4 hours. The next day, the precipitated product filtered and washed with methanol.

So get to 16.9 g (76.5%) of the named product. Melting point (after recrystallization from water): 240-242oC.

Example 28

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole hydrochloride

To suraida in 45 ml of acetic acid is added a solution of 26 g (0.09 mol) of ferric chloride(III) of uranyl in water (30 ml) at 25oWith under stirring. Then the reaction mixture is boiled for 0.5 hour. The next day, the precipitated product filtered and washed with methanol.

So get 11.5g (67,2%) of the named product. Melting point (after recrystallization from water): 267-270oC.

Example 29

2-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 5,86 g (0.015 mol) of 1-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 50 ml of tetrahydrofuran, add 4.09 g (0.018 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. To the reaction mixture is added 150 ml of 5% aqueous sodium hydroxide solution and stirred for another 0.5 hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 3,55 g (60,9%) of the named compound. Melting point (after recrystallization from acetonitrile): 180-182oC.

Example 30

2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-aminopropoxy)benzyliden/carbothioamides in 15 ml of tetrahydrofuran type of 1.36 g (0,006 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

Thereby obtaining 2.0 g (87.4 per cent) of these compounds. Melting point (after recrystallization from acetonitrile): 161-163oC.

Example 31

2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension 5,79 g (0,013 mol) 1-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-N-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 40 ml of tetrahydrofuran, add to 3.41 g (0.015 mol) of DDQ at 25oWith stirring and cooling. The suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate was added 100 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. Usadanielle reactions and acetonitrile.

Thus obtained 4.1 g (71,1%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of acetonitrile and 1 volume of 2-propanol): 169-171oC.

Example 32

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension ceiling of 5.60 g (0,013 mol) of 1-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 50 ml of tetrahydrofuran, add to 3.41 g (0.015 mol) of DDQ at 25oWith stirring and cooling. The suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get of 5.1 g (91,7%) of the named compound. Melting point (after recrystallization from methanol): 179-181oC.

Example 33

2-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 5,19 g (0.012 mol) of 1-(5-ATURAN add 3,18 g (0.014 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

Thus obtained 4.3 g (83,3%) of the named compound. Melting point (after recrystallization from methanol): 180-182oC.

Example 34

2-[5-amino-3-/4-(3-chlorophenyl)piperazine-1-yl/-1H-1,2,4-triazole-1-yl] -5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 6.78 g (of 0.0125 mol) of 1-[5-amino-3-/4-(chlorophenyl)-piperazine-1-yl/-1H-1,2,4-triazole-1-yl]-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 60 ml of tetrahydrofuran, add 3.13 g (0,0138 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 14 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. Usadanielle reaction.

Thus obtain 5.8 g (85,9%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of acetonitrile and 1 volume of tetrahydrofuran): 205-209oC (with decomposition).

Example 35

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(2-dimethylaminoethoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 5.9 g (0.015 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/3-(2-dimethylaminoethoxy)benzyliden/-carbodiimide in 50 ml of tetrahydrofuran added 3.75 g (0,0165 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 8 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

Thus obtained 4.3 g (76,0%) of the named compound. Melting point (after recrystallization from acetonitrile): 162-163oC.

Example 36

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(2-diethylaminoethoxy)phenyl/-1,3,4-thiadiazole

To a suspension 10,54 g (0,025 mol) 1-uranium type for 6.81 g (0.03 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 8 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

So get with 8.05 g (79.5%) of these compounds. Melting point (after recrystallization from a mixture of 1 volume of acetonitrile and 1 volume of 2-propanol): 163-164oC.

Example 37

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(2-dimethylaminoethoxy)phenyl/-1,3,4-thiadiazole

To a suspension 9,11 g (0,024 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/4-(2-dimethylaminoethoxy)benzyliden/carbodiimide in 100 ml of tetrahydrofuran type of 6.02 g (0,0265 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 4 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 75 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. Besieged p is Inoi reaction.

Thus obtain 6.0 g (66.3 per cent) of these compounds. Melting point (after recrystallization from a mixture of 1 volume of water and 1 volume of 2-propanol): 183-184oC.

Example 38

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-(4-(methylpiperazin-1-yl)-propoxy/phenyl]-1,3,4-thiadiazole

To the suspension is 4.93 g (to 0.011 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-[2-/3-(4-methylpiperazin-1-yl)propoxy/benzyliden]carbodiimide in 30 ml of tetrahydrofuran, add 2,95 g (0,013 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 6 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 3,98 g (81,1%) of the named compound. Melting point (after recrystallization from ethanol): 177-178oC.

Example 39

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-piperidinyloxy)phenyl/-1,3,4-thiadiazole

To a suspension 6,59 g (0,0152 mol is rufuran add 4.09 g (0.018 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 6,04 g (93,3%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of ethanol and 1 volume of acetonitrile): 185-186oC.

Example 40

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(2-dimethylaminoethoxy)phenyl/-1,3,4-thiadiazole

To a suspension 8,01 g (0,021 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(2-dimethylaminoethoxy)benzyliden/carbothioamides in 40 ml of tetrahydrofuran, add the 5.45 g (0,024 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 80 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. Oy until neutral and acetonitrile.

So get of 7.24 g (91.3 percent) of these compounds. Melting point (after recrystallization from acetonitrile): 193-195oC.

Example 41

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-morpholinoethoxy)phenyl/-1,3,4-thiadiazole

To a suspension 6,53 g (0.015 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-morpholinopropan)benzyliden/carbodiimide in 50 ml of tetrahydrofuran, add 4.09 g (0.018 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 13 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 80 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get of 5.68 g (87.4 per cent) of these compounds. Melting point (after recrystallization from acetonitrile): 205-206oC.

Example 42

2-/5-amino-3-(4-chlorobenzylthio)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To the suspension a 4.53 g (0,009 mol) 1-/5-amino-3-(4-chlorobenzylthio)-1H-1,2,4-the 0,0108 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 13 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 4,19 g (92,9%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of n-butanol and 1 volume of acetonitrile): 183-184oC.

Example 43

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-pyrrolidinyloxy)phenyl/-1,3,4-thiadiazole

To a suspension of 9.02 g (0,0215 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-pyrrolidinyloxy)benzyliden/carbothioamides in 70 ml of tetrahydrofuran, add 5,61 g (0,025 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 21 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 20 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one h and water until neutral and acetonitrile.

So get to 8.34 g (93%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of ethanol and 1 volume of acetonitrile: 169, 5mm-171oC.

Example 44

2-(5-amino-3-pyrrolidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 10.0 g (0,024 mol) of 1-(5-amino-3-pyrrolidino-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 80 ml of tetrahydrofuran, add 6,13 g (or 0.027 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 21 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 80 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get of 8.92 g (89,7%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of n-butanol and 1 volume of acetonitrile): 209-211oC.

Example 45

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-di(2-methylethyl)aminopropoxy)phenyl]-epoxy/benzyliden]carbodiimide in 40 ml of tetrahydrofuran, add 4.09 g (0.018 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 6 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get the ceiling of 5.60 g (78.2%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of ethanol and 1 volume of acetonitrile): 177-178oC.

Example 46

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-diethylaminopropyl)phenyl/-1,3,4-thiadiazole

To the suspension to 7.59 g (0.018 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-diethylaminopropyl)benzyliden/carbothioamides in 70 ml of tetrahydrofuran type of 4.54 g (at 0.020 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 22 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 60 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one Cassady until neutral and acetonitrile.

So get of 5.83 g (77.2 percent) of these compounds. Melting point (after recrystallization from 2-propanol): 142-144oC.

Example 47

2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/4-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension 8,51 g (0,0185 mol) 1-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-N-/4-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 50 ml of tetrahydrofuran, added with 4.65 g (0,0205 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 6 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 60 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 6,12 g (72.3 per cent) of these compounds. Melting point (after recrystallization from a mixture of 1 volume of 2-propanol and 1 volume of acetonitrile): 172-174oC.

Example 48

2-(3,5-diamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To suspen 40 ml of tetrahydrofuran, add 3,86 g (of 0.017 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 4,22 g (75,6%) of the named compound, which is then suspended in 15 ml of acetonitrile and intensively stirred for 2 hours. The crystals are filtered and washed thoroughly with acetonitrile. Thus obtain 3.57 g of pure product. Melting point: 217-222oC.

Example 49

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension 5,98 g (0,0135 mol) of 1-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 30 ml of tetrahydrofuran, add to 3.41 g (0.015 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 4 hours at room temperature. The tetrahydrofuran is removed from the reaction cm is within one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 4,24 g (71.3 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H): 136-140oC.

Example 50

2-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

To a suspension 2,95 g (to 0.007 mol) of 1-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 20 ml of tetrahydrofuran, add a 1.75 g (0,0077 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for one hour at room temperature. The precipitated product was filtered, added to 30 ml of 5% aqueous sodium hydroxide solution and stirred for 2 hours at room temperature. The insoluble part is filtered, washed with water and then with tetrahydrofuran.

So get 2,32 g (79,2%) of the named compound. Melting point: 147-150oC.

Example 51

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylamino-2-methylpropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 4.57 g (0.01 mol) of 1-(5-amino-3-dalilama added 2.50 g (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 40 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

So get to 3.92 g (86,3%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H): 135-137oC.

Example 52

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylamino-2-methylpropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 4.57 g (0.01 mol) of 1-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-N'-/4-(3-dimethylamino-2-methylpropoxy)benzyliden/carbothioamides in 25 ml of tetrahydrofuran added 2.50 g (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered the product is dissolved in chloroform, the resulting solution was washed with saturated aqueous sodium chloride, dried and evaporated to dryness.

So get 3,63 g (79.8 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 105-107oC.

Example 53

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylamino-2-methylpropoxy)phenyl/-1,3,4-thiadiazole

To a suspension of 4.57 g (0.01 mol) of 1-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-N'-/3-(3-dimethylamino-2-methylpropoxy)benzyliden/carbothioamides in 25 ml of tetrahydrofuran added 2.50 g (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 40 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

Thus obtained 4.0 g (79.8 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 130-132othe azole

To a suspension of 4.57 g (0.01 mol) of 1-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-N'-/2-(2-diethylaminoethoxy)benzyliden/carbothioamides in 25 ml of tetrahydrofuran added 2.50 g (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 2 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

So get of 3.84 g (84.4 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H): 124-126oC.

Example 55

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-dimethylaminoethoxy)-phenyl/-1,3,4-thiadiazole

To a suspension of 7.50 g (0.018 mol) of 1-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-N'-/2-(2-dimethylaminoethoxy)benzyliden/carbodiimide in 50 ml of tetrahydrofuran, add 4,54 (0.02 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture is within one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

So get to 6.75 g (81.4 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 189-191oC.

Example 56

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/2-(2-dimethylaminoethoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 4,28 g (0.01 mol) of 1-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-N'-/2-(2-dimethylaminoethoxy)benzyliden/carbothioamides in 45 ml of tetrahydrofuran, add 2,50 (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

Thus obtained 3.8 g (89,0%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H): 138-140oC.

Example 57oWith stirring and cooling. Then the suspension is stirred for one hour at room temperature. The precipitated product was filtered, added to 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred at room temperature for 2 hours. The insoluble part is filtered, washed with water and then with tetrahydrofuran.

So get 2,98 g (79.5%) of these compounds. Melting point: 169-172oC.

Example 58

2-(5-amino-3-benzylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 3,76 g (0,008 mol) of 1-(5-amino-3-benzylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 20 ml of tetrahydrofuran, add 2,04 (0,009 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for one hour at room temperature. The precipitated product was filtered, added to 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred at room temperature for 2 hours. The insoluble part is filtered, washed with water and then with tetrahydrofuran.

Thus obtained was 2.76 g (73.8%) of these compounds. Melting point: 189-191oC.

Example 59
oC for 3 hours. From the obtained melt is evaporated the excess amine under reduced pressure, to the residue add 70 ml of water and left for crystallization. The resulting crystals are filtered, washed with water and then with acetonitrile.

So get to 4.16 g (89,2%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 148-150oC.

Example 60

2-(5-amino-3-n-hexylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension of 0.99 g (0,0036 mol) of 1-(5-amino-3-n-hexylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 10 ml of tetrahydrofuran, add 0,83 (0,004 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness, the residue is suspended in a small amount of ethyl acetate, filtered and washed with ethyl acetate.

So get 0,94 g (56.6 per cent) of these compounds. Melting point: 114-117oC.

Example 61

2-(5-benzylamino-3-metalicity-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To suspensionbridge in 50 ml of tetrahydrofuran, add 2,73 (0.012 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 4,88 g (95,8%) of the named compound. Melting point: 101-102oWITH

Example 62

2-(5-benzylamino-3-amino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension of 1.81 g (0,004 mol) of 1-(5-benzylamino-3-amino-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 15 ml of tetrahydrofuran, add 1,02 (0,0045 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 4 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane. The organic fraction is extracted with 5% aqueous sodium hydroxide solution and washed neskolkih (61,0%) of the named compound. Melting point (after recrystallization from acetonitrile): 180-183oC.

Example 63

2-(5-amino-3-benzylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension of 3.3 g (0,0073 mol) of 1-(5-amino-3-benzylamino-3-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 35 ml of tetrahydrofuran, add 1,84 (0,0081 mol) DDQ at 25oWith stirring and cooling, Then the suspension is stirred for further 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 30 ml of 5% aqueous sodium hydroxide solution, the precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral.

Thus obtain 3.12 g (94,8%) of the named compound. Melting point (after recrystallization from a mixture of 1 volume of acetonitrile and 1 volume of ethanol): 172-173oC.

Example 64

2-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To the suspension is 5.18 g (0.01 mol) 1-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2.4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get 4,65 g (90,1%) of the named compound. Melting point: 133-134oC.

Example 65

2-/5-(4-chlorobenzylamino)-3-metalicity-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 2,73 g (0,005 mol) 1-/5-(4-chlorobenzylamino)-3-metalicity-1H-1,2,4-triazole-1-yl/-N-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 30 ml of tetrahydrofuran, add a 1.50 (0,006 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture under reduced pressure, to the precipitate add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for one hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

the example 66

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(2-diallylamine)-phenyl/-1,3,4-thiadiazole

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and to 7.77 g (9,9 ml, 0.08 mol) of diallylamine stirred at 120oC for 3 hours. The resulting solution was crystallized by cooling. Add 30 ml of ether to the reaction mixture, which is stirred for 30 minutes. The resulting crystals are filtered, washed with ether and then with acetonitrile.

Thus obtain 3.11 g (83,3%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 163-166oC.

Example 67

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(4-di-n-butylaminoethyl)-phenyl/-1,3,4-thiadiazole

The mixture 0,465 g (0.001 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(4-bromobutoxy)phenyl/-1,3,4-thiadiazole and 1.29 g (0.01 mol) of di-n-butylamine is stirred at 120oC for 2 hours. Add 5 ml of water to the reaction mixture, which is stirred for 30 minutes. The resulting crystals are filtered, washed with ether and then with acetonitrile.

Thus obtain 0.40 g of the named compound, which is subjected to chromatography is oC.

Example 68

2-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole

To a suspension 3,34 g (0,008 mol) of 1-(5-amino-3-propylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 20 ml of tetrahydrofuran, add a 2.0 (0,088 mol) DDQ at 25oWith stirring and cooling. The precipitated product is filtered and added to 30 ml of 5% (g/ml) of an aqueous solution of sodium hydroxide, the mixture is stirred at room temperature for 2 hours. The insoluble part is filtered, washed with 5% aqueous sodium hydroxide solution, water and tetrahydrofuran.

Thus obtain 1.86 g (56,0%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 181-183oC.

Example 69

2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-[3-/3-(4-phenylpiperazin-1-yl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 4.35 g (0.01 mol) 2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/3-(3-bromopropane)/phenyl-1,3,4-thiadiazole and to 4.98 g (0.03 mol) of 4-phenylpiperazine stirred at 150oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, the resulting crystals are filtered.

oC.

Example 70

2-/5-amino-3-(2-methylthio)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-/4-(2-methoxyphenyl)-piperazine-1-Il/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,07 g (0.01 mol) 2-/5-amino-3-(2-methylthio)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)/phenyl-1,3,4-thiadiazole and 5,88 g (0.03 mol) of 4-(2-methoxyphenyl)-piperazine was stirred at 180oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, the resulting crystals are filtered.

Thus obtain 3.80 g (79,0%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 159-161oC.

Example 71

2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-[2-/3-(4-phenylpiperazin-1-yl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 4.35 g (0.01 mol) 2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)/phenyl-1,3,4-thiadiazole and to 4.98 g (0.03 mol) of 4-phenylpiperazine stirred at 160oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, the resulting crystals are filtered.

So get 3,55 g (74,0%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 212-214o
A mixture of 4.35 g (0.01 mol) 2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)/phenyl-1,3,4-thiadiazole and 5,88 g (0.03 mol) of 4-(2-methoxyphenyl)-piperazine was stirred at 160oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, the resulting crystals are filtered.

So get 4,28 g (84,0%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 159-160oC.

Example 73

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-methoxy-2-(3-morpholinoethoxy)-phenyl/-1,3,4-thiadiazole

A mixture of 3.96 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-methoxy-2-(3-bromopropane)/phenyl-1,3,4-thiadiazole and 15 g (0,172 mol) of the research was stirred at 140oC for 10 hours. After cooling, the excess of the research is distilled off under reduced pressure, to the residue is added dropwise 40 ml of water, the resulting crystals are filtered.

So get 3,40 g (85%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 160-163oC.

Example 74

2-(5-benzylamino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylamino)-propeciagenericsm)benzyliden/carbothioamides in 40 ml of tetrahydrofuran, add a 2.5 (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 4 h at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, the residue is purified by chromatography on a column filled with Kieselgel N (Kieselgel H).

Thus obtain 4.09 g (78.5 per cent) of these compounds. Melting point (after recrystallization from acetonitrile): 100-101oC.

Example 75

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-2-(3-diallylamine)-phenyl/-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 9,72 g (0.1 mol) of diallylamine stirred at 120oC for 1.5 hours. The resulting solution crystallizes upon cooling. Add 30 ml of ether to the reaction mixture, which is stirred for 30 minutes. The resulting crystals are filtered, washed with ether and then with acetonitrile.

So get the 3.65 g (78,3%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 128-131oC.

Example 76

2-(5-amino-3-diethylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylamino)propoxyphenyl/-1,3,4-tideline/carbothioamides in 25 ml of tetrahydrofuran, add a 2.0 (0,0088 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 3 hours at room temperature. To the reaction mixture is added 40 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for 0.5 hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

Thus obtained 2.8 g (84,1%) of the named compound. Melting point (after recrystallization from acetonitrile): 159-160oC.

Example 77

2-(5-amino-3-heptamethylnonane-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylamino)-propoxyphenyl/-1,3,4-thiadiazole

To the suspension is 6.19 g (0,0135 mol) of 2-(5-amino-3-heptamethylnonane-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 30 ml of tetrahydrofuran, add to 3.41 g (0.015 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue are added 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for another hour. The precipitated product is filtered, washed with 5% aqueous hydroxide solution natut of 5.05 g (81.9 percent) of these compounds. Melting point (after recrystallization from methanol): 164-167oC.

Example 78

2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylamino)-2-methylpropionitrile/-1,3,4-thiadiazole

To a solution of 15,72 g (0,0339 mol) of 2-(5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-N-/2-(3-dimethylamino-2-methylpropoxy)-benzyliden/carbodiimide in 100 ml acetic acid is added a solution of 26 g (0.09 mol) of ferric chloride(III) in 30 ml of water at 25oWith cooling, then the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 100 ml of isopropanol, and the precipitated product filtered and washed thoroughly with isopropanol.

Thus obtain 21.1 g of the hydrochloride of the mentioned product to which is added 200 ml of chloroform and 30 ml of triethylamine, the solution is extracted twice using 100 ml of water, dried over anhydrous sodium sulfate, the solvent is distilled off.

Thus obtain 8.5 g (49.9 percent) of these compounds. Melting point (after recrystallization from acetonitrile): 170-172oC.

Example 79

2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylamino)-propoxyphenyl/-1,3,4-thiadiazole

To a suspension of 5.53 g (0.01 ml of tetrahydrofuran, add 3,18 g (0.014 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 4 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue are added 50 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for another hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

Thus receive and 3.72 g (67,5%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H): 138-141oC.

Example 80

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylamino)-propoxyphenyl/-1,3,4-thiadiazole

To a suspension of 4.3 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-N'-/4-(3-dimethylaminopropoxy)benzylidene/carbothioamides in 25 ml of tetrahydrofuran added 2.50 g (to 0.011 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for further 5 hours at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue add 30 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for another hour. The precipitated product Phi is tion and acetonitrile.

Thus obtain 3.28 g (76.6 percent) of these compounds. Melting point (after recrystallization from acetonitrile): 185-189oC.

Example 81

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/3-(4-methylpiperidin-1-yl)-propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 3.25 g (to 0.007 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl-1,3,4-thiadiazole and 11.4 g (0,115 mol) 4-methylpiperidine stirred at 130oC for 2 hours. After cooling, the excess 4-methylpiperidine distilled off under reduced pressure, to the residue is added dropwise 40 ml of water, the resulting crystals are filtered.

So get up 3.22 g (95.3 per cent) of these compounds. Melting point (after recrystallization from acetonitrile): 155-159oC.

Example 82

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-heptamethylnonane-1-yl-propoxy)phenyl/-1,3,4-thiadiazole

A mixture of 2.56 g (0,006 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl-1,3,4-thiadiazole and 9,92 g (0,0883 mol) heptamethylnonane stirred at 120oC for 3 hours. After cooling, the excess heptamethylnonane distilled off under reduced pressure, to the residue is added dropwise 40 ml of water, the resulting crystals are filtered.

oC.

Example 83

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-heptamethylnonane-1-yl-propoxy)phenyl/-1,3,4-thiadiazole hydrochloride

0,46 g (0.001 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-heptamethylnonane-1-yl-propoxy)phenyl/-1,3,4-thiadiazole obtained as described in Example 82, dissolved in 20 ml of methanol, to the solution add 5 ml of ethanol containing 20 wt./vol.% hydrogen chloride. After cooling, the resulting crystals are filtered and washed with cold ethanol.

So get of 0.44 g (88.6 per cent) of these compounds. Melting point: 182-186oC.

Example 84

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-thiomorpholine)phenyl/-1,3,4-thiadiazole

A mixture of 3.43 g (0,008 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 6.38 g (0,062 mol) thiomorpholine stirred at 120oC for 8 hours. After cooling, the excess thiomorpholine distilled off under reduced pressure, to the residue is added dropwise 40 ml of water, the resulting crystals are filtered.

So get of 3.32 g (92.3 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from tetrahydrofuran): 196 to 199<-thiadiazole

1,71 g (0,004 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole obtained as described in Example 28, is suspended in 100 ml of chloroform. To the suspension is added 2 ml of triethylamine and stirred for 5 minutes. Then add 50 ml of water, the phases are separated, the organic phase is extracted with another portion of water, dried and evaporated to dryness. The residue is purified by chromatography layer Kieselgel 60 H and recrystallized from acetonitrile.

So get of 1.46 g (93,2%) of these reasons. Melting point: 192-193oC.

Example 86

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole

2,19 g (0,004 mol) tetrabutylammonium salt of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole are dissolved in 15 ml of acetonitrile at 80oWith, to the resulting solution was added 3,94 ml (0.01 mol) solution of 3-dimethylaminopropylamine in hexane with a concentration of 40 weight. /about. % under stirring. The reaction mixture was stirred at 100oWith 1 hour. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in chloroform, extracted with 1N-sodium hydroxide solution, then with water, dried first. Melting point (after chromatography layer Kieselgel 60 N): 177-179oC.

Example 87

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(4-morpholinoethoxy)phenyl/-1,3,4-thiadiazole

A mixture of 0.48 g (0.001 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(4-bromobutoxy)phenyl/-1,3,4-thiadiazole and 0.87 g (0.01 mol) of the research was stirred at 100oC for 0.5 hour. To the reaction mixture add 5 ml of water, the mixture is stirred for 30 minutes. The resulting crystals are filtered, washed with ether, and acetonitrile.

So get 0,42 g (86.6 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 148-150oC.

Example 88

2-(5-benzylamino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylamino)-propoxyphenyl/-1,3,4-thiadiazole

To a suspension 4,56 g (0.01 mol) of 2-(5-benzylamino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-/2-(3-dimethylaminopropoxy)benzylidene/carbodiimide in 50 ml of tetrahydrofuran, add 2,73 g (0.012 mol) of DDQ at 25oWith stirring and cooling. Then the suspension is stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue add 30 ml of 5% is myauth 5% aqueous solution of sodium hydroxide, then with several portions of water until neutral and acetonitrile.

So get 4,20 g (87,2%) of the named compound. Melting point: 127-128oC.

Example 89

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-methoxy-4-(3-morpholino-propoxy)phenyl/-1,3,4-thiadiazole

A mixture of 0.49 g (0.001 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-methoxy-4-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 1.0 g (0,0115 mol) of the research was stirred at 100oC for 2 hours. After cooling, the excess of the research is distilled off under reduced pressure, to the residue is added dropwise 40 ml of water. The resulting crystals are filtered, washed with 5 wt./vol.% the sodium hydroxide solution, water and acetonitrile.

Thus obtain 0.21 g (42%) of the named compound, which is purified by chromatography in a layer of Kieselgel 60 H and recrystallization from acetonitrile.

Example 90

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[2-/2-ethyl-2-(2-hydroxyethyl)amino/ethoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 10 ml of ethylaminoethanol stirred at 120oC for 3 hours. To the resulting melt, add 30 ml of water, producrion.

So get 4,19 g (91,4%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 169-172oC.

Example 91

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-(2-morpholinoethyl)-amino/-ethoxy]phenyl-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 13 g (0.1 mol) 2-aminoethylamino stirred at 120oC for 3 hours. To the resulting melt, add 30 ml of water, the product is left for crystallization. After cooling, the selected crystals are filtered, washed with water and acetonitrile.

So get to 4.52 g (90,5%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 162-164oC.

Example 92

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[2-/2-bis(2-hydroxyethyl)-amino/ethoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 10 ml of diethanolamine is stirred at 120oC for 3 hours. To the reaction mixture 50 ml of water, the product is left for crystallization. After Oh 4.42 g (93,2%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 181-184oC.

Example 93

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[2-/2-(3,4-acid), acylamino/ethoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 9.4 g of N-methyl-N-/2-(3,4-acid)ethyl/Amin stirred at 120oC for 1 hour. The excess amine is evaporated from the reaction mixture under reduced pressure, to the residue add 40 ml of water, the mixture is left for crystallization. The resulting crystals are filtered, washed with water and diethyl ether.

So get to 4.01 g (71.0 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 104-106oC.

Example 94

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 4-[2-/2-ethyl-2-(hydroxyethyl)-amino/ethoxy]phenyl}-1,3,4-thiadiazole

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 7,13 g (7.8 ml, 0.08 mol) of ethylaminoethanol stirred at 120oC for 1 hour. To the resulting melt, add 40 ml of water, the product is left for cu Thus gain of 3.45 g (94.2 percent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 181-184oC.

Example 95

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 4-[2-/bis(2-hydroxyethyl)amino/-ethoxy]phenyl}-1,3,4-thiadiazol

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 8.41 g of diethanolamine is stirred at 120oC for 3 hours. To the reaction mixture is added 40 ml of water, the product is left for crystallization. After cooling, the selected crystals are filtered, washed with water and acetonitrile.

So get to 3.52 g (92.8 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 179-182oC.

Example 96

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{4-[2-/2(morpholinoethyl)amino/-ethoxy]phenyl}-1,3,4-thiadiazole

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and a 10.74 g (10.5 ml, 0.08 mol) of 2-aminoadamantane stirred at 120oC for 1 hour. To the resulting melt, add 30 ml of water, the product is left for crystallization. After cooling, the selected crystals are filtered, washed in the Oia (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 175-177oC.

Example 97

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 4-[2-methyl-2-/2-(3,4-acid), acylamino/-ethoxy]phenyl}-1,3,4-thiadiazole

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/4-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and of 9.21 g (0,047 mol) N-methyl-N-/2-(3,4-acid)ethyl/Amin stirred at 120oC for 1 hour. After cooling, to the reaction mixture is added dropwise 30 ml of methanol, isolated crystals are filtered, washed with water and diethyl ether.

So get as 4.02 g (89,1%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 133-136oC.

Example 98

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

A mixture of 3.27 g (0,008 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and of 9.21 g (0,047 mol) N-methyl-N-/2-(3,4-acid)propyl/amine is stirred at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 3.38 g (78%) of these so-140oC.

Example 99

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxy-phenylethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

A mixture of 3.60 g (0,008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and of 9.21 g (0,047 mol) N-methyl-N-/3-(3,4-acid)propyl/amine is stirred at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 4.68 g (81%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 125-127oC.

Example 100

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-(2-morpholinoethyl)amino/-propoxy]phenyl}-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 3,90 g (0.03 mol) of 2-morpholinoethyl stirred at 160oC for 0.3 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 3,91 g (82%) of the named compound. The melting temperature (the

2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,07 g (0.01 mol) 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 5,88 g (0.03 mol) N-methyl-N-/2-(3,4-acid)propyl/amine is stirred at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 4.44 g (78%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 133-134oC.

Example 102

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-(2-hydroxyethylamino)-propoxy/phenyl]-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 1.83 g (0.03 mol) of 2-hydroxyethylamine stirred at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 2,90 g (71%) of the named compound. Melting point (after chromatography in the layer is-1,2,4-triazole-1-yl)-5-[2-/3-(1,2,2-trimethylpropyl)-propoxy/phenyl]-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 1.83 g (0.03 mole) of 1,2,2-trimethylpropyl stirred at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 3.09 g (69%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 174-176oC.

Example 104

2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-[2-/3-(1,2,2-trimethylpropyl)propoxy/phenyl]-1,3,4-thiadiazole

The mixture 4,07 g (0.01 mol) 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 1.83 g (0.03 mole) of 1,2,2-trimethylpropyl stirred at 100oWith in 48 hours. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

Thus obtain 4.09 g (86%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 184-185oC.

Example 105

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 5,88 g (0.03 mol) N-methyl-N-/2-(3,4-acid)propyl/amine is stirred at 140oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get of 3.95 g (73%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 112-114oC.

Example 106

2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,07 g (0.01 mol) 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 5,88 g (0.03 mol) N-methyl-N-/2-(3,4-acid)propyl/amine is stirred at 140oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get of 4.05 g (71%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 98-100oC.

Example 107

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 4-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-trussebut at 140oC for 1 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 3,17 g (68%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 138-140oC.

Example 108

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 4-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 5,88 g (0.03 mol) N-methyl-N-/2-(3,4-acid)propyl/amine is stirred at 140oC for 0.5 hour. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 4.73 g (83%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 127-129oC.

Example 109

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[4-/3-(1,2,2-trimethylpropyl)propoxy/phenyl]-1,3,4-thiadiazole

The mixture 3,79 g (0.01 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/4-(3-bromopropane)flavors cooling to the reaction mixture is added dropwise 40 ml of water, selected crystals are filtered, washed with water and diethyl ether.

So get of 3.27 g (73%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 154-155oC.

Example 110

2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-[4-/3-(1,2,2-trimethylpropyl)propoxy/phenyl]-1,3,4-thiadiazole

The mixture 4,07 g (0.01 mol) 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-/4-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 1.83 g (0.03 mole) of 1,2,2-trimethylpropyl stirred at 100oWith in 48 hours. After cooling, to the reaction mixture is added dropwise 40 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get 3,76 g (79%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 154-156oC.

Example 111

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[2-/2-butyl-2-(2-hydroxyethyl)amino/ethoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,65 g (0,013 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 10 ml of butylaminoethyl stirred at 110oC for 2 hours. To the obtained is filtered, washed with water and acetonitrile.

Thus obtain 4.6 g (91,8%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 152-155oC.

Example 112

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[3-/2-ethyl-2-(2-hydroxyethylamino)ethoxy/phenyl]-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 10 ml of ethylaminoethanol stirred at 110oC for 1.5 hours. To the reaction mixture is added 40 ml of water, the mixture is left for crystallization. After cooling, the selected crystals are filtered, washed with water and acetonitrile.

So get of 3.9 g (85.0 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 138-141oC.

Example 113

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/3-bis(2-hydroxyethyl)-aminoethoxy/phenyl]-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 10 ml of diethanolamine is stirred at 120oC for 2 hours. To the reaction mixture is added 40 ml of water, the mixture is left DL is

So get 4,22 g (88,9%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 152-155oC.

Example 114

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[4-/3-(2-morpholinoethyl)-aminoethoxy/phenyl]-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 13.2 g (0.1 mol) 2-aminoethylamino stirred at 120oC for 1.5 hours. To the reaction mixture is added 40 ml of water, the mixture is left for crystallization. After cooling, the selected crystals are filtered, washed with water and acetonitrile.

So get 4,27 g (85%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from carbon tetrachloride): 136-137oC.

Example 115

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 3-[2-methyl-2-/2-(3,4-acid), acylamino/ethoxy]phenyl}-1,3,4-thiadiazole

The mixture 4,50 g (0.01 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/3-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 9.4 g of N-methyl-N-/2-(3,4-acid)ethyl/Amin stirred at 120oC for 1 hour. The excess amine is evaporated under reduced pressure from recrystalli filter, washed with water and diethyl ether.

So get of 5.1 g (90.3 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from carbon tetrachloride): 147-149oC.

Example 116

2-/5-benzylamino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-[2-/3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 2.00 g (0,0036 mol) of 2-(5-benzylamino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 4,56 g (0.035 mol) of 2-morpholinoethyl stirred at 80oWith over 7 hours. After cooling, to the reaction mixture is added dropwise 98 ml of water and 2 ml of ethyl acetate, the mixture is stirred at room temperature for 1.5 hours. Selected crystals are filtered, washed with water and diethyl ether.

So get 2,11 g (96.9 percent) of these compounds. Melting point: 61-63oC.

Example 117

2-/5-(4-chlorobenzylamino)-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-[2-/3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 1.90 g (0,0032 mol) of 2-(5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 3.80 g (0,029 mol) of 2-morpholinoethyl stirred at 80oWith over 7 hours. After the Noah temperature for 1.5 hours. Selected crystals are filtered, washed with water and diethyl ether.

So get a 1.96 g (95.2 percent) of these compounds. Melting point: 118-120oC.

Example 118

2-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2,4-triazole-1-yl/-5-[2-/3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 5.00 g (0,009 mol) 2-/5-(4-chlorobenzylamino)-3-methylthio-1H-1,2,4-triazole-1-yl/-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 5,90 g (0.045 mol) of 2-morpholinoethyl stirred at 80oWith over 7 hours. After cooling, to the reaction mixture is added dropwise 98 ml of water and 2 ml of ethyl acetate, the mixture is stirred at room temperature for 1.5 hours. Selected crystals are filtered, washed with water and diethyl ether.

So get 4,39 g (80,6%) of the named compound. Melting point: 124-126oC.

Example 119

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The mixture 0,043 g (0.0001 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and of € 0.195 g (0.001 mol) of N-methyl-N-/2-(3,4-acid)propyl/amine was stirred at 100oC for 15 minutes. The reaction mixture is left at Canalsat 1 hour, filtered, washed with water, acetonitrile and diethyl ether.

So get 0,046 g (to 85.2%) of these compounds. Melting point: 138-141oC.

Example 120

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

A solution of 1.8 g (0,0066 mol) tetrabutylammonium salt of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-(2-hydroxyphenyl)-1,3,4-thiadiazole and 1.10 g (0.002 mol) of N-methyl-N-/2-(3,4-acid)ethyl/-N-(3-chloropropyl)amine in 10 ml of acetonitrile was stirred at room temperature for 67 hours. The isolated product was filtered, washed with acetonitrile.

So get 0,79 g (73.1 per cent) of these compounds. Melting point (after chromatography on a column filled with alumina using mixtures of hexane/chloroform with increasing polarity as eluent): 147,5-148,5oC.

Example 121

2-/5-amino-3-(n-hexylthio)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy]phenyl}-1,3,4-thiadiazole

The solution 0,742 g (0,0012 mol) tetrabutylammonium salt 2-/5-amino-3-(n-hexylthio)-1H-1,2,4-triazole-1-yl/-5-(2-hydroxyphenyl)-1,3,4-thiadiazole and 0,652 g (0,024 mol) N-methyl-N-/2-(3,4-dimetho is. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform, the organic solution is extracted with water, dried over anhydrous sodium sulfate, and again evaporated to dryness under reduced pressure.

So get 1,11 g of black oil, which chromatographic on a column filled with alumina using mixtures of hexane/chloroform with increasing polarity as eluent with the receipt of 0.44 g (44,4%) of pure titled product. Melting point 106-107,5oC.

Example 122

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/-propoxy]phenyl}-1,3,4-thiadiazole

To a suspension 0,435 g (0,0008 mol) of 1-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-N'-{ 3-[N-/2-(3,4-acid)-ethyl/-N-methyl] propoxy}benzenedicarbonitrile in 10 ml of tetrahydrofuran, add 0,204 g (0,0009 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue is added 15 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for another 2 hours. The precipitated product is filtered, the ptx2">

Thus obtain 0.39 g (90,1%) of the named compound. Melting point (after chromatography in a layer of aluminum oxide): 147-149oC.

Example 123

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-methyl-2-(2-hydroxyethylamino)ethoxy/phenyl]-1,3,4-thiadiazole

To a suspension of 3.13 g (to 0.007 mol) of 1-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-N'-{ 2-[N-/2-(hydroxyethyl)-N-methyl/ethoxy] benzylidene} carbothioamides in 30 ml of tetrahydrofuran, add a 1.75 g (0,0077 mol) DDQ at 25oWith stirring and cooling. Then the suspension is stirred for another hour at room temperature. The tetrahydrofuran is removed from the reaction mixture by evaporation under reduced pressure, to the residue add 45 ml of 5% aqueous sodium hydroxide solution, the mixture is stirred for another hour. The precipitated product is filtered, washed with 5% aqueous sodium hydroxide solution, then with several portions of water until neutral and acetonitrile.

So get of 2.92 g (93,8%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H): 170-173oC.

Example 124

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[4-/3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 4.1 g (0,009 mol) of 2-(5-amino is eshivot at 140oC for 0.3 hour. After cooling, to the reaction mixture is added dropwise 100 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 3.41 g (76,8%) of the named compound. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 153-154oC.

Example 125

2-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-5-[4-/3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 0.85 g (0.002 mol) of 2-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 2.6 g (0.02 mol) of 2-morpholinoethyl stirred at 140oC for 0.3 hour. After cooling, to the reaction mixture is added dropwise 50 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 0.47 g (49.5 per cent) of these compounds. Melting point (after chromatography in the layer of Kieselgel 60 H and recrystallization from acetonitrile): 160-162oC.

Example 126

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(2-morpholinoethoxy)-phenyl/-1,3,4-thiadiazole

A mixture of 1.45 g (0,0035 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 4,56 g (0,035 mo is billaut dropwise 10 ml of water, selected crystals are filtered, washed with water and diethyl ether.

Thus obtain 1.48 g (91,9%) of the named compound. Melting point: 171-174oC.

Example 127

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/2-(3-morpholinopropan)-ethoxy/phenyl]-1,3,4-thiadiazole

A mixture of 1.45 g (0,0035 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and of 5.05 g (0.035 mol) of 2-morpholinopropan stirred at 80oC for 3 hours. After cooling, to the reaction mixture is added dropwise 10 ml of water, isolated crystals are filtered, washed with water and diethyl ether.

So get to 1.59 g (95,8%) of the named compound. Melting point: 188-191oC.

Example 128

2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-methyl-3-(2-morpholinoethyl)propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 1.50 g (0,0035 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and 3.30 g (0.03 mol) of 2-methyl-2-morpholinoethyl stirred at 80oC for 3 hours. After cooling, to the reaction mixture is added dropwise 10 ml of ether, isolated crystals are filtered, washed with water and ether.

Thus poluchaetsya-1H-1,2,4-triazole-1-yl)-5-[2-/3-(3-morpholinopropan)-propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 1.45 g (0,0035 mol) of 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromopropane)phenyl/-1,3,4-thiadiazole and of 5.05 g (0.035 mol) of 3-morpholinopropan stirred at 80oC for 1 hour. After cooling, to the reaction mixture is added dropwise 20 ml of water, isolated crystals are filtered, washed with water and acetonitrile.

Thus obtain 1.48 g (86,5%) of the named compound. Melting point: 157-160oC.

Example 130

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[4-methyl-4-/2-(3,4-acid), acylamino/butoxy]phenyl}-1,3,4-thiadiazole

A mixture of 0.48 g (0.001 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(4-bromobutoxy)phenyl/-1,3,4-thiadiazole and 1.95 g (0.035 mol) of N-methyl-N-/2-(3,4-acid)ethyl/amine was stirred at 100oC for 1 hour. After cooling, to the reaction mixture is added dropwise 10 ml of ether, isolated crystals are filtered, washed with water and diethyl ether.

So get to 0.29 g (49.1 per cent) of these compounds. Melting point: 120-122oC.

Example 131

2-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-5-[2-/3-(2-morpholinoethyl)-propoxy/phenyl]-1,3,4-thiadiazole

A mixture of 1.45 g (0,0035 mol) of 2-(5-amino-3-morpholino-1H-1,2,4-triazole-1-yl)-5-/2-(3-bromine is impressive. After cooling, to the reaction mixture is added dropwise 30 ml of water, isolated crystals are filtered, washed with water and ether.

Thus obtained 1.51 g (83,9%) of the named compound.

Example 132

2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-methyl-2-(2-hydroxyethylamino)ethoxy/phenyl]-1,3,4-thiadiazole

A mixture of 0.36 g (0,0008 mol) of 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(2-bromoethoxy)phenyl/-1,3,4-thiadiazole and 1 ml of 2-methylaminoethanol stirred at 100oC for 1.5 hours. After cooling, to the reaction mixture is added dropwise 5 ml of water, isolated crystals are filtered, washed with water and acetonitrile.

Thus obtain 0.21 g (73.5 percent) of these compounds.

1. Derivative 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I

< / BR>
where R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro, C1-4alkoxygroup, (C1-4alkyl)amino and di(C1-4alkyl)amino group; or a group of the formula

< / BR>
where Z means a hydrogen atom or a C1-4alkoxygroup;

R0means the group is EPI, R4and R5signify, independently from each other, a hydrogen atom, a C2-6alkenylphenol group, C1-8alkyl group which may be substituted by the Deputy selected from the group consisting of hydroxy-group, (C1-4alkyl)amino, di(C1-4alkyl)amino group, phenyl group, the latter can be locked from 1 to 3 WITH1-4alkoxygroup(groups), 6-membered saturated heterocyclic group containing a nitrogen atom and an oxygen atom and is attached via the nitrogen atom, with the specified heterocyclic group may be substituted C1-4alkyl group, or R4and R5form together with the adjacent nitrogen atom and possibly one or more atom(atoms) of nitrogen and/or oxygen and/or sulfur from 5 - to 7-membered saturated heterocyclic group which may be substituted C1-4alkyl group or phenyl group, the latter can be replaced WITH1-4alkoxygroup;

one of R2and R3is an amino group, then the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atoms(s) of nitrogen and/or oxygen, and attached via its nitrogen atom, and indicated the strong group, or the last of the R2and R3is a group of the formula-SR, where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group, and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

and its pharmaceutically acceptable salts accession acids.

2. Derivative 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole under item 1, where R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl)amino and di(C1-4alkyl)amino groups, one of R2and R3is an amino group, then the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen, and attached via its nitrogen atom, and casinoinlinea group, or the last of the R2and R3is a group of the formula-SR, where R is C1-8alkyl group, a C2-6alkenylphenol group or a C2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group, and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group, and its pharmaceutically acceptable salts accession acids.

3. Derived 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula

< / BR>
under item 1,

where R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, R4and R5signify, independently from each other, C1-6alkyl group or a C2-6alkenylphenol group, or R4and R5form together with the adjacent nitrogen atom and possibly one or more atom(atoms) of nitrogen and/or oxygen and/or sulfur from 5 - to 7-membered saturated heterocyclic group which may be substituted WITH1-4alkyl group or the kind or1-4alkoxygroup;

one of R2and R3is an amino group, then the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atoms of nitrogen and/or oxygen, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR, where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group, and one or both amino groups can be someseni one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl(C1-4alkyl) group or halogenarenes(C1-4alkyl)group,

and its pharmaceutically acceptable salts accession acids.

4. Derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula

< / BR>
under item 1,

where one of R2and R3is an amino group, then the other is an amino group or a 5-6-cleenol through its nitrogen atom, moreover, the specified heterocyclic group may be substituted C1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR, where R is C1-8alkyl group, a C2-6alkenylphenol group or a C2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group, and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, a C2-6alkenylphenol group, phenyl (C1-4alkyl) group and halogenarenes(C1-4alkyl) group;

Alk is C1-6alkalinous group;

R4and R5denote, independently of one another, hydrogen or C1-8alkyl group which may be substituted by the Deputy selected from the group consisting of hydroxy-group, (C1-4alkyl)amino, di-(C1-4alkyl)amino group, phenyl group, the latter may be substituted by 1 to 3 C1-4alkoxygroup(groups), 6-membered saturated heterocyclic group containing a nitrogen atom and an oxygen atom and is attached via the nitrogen atom, with the ski acceptable salt accession acids.

5. Derivative 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole under item 1 or 2, where R1means a hydrogen atom, a methyl, ethyl or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, metoxygroup and dimethylaminopropyl, R2means an amino group which may be substituted halogenosilanes group, R3means piperidine-1-ilen, piperazine-1-ilen, morpholine-1-ilen, or 4-methylpiperazin-1-ilen group or a group of the formula-SR, where R is a methyl group, and its pharmaceutically acceptable salts accession acids.

6. Derived 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole under item 1 or 3, where R0means a group of the formula Alk-NR4R5where Alk is ethylene or propylene group, R4and R5signify, independently from each other, C1-3alkyl group, or R4and R5together with the adjacent nitrogen atom form pyrrolidinyloxy group, R2is an amino group, R3is an amino group or piperidinyl, or 4-methylpiperidino group, and these groups are attached through the nitrogen atom, or a group of the formula-SR, where R is C

7. Derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole, under item 1 or 4, where R4means a hydrogen atom or a C1-2alkyl group, R5means ethyl group substituted by a Deputy selected from the group consisting of hydroxy-group, dimethoxyphenyl group and morpholino group, R2is an amino group, R3is piperidino group or a group of the formula-SR, where R is a C1-3alkyl group,

Alk is C2-3alkalinous group, and its pharmaceutically acceptable salts accession acids.

8. Any of the following compounds on p. 1:

1. 2-/5-amino-3-(4-methylpiperazine)-1H-1,2,4-triazole-1-yl/-5-(2,6-dichlorophenyl)-1,3,4-thiadiazole,

2. 2-(5-Amii-3-methylthio-1H-1,2,4-triazole-1-yl)-5-/3-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

3. 2-(5-amino-3-dimethylamino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

4. 2-/5-amino-3-(2-metalicity)-1H-1,2,4-triazole-1-yl/-5-/2-(3-dimethylaminopropoxy)-phenyl/-1,3,4-thiadiazole,

5. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

6. 2-(5-amino-3-Matilde-5-/2-(3-pyrrolidinyloxy)phenyl/-1,3,4-thiadiazole,

8. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-[2-/3-di(2-methylethyl)aminopropoxy/phenyl] -1,3,4-thiadiazole,

9. 2-/5-amino-3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazole-1-yl/-5-/4-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

10. 2-(5-amino-3-diallylamine-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

11. 2-(5-amino-3-pyrrolidino-1H-1,2,4-triazole-1-yl)-5-/2-(3-dimethylaminopropoxy)phenyl/-1,3,4-thiadiazole,

12. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[2-/2-ethyl-2-(2-hydroxyethyl)amino/ethoxy] phenyl} -1,3,4-thiadiazole,

13. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-[2-/2-(2-morpholinoethyl)amino/ethoxy] phenyl-1,3,4-thiadiazole,

14. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy] phenyl} -1,3,4-thiadiazole.

15. 2-(5-amino-3-piperidino-1H-1,2,4-triazole-1-yl)-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy] phenyl} -1,3,4-thiadiazole.

16. 2-/5-amino-3-(1-metalicity)-1H-1,2,4-triazole-1-yl/-5-{ 2-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy] phenyl} -1,3,4-thiadiazole.

17. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 3-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)amino/propoxy] phenyl} -1,3,4-thiadiazole.

18. 2-(5-amino-3-methylthio-1H-1,2,4-triazole-1-yl)-5-{ 4-[3-methyl 3-/2-(3,4-dimethoxyphenethyl)am the>/P>9. The method of obtaining the derivative 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, where R1, R2and R3such as specified in paragraph 1, or its pharmaceutically acceptable salt accession acid, characterized in that conduct the cyclization of the hydrazone thiocarbonic acid formula

< / BR>
where R1, R2and R3such as above, with an oxidizing agent,

and, if necessary, turn the thus obtained compound of formula I, its pharmaceutically acceptable salt accession acid, or select a compound of formula I from its salts.

10. The pharmaceutical composition affecting the circulatory system and heart, and Central nervous system, containing as active ingredient a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, where R1, R2and R3such as specified in paragraph 1, or its pharmaceutically acceptable salt accession acid in a mixture with one or more traditional media.

11. The pharmaceutical composition according to p. 10, containing as active ingredient a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, where R1, R2and R3such as specified in paragraph 2, or pharmaceutical is the quality of the active ingredient derived 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ia, where R0, R2, R3and Z such as indicated in paragraph 3, or its pharmaceutically acceptable salt accession acid.

13. The pharmaceutical composition according to p. 10, comprising as an active ingredient derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ib where R2, R3, R4, R5and Alk such as indicated in paragraph 4, or its pharmaceutically acceptable salt accession acid.

14. The pharmaceutical composition under item 10 or 11, comprising as active ingredient a derivative of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, where R1, R2and R3such as indicated in paragraph 5, or its pharmaceutically acceptable salt accession acid.

15. The pharmaceutical composition according to p. 10 or 12, comprising as an active ingredient derived 5-phenyl-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ia, where R0, R2, R3and Z such as indicated in paragraph 6, or its pharmaceutically acceptable salt accession acid.

16. The pharmaceutical composition according to p. 10, or 13, comprising as an active ingredient derived 5-(aminoalkoxide)-2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula Ib where R2, R, R4, R5rmaceuticals composition p. 10, comprising as an active ingredient any one of the compounds on p. 8 or its pharmaceutically acceptable salt accession acid.

18. The intermediate product of the formula

< / BR>
where R7means a group of formula-Alk-L, where Alk denotes a straight or branched C1-6alkylenes chain, L is a halogen atom or a hydroxy-group,

Z means a hydrogen atom or a C1-4alkoxygroup,

one of R2and R3is an amino group, then the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atoms(s) of nitrogen and/or oxygen, and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula-SR, where R is C1-8alkyl group, a C2-6alkenylphenol group or2-6alkylamino group, with the alkyl group may be substituted by phenyl group or kalogeropoulou group, and one or both of the amino group may be substituted by one or two substituents selected from the group consisting of C1-6alkyl group, PPy,

and its salts accession acids.

 

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