JPS59108770A - Manufacture of novel triazole derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of new triazole derivatives and their acid salts, to the new substances themselves and to the pharmaceutical formulations thus obtained, and to therapeutic uses of the new substances.

The novel triazole derivatives according to the present invention have the following general formula (I
).

11 (in the formula, R1 and R2 are each independently a hydrogen atom or a hydrocarbon group having up to 10 carbon atoms each, and if they are lower argyl groups, they are directly bonded) or an oxygen atom in the β- or γ-position,
They may be bonded via a sulfur atom, an imino group, or a lower alkylimino group. R3 is a lower alkyl group; R4 is a hydrogen atom or a lower alkyl group; or may be bonded at the β- or γ-position via an oxygen atom, a sulfur atom, or an imino group or a lower alkylimino group; mA and B, independently of each other, may be unsubstituted or Addition salts of the triazole derivatives of the above general formula (1) with inorganic or organic acids also belong to the scope of the present invention.

The substituents R1 and R2 of the carbamoyl group are, on the one hand, in particular monovalent hydrocarbon radicals with up to 10 carbon atoms (for example norobyl, isonorobyl, butyl, isobutyl, 5eC-butyl, anthyl (lower alkyl groups such as isomethyl, neonate, hexyl or heptyl, especially methyl or ethyl), or carbonized aromatic aliphatics having from 7 to 10 carbon atoms. Hydrogen groups (e.g. benzyl group, phenethyl group, α-1
0-1+n-t ft hap-methylpennol group, 3-
on the other hand, directly following the definitions of R5 and R4, or on the other hand, β- or A lower alkyl group bonded in the γ-position via an oxygen atom, a sulfur atom, an imino group or a lower alkylimino group, which together with the adjacent nitrogen atom can form, for example, a 1-azilinonyl group, a 1- Avitinonyl group, 1-1:! 'Lolinonyl group, piperitno group, hexahyto90-I H-azepin-1-yl group, morpholino group, thiomorpholino group,
1-e <u'nonyl group or hexahydro-I H-
A 1,4-diazepin-1-yl group is formed, in which case the last two groups in the 4-position, i.e., the imino group, are methyl, ethyl, norobyl, isopropyl, butyl or isobutyl. , and all the above-mentioned cyclic groups may also be substituted on the carbon atoms by ethyl, norobyl or, in particular, methyl.

The lower alkyl group R5 and the lower alkyl group R4 are, for example, norobyl group, isonorobyl group, butyl group, isobutyl group, 8cc-ethyl group, pentyl group,
Impentyl, neopentyl, hexyl or heptyl, and especially methyl or ethyl. R3 and R4 are bonded to the base as defined above and together with the adjacent nitrogen atoms, for example, the above-mentioned cyclic j, (, especially 1-pyrrolinonyl group, piperitno group / form a group.

1111 As far as the lower groups mentioned or mentioned below are concerned,
It is to be understood as a group having up to 7 carbon atoms and up to 4 carbon atoms 1, iA,! : Each of B may have any number of substituents, but preferably 33 A is monosubstituted and 4B is preferably unsubstituted or disubstituted,
Especially - replaced. Regarding 16 substituents, for example, halokene atoms with atomic numbers up to 35, trifluoromethyl groups, nitro groups, lower alkyl groups, and lower alkoxy groups are problematic. The substituents on the ring are preferably in the 4-position relative to the triazole ring, and the substituents on ring B are in the two ortho positions to the carbinyl group. The halogen atom as a substituent for mA and B is a fluorine atom, a chlorine atom and a bromine atom, and the mono-lower alkyl group includes, for example, a methyl group, an ethyl group, a furoyl group, an isop group, an impentyl group, a neopentyl group, a tert - pentyl, hexyl or hemethyl group; examples of lower alkoxy groups include butoxy, ethoxy, noropoxy, imbutoxy, butoxy, imbutoxy, pentyloxy, isopentyloxy, hexyloxy To base or to! A thyloxy group is considered. W1 occlusion of ring A;
Preferably, the substituent in the 4-position relative to the trianol ring is in particular a halo atom as mentioned above, especially a chlorine atom, and also a nitro group (a hatrifluoromethyl group. Ring B is preferably unsubstituted or 1
is a fluorine atom, a chlorine atom, a bromine atom or a trifluoromethyl group (which may be substituted at the f position, but by a fluorine atom or a chlorine atom).
Preferably, it is substituted in position.

The triazole derivatives of general formula (1) and their salts with inorganic or organic acids have useful pharmacological properties, in addition to their antispasmodic action. For example, the mouse bentetrazole convulsion test (Pentetrazole)
The compound, for example, 1-( 2-(o-chlorobenzoyl)-4-10ruphenyl]-5-(morpholinomethyl)-] H-1,2,4-triazole-3-calzexamide or N,N-tumethyl-1-( 2-(o-
Fluorinzoyl)-4-chlorophenyl, 1-5-
((tumethylamino)-methyl] -1H-1,2,4
-) Liaguru; its effectiveness can be confirmed using 3-carpoxamide. The triazole derivatives of general formula (I) and their acid addition salts further have moderate central nervous system depressant activity. Properties listed above and other effects V'1, selected standard tests (W, Theo
bald and ILA, Kunz + Arzne
imittelforsch, 17 + 561 (1
967)], which is proved by the general formula (
The trianol derivatives of 1) and their addition salts with pharmacologically acceptable inorganic and tangential acids are characterized as active substances for antispasmodic agents and tranquilizers.

These drugs are used, for example, to treat epilepsy and catatonia or anxiety. The various triazole derivatives of general formula (1) are furthermore suitable as intermediates for the preparation of compounds included in this general formula.

In particular, in the general formula (1), R,, R2゜R
3 and R4 have the meanings given in this formula, and ring A is a halokene atom up to atomic stone 35 in the 4-position of the tria/- group, especially a chlorine atom, or a nitro group or a trifluoromethyl group. is substituted and ring B is unsubstituted,
Concerning such triazole derivatives which are substituted with a halogen atom or a trifluoromethyl group up to atom δ♀35 in the - or - position, but preferably with a fluorine or chlorine atom in the - position. . Within the scope of general formula (1), trianol derivatives that are particularly important for their pharmacological properties and are among the limited group of compounds having the above definition are those in which R1 and R2 are independently hydrogen atoms. is or a lower alkyl group with up to 3 carbon atoms (e.g. methyl, ethyl or isopropyl) or a morpholino group or a 5- to 6-membered alkylene group which is still bonded to the 14i-adjacent nitrogen atom. It is an imino group (eg, 1-pyrrolinonyl group or piperidino group).

In such a group of compounds, R1 and R2 have the formula (1
), but preferably a methyl or ethyl group, or a morpholino group or a 5- to 6-membered 'alkyleneimino group (for example: -♂rolinonyl group or pihasutsu group), and on the other hand, terms A and ■3 are independently unsubstituted or substituted, and when substituted, preferably With the group of substituents mentioned above, especially the substituents specifically mentioned.

The details described in Section 2 also apply to the addition salts of the triazole derivatives contained in the general formula (1) listed above with inorganic and organic compounds, especially pharmacologically acceptable acid addition salts. That's true.

The acid addition salt thereof is prepared according to the invention as follows.

General formula ■; Co -0) A carboxylic acid or a functional derivative thereof of the general formula (1) is reacted with a compound of the general formula (1), in which R1 and R2 have the meanings given in formula I, or a reactive functional derivative thereof. Then, if desired, the obtained triazole derivative is converted into a salt with an inorganic or organic compound.

In order to carry out the above method, for example, carbunoic acid of general formula (II) is converted into carboxylic acid of formula (II). react with a compound of general formula (Ill) in the presence of a noamide (eg dicyclohexylcarbodiamide) in an inert solvent such as tetrahydrofuran. , Kuzu et al. also reacted the carbic acid of the general formula (II) with a lower alkyl isocyanate or a lower alkyl isothiocyanate as a reactive functional derivative of the compound of the general formula (1), and the reaction product as such; Heating can be continued until the evolution of carbon oxide or carbinyl sulfide ceases.

For example, lower alkyl esters thereof are suitable as the reactive h[, uM] form of carbic acid of general formula (11). This ester is reacted with the compound of general formula (1), but depending on the reactivity and randomization point of the compound of general formula (III) used, in some cases it can be reacted at room temperature, and if necessary at 7JO temperature. and optionally react in a closed tube. The reaction medium in this case is a lower alkanol such as methanol or ethanol or another inert organic solvent such as tetrahydrofuran or dioxane, but in some cases the general formula (II
Used with an excess of the compound of I).

Other reactive functional derivatives of carboxylic acids of general formula (n) are their halodides, especially their chlorides, especially those in the salt form, such as the hydrochloride. These are prepared by combining the corresponding free calzenic acid and a suitable acid halide (for example, thionyl chloride, oxalyl chloride or phosphorus tribromide), preferably immediately before reaction with a compound of the following general formula (III). The caldenic acid halide or its hydrohalodanide is preferably prepared from a compound of general formula (fil) and used in the next reaction without purification. in the presence or in the presence of a corresponding excess of the compound of general formula (III) to be reacted and in the presence or absence of an inert organic solvent such as dioxane, tetrahydrofuran, benvin or dimethylformamide. , at about 0° to 100° C. or the boiling point of the reaction medium.) The acid binders mentioned above include, for example, triethylamine, N-ethylnoiso!ropylamine, viricun or S-collidine, but if these are present in excess Under similar reaction conditions, a mixed anhydride of a cartonic acid of general formula (II), especially an alkali metal base of such a cartonic acid and a chlorinated formate (particularly a lower alkyl Mixing with carbonic acid semi-ester obtained by reaction of ester;
It is also possible to react the water proboscis with a compound of general formula (III).

Other reactive functionalities N of cartonic acids of general formula (II)
Examples of the 27% isomer include reactive esters such as 0-nitrophenyl ester and cyan methyl ester. They are reacted with the compound of general formula (III) in an inert solvent, if necessary with heating. Under these conditions, the 1-imidazolide of the general formula (n) is reacted with the compound of the general formula (lt[). As a reactive functional derivative of the compound of the general formula (I[l), Although lower alkyl isocyanates and lower alkyl isothiocyanates are mentioned, they are derived from compounds of general formula (III) having a hydrogen atom as R2. The reaction of the carboxylic acids of the general formula (II) with them is carried out in the presence or absence of an inert organic solvent with a sufficiently high boiling point or boiling range, such as toluene or xylene or xylene mixtures. Other reactive functional derivatives of the compound of general formula (1) having a hydrogen atom as R2 include, for example, these compounds 9 and tri(lower alkyl)-silyl chloride such as trimethylsilyl chloride. Examples include N-IJ-(lower alkyl)-silyl derivatives obtained by reacting N-IJ-(lower alkyl)-silyl in an inert anhydrous organic solvent. When it is reacted with the reactive functional derivative of cartonic acid of general formula (II) in an inert organic solvent, it becomes an N-)ly(lower alkyl)-silyl derivative of carboxamide contained in general formula (1). If this is decomposed with water or a lower alkanol, the desired carboxamide is liberated.

A general formula in which both R4 and R5 are hydrogen atoms ([
Examples of functional derivatives of the compound (ii) include its N-
Chlorocarbunyl derivatives are considered.

This is done by reacting a salt (e.g. an alkali metal salt) of a cartonic acid of general formula (II) in the presence or absence of an inert organic solvent such as toluene or dimethylformamide, and the reaction mixture initially formed. The mixture is heated until an equal amount of carbon dioxide is liberated from the calcaric acid-caramic acid anhydride. Similarly, R1 and R2 have meanings other than hydrogen atoms. Compound color of formula (1), e.g. sulfite-
A monoalkyl nisfluor monoamide is derived. When this is reacted with the cal of the general formula (U) and citric acid in an organic solvent (e.g. pyridine, nooxane, trimethylformamide or benvin), the desired cal contained in the general formula (()) produces a xamide. .

The present invention also relates to the above-mentioned process and its preliminary steps, in which the process is interrupted, or a compound formed as an intermediate in one step is used as a starting material to complete the remaining steps, or a reaction is performed. It also concerns the transformation process under which the starting material is made or optionally used in salt form, if the required starting material is optically active, using racemic or separated enantiomers. or, in the case of theastereomeric compounds, either racemic mixtures or specific racemates, or similar separated enantiomers, can be used. The starting materials preferably used for carrying out the separated reactions of the invention are the group of final materials obtained according to the specific references mentioned at the beginning of the specification.

Depending on the conditions and starting materials of this process, the final material may be in free form, in the form of its acid addition salts, which are still included in the present invention;
In some cases, they are also obtained in the form of the last-mentioned hydrates. The acid addition salts of this new compound of general formula (1) can be converted with free bases (eg base agents such as alkalis or ion exchangers) in a known manner. On the other hand, the compound of general formula (1) obtained by the method of the present invention can be converted into an inorganic or organic acid addition salt by a conventional method, if necessary. For example, as a salt component, the desired +t is added to a solution of the compound of general formula (1) in an organic solvent.

The solvent preferably used in the reaction is one in which the resulting salt is poorly soluble, and such a salt can be separated by filtration. Examples of such solvents include vinegar+! Ethyl, methanol, ether, acetone, methyl ketone, acetone/
Ethanol, methanol/ether oyohi ethanol/
It is ether.

Instead of the free bases, it is possible to use pharmaceutically acceptable acid additions (for example salts of anions with acids that are non-toxic as far as dosage is concerned) as pharmaceutically active substances. Furthermore, if the salt used as the pharmaceutically active substance JIj↓ is easily crystallized and not hygroscopic, it is advantageous if it is still only slightly hygroscopic.General formula (1)
For example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, butyric acid, succinic acid, fumaric acid, maleic acid. , phosphoric acid, tartaric acid,
It is possible to use citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and em-genic acid.

Depending on the choice of the starting materials and the method of operation, the new compounds can be produced either as optical antipodes or as racemates or as isomeric mixtures (if they have at least two asymmetric carbon atoms).
They can also exist as racemic mixtures). Isomer mixtures (racemic mixtures) are obtained by separating two pure racemic noastereomers by conventional methods, such as chromatography and ('-1,) fractional crystallization, due to differences in the physicochemical properties of the components. can do.

The racemate obtained can be prepared by methods known for optical enantiomers, for example by recrystallization with the aid of microorganisms from optically active solvents.
Alternatively, the desired compound is reacted with a racemic salt-forming optically active acid, and the salts thus obtained are separated into, for example, noastereomers based on their different solubilities, from which the appropriate reagents are prepared. It can be separated into enantiomers by action. Optically active acids which are particularly used are, for example, D- and L-tartaric acid, non-o-toluyltartaric acid, malic acid, mandelic acid, camphoric sulfonic acid or quinonic acid. It is advantageous to separate the more active of the two enantiomers.

4 [Fatty compounds can be administered orally, rectally or parenterally. Dosage depends on method of administration, species, age, and individual conditions. The daily dose of the isolated base or its pharmaceutically acceptable salts is 0.1 mg) 7k for warm-blooded animals.
g and 3 my/ktt. A suitable dosage unit (eg dragee, tablet, herbal medicine or annol) preferably contains from 0.5 to 50 mg of the active substance according to the invention.

Oral dosage units preferably contain the active substance of the general formula (1).
The compound contains a pharmaceutically acceptable salt in the range of 0.5 to 50%. The dosage unit contains the active substance in a solid powder carrier such as lactose, sucrose, sorbitol or mannitol; starch (e.g. potato starch, corn starch) as well as the amine baritin, oxda laminaria powder or sweet potato starch. Powders; prepared by admixing cellulose derivatives or gelatin, optionally with the addition of lubricants (e.g. magnesium or calcium stearate or polyethylene glycol), and thus forming the core of the tablet or dragee. (8. ) coated with lacquer dissolved in konji liquid.

Dyes can be added to these coatings, for example, to identify different dosage amounts.

Further suitable dosage units are hard gelatin capsules as well as soft sealed cassettes made of pyratine and softeners such as glycerin. Hard piratine capsules contain the active substance, preferably in granular form, with excipients (e.g. corn starch) and/or lubricants (e.g. talc or magnesium stearate) and optionally stabilizers. agents (e.g., sodium pyrosulfite (Na2
S2O5) or ascorbic acid). In soft cassicles, the active substance is preferably dissolved or clouded in a suitable liquid (eg polyethylene glycol), to which stabilizers are likewise added.

Dosage units suitable for enteral administration are, for example, herbal medicines which consist of an admixture of the active substance and a suppository base. Substances that can be used as suppository bases include, for example, natural or synthetic triglycerides,
These are seven rough-hewn hydrocarbons, polyethylene glycol extracts, or higher alkanols. A suitable enteral capsule consists of an active substance and a carrier. :ia l;7J bases are, for example, liquid triglycerides, polyethylene glycols or graphene hydrocarbons. Angles for parenteral administration, especially for intramuscular administration, preferably contain a salt of the active substance, preferably in a concentration of 0.2 to 5 parts, optionally with suitable stabilizers and buffers in aqueous solution. Contains.

The following examples specifically illustrate the preparation of tablets, sugar-coated tablets, tablets, and enmolants.

(a) 1- c 2- (0-chlorochunzoyl)
-4-chlorophenyl] -5-,, (morpholinomethyl)-1H-1,2,4-1-ryanol-3-car+
1? Mix 50.0 g of Kizamide with 500 g of lactose and 292 g of potato starch. Add gelatin 8I to the mixture
Moisten with alcohol solution and granulate through a sieve. After drying the granules, add 60g of potato starch, 60g of talc,
Magnesium stearate 10.9 and highly dispersed silicon dioxide 2()I are mixed into granules and the mixture is
It is compressed into 10,000 tablets weighing 100.0 Tn9 and containing 5.0 g of active substance. Tablets can be grooved to allow for precise dosing.

(b) N,N-trimethyl-], -[2-(o-fluoropennoyl)-4-chlorophenyl)-5-(trimethylamino)methyl) -1H-1,2,4-tria/-3- Kalzu? 12.50g of grains, 16g of corn starch and highly dispersed silicon dioxide 6
Mix in g. Add about 70 m of Imprononol to the mixture.
Moisten with a solution of 2 g of stearic acid, 6 g of ethylcellulose and 6 g of stearin in 1. Sieve III (Ph
, He1v, V). Approximately 1 granule
Dry for 4 hours and pass through sieves III-IIIa.

Next, 16 g of corn starch, 16,9 talc and 2 g of magnesium stearin are mixed, and the mixture is pressed to form lOO0 dragee cores. Lacquer (shellac) 2g, gum arabic 7.511 dye 0.15.9
．． Coating with a thick syrup consisting of 2 g of highly dispersed silicon dioxide, 25.9 g of talc and 53.35.9 g of sugar and finally drying. Dragee-coated tablets with a weight of 162.5 m9 and an active substance content of 2.5 n9 are obtained.

(c) 1-(2-(o-chloroben/yl)-4
-chlorophenyl)-5-(molpolizmethyl)-1H
-1,2,4-) lyazole-3-carlagekizamide i
o, og and finely ground suppository base (e.g. cocoa butter) 1990.9 are thoroughly mixed and dissolved. After melting and stirring, the weight is 2 g and the active substance content is 10
Make 1000 'ny herbal medicines.

(d) 1-(2-(o-rioopen/yl)-4-chlorophenyl)-3,5-bis[(dimethylamine)methyl)-1H-1,2,4-triazol dihydrochloride in 1 liter of water. Salt 5. Fill 1000 annol with OS solution and sterilize it. Each angle contains the active substance 5·n2 as a 0.5% solution.
The method for producing the new compound represented by the general formula (1) and the starting material not currently known will be specifically explained, but this is not intended to limit #i12 of the method of the present invention. Temperatures are expressed in degrees Celsius.

Example 1 l-(2-benzoyl-4-chlorophenyl)-5-(
morpholinomethyl) -1H-1,2,4-triazole-3-cal, I? 7.6g (0,
017 mol) was covered with 340 ml of methanol and 69 ml of concentrated aqueous ammonia solution. 400 while stirring the mixture.
Heat for 4 hours. During this time, the starting material gradually goes into solution. The reaction mixture is left at room temperature for 18 hours, then concentrated in vacuo. Add water to the residue and extract twice with methylene chloride. The organic phase is washed twice with water-cooled IN sodium bicarbonate solution, once with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isonorol and dried in vacuo to give 1-(2-benzoyl-4-chlorophenyl)-5-remorpholinomethyl)-1It-1,2
, 4-triazole-3-carboxamide, 1. i Small point 146-149° is obtained.

The starting material is prepared as follows.

(a) 224 m of 6N hydrogen chloride bath in methanol
1-(2-ben/yl-41'rollofenyl)-5-(chloromethyl)-L H-1,2,4-)riazole-3-cal,pic acid 1] in methanol 112 Q lnl , 2.2 g of the solution and the whole is refluxed for 12 hours. Next, methanol 800 at normal pressure
evaporate and form a concentrated solution over 18 hours at room temperature. The crystallized product is filtered off with suction and washed with cold methanol and hexane. After drying in vacuo, 1-(2-hensoyl-4-chlorophenyl)-5-(chloromethyl)
-1,H-1,2,4-triazole-3-carboxylic acid methyl ester, melting point 1:32-134° is obtained.

(b) 1-(2-benzoyl-4-10lophenyl)-5-(chloromethyl)-I in 1000 g of acetone
A solution of H-1,2,4-) lyazole-3-carboxylic acid methyl ester (51.6 g, 11°, 132 mol) and 29.89 (0,198 mol) of sodium toiodide is refluxed for 45 minutes. Concentrate the reaction mixture in vacuo. Add water to the residue and extract twice with methylene chloride. The organic phase was diluted once with dilute aqueous sodium sulfide solution and once with saturated sodium chloride solution.
(Wash twice with sulfuric acid) l) Dry in a ram and concentrate in vacuo. Trituration of the residue with ether gives the reaction product in crystalline form.

After suction filtration and drying in vacuum, 1-(2-benzyl-
4-chlorophenyl)-5-(iodomethyl)-1H
-1,2,4-triazole-3-car-pic acid methyl ester, melting point 139-142°, is obtained.

(c) 1-(2-benzoyl-4-chlorophenyl)-
5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester 8.8.9 (0,
018 mol) and mo/l/hori 73.5 ml (0,0
40 mol) in 175 methanol at 40 °C.
Stir for 6 hours. The reaction mixture is concentrated in vacuo, water is added to the residue and extracted twice with methylene chloride.

The organic phase is washed three times with water and once with a saturated solution of sodium chloride, dried over a ram of sodium sulfate and concentrated in vacuo.

Trituration of the residue with ether gives the reaction product in crystalline form. Suction filtration, drying in vacuum, kf &, 1- (2
-ben/yl-4-chlorophenyl)-5-(morpholinomethyl)-1H-1,2,4-triazole-3-
Carboxylic acid methyl ester, melting point 165-17 (10
will be rejected.

The following compounds are prepared in a similar manner.

1-(2-pensoyl-4-1'rolofetriyl)-5-
[(trimethylamine)methyl,]-1H-1,2,4-
) from lyazole-3-carboxylic acid methyl ester and ammonia to produce 1-(2-
Benzoyl-4-chlorophenyl)-5-[(tumethylamine)methyl]-1H-1,2,4-)riazole-
3-Calzexamide hydrochloride is obtained; 1-(2-(o-fluoroben/yl)-4-chlorophenyl)-5-((tumethylamine)methyl)-11
(from -1,2,4-triazole-3-carboxylic acid methyl ester and trimethylamine, melting point 140-142
3 -Caryl'quizamide is obtained.

Example 2 l-(2-pensoyl-4-chlorophenyl)-5-C
(Tumimethylamino)methyl)-1H-1,1214-)
') Azole-3-carginic acid methyl ester 17.
5! 9 (0,044 mol) is covered with 850 M methanol and 175 ml of concentrated aqueous ammonia solution.

The reaction mixture is stirred at room temperature for 7 hours, concentrated to dryness in vacuo, water is added to the residue and extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate ram and concentrated to dryness in vacuo. The residue is dissolved in 300 ml of ethyl acetate and ethereal hydrogen chloride solution is added until PI3 is 2. The crystalline product is filtered off with suction and washed with ethyl acetate and ether. When dried in vacuo, x-(2-pensoyl-4-chlorophenyl)-5-C(tumethylamine)methyl]-i rI-1 with melting point 250-255° (with decomposition)
,2,4-t'J7nol-3-carboxamide hydrochloride is obtained.

The starting material is produced as follows.

1-(2-pen/yl-4-10 phenyl)-5-(
iodomethyl) -1H-1,2,4-triazole-
3-carboxylic acid methyl ester C real JA fjl) 1(
(see a) and (b)) 24.0 &< 0.05
0 mol) and 33 cetanolic trimethylamine solution in 480 methanol 20.51 + 17! The mixture is refluxed at room temperature for 2 hours. The reaction solution is concentrated in vacuo, water is added to the residue and extracted twice with methylene chloride.

The organic phase is washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness in vacuo. The amorphous residue is dissolved in 150 ml of ether. At the same time as the reaction product crystallizes, the solution is allowed to stand. After suction filtration, washing with ether, and drying, the melting point is 1.
18-121° 1-(2--?mesoyl-4-10lophenyl)-5-[(trimethylamine)methyl)-1
H-1,2,4-triazole-3-carboxylic acid methyl ester is obtained.

Example 3 Crude 1-(2-(o-chloropen/yl)-4-chlorophenyl)-5-(morphoIJ/methyl)-1H-1
,2,4-triaguru-3-carzene hydrochloride 9.0
0,! 9 (0,018 mol) to thionyl chloride 90m
Reflux with 1 for 90 minutes. Clear 44 liquid in vacuum 40
To completely remove thionyl chloride, the residue is dissolved in 100 g of anhydrous toluene and concentrated again by evaporation.

The crude acid loli P hydrochloride is covered with 90 g of concentrated aqueous ammonia solution, and the whole is stirred at room temperature for 18 hours.

The reaction mixture is then cooled with ice water for 2 hours, and the precipitated crude product is filtered off and then thoroughly washed with cold water.

When recrystallized from isozolo 2-nor, the melting point is 165-1
67° 1-(2-(o-chloropen/yl)-4-chlorophenyl]-5-(morpholinomethyl)-1H-
1,2,4-) lyazole-3-carboxamide is obtained.

The starting material is produced as follows.

(a) Sodium iodide o, i o g in 10 g of ethanol (1-(2-(o-rioobenzoyl)-4-chlorophenyl)-5-(chloromethyl)-
111-1,2,4-) lyazole-3-cal, pinic acid (see German Patent Publication No. 2,159,527, page 32) 9.3 g (0,0226 mol) and morpholine 9.5 g
g (0.11 mol) and the whole is refluxed for 2 hours.

The reaction mixture was ↓′ (dried in air, the residue was dissolved in water,
Then 2N hydrochloric acid is added until an acidic reaction to Congo red is obtained. The precipitated hydrochloride salt of the reaction product is extracted twice with 100 ml of methylene chloride. Wash with saturated sodium chloride solution, dry with sodium sulfate,
1-(2-(o-chloropene/yl)) is then concentrated by evaporation and leaves the organic phase as an amorphous yellow foam.
-4-chlorophenyl]-5-(morpholinomethyl)
-1H-1,2,4-triazole-3-carpine acid salt B is obtained and used directly in the next step.

Example 4 In the same manner as in Example 1, the following compound is obtained.

ff1l-(2-pensoyl-4-chlorophenyl)-
s-((+-pyrrolinonyl)methyl:]-1) 1-1.
Starting from 7.3 g (approximately 0.017 mol) of 2.4-triazole-3-carboxylic acid methyl ester, the amorphous form (
7) 1-(2-henshiyl-4-chlorophenyl)-
5-((1-pyrrolinonyl)methyl]-1F(-L2.
4-) Riazole-3-carpixamide is obtained and the hydrochloride salt prepared from an ethereal hydrogen chloride solution in ethyl acetate has a melting point (with decomposition) of 236° upon recrystallization from isonoro-zonol.

[1-(2-pensoyl-4-10lophenyl)-5-
(piperitunomethyl)-1H-1,2,4-triazole-3-cal-12-acid methyl ester 7.5I (approximately 0
．． Starting from 017 mol), 1-(2-pen/yl-
4-1'rollophenyl)-5-(pi-critnomethyl)
-t H-1,2,4-) Liagulu 3-cal? Quizamide was obtained, the hydrochloride was prepared in the same manner as above, and recrystallized from isozolo 9-nol, the melting point was 255-260° (
(with decomposition).

Starting material tiii: Produced as follows.

(,) 2.9g of pyrrolinone instead of morpholine
(0,041 mol) and piperinone 3.0 g (0,04
1 mol) in the same manner as in Example 1, the crude 1-(2
-penquil-4-/'lorophenyl)-5-((1-
(pyrrolinonyl) methyl) -L H-1,2,4-tria/-3-carpic acid methyl ester Oyohi 111
1- (2-pensoyl-4-chlorophenyl) = 5-
(Piperitunomethyl)-1H-1,2,4-triazole-3-cardoic acid methyl ester is obtained, respectively.

Example 5 Crude 1-(2-pensoyl-4-nitrophenyl)-5
-((dimethylamine)methyl)-14-[214-'
) IJ 71-3-carbic acid ethyl ester (
(see below) 7.0. @ (0,0165 mol), ethanol 200- and concentrated ammonia water I liquid 20I + 17! and leave the reaction mixture at room temperature for 3 days. The reaction mixture is concentrated in vacuo, water is added to the residue and extracted twice with ethyl acetate. The several phases are washed twice with cold IN sodium bicarbonate solution and twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate/isozolo-9ol (5:1) and chromatographed on a column of silica gel 150y.

The eluent used was ethyl acetate/isopropanol (5
:1). Fractions containing the desired product are collected and concentrated by evaporation. The residue is recrystallized from ethanol and dried in vacuo to give 1-
(2-pennoyl-4-nitrophenyl)-5-C(trimethylamine)methyl]-1)(-1,2,4-)riazole-3-cal d? Oxamide is obtained.

The starting material is produced as follows.

36% formaldehyde aqueous solution 16d (0,072 mol)
6-phenyl-8-nitro in 85% formic acid
-4H-s-) riazoo (1,5-a ] [1,4]
] Bensonoazebin-2-carzenic acid ethyl ester (see German Patent Publication No. 2,304,307) 7.5
Add 5 ji (0,020 mol) to the solution. The mixture is then heated at 100° for 2 hours. Pour the reaction mixture into ice water 2
The insoluble yellow by-product can be removed by filtering through pure diatomaceous earth. Add sodium carbonate to the filtrate while cooling on ice until lI becomes 9.

Extract twice with ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution, dried (sodium chloride) and concentrated in vacuo.
-(2-benzoyl-4-nitrophenyl)-5-[(
Dimethylamino)methyl]-1H-1,2,4-)lyazole-3-cal, contains 1 gram of ethyl ester and is directly used for ammonia decomposition.

Example 6 l-(2-(o-chloropen/yl)-4-chlorophenyl]-5-(morpho'J/mefyl)-L H
-1,2,4-triazole-3-cal, 28.5 g (0.06 mol) of bic acid methyl ester was added to methanol 7
Cover with 30M and 1t290rnlV of concentrated ammonia water. The mixture is heated at 400 °C for 4 hours without stirring, and the starting material gradually goes into solution. The reaction solution is left at room temperature for 18 hours and then concentrated in vacuo. Add water to the remaining
Extract twice with ethyl acetate. Combine the organic extracts, shake with ice 1), and add enough 2N hydrochloric acid to bring the pH to 3. The hydrochloride salt obtained in crystalline form is washed with water and ethyl acetate. The acidic aqueous phase is separated from the filtrate and combined with the suction filtration residue. Add 5N sodium hydroxide solution until Pll is 9. The precipitated base is dissolved in methylene chloride. The methylene chloride solution is washed once with water and twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in a mixture of methylene chloride and inzolo-zonol. Methylene chloride is distilled off at normal pressure and the mixture is cooled to room temperature. The crystalline reaction product is filtered off with suction and washed with isonoro-zonol and ether. Upon drying in the bottom wall, I-[2-(o-chloroben/yl)-4-chlorophenyl]-5-(morpholinomethyl)-1T(-1,2,4-)lyazole-3=
Carboxamide, melting point 165-167°.

Example 8 1-(2-(o-chlorobenzoyl)-4-chlorophenyl)-5-[(tumethylamine)methyl)-1H-1
, 8.66.9 (0,020 mol) of methyl nisdel 2,4-triazole-3-carboxylate was dissolved in methanol 4
00 ml and 80 ml of concentrated aqueous ammonia solution. The mixture is stirred at room temperature for 16 h (:L) and then concentrated to dryness in vacuo. Water is added to the residue and extracted twice with methylene chloride. The organic phase is extracted with water-cold IN sodium hydroxide solution. 2
Wash twice and extract twice with 2N hydrochloric acid solution. In the acidic aqueous phase,
Add water and enough 5N sodium hydroxide solution (to bring the pH to 10). Take the precipitated base into chloride solution. The organic phase is washed twice with water and once with saturated aqueous sodium chloride solution. Dry with 'fj&ta sodium and concentrate to dryness by evaporation. When the remaining amorphous form is triturated with ether, the reaction product precipitates out as crystals. Filter with suction and wash with ether. After drying,
1-C2-(o chloroben/yl)-4-chlorophenyl]-5-((dimethylamine)methyl]-I
H-1,2,4-triazole-3-carboxamide, melting point 177-180, is obtained.

The starting material is produced as follows.

) 270 d of 6N hydrogen chloride solution in methanol was added to 1(2-(o-ri0lopensoyl)-4-chlorophenyl)-5-(-'yfluorotyl)-11(-1,2,4) in 140 Qd of methanol. -) Riazole-3-cal d
? 133.
Add to a solution of 0.9 (0.30 mol). 18 total
Reflux for an hour. The reaction mixture is reduced to Jλ in vacuo, water is added to the residue and extracted twice with methylene chloride. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution, dried over sodium chlorate and concentrated in vacuo.

The residue is recrystallized from methanol 11. After drying, 1-(
:2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(rioo,)zchi/1=)-1H-1,2,4
-) Riazole-3-cal?・Remethyl ester,
A melting point of 13°-132° is obtained.

(b) 1-[2-(o
-chlorobenzoyl)-4-chlorophenyl, ]-5-
(chloromethyl) -1H-1,2,4-tria/-ru-3-carboxylic acid methyl ester and sodium iodide 5
6.2,! 9 (0,375 mol) at night 40
Reflux for minutes. Concentrate the reaction mixture in vacuo. Add water to the residue and extract twice with methylene chloride.

The organic phase is washed twice with dilute aqueous sodium sulfide solution and then twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in a minimum amount of methylene chloride and 400 g of ether is slowly added with gentle stirring to crystallize the reaction product. After suction filtration and drying in vacuo, 1-[
2-(o-chloropen/yl)-4-chlorophenyl)
-5-(iodomethyl)-1F(-1,2,4-)liagulu-3-carboxylic acid methyl ester is prepared (c) 1-(2-(0) in 250 ml of methanol.
-chlorobenzoyl)-4-chlorophenyl)-5-(
iodomethyl) -1H-1,2,4-triazole-
3-Calyl? A mixture of 12.90.9 (0.025 mol) of methyl ester (see Example 8(b)) and 11 ml of a 33-functional ethanolic trimethylamine solution is stirred at room temperature for 7 hours. The reaction solution is concentrated in vacuo, water is added to the residue and extracted twice with methylene chloride. The organic phase was washed twice with water and once with saturated sodium chloride solution,
Dry with sodium sulfate and concentrate to dryness in vacuo. The amorphous residue is dissolved in 130 ml of ether and the solution is allowed to stand to crystallize out the reaction product. Filter with suction and wash with ether. When dried, 1-C2- with melting point 131-134°
(o-ricoloben/yl)-4-10lovenil)-
5-[(trimethylamine)methyl) -1I(-1,2
, 4-triazole-; u-cargenic acid methyl ester is obtained.

Although the present invention has been described in detail above, the detailed examples of the present invention can be summarized as follows.

In the general formula (1), R1 and R2 are independently hydrogen, lower alkyl having at most 3 carbon atoms, or together with the adjacent nitrogen atom, morpholino or 5- to 6-membered alkyleneimino. R5 and R4 are lower alkyl having at most 2 carbon atoms, or are morpholino or ζ is an alkylene imino of 5 to 6 L-Lm; ; rings A and B are, independently of each other, unsubstituted or not yet atomic;
A process as claimed in the preceding claims for preparing trifluoromethyl or nitro-substituted compounds and salts of inorganic and organic acids.

2. In the general formula (1), R and R2 are independently hydrogen, lower alkyl having at most 3 carbon atoms, or together with the adjacent nitrogen atoms, morpholino or 5- to 6-membered alkylene imino; R3 and R4 are lower alkyl with at most 2 carbon atoms, or together with adjacent nitrogen atoms are morpholino or alkyleneimino with 5 to 6 negative implants and ring 1 is the 4- At the position, atomic number 3
Substituted with up to 5 halogens, especially with chlorine or with nitro; option B is unsubstituted or with atomic number 35
A process as claimed in the preceding claims for preparing addition salts of inorganic and organic acids and compounds of up to halogen, especially those in which fluorine is substituted in the ortho position with chlorine.

3. In the method as defined in the claims, a compound formed as an intermediate in one step is used as a starting material to complete the remaining steps, or the starting material is prepared under reaction conditions; A variant method used in some cases in the form of salt.

4. A method according to the claims for producing addition salts of the compounds described in the embodiments of formula (1) and inorganic and organic acids.

5.1-(2-pensoyl-4-chlorophenyl)-5
-[(trimethylamine)methyl) -1H-1,2,4
-1-ryanol-3-kahlua 1? A process as claimed in the preceding claims for preparing xamide and its inorganic and organic acid salts.

6, 1-(2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(morpholinomethyl)=11(,-
A method as claimed in the preceding claims for preparing 1,2,4-triazole-3-cardexamide and its inorganic and organic acid addition salts.

7, N,N-tumethyl-1-(2-(o-fluorobenzoyl)-4-chlorophenyl)-54(/methylamine)methyl]-1H-1,2,4-)riazole-3-cardexamide and A process according to said Patent J1-claim for preparing the inorganic and organic acid addition salts thereof.

Claims (1)

[Claims] General formulas I-II (wherein R1 and R2 are, independently of each other, hydrogen atoms or hydrocarbon groups each having up to 10 carbon atoms, and they are lower alkyl groups) In the case of and R4 is a hydrogen atom or a lower alkyl group,
Alternatively, R3 and R4 are directly bonded as a lower alkyl group, or an oxygen atom at the β- or γ-position,
(A and B are independently unsubstituted or substituted) and their inorganic and In the method for producing addition salts with organic acids, the general formula ■
: Co -OH (in the formula, R3 and R4 have the meanings given in formula (1),
And iA and B may be substituted as shown in formula (1)) Cal 4? phosphoric acid or a reactive functional derivative thereof is reacted with a compound of the general formula (1): (wherein R1 and R2 have the meanings given in formula I) or a reactive functional derivative thereof. , Process for the preparation of novel triazole derivatives of the general formula (D), characterized in that, if desired, the triazole derivative obtained is converted into an addition salt with an inorganic or organic base.