DE2541464A1 - 1,2,4-TRIAZOLE DERIVATIVES, PROCESS FOR THE PREPARATION OF THE SAME AND PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

TiEDTKE - BüHLING - KlNiJE

Patent attorneys:

Dipl.-Ing. Tiedtke Dipl.-Chem. Bühling Dipl.-Ing. Chins

8 Munich 2, PO Box 202403 Bavariaring 4

Tel .: (0 89) 53 96 53-56 Telex: 5 24845 tipat

cable: Germaniapatent Munich

B 6838 / MFP-968 Takeda September 17, 1975

Takeda Chemical Industries, Ltd.
Osaka, Japan

1,2,4-triazole derivatives, processes for producing the same and pharmaceutical compositions containing them

The invention relates to new triazole derivatives that are usable as medicaments and of the general formula (I) correspond:

(D

CH - II '

2 in which R and R, which can be the same or different, mean an alkyl or aralkyl group, one of the

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■ - 2 - '254 · ?! 464

1 2
R and R radicals can also be a hydrogen atom or 12

R and R together with the neighboring nitrogen atom form a heterocyclic ring; R ^ stands for a hydrogen atom, an alkyl group or an aralkyl group; R is a hydrogen atom or a lower alkyl group; the ring A can either be unsubstituted or substituted with halogen, nitro, alkyl, alkoxy or trifluoromethyl and Ar denotes an optionally substituted phenyl group or a pyridyl radical »The invention further includes pharmaceuticals acceptable acid addition salts of these compounds and a process for the preparation thereof and containing them pharmaceutical agents.

The compounds (I) or their pharmaceutically acceptable acid addition salts have central nervous system actions pharmacological properties such as muscle relaxant, anticonvulsant, sedative, anxiety-relieving, tranquillizer and sleep-inducing effectiveness and they are thus as pharmaceuticals in human and veterinary therapy e.g. as muscle relaxants, anticonvulsants, sedatives, anxiety-relievers Medium, small tranquillizers and (compulsory) sleeping pills can be used.

The ϊη of the above formula represented by R and R. Alkyl groups are preferably lower alkyl groups having 1 to 6 carbon atoms that are straight, branched or cyclic

7 0 9 8 0 9/1206

could be. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, hexyl, Cyclopropylmethyl, cyclopentyl and cyclohexyl. Examples

12th
are for the aralkyl groups represented by R and R.

1 2

Benzyl or phenetyl. When R and R together with the neighboring one Nitrogen atom form a heterocyclic ring, this is preferably 5 to 7-membered and it can 1 to

Contain 2 further nitrogen and / or oxygen atoms as heteroatoms; Examples are pyrrolidine, piperidine, Piperazine, morpholine, N-substituted piperazine (e.g. N-methyl-piperazine, N-ethyl-piperazine, N- (2-hydroxyethyl) -

1 p

piperazine etc.), homopiperidine etc. As indicated by R and R represented groups become lower alkyl groups with 1 to

3 carbon atoms and 5 to 6-membered heterocyclic Rings are particularly preferred.

The alkyl groups represented by R are pre-

12th

preferably the same as represented by R and R. i.e. lower alkyl groups with 1 to 6 carbon atoms, which can be straight, branched or cyclic.

The aralkyl groups represented by R ^ can also

1 2

if the same as represented by R and R. As groups or radicals represented by R ^, a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms are particularly preferred.

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The lower alkyl groups represented by R preferably have 1 to 4 carbon atoms; Examples are Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl etc.

If the ring A is substituted with halogen, nitro, alkyl, alkoxy or tri fluorine thy 1, the number of these Substituents at any suitable positions on ring A can be chosen freely. Among the substituents on ring A possible halogen atoms include fluorine, chlorine, bromine and iodine. To lower alkoxy groups, which are used as substituents on ring A come into question include, for example, lower alkoxy groups with 1 to 4 carbon atoms such as methoxy, ethoxy, Propoxy and butoxy. Examples of possible alkyl groups as substituents on ring A are the same lower alkyl groups having 1 to 4 carbon atoms as represented by R. Halogen is preferred as the substituent on ring A. and as the position of the substituent, the 4-position on ring A in formula (I); 4-bromine are particularly preferred and 4-chlorine.

The phenyl group represented by Ar can also be either unsubstituted or with the same substituents, as they are possible on ring A, be substituted, the number of these substituents in any suitable positions of the phenyl ring is freely selectable. When the Ar-

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254U64

given phenyl radical has one or more substituents, a halogen atom, in particular Chlorine or fluorine, in the ortho position or positions on the Phenyl radical preferred.

The pyridyl group represented by Ar corresponds to the formula {'^ N, with the 2-pyridyl group being preferred,

The compounds of formula (I) can by a process be prepared, which is a reaction of a compound of the general formula (II):

(ID

3 A

in which R, R, Ar and the ring A correspond to the definition already given and X is a halogen atom or a re « is the active ester residue of a hydroxyl group, with a compound of the general formula (III):

HN:

(III)

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254U64

12th
in which R and R have the meanings already given. . ■ '. .

That represented by X in the above formula (II) Halogen atom includes the same halogen atoms as given as examples of substituents on the A ring. Examples of the reactive hydroxyl group derivative represented by X are sulfoxy groups (-OSCUH), alkylsulfonyloxy groups such as methylsulfonyloxy, arylsulfonyloxy groups such as Phenylsulfonyloxy, p-tolylsulfonyloxy, etc.

The process according to the invention is carried out by reacting the compound (II) with the compound (III). The amount of the compound (III) to be used is usually about 1 to 20 moles per mole of the compound (II). The reaction can proceed in the absence of solvents, but it proceeds more smoothly in the presence of a solvent. Examples of such solvents are alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol etc.), aliphatic, aromatic or halogenated hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, chloroform, dichloromethane, dichloroethane etc.), dialkylformamides (e.g. dimethyl - or diethylformamide etc.), ketones (e.g. acetone, methyl ethyl ketone, cyclohexane etc.), ethers (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane etc.), pyridine, dimethyl sulfoxide etc. The reaction temperature is expediently in the range from room temperature to 150 ^° C. ; 709809/1206

When using a solvent, the reaction temperature is usually around the boiling point of the solvent used.

In this reaction, a hydrogen halide corresponding to X of the compound (II) or such a sulfonic acid becomes educated. To trap the hydrogen halide or of the sulfonic acid, the compound (III) can be used in excess or, alternatively, a suitable basic substance can be added to the reaction system (e.g. a tertiary Amine such as triethylamine or pyridine or an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, Sodium bicarbonate or potassium bicarbonate). When a compound (II) with X ■ chlorine or bromine as a starting material is used, the reaction can be smoother in the presence of a catalytic or equimolar amount of potassium iodide or sodium iodide run off.

The compound (I) according to the invention thus obtained can be prepared by methods known per se (e.g., column chromatography or recrystallization) isolated or purified. Alternatively, it can be obtained by recrystallization an acid addition salt are purified, which, according to Wunech, an alkali treatment for conversion into the free base can connect. The compound (I) has basic nitrogen in the molecule and can be converted into a corresponding one

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■ - 25AU64

Acid addition salts are converted. examples for such acid addition salts, which are usually water-soluble, are salts with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and Phosphoric acid) or organic acids (e.g. acetic acid, oxalic acid, succinic acid, malonic acid, tartaric acid, fumaric acid, Maleic acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid), which can be produced in a conventional manner. The compounds according to the invention can thus be used in In the form of pharmaceutically acceptable acid addition salts such as salt with the acids mentioned above will.

When the compounds (I) of the present invention or their pharmaceutically acceptable acid addition salts are used as medicaments in human and veterinary therapy, for example, as muscle relaxants, anticonvulsants, sedatives, and anti-anxiety agents Means, small tranquillizers or (compulsory) sleeping pills are used, they can be taken orally or parenterally as such or in a suitable form such as powder, granules, tablets, capsules, injectable preparations, Suppositories, etc. administered in admixture with pharmaceutically acceptable carriers, excipients or diluents will. The dose of the compound (I) or its pharmaceutically acceptable acid addition salt to be administered varies with the type of complaint to be treated, the

, 709809/1206

clinical condition and the specific compound to be used, but it usually falls within the range of about 1 to 100 mg per day when administered orally to adults.

Regarding specific compounds of the general formula (I) including those given below Illustrative examples shown include the following:

Connections (I)

l- (2-benzoyl ^'! l-chloro-phen _I yl) -3-meth.yl-5-methylaminomethyllH-l, 2,4-triazole

1- (2-Ben7oyl-'4-chlorophenyl) -5-dimethylaminomethyl-3-methyl-I] I-] , 2, h -triazole

1- (2-Benzoyl- ⁱ l-chloro-phenyl) -5-dimethylaminomethyllH-l, 2, i | -triazole

1- (2.-r> pn7, oyl - ^ - chlorophenyl) -5-ethylmethylaniinomethyl-3-niethyl-lH-1,2, i | -triazole
1- (2-Benzoyl- ^; -I-chlorophenyl) -5-diethylaminomethyl-3-ynethyl ~

1- (2-Benzoyl-14-chloro-phenyl) -3-benzyl-5-diethylaminonethyl If I-Ij 2, ^ -triazole

1- (2-Benzoyl - ^ - chlorophenyl) -5-di-n-propylaminoi7iethyl-3-methyl-3-methyl 1- ^ 1H-1,2,4-triazole

1- (2-I.ienzo.yl- ⁱ l-chlorophenyl) -3-methyl-5-niorpholinomethyllH-1,2,1 | -triazole

1- (2 ~ Benzoy 1 - '<- chloro-phenyl) -3-me thy 1-5-pyrro Ii dinorr.e thy 1-iH-i, 2, n ~ triazoj 7ο9809 / 1 206.,

1- (2-Eenzoyl-4-chloro-phenyl) -3-ethyl-5-piperidinomethyl-1H-1,2,2, * J-triazole . ·

1- (2-BeHZOyI - ^ - ChIor-phenyl) -3 - πlethyl · -5 -] ^ iperazinylmethyllH-l _s 2, ll-triazole. 1- (2-Benzoyl - ^ - chloro-phenyl) -3-methy 1-5- (4-niethylpiperazinyl) methyl-1'Hl, 2, i | - triazole. *. 1 ~ (2-Benzoyl-4-chloro-phenyl) -5- [ ⁱ t- (2-hydroxyl) -piperazinyl] iriethyl-1K-1 ·, 2, ¹ * -triazcl

1- [i (-Chlor- 2- (2-chloro-benzoyl) phenyl] -5-dimethyl laminomethyl 3-methyl-1 H-1,2,4-triazole '. '

l- [4-chloro-2- (2-chloro-benzoyl) phenyl] -5-dläthylamincmethyl-3 - r.ethyl-lH-l, 2 4-triazol ₃ "■

1- [II -chloro-2- (2- chloro-benzcyl) phenyl] -3-methyl-5-i "iorpholinomethyl-1H-l j 2,4-triazole
1 - [^ - chloro-2- (2r-chloro-benzoy 1.) phenyl] -3-methy 1-

1- [it-chloro-2- (2-chloro-benzoyl) phenyl] -5-diethy laminomethyl 1-Hi-l ₃ 2 ₃ i | - triazole

1- [^ - chloro-2- (2-fluoro-behzoyl) phenyl] -5-dimethylaminomethyl 3-ethyl-lH-l., 2,4-triazole

1- (2-Benzoyl-4-chloro-phenyl) -5-dimethylaminomethyl-3-athy1-1H-1,2,4-triazole

! - (P-Benzoyl - ^ - chloro-phenyD-S- (1-dlmethylaminoethyl) -3-methyl-1H-1,2,4-triazole

l- (2-benzoylphenyl) -5-dimethylaminomethy1-3-methy1-lH-l, 2 _3-triazol iJ

l- (2 - Benzoyl-4-nitrophenyl) -5-dlmethylaminomethyl-

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25AH64

1- (2-Benzoyl-4-trifluoro_methylphenyl) -5-dirnethylaminomethyl-3-r.ethyl-1H-1,2, iirtriazole 1- (2-Benzpyl- ^, 5-dimethoxyphenyl) -5-diethylaminomethyl-3-m 'ethyl-lH-l., 2,4-triazole l- (2-Bensoyl-4-methoxyphenyl) -5-dimethylamlnomethyl-3-methy1-lH-l, 2,4-triazole l- (2-benzoyl- ^I l-methylphenyl) -5-dlraethylaminomethyl-3-methy1-lH-l, 2,4-triazole l - [^ - bromo-2- (2-pyridyl-carbonyl) phenyl] -5-dimethylaminomethyl-3-ethyl- lH-l, 2, ^ - triazole

l- [IJ BroiTi- 2-C2-pyridyl-carbo.nyl) phenyl] - X 5 d.iäthylair: inomethyl-3-ethyl-lH-l, 2, ⁱ <triazol -2- (2-pyridyl carbonyl) phenyl] -

1_ [ij-bromo-2- (2-pyrldyl-carbony 1) phenyl] -3-ethyl-5-niorpholinomethyl-1H-i, 2 j ^ -triazole 1- [ί »· -Η) Γθπ- 2- ( 2-pyridyl-carbonyl) phenyl] -3-ethyl ~ 5-plperldlnomethyl-lH-l, 2 _i ^ -triazOl l- [ü_BroiT! - 2 -. (2-pyridyl-carbonyl) phenyl] -3-ethyl-5-piporazinylTtie thy 1-IH-1,2, ^ -triazole! - [^ - BroiTi-2- (2-p.yridyl-carboriyl ) phenyl] -3-ethyl-5_ (ü-methylpiperazinylmethyl) -IH-I, 2, ^ - triazole l .- [if-bromo-2- (2-pyridyl-carbonyl) phenyl] -3-a thy 1- 5 [^ ~ (2-hydroxyethyl) piperazinylmethyI] -IH-I, 2,4-triazole 1- [4-chloro-2- (2-pyridyl-carbonyl) phenyl] -5-diethylaminomethyl-3-ethyl-1, 2, ^ - triazole

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1 C 1-4 chloro-2- (2-pyridyl-carbonyl) phenyl] -5-dimethylaminomethyl-3-ethyl-1 H-1 ₅ 2, 4-triazole 1- [4-chloro-2- (2-pyrid yl-carbonyl) phenyl] -5-dimethylaminomethyl-3 ~ mothyl-lH-l, 2 _J 4-triazole l- [4-bromo-2- (2-pyridyl-carbonyl) phenyl] -5 - dimethylaminomethyl'-3 -methyl-lH-l ₃ 2 j 4-triazole l- [4-bromo-2- (2-pyridyl-carbonyl) phenyl] -5-diethylamine / methyl-3-methyl-lH-l, 2,4-triazole l - [4-Bromo-r 2- (2-pyridyl-carbonyl) phenyl] -3-methyl-1-5-morpholinomethyl-1H-1,4-triazole 1- [4-Brotn- 2-. (2-pyridyl-carbonyl) phenyl] -3-methy 1-5-piperidinomethyl-1-IH-1,2,4-triazole 1- [4-ßrom-2- (2-pyridyl-carbonyl) phenyl] -3-roethyl -5_ (4-methylpijperaziny! Methyl) -IH-1,2,4-triazole

1- [4-Bromo-2 - (2-pyridyl-carbonyl) phenyl] -3-i- ^T iethyl-f) -pyrrolidinomethyl-1 H-1,2 _} 4-triazole 1- [4 <-Brom-2 "(4-pyridyl-carbonyl) phenyl] - ^r ) -dimethyiaiTiinomethyl-3-ynethyl-1H-l ₃ 2, 4-triazole 5-Dimethyland nomethyl-3-ethy1-1- [2- (2-pyridyl-carbonyl) · Phenyl] - 1H-1,2-, 4-triazole

5-diethylaminomethyl 1-3-methy1-1- [2- (2-pyridyl-carbonyl) pherjyl] -1H-1,2,4-triazole

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The compounds (II) can be synthesized, for example, by a procedure similar to that described in the GB-PS 758 921 is indicated and - apart from stage (e) is represented by the following reaction scheme:

CHX · Level

0 (1) NH

(2) deoxidize. Medium or catalytic (V) hydrogenation

Step (!

R ^ -C (Or-; ¹ )

(TX)

N = C - R

(VI)

Level Cc)

NH.

IJ = .C - R ^J

(VIl)

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Stage (d)

(1) oxidizing agent

(2) deoxidizing agent or catalytic hydrogenation '

(VIII)

Stage (s)

^ Connection (II)

(l) implementation
of contracts. (VIII), the 5-nitrogen of which has no oxygen atom, with alkali, metal nitrite and hydrohalic acid

(2) Halopening or Esterification means

In the above formulas, R, R, Ar and the ring A have the meanings already given, X ¹ is the same halogen atom as it is represented by X and R ¹ is a lower alkyl radical (eg methyl, ethyl, propyl). Furthermore, the nitrogen atom in the 4-position in the above general formulas (V) to (VII) is optionally connected to an oxygen atom, which also applies to the above general formula (VIII) (with regard to the nitrogen atom in the 5-position).

The compound (VII) can be used in tautomeric forms

the following formulas are available:

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Ar

(VII ¹ ) or

N-C- Η

(VII ')

where R, R, Ar and the ring A correspond to the definition already given. In step (a) - (l), the reaction between the compound (IV) and ammonia can be carried out according to a similar procedure as in the Journal of Organic Chemistry, 2 & _ (1961) 1111 and in the Journal of Pharmaceutical Science, _5J5. (1964) 264, whereupon the compound (V) is obtained, the nitrogen atom of which is connected to an oxygen atom in the 4-position. In step (a) - (2), the produced compound (V) in which the 4-nitrogen atom has an oxygen atom is treated with a deoxidizing agent if necessary or subjected to catalytic hydrogenation to obtain a compound (V) whose 4- Nitrogen atom has no oxygen. Examples of such deoxidizing agents include phosphorus compounds such as tri-substituted phosphines (e.g. triphenylphosphine, trimethylphosphine), tri-substituted phosphite (e.g. triethyl phosphite) and phosphorus halide (e.g. phosphorus trichloride, phosphorus tribromide). The reaction between the compound (V), the 4-nitrogen of which is linked to oxygen, and the deoxidizing one

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Means can be done in the absence of solvents, but it is smoother in the presence of an inert solvent such as halogenated hydrocarbon (e.g. dichloromethane, chloroform, carbon tetrachloride) and acetic acid. The reaction temperature is usually in the range from 0 to 150 ^° C. The amount of deoxidizing agent to be used is usually about 1 to 20 mol per mol of the compound (V). The catalytic hydrogenation of the compound (V), the 4-nitrogen of which is bonded to an oxygen atom, is usually carried out using metal catalysts (for example Raney nickel, palladium-carbon) at about 0 to 100 ^° C. in the region of atmospheric pressure and in one Solvents such as alcohols (e.g. methanol, ethanol).

The process of step (b) is carried out by reacting the compound (V) with an ortho ester of the general formula (IX). In general, the reaction proceeds smoothly with heating to a suitable temperature of about 80 to 200 ^° C. An ortho ester of the formula (IX) is generally used in a suitable amount of more than 1 mole, usually 2 to 10 moles, based on 1 mole of the compound (V). The reaction can be carried out in the presence of a suitable inert solvent having a boiling point sufficient to allow the reaction to proceed. Hydrocarbons such as benzene, toluene and xylene can preferably be used as solvents. When the ortho ester (IX) is in liquid form

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is present, the ortho-ester itself also serves as a solvent. The reaction can be carried out with advantage in the presence of an acidic Catalyst (e.g. hydrochloric acid, sulfuric acid, acetic acid). The acid catalyst can be in the form of an acid addition salt the compound (V) can be added.

The process of step (c) is carried out by reacting the compound (VI) with excess amounts of ammonia. Of the Ammonia can lower in the form of liquid ammonia, concentrated aqueous ammonia, or saturated ammonia Alkanol (e.g. methanol, ethanol, propanol) are present.

The reaction can generally in the presence of a Run off solvent at room temperature. However, if desired, the reaction can be carried out with heating or cooling be performed. Alcohols (e.g. methanol, ethanol) can preferably be used as solvents.

The process from step (d) - (l) is an oxidative cyclization reaction. The cyclization takes place by treatment the compound (VII) with a suitable oxidizing agent to form the compound (VIII). The oxidizing agent can, for example, lead tetraacetate or a salt of a hypohalous acid (e.g. sodium or potassium hypochlorite or hypobromite). The amount of oxidizing agent used is generally 1 to 2 molar equivalents

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based on 1 mole of the compound of the general formula (VII).

The cyclization can usually be carried out in the presence of a solvent. The solvent will selected depending on the types of oxidizing agents and 'compounds (VII).

For example, when a salt of a hypohalous acid is employed _r are preferably used alcohols (eg methanol, ethanol). In the case that lead tetraacetate is used, acetic acid, hydrocarbons (e.g. benzene, toluene) and a mixture thereof are preferably used. Generally, the cyclization proceeds preferably at a temperature of 0 ° to 30 ⁰ C, the reaction jedoch.kann if required at a temperature outside the above range are performed "

In step (d) - (2), the compound (VIII) in which the 5-nitrogen atom is bonded to oxygen can be used if necessary can be converted into the compound (VIII), the 5-nitrogen of which has no oxygen atom, which is confirmed by treatment of the former compound (VIII) is achieved with the same deoxidizing agent as described in step (a) or by subjecting the former compound (VIII) to the same catalytic hydrogenation as in step (a) - (2) described subject.

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The thus prepared compounds (V), (VI), (VLI) or (VIII), in the desired purity by processes known per se be isolated (for example by distillation recrystallization ₁₎ in the respective reaction stages. The above series of reaction steps can be carried out in stages or in one go.

The process of step (e) is carried out by treating the compound (VIII), the 5-nitrogen of which has no oxygen atom, with nitrous acid or an alkali metal salt thereof and hydrohalic acid. In the reaction of the compound (VIII), the 5-nitrogen of which has no oxygen atom, with nitrite, the compound (II) with X "halogen" is obtained together with the compound (II) with X "hydroxyl. The hydrohalic acids to be used in the context of the invention include hydrochloric acid, hydrobromic acid and hydroiodic acid. The nitrites are salts of nitrous acid with sodium, potassium, etc. The hydrohalic acid and nitrous acid or its alkali metal salt are usually used in excess of the compound (VIII), the 5-nitrogen of which has no oxygen atom. For example, the hydrohalic acid is preferably used in at least 3 molar equivalents and the nitrous acid or its alkali metal salt in about 1 to 20 times (in mols) per mol of the compound (VIII). The conversion takes place in general at 0 to 30 ⁰ C. Since the halogen water

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chemical acid and the alkali metal salt of nitrous acid usually used in the form of aqueous solutions, any other solvents are not particularly necessary.

In the reaction of this stage, when the hydrohalic acid is replaced by a mineral acid (e.g. sulfuric acid) or an organic acid (e.g. acetic acid) is usually obtained in which X is a Is hydroxyl group. The compound (II) with X »OH thus obtained is used as a mixture with the compound in which X is a Is halogen atom or after separation by methods known per se (e.g. column chromatography or recrystallization) treatment with a halogenating agent such as thionyl chloride or phosphorus halide (e.g. phosphorus trichloride, Phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide etc.) or an esterifying agent such as alkylsulfonyl chloride (e.g. methanesulfonyl chloride) or arylsulfonyl chloride (e.g. Benzenesulfonyl chloride, para-toluenesulfonyl chloride) to achieve the compound (II). These halogenation or esterification reactions are usually in one inert solvents (e.g. chloroform, ethyl ether, benzene) at about 0 to 30 ° C using at least equimolar Quantities (a.B. from about 1 to 20 times in moles) of reagent carried out. The compound (II) thus produced can in the desired purity according to known separation or

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Purification methods (recrystallization or chromatography) can be isolated. The compound (II) in which X is an active Is an ester residue of a hydroxyl group, can easily in a conventional manner from the compound (II) with X ■ halogen and an acid with the corresponding active ester residue. For example, by implementing the Compound (II) with toluenesulfonic acid or methanesulfonic acid be made with an alkali metal salt.

Furthermore, the compound (VIII) in which Ar is a pyridyl group, that is, a compound of the general formula (VIII ¹ )

(VIII ¹ )

5 4

in which R, R and the ring A correspond to the meaning already given, Py is the pyridyl group represented by Ar and the nitrogen atom in the 5-position is optionally connected to an oxygen atom, also by reaction of the compound (II) in which Ar is a Is a pyridyl group, ie a compound of the general formula (II ¹ )

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(II ')

in which R, R, Py, X and the ring A correspond to the definition already given, with ammonia, hexamethylenetetramine
or hydroxylamine can be produced. In the above reaction, when ammonia is used as a reactant, a compound (II ¹ ) is formed as intermediate (A) in which X has been replaced by an amino group:

(A)

■ ζ α

where R, R, Py and the ring A correspond to the definition given above (or an acid addition salt thereof is formed) and this intermediate (A) is converted to compound (VIII ¹ ) under dehydrating conditions

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cyclized in which the nitrogen atom in the 5-position is not is connected to an oxygen atom. When hexamethylenetetramine is used as one of the reactants, it is formed the following intermediate adduct (B):

(B)

in which R, R, Py, X and the ring A correspond to the definition already given; this adduct is then decomposed to give intermediate (A) and finally the latter is ^{cyclized under dehydrating conditions to give compound (VIII 1} ) in which the nitrogen atom in the 5-position is not bonded to oxygen. Furthermore, when using hydroxylamine as a reaction partner, the following intermediate compound (C) is formed:

(C)

C = O

7098Ö9 / 1206

Py

in which R, R, Py and the ring A correspond to the definition already given and this intermediate (C) is then ^{cyclized under dehydrating conditions to give compound (VIII 1} ) in which the nitrogen atom at the 5-position is bonded to an oxygen atom.

The reaction between compound (II ¹ ) and ammonia is preferably carried out using excess amounts of liquid ammonia, concentrated aqueous ammonia or saturated ammoniacal lower alkanol (e.g. methanol, ethanol, propanol) in a suitable solvent such as lower alkanol (e.g. methanol, ethanol) , halogenated hydrocarbon (e.g. chloroform, dichloromethane) or dimethylformamide. This reaction can be carried out in a sealed container. The reaction temperature is usually in the range from about -30 to 150 ^° C.

In general, the reaction between the compound (II ¹ ) and hexamethylenetetramine is preferably carried out in a solvent such as lower alkanol (for example methanol, ethanol, propanol, butanol) under reflux. The amount of hexamethylenetetramine to be used is usually about 1 to 10 mol ρςο mol of the compound (II ¹ ) The reaction temperature is usually in the range from about 20 to 150 ^° C.

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The reaction between the compound (II ¹ ) and hydroxylamine is usually carried out in a solvent such as lower alkanol (e.g. methanol, ethanol, propanol, butanol), hydrocarbons (e.g. chloroform, dichloromethane, benzene, toluene), tertiary amines (e.g. pyridine) and dimethylformamide at a temperature in the range from room temperature to around the boiling point of the solvent used.

The amount of hydroxylamine to be used is usually about 1 to 20 moles per mole of the compound (11 *) In the case that a mineral acid addition salt of hydroxylamine such as the hydrochloride is used in the reaction, the addition of the salt to the reaction system after its neutralization with a suitable basic substance or the addition of the salt to the reaction system together with a suitable basic substance is preferred. Alkali metal carbonates or bicarbonates (for example sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate) and tertiary amines (for example triethylamine, pyridine) are suitable as basic substances. In the present R _e action between the compound (II ¹⁾ and ammonia, hexamethylenetetramine, or hydroxylamine, the addition of an excess amount of the above basic substance is preferred as an acid acceptor to the reaction system so as formed during the reaction ^]) hydrogen halide or sulfonic acid X correspond to compound (II *), to be removed.

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Furthermore, when using a compound (II ¹ ) with X «chlorine or bromine as the starting material, the reaction can be carried out more smoothly in the presence of a catalytic or equimolar amount of potassium iodide or sodium iodide.

The compounds (II) and (VIII ') thus formed are new compounds and as an intermediate for the production of pharmaceuticals such as compounds (I) useful. Furthermore, the compound (VIII ') is basic Nitrogen in the molecule and can be converted into corresponding acidic acid salts by methods known per se by treating this compound (VIII) with the same inorganic acids or organic acids, as described above in connection with the acid addition salt of the compound (I) are indicated. These compounds (VIII *) and their acid addition salts have central nervous system acting pharmacological properties that of those of the compounds (I) are similar and they are also as medicaments in human and veterinary therapy such as Muscle relaxants, anticonvulsants, sedatives, anti-anxiety agents, small tranquillizers and (compulsory) sleeping pills can be used.

When the compounds (VIII ¹ ) or their pharmaceutically acceptable acid addition salts are used as medicaments as described above, they can be administered orally or parenterally as such or in a suitable form as a powder, grade

7098097 1206

Nalien, tablets, capsules, injectable preparations, Suppositprien etc. are administered mixed with pharmaceutically acceptable carriers, excipients or diluents * The dosage to be administered of the compound (VIII ¹⁾ or its pharmaceutically acceptable acid addition salt varies with the type of condition being treated, the clinical Condition and the specific compound used, but it usually falls in the range of about 1 to 100 mg per day when administered orally to adults »

Special compounds of the general formulas (II) and (VIII) are as follows:

Connections (II)

l ~ (2-Bensoyl "4-ehlor-phenyl) -5-chloro-methyl-3-methyllH-l, 2 ₃ 4 - triazole 1- (2-benzoyl-fJ-chloro-phenyl) -5-chloro- methy 1-3-äLhy 1-lH-l, 2, i »-triazole l- (2-benzoyl-1-ehlor-phenyi) -5-chloro-methy1-3-n-propy1-lH-l, 2, il-triazole, 1- (2 ~ benzoyl - 4-chloro ^ phenyl) -5-chloro-methyl - lH-1,2,4-triazole 1- (2-benzbyl-i »-chlorophenyl) - 3-benzyl-5-chloro-methyllH-l, 2, ii-triazole 1- (2-benzoyl-il-chloro-phenyl) - 5- (l-chloro-ethyl) -3-methyllH-l ₃ 2, i | -triazole

709809/1206

1- [4-chloro-2- (2-chloro-benzoyl) phenyl] -5-chloro-methyl-1-3-methyl-1fl-1 _s 2,4-triazole

1 _ [!} - chloro-2- (2-chloro-benzoyl) phenyl] -5-chloro-methyl-3-ethylr-1H-1,2 , ir-triazole

! _ ■ [Ij-chloro-2- (2-fluoro-benzoyl) phenyl] -5.-chloro-me thy 1-3-methyl-lH-l, 2, ^ -triazol

l- (2-Benzoyl- ⁱ l-nitro.phenyl) -5-chloro-methyl-lH-

1,2,4-triazole. "'

1- (2-Benzoyl-4-trifluoro_raethylphenyl) -5-chloro-methyl ~ 3-methyl-1H-1, .2, ii-triazole

1- (2-Benzoyl- ⁱ * -nethoxyphenyl) -5-chloro-methyl-3-n-ethbyl-

lH-l, 2, i | -triazole '

1- (2-Benzoyl- ⁱ } -methylphenyl) -5-chloro-methyl-3-neth.yl-

lH-l, 2, ii-triazole ■ ■ '

l ~ (2 ~ benzoyl- ⁱ l-chloro-phenyl) -5-bro! n-methyl-3-niethyl-

1- (2-Benzoyl-4-chlorophenyl) -3-niethyl-5-methylsulfonyloxyinethyl-1H-1,2, iJ-triazole

l- [i | bromo-2 '- (2-pyrΙφΊ- carbonyl) phenyl] -5-chlor_methyl-3-methyl-lH-l, 2 _a 4-triiizol

Ι-Γ'4-Bron-2- (2-pyrldyl- carbonyl) phenyl]] -5-chloro-methyl-1-3-Sthy 1-lH-l, 2. _3-triazol il

l- [4-bromo-2- (2-pyridyl carbonyl) phenyl] -5-chloro-methy1-3-n-propyl-lH-l, 2, 4-triazole

1- [ ⁱ -3rom- _T -2- (2-pyridyl- ^ carbonyl) phenyl] -5-chloro-methy 1-lH-1 ₃ 2 ₅ M-trlazole

1- [4-chloro-2- (2-pyr3dyl-carbonyl) phenyl] -5-chloro-methy1-3-methyl-lH-1,2,4-trlazole

709809/1206

! - [! {- Chlorine-2- (2-pyridyl-carbonyl) phenyl] -5-chloro-methyl-3-ethyl-1H-1,2,1-triazole l_ [Z | _Brom-2- (4-py "ridyl-carbonyl) phenyl] -5-chloro-methyl-

yl-1- C2- (2-pyridyl-carbonyl) phenyl] -lH-1,2,4-triazole
5-chloro-methyl-3-ethy1-1-C2- (2-pyrid yl-carbonyl) phenyl] -

Links . (VIII ')

2-methyl-6- (2-p.yriäy.l} -ilH-s-triazolo [l _J 5-a3 [l _J i}] -benzodiazepine and its 5N-oxide 8-bromo-2-thyl-6- (2-pyridyl) -iJH-s-triazolo [1, S-alCl, 4] -benzodiazepine and its 5N-oxide 8-3rom-2-n-propyl-6- (2-pyridyl) -4H-s-triazolo [l _J 5-a] [l, ⁱ i] -benzodiazepine and its 5N ^ oxide 8-droin-6- (2-pyridyl) -i5H-s-triazolo [l, 5-a] [1, H] - benzodiazepine and its 5H-oxide δ-bromo-2 _J 4-dinethyl-6- (2-pyridyl) -flH-s-triazolo- [1,5-B] [I ₃ ^ I] benzodiazepine and its 5H-oxide 8 -Drorn — 2-methyl-6- ( ⁱ l-pyridvl) - * IH-3-triazolo- [ij ^ -aJElj ^ lbenzodiazepine and its 5i'-oxide O-bromo-2-methyl-6- (3- pyridyl) - ^ H-3-triazolo [l, 5-a] [l, i |} -benzodiazfpin and its 5H-oxide 8-chloro-2-methyl-6- (2-pyridyl) -4H-s-triazolo [1,5-a] El, 4] -benzodiazepine and its 5N-oxide δ-chloro-2-ethyl-6- (2-pyridyl) -4H-s-triazolo [1,5-a} [1,4 ] -benzodiazepi-n and its 5N-oxide

2-methyl-6- (2-pyridyl) -4H-s-triazolo [i, 5-a] [1, ¹ I] -benzodiasepine- and its ^ N-oxide 2-ethyl-6- (2 ~ pyridyl} -4H-s-triazolo [1 _J 5-a] [1,4l · benzodiazepine and its 5N-oxide 8,10-dibromo-2-oleyl-6-X2-pyridyl) -4H-s-triazolo- [ l ₃ 5-3] [l, ^ί Obeήzodiazβpin and its 5M-oxide 2 _J 3-dimethyl-6- (2-pyridyl) -4H-s-triazoloCl, 5-a] [l, ^I t] benzodiazepine and its 5N- oxide 8 - methoxy-2-methyl-6- (2-pyridyl) - IH ^i-s-triazolo _[l:, 5 ~ a] _[l;> '4] benzodiazepiii vma be 5N-oxide.

benzodiazepio and its 5N-oxide ■

2 ~ methyl-8-trifluoromethyl-6- (2-pyridyl) -4H-s-triasolo- [l, 5-a] [l, if] b> enzod! Iazepin'.and its 5M oxide

The invention will be described in greater detail below explained by examples, which are accessible to various modifications.

Reference example 1 To 200 al of saturated ammoniacal ethanol were

9 g of 2-chloromethyl-4- (2-pyridyl) -quinazoline-3N-oxide were added. After stirring the mixture at room temperature for 20 hours, precipitated colorless crystals were collected by filtration, washed with water, ethanol and ether in that order, and dried. This procedure gave 2-amino-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide in the form of crystals. Recrystallization from methanol gave ^{colorless prisms melting at 243 to 245 °} C. (decomposition).

In a manner similar to the above, the following became Compound made from the corresponding quinazoline 3N oxide derivative:

2-amino-7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide; colorless needles (recrystallized from ethanol) which ^{melt at 233 to 234 0} C (decomposition).

Reference example 2

(i) To a suspension of 2.1 g of 2-amino-7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide 4.2 ml of ethyl orthoacetate and 2.1 ml of acetic acid were added in 100 ml of benzene and refluxing the mixture for 80 minutes. After cooling it became the reaction mixture a saturated aqueous sodium bicarbonate solution was added and the entire mixture was extracted with ether.

709809/1206

The ether layer was washed with water and over

Dried sodium sulfate. By evaporating off the solvent, crystalline 7-bromo-2- (l-ethbxyethylideneamino) -5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide was obtained. Colorless needles melting at 141 to 142 ^{° C. were obtained by recrystallization from ether.}

Elemental analysis for C, g calculated C: 53.87%; H: 4.27%; N: 13.96% found C: 53.89%; H: 4.31%; N: 13.97%

(ii) 1.75 g of the 7-bromo-2- (l-ethoxyäthylidenaraino) -5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide thus produced were added to 60 ml of saturated ammoniacal ethanol while cooling with ice added. After stirring for one hour while cooling with ice, the precipitated crystals were collected by filtration, washed with ethanol and ether in the order mentioned and dried to give crystalline 2- (l-aminoethylideneamino.) - 7-bromo-5- (2-pyridyl) -3H -1,4-benzodiazepine-4N-oxide. The resulting mother liquor and washings were combined and concentrated to obtain additional amounts of crystals. Melting point: 220 to 221 ^° C. (decomposition).

Elemental analysis for C ₁ gH ^ ₅ calculated C: 51.62%; H: 3.79%; N: 18.82%, found C: 51.82%; H: 3.82%; N: 19.06%

709809/1206

In a manner similar to above, the following compounds were created:

By reaction between 2-amino-7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide and ethyl ortho-propionate was 7-bromo-2- (1-ethoxypropylideneamino) -5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide in the form of colorless prisms that melt at 172 to 173 ° C (recrystallized from acetone) » The benzodiazepine-4N-cxide derivative thus formed was with Treated ammonia to give 2- (l-aminopropylideneamino) -7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide in the form of colorless crystals that melted at 219 to 220 ° C (decomposition).

By reacting 2-amino-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide with ethyl ortho-acetate, 2- (l-ethoxyethylideneamino) -5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide was obtained in the form of colorless prisms that melt at 132 to 134 ° C (recrystallized from ether). The benzodiazepine-4N-oxide thus formed was treated with alcoholic ammonia to give 2- (l-aminoethylideneamino) -5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide in the form of colorless crystals containing 1 mol of water of crystallization. Melting point: 135 to 140 ° C.

Reference example 3

To a solution of 0.56 g of 2- (l-aminopropylideneamino) -7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide in 40 ml

7 09809/1? D6

Chloroform was added to 5 ml of an aqueous sodium hypochlorite solution containing 5% by weight of chlorine while stirring and cooling with ice. After stirring for 15 minutes with ice-cooling and a further 5 hours at room temperature, the mixture was diluted with water and extracted with chloroform, and the chlorofont layer was washed with water and dried over sodium sulfate. Was crystalline 8-bromo-2-ethyl-6- (2-pyridyl) -4H-s-triazolo [l _t 5-a] [l, 4 by evaporation of the solvent | obtain beiitzodiazepln-5N-oxide. Colorless prisms which melted at 204 to 205 ^° C. (decomposition) were obtained by recrystallization from acetone.

Bleutentar analysis for C
Calculated C: 53.1496; H: 3.67%; N: 18.23%

found

C: 53.18%; H: 3.67%; N: 18.20%

Similar to the above, the following Connections created:

created connection

2- (1-Aminoethylldenamino) -7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepine-4N-oxide

8-bromo-2-methyl-6- (2-pyridyl) .4H-s-triazolo- [1,5-a] [1,4-benzodiazepine-5N-oxide; colorless needles (recrystallized from acetone) _f which melt at 207 to 208 ⁰ C (decomposition)

25AH64

Outgoing connection created connection 2- (l-Aminoäthylidenamino) -5- 2-methyl-6- (2-pyridyl) -4H-S- (2-pyridyl) -3H-1,4-benzo- triazolo [l, 5-aj | _1 »4J -benzo- diazepine-4N-oxide diazepine-5N-oxide; colorless pris men (recrystallized from Acetone) at 173 to 175 ° C melt

Reference example 4

A solution of 0.26 g. e-bromo - ^ - ethyl-e- (2-pyridyl) -4H-s-triazolo [1,5-aj [1,4Jbenzodiazepine-5N-oxide and 0.2 g triphenylphosphine in 3 ml acetic acid were added for 10 minutes brought to reflux conditions after which the solvent was evaporated. The resulting residue became one Silica gel chromatography using a column of 10 g of silica gel and a mixture of chloroform, methanol and ethyl acetate (85: 10: 5) as the eluent. Fractions # 1 to # 4 (8 ml per fraction) were pooled and the solvent evaporated. The resulting residue was partitioned between 1 η hydrochloric acid and ethyl acetate. The hydrochloric acid layer was separated off and neutralized with 2 η sodium hydroxide solution and then extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. By evaporating the solvent became crystalline 8-bromo-2-ethyl-6- (2-pyridyl) -4H-s-triazolo jl, 5-a] - {_ 1,4J benzodiazepine. By recrystallization

709809/1 206

colorless prisms melting at 166 to 167 ^{° C. were obtained from ether.}

Elemental analysis for C.7H ,. < BrN, -: calculated C: 55.44%; H: 3.83%; N: 19.02% found C: 55.74%; H: 3.55%; N: 18.99%

In a manner similar to the above, the following Connections made:

Output compound created connection 8-bromo-2-methyl-6- (2-pyridyl) - 8-bromo-2-methyl-6- (2-pyridyl) - 4H-s-triazolo [l »5-aJ [l, 4J -benzo- 4H-s-triazolo- [l, 5-a] [l, 4J- diazepine-5N-oxide benzodiazepine; colorless pris men (recrystallized from Acetone), the at I69 to 170 ⁰ C. melt 2-methyl-6- (2-pyridyl) -4H- 2-Methy1-6- (2-pyri dy1) -4H-s- s-triazolo \ l , 5 ~ a] [i, 4] - triazolo jjL, 5-aj [l, 4j-benzo- benzodiazepine-5N-oxide diazepine; colorless prisms (recrystallized from Acetone), which at 143 to 144 ⁰ C melt

Reference fairy example 5

A mixture of 0.1 g of 1- [4-bromo-2- (2-pyridylcarbony 1) phenyl] -S-chloromethyl ^ -ethyl-1H-1,2,4-triazole

709809/1206

and 4 ml of 20 gew.tigern ammoniacal methanol was heated in a sealed tube for 5 hours at 80 ⁰ C. After evaporating the solvent, the resulting residue was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent gave 8-bromo-2-ethyl-6- (2-pyridyl) -4H-s-trlazolo [l »5-aj (JL, 4] benzodiazepine in the form of colorless, melting at 164 to 166 ° C This product was identical in IR spectrum to that obtained in Reference Example 4. In the procedure of Reference Example 5, hexamethylenetetramine was used instead of 20% ammoniacal methanol for the reaction with 1-J4-bromo-2- (2-pyridyl carbonyl) phenyl] -5-chloromethyl-3-ethyl-lH-l, 2,4-triazole in ethanol is used.

The resulting solution was refluxed for 6 hours. After evaporation of the solvent, the residue was treated in a similar manner to Reference Example 5 to give crystalline 8-bromo-2-ethyl-6- (2-pyridyl) -4H-s-triazolo [1,5-benzodiazepine. With regard to its melting point IR spectrum, this product was identical to that produced according to Reference Example 5.

Example 1 .

To a solution of 2.7 g of e-chloro ^ -methyl-ö-phenyl ^ 4H-s-triazole © | l _f 5-a | 1,4J benzodiazepine in 25 ml of 6 η hydrochloric acid was added to a solution of 2.7 g of sodium nitrite in 10 ml of water while cooling in ice water. The mixture was stirred for 10 minutes and then further for 1 hour at room temperature. The resulting mixture was extracted with chloroform, and the chloroform layer was washed with water and dried over sodium sulfate. Thereafter, the solvent was evaporated, the residue was dissolved in 40 ml of chloroform, and 2.0 ml of thionyl chloride was added to the resulting solution at room temperature, followed by stirring for 30 minutes. After evaporating the solvent, the residue was neutralized with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel chromatography using a column of 20 g of silica gel and a mixture of η-hexane and acetone (3ί1) as an eluent. Fractions 1 to 10 (each 20 ml per fraction) were combined and the solvent was evaporated. This procedure provided crystalline 1- (2-benzoyl-4-chlorophenyl) -3-methyl-5-chloromethyl-1H-1,2,4-triazole. Recrystallization from isopropyl ether gave colorless grains melting at 97 to 98 ° C.

■ .- 39 - 254H64

Elemental analysis for C ^ «H« j, Cl ₂ N ^ O:

calculated C: 58.97%; H: 3.78%; N: 12.14% found C: 59.02%; H: 3.49%; N: 12.40%

Example 2

To a solution of 2.0 g of 8-bromo-2-ethyl-6- (2-pyridyl) -4H-s-triazolo [1,5-aJ [1,4j benzodiazepine in 17 ml 6 η hydrochloric acid a solution of 3.0 g of sodium nitrite in 10 ml of water was added dropwise with ice-cooling. the The mixture was stirred for 3 hours at room temperature and then with a saturated aqueous sodium bicarbonate solution neutralized and then extracted with chloroform. The chloroform layer was washed with water and over Dried sodium sulfate. After evaporation of the solvent, the residue was dissolved in 40 ml of chloroform and the resultant 4.0 ml of thionyl chloride were added. The mixture was stirred for 2.5 hours at room temperature, after which the solvent was evaporated. The residue was with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent gave crystalline 1-

4-Bromo-2 - (2-pyridyl-carbonyl) phenyl] -5-chloromethyl 1-3-ethyl-1 H-1,2,4-triazole. obtain. Recrystallization from ethyl ether resulted in colorless melting at 130 to 131 ° C Prisms won.

709809/1206

~ ^4o ~ "254H64

Elemental analysis for C ₁ -, H ₁ ^ BrClN ^ O:

calculated C: 50.53%; H: 3.48%; N: 13.81% found C: 50.31%; H: 3.3%; N: 13.83%

Example 3

A mixture of a solution of 0.25 g of 1- (2-behzoyl-4-chlorophenyl) -3-methyl-5-chloromethyl-lH-l, 2,4-triazole in 10 ml of ethanol and 0.3 ml of morpholine was Bred to reflux for 2 hours. After evaporating the solvent, the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. The solvent was then evaporated and the residue was subjected to silica gel chromatography using a column of 10 g of silica gel and a mixture of η-hexane and acetone (3: 1) as the eluent. Fractions No. 8 to 22 (8 ml per fraction) were combined and purified to give crystalline 1- (2-benzoyl-4- chlorophenyl) -3-methyl-5-morpholinomethyl-1 H-1,2,4-triazole . Colorless prisms (with 1/2 ether) melting ^{at 105 to 106 °} C. were obtained by recrystallization from ether.

Elemental analysis for C ₂₁ H _{21 ClN 4} O ₂ ^ (C ₂ H ₅ ) ₂ 0:

calculated C: 63.66%; H: 6.04%; N: 12.91%, found C: 63.56%; H: 5.85%; N: 13.03%

709809/1206

254U64

Example 4

A mixture of 0.25 g of 1- [4-bromo-2- (2-pyridylcarbonyl) phenylj-5-chloromethyl-3-ethyl-lH-1,2,4-triazole in 10 ml of ethanol and 0.25 ml of 1 -Methylpiperazine was brought to reflux conditions for 3 hours. After evaporating the solvent, the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water and dried over sodium sulfate. Evaporation of the solvent made it crystalline. 1 - [_ 4-Bromo-2- (2-pyridyl-carbonyl) phenyl] -3-ethyl-5 - [(4-methylpiperazino) -methyl] -1H-1,2,4-triazole was obtained. Colorless prisms melting ^{at 130 to 131 °} C. were obtained by recrystallization from ethyl ether.

Elemental analysis for CppHog

Calculated C: 56.2996; H: 5.3796; N: 17.91%

found C: 56.12%; H: 5.20%; N: 17.92%

The following compounds can be made in the same manner as in Examples 3 and 4 above:

1- (2-Benzoyl-4-chlorophenyl) -5-dimethylamino-methyl-3-methyl-1H-1,2,4-triazole; colorless grains (recrystallized from ether-n-hexane) which ^{melt at 74 to 75 °} C ";

1-J4-bromo-2- (2-pyridyl-carbonyl) phenyl] -5-dimethylaminomethyl-3-ethy1-1H-1,2,4-triazole; an oily product;

709809/1206

Infrared absorption spectrum: λ ^ ¹ "Ι6" 8θ cm " ¹

■ ITIcLX

OC = O). MMR spectrum (CDCl ₃ ): δ O ₇ 97 (3Hi t; J = O.75Hz ;

. -. -CH ₂ CH ₃ ; j = o _} 75Hz) _;

2 _; 32 (6Hj si N (CHO ₂ ); 3.50 (2Hi S; -CH ₂ -); 7.1 to 8 ', 3 (7H-. Χα-, aromat, proton)

Example 5

This example shows a practical recipe for using a compound according to the invention as a tranquillizer specifiedi

Tablets

(1) 1- (2-Benzoyl-4-chlorophenyl) -5-dimethyl- 1 mg aminomethyl-3-methyl-1H-1,2,4-triazole

(2) lactose

(3) corn starch

(4) hydroxypropyl cellulose

(5) magnesium stearate

73 mg 40 mg VJl »5 mg 0 , 5 mg 120 , 0 mg per tablet

Components (1), (2), 9/10 of the amount of (3) and (4) were carefully mixed and the mixture after one

709809/1206

Wet granulation process, granulated. The remaining amount of (3) and (5) were added to the grains, which were compressed into tablets. Tablets produced in this way can also be coated with a suitable coating material such as sugar being coated.

709809/1 206

Claims (27)

Claims 1, compounds of the general formula (I) CH - n; (D C = 0 Ar in which R ₁ and R, which can be the same or different, represent an alkyl or aralkyl group, one of the 12 1 R and R radicals can be a hydrogen atom or R and R together with the neighboring nitrogen atom form one heterocyclic ring; R is a hydrogen atom or an alkyl or can be aralkyl; R is hydrogen or lower alkyl means; the ring A either unsubstituted or substituted by halogen, nitro, alkyl, alkoxy or trifluoromethyl and Ar is an optionally substituted phenyl group or a pyridyl radical and their pharmaceutically acceptable Acid addition salts. 2. A compound according to claim 1, characterized in that R and / or R is an alkyl 709809/1206 25AU64 rest, in particular a lower alkyl radical with 1 to 3 mean carbon atoms, while the other radical, if any, is formed by a hydrogen atom. 3. Compound according to claim 1, characterized in that 12th
that R and R together with the adjacent nitrogen atom form an in particular 5 to 6-membered heterocyclic ring which preferably contains 1 to 2 nitrogen and / or oxygen atoms and preferably from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, N-mono-lower alkyl-substituted Piperazine and homopiperazine is selected. 4. Compound according to claim 1, characterized in that that R is an alkyl radical and in particular a lower alkyl radical having 1 to 3 carbon atoms. 5. A compound according to claim I _1, characterized in that R ^ is a hydrogen atom. 6. A compound according to claim 1, characterized in that 4th
that R is a hydrogen atom. 7. A compound according to claim 1, characterized in that Ar is a pyridyl radical and in particular a 2-pyridyl radical, 709809/1206 8. A compound according to claim 1, characterized in that Ar is a non-substituted phenyl radical. 9. A compound according to claim 1, characterized in that Ar is a halogen-substituted phenyl radical, in particular Chlorine or fluorine in the ortho position as substituents contains. 10. A compound according to claim 1, characterized in that that the ring A with a seated in particular in the 4-position Halogen atom is substituted. 11. The compound of claim 1, wherein R is lower Is an alkyl group with 1 to 3 carbon atoms, thereby 1 2 indicates that both R and R are denoted by a lower Alkyl group having 1 to 3 carbon atoms is formed or 12th R and R together with the adjacent nitrogen atom form a heterocyclic ring from the group consisting of pyrrolidine, piperidine, Piperazine, morpholine, N-mono-lower alkyl-substituted Form piperazine and homopiperazine. 12. A compound according to claim 11, characterized in that R is a hydrogen atom. 13 «Connection according to claim 12, characterized in that that Ar is a pyridyl radical. 709809/1206 14. A compound according to claim 13, characterized in that the pyridyl radical is a 2-pyridyl radical. 15. A compound according to claim 14, characterized in that the ring A with a halogen atom - and in particular with
Chlorine or bromine in the 4-position - is substituted. 16. A compound according to claim 12, characterized in that that Ar is an unsubstituted phenyl radical. 17. A compound according to claim 16, characterized in that the ring A with a halogen atom - preferably with chlorine or bromine in the 4-position - is substituted. 18. A compound according to claim 12, characterized in that that Ar is a halogen-substituted phenyl group. 19. A compound according to claim 18, characterized in that the phenyl group with chlorine or fluorine in the ortho position
is substituted. 20. A compound according to claim 19, characterized in that the ring A with a halogen atom - in particular with
Chlorine or bromine in the 4-position - is substituted. 21. l- (2 - Benzoyl-4-chlorophenyl) -3-methyl-5-inorpholinomethyl-lH-1,2,4-triazole, 7 09809/1206 254H6A 1- [A ~ bromo-2- (2-pyridyl-carbonyl) -phenyl] -3-M ^ yI-S- [(4- methyl piperazino) methyl].-1H-1,2,4-triazole, 1- (2-Benzoyl ~ 4-chloropheny1) -5-dimethylaminomethyl-3-methyl-IH-1, 2,4-triazole and l- [4-bromo-2- (2-pyridyl-carbonyl) -phenyl] -5-dimethylamino- methyl-3-ethyl-lH-1,2,4-triazole as compounds according to claim 1. 22, compounds of the general formula (II): (II) 3 4
in which R, R, Ar and the ring A correspond to the meaning already given and X is a halogen atom or an active ester residue of a hydroxyl group. 23 · Compound according to claim 15, characterized in that X is a halogen atom, 24. 1- (2-Benzoyl-4-chlorophenyl) -3-methyl-5-chloromethyl-IH-I, 2,4-triazole and 709809/1 206 254H6A 1- [4-BrOm-Z- (2-pyridyl-carbonyl) -phenyIJ -5-chloromethyl-3-ethyl-1H-1,2,4-triazole as compounds according to claim 15. 25. Process for the preparation of a compound according to claim 1, characterized in that a compound of the general formula (II): (II) 3 4 in which R, R, Ar and the ring A have the meaning already given and X is a halogen atom or an active ester residue of a hydroxyl group with a compound of general formula (III): HNt (III) • R " 12th
converts, in which R and R have the meaning already given. 26, a method for producing a compound according to claim 1, characterized in that a compound 709809/1 206 25AH64 of the general formula (VIII): (VIII) 3 4
in which R, R, Ar and the ring A correspond to the meaning already given, with nitrous acid or an alkali metal salt thereof and hydrohalic acid to form a compound of the general formula (II), which then reacts with a compound of the general formula (III) is brought. 27. A pharmaceutical composition, characterized by a content of at least one compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof. 709809/1206