DE2167258C2 - s-Triazolyl-benzophenone derivatives - Google Patents

Description

CH ₂ Z

(Π)

45 in which R is hydrogen or lower alkyl and Z is halogen.

R is preferably a lower alkyl radical having 1 to 3 carbon atoms, e.g. B. a methyl radical, ethyl radical, n-propyl radical and isopropyl radical. The compounds according to the invention can with a compound of the general formula

HX-Y-NH ₂

in which X is -O- or -NH-, and Y is an ethylene radical or trimethylene radical, the ethylene or Trimethylene radical in any position is a lower alkyl radical, preferably with 1 to 3 carbon atoms, e.g. B. Methyl, ethyl, n-propyl and isopropyl, can be reacted, benzodiazepine derivatives being the general Formula (I) can be obtained.

(D

The benzodiazepine derivatives obtained with the aid of the intermediate products according to the invention of the general Formula (I) have a surprisingly favorable ratio of tranquilizing to muscle-relaxing effectiveness compared to the known compound oxazepam, as can be seen from the following comparative experiments

Tested connection

Tranquilizing effect (antimorphine effect *) ED ₅₀ (mg / kg), po in mice (A)

Muscle relaxation effect **) ED ₅₀ (mg / kg), po in mice (B)

According to the invention compound a

> 500

<0.02

Connection b

15th

12th

> 500

> 400

<0.03

<0.03

continuation

Established connection

Tranquilizing effect (anlimorphine effect *) ED ₅₀ (rag / kg), po in mice (A)

Muscle tensioning effect **) ED ₅₀ (mg / kg), po in mice (B)

¹⁰ connection d

108

,. Oxazepam

(Comparison connection)

61

OH

*) Antimorphine effect in mice:

Groups of 5 mice were treated with subcutaneous injections of 50 mg / kg of morphine-HCl 30 min after oral administration of either the test agent or physiological saline. The animals were placed individually in a 1-1 beaker, and the frequency of circular movements and the maximum tail reaction were each determined 6 times over a period of 30 s at 10-minute intervals after the administration of morphine. The tail reaction was carried out according to the Holton method. Acta pharmac. tox. 13, 113 (1957). The total value for 6 determinations of each reaction was calculated in each group and the ED ₅₀ causing a 50% decrease in the value was determined on semi-logarithmic paper.
**) Muscle relaxing effect in mice:

The muscle relaxant effect was evaluated after the inclined mesh test at 10-minute or 30-minute intervals after the oral administration of the test agents in groups of 5 to 8 mice. The muscle relaxant ED ₅₀ was determined based on the number of mice that slid down within 1 minute after being placed on a 60 ° inclined net made of steel wire.

As can be seen from the data in the table, those from the compounds according to the invention have the general Formula (II) preparable compounds of the general formula (I) only half as large or even smaller Values for (A) / (B) as the oxazepane to be used as a reference compound.

In addition, the respective ED ₅₀ values of the muscle-relaxing effect (B) of the compounds of the general formula (I) must be observed in particular. These results show that the compounds of the general formula (I) are absolutely weak with regard to their muscle-relaxing activity, in other words also have only low toxicity. As a result, the compounds of the general formula (I) can be administered in a simple manner or processed into pharmaceutical formulations.

The toxic data are usually determined by administering an active ingredient to test animals in gradually increasing amounts. Accordingly, an ED ₅₀ value of muscle relaxing effect of 400 mg / kg shows that up to the dose of 400 mg / kg the ED ₅₀ could not be determined. Such a dose is, however, of satisfactory safety, so that it is practically considered unnecessary to continue the measurements with higher doses.

The compounds of the invention can be prepared by the following reaction steps:

NH,

N = C

RC (OR ') ₃

or corresponding acylating agents

OR ²

NH ₂ NH ₃

NH,

(1) haloacetylation

(2) treatment with
a weak acid

CH ₂ Z

(3)

In this Reaktior.sschema R and Z have the meanings given above. R ¹ is a lower alkyl radical, e.g. a methyl radical, an ethyl radical and a propyl radical, and R ² stands for a hydrogen atom or the radical R ¹ .

1 mol of the compound of the formula (1) is reacted with about 1 to 10 mol of an orthoester of the general formula RC (OR ¹ ) ₃ or an acylating agent (e.g. formic acid, acetic acid, acid halides or anhydrides of an acid of the formula RCOOH) reaction with the Orthoester (z., toluene and benzene), generally by heating at about 50 to 16O ⁰ C in the presence of a solvent and an acid catalyst (for. example, an inorganic acid such as hydrochloric acid and sulfuric acid or an organic acid such as acetic acid , Propionic acid and p-toluenesulfonic acid). The reaction with the acylating agent can easily be carried out by methods known per se.

1 mole of the obtained compound of general formula (2) is with about 1 to 5 moles of hydrazine in the presence a solvent (e.g. methanol, ethanol, propanol and isopropanol) and, if necessary, one Catalyst (e.g. an organic or inorganic acid such as hydrochloric acid, sulfuric acid, acetic acid, propionic acid and p-toluenesulfonic acid) at room temperature or with heating to the boiling point of the one used Solvent carried out.

The resulting compound of the general formula (3) is first subjected to haloacetylation using an acid halide or an anhydride of a haloacetic acid at about 0 to 100 ° C in the presence of a solvent (e.g. chloroform, dichloromethane, ethyl ether, benzene, dimethylformamide, pyridine, Acetic acid and monochloroacetic acid) and optionally in the presence of an acid acceptor (e.g. sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, triethylamine, imidazo and 2-methylimidazole), the corresponding haloacetyl derivative of the compound of the general formula (3) being formed , the chemical structure of which has not yet been precisely clarified.The haloacetyl derivative is then treated with a weak acid, for example an aliphatic carboxylic acid (e.g. formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, propionic acid and butyric acid), an aromatic carboxylic acid (e.g. benzoic acid and Salicylic acid) or an aromatis ch-aliphatic carboxylic acid (e.g. B. phenylacetic acid) optionally treated in the presence of a solvent such as chloroform, dichloromethane, benzene and toluene at room temperature or with heating to about 150 ^° C. In this way, the compound according to the invention is obtained.

In the following examples, the parts are understood to be parts by weight, unless otherwise stated.

example 1

34.7 parts of 2-amino-5-chlorobenzophenone are dissolved in 100 parts by volume of formic acid. The solution is Heated to reflux for 1.5 hours. The formic acid is removed under reduced pressure and the residue Dissolved in 300 parts by volume of ethyl acetate. The solution is with saturated sodium carbonate solution and then washed with water and then dried. The solvent is removed and the residue with Treated hexane, leaving 5-chloro-2-formamidobenzophenone in the form of yellow crystals from melting point 92.5 to 93 ° C is obtained.

2.7 parts of the S-chloro ^ -formamidobenzophenone prepared in the manner described are in 40 Parts of the volume of ethanol dissolved. 2.5 parts by volume of hydrazine hydrate (100%) are added to the solution, whereupon 20 Is heated to reflux for minutes. The resulting mixture is cooled. The deposited crystals will be isolated, washed with ethanol and then with ether and dried. Here, S-amino-o-chloro ^ -dihydro-4-hydroxy-4-phenyIquinazolin obtained in the form of crystals with a melting point of 189 to 192 ° C.

A mixture of 68.4 parts of this compound, 75 parts of anhydrous sodium carbonate, 600 parts by volume of water and 600 parts by volume of chloroform is cooled with a cold mixture. Then 60 parts by volume of chloroacetyl chloride are added dropwise at a temperature below 10 ° C. over the course of 30 minutes. The mixture is stirred for a further 20 minutes and the deposited precipitate is filtered off, washed with water and chloroform and dried, a compound corresponding to a di (chloroacetyl) derivative being obtained in crystal form. Colorless needles with a melting point of 157 to 158 ° C. are obtained by recrystallization from chloroform-methanol. The values of the elemental analysis agree with the values calculated _{for Ci 8} H ₂₄ Cl ₃ N ₃ O _2.

A mixture of 12.8 parts of the di (chloroacetyl) derivative prepared in the manner described above and 250 parts by volume of acetic acid is refluxed for 1 hour. The acetic acid is released under reduced pressure distilled off, whereupon a saturated aqueous sodium bicarbonate solution was added to the residue and that Mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and washed over Sodium sulfate dried, whereupon the solvent is distilled off. The residue is in a mixture dissolved by ethanol and ether. Saturated ethanolic hydrochloric acid is added to the solution. The departed Crystals are filtered off, washed with ether and a small amount of acetone and dried, whereby S-chloro ^ -Q-chloromethyl-s-triazoM-ylJbenzophenone hydrochloride is obtained. By recrystallization Ethanol-ether, colorless crystals with a melting point of 176 to 178 ° C. are obtained.

Elemental analysis:

Calculated for C ₁₆ H _n Cl ₂ N ₃ O · HCl: C 52.13 H 3.28 N 11.40 Found: C 52.27 H 2.94 N 11.17

The free base of this compound is in the form of colorless prisms with a melting point of 144 to 145 ° C (from Recrystallized ethanol).

Example 2
The following connection is also established in the manner described above:

S-chloro ^ -Q-chloromethyl-S-methyl-s-triazoM-yobenzophenone, melting point 141 to 142 ° C.

Application example 1

A solution of 3.7 parts of S-chloro ^ -iS-chloromethyl-s-triazol ^ -yobenzophenone hydrochloride and 3 parts by volume Monoethanolamine in 30 parts by volume of ethanol is refluxed for about 4 hours. By evaporation of the solvent, crystals are obtained which are isolated and recrystallized from chloroform-methanol will. Here, 10-chloro-8a-phenyl-4,6,7,8a-tetrahydrooxazole [3,2-d] -s-triazole [4,3-a] [1,4] benzodiazepine in Obtained in the form of colorless needles or rods with a melting point of 255 to 256 ° C.

Elemental analysis:

Calculated for C ₁₈ H _{! 5} C1N ₄ O: C 63.81 H 4.46 N 16.54 Found: C 64.74 H 4.33 N 16.46

Application example 2

In the manner described in Application Example 1, the compounds mentioned below are prepared.

55 Intermediate product according to the invention

Amine

Recrystallization solvent

End product

Melting point, ⁰ C (crystal form)

5-chloro-2- (3-chloromethyl-s-triazol-4-yl) - benzophenone

5-chloro-2- (3-chloromethyl-5-methyls-triazol-4-yl) benzophenone

Isopropanol ethyl acetate

amine

Ethanolamine chloroform-methanol

10-chloro-1-methyl-Sa-phenyl-220-221

4,6,7,8a-tetrahydrooxazole (colorless

[3,2-d] -s-triazole [4,3-a] rods) [1,4] -benzodiazepine

10-chloro-1-methyl-Sa-phenyl-258 to 261

4,6,7,8a-tetrahydrooxazole (colorless

[3,2-d] -s-triazolo [4,3-a] [1,4] benzo-prisms) diazepine

continuation

According to the invention Intermediate product

Amine

Recrystallization solvent

End product

Melting point, ⁰ C (crystal form) 5

5-chloro-2- (3-chloromethyl-5-methyls-triazol-4-yl) benzophenone

Isopropanolamine

Ethylenediamine

Acetone-ethyl acetate

Chloroform-methanol

Propanolamine in methanol 10-chloro-1J-dimethyl-Sa-phenyl-4,6,7,8a-tetrahydrooxazole- [3,2-d] -s-triazolo [4,3-a] [1,4] benzodiazepine

10-Chloro-1-methyl-Sa-phenyl-4,6,7,8a-tetrahydro-8H-imidazo- [1,2-d] -s-triazolo [4,3-a] [1,4] benzodiazepine

ll-chloro-l-methyl ^ a-phenyl-4,6,7,9a-tetrahydro-8H-oxazine-

diazepine

219 to 221

(colorless

Prisms)

225 to 235

(colorless

Tile)

260 to 261

(colorless

Prisms)

The following compounds can be produced analogously to the manner described above:

10-chloro-1-ethyl-8a-phenyl-4,6,7,8a-tetrahydrooxazol [3,2-d] -s-triazol [4,3-a] [1,4] benzodiazepine 10-chloro-1-ethyl-7-methyl-8a-phenyl-4,6,7,8a-tetrahydrooxazole [3,2-d] -s-triazolo [4,3-a] [1,4] benzodiazepine lO-Chlor-l-äthyl-Sa-phenyM.oJ.Sa-tetrahydro-SH-imidazolfl ^ -dl-s-triazol ^^ - altl ^ Jbenzodiazepine llCh

10

15th

20th

25th

30th

35

40

45

50

55

60

65

Claims (2)

Claims: 1. Compounds of the general formula CH ₂ Z in which R is a hydrogen atom or a lower alkyl radical and Z is a halogen atom. 2. S-chloro ^ -P-chloromethyl-s-triazoM-yObenzophenone. The invention relates to compounds of the general formula (II)