CH630630A5 - Processes for preparing substituted 6-aryl-4H-s-triazolo-(3,4-c)-thieno-(2,3-e)-1,4-diazepines. - Google Patents

Abstract

6-Aryl-4H-s-triazolo-(3,4-c)-thieno-(2,3-e)-1,4-diazepines of the formula VII are prepared by starting from a compound of the formula I. The substituents in the formulae have the meaning given in the independent claims. The reaction steps comprise, consecutively, reduction, cyclisation, treatment with phosphorus pentasulphide, trialkyloxonium fluoroborate or a phosphorus pentahalide, reaction with an acid hydrazide, cleavage of the oxazepine ring, halogenation, reaction with ammonia or with a substance yielding ammonia, and dehydration. The compounds of the formula VII and their acid addition salts possess pharmaceutical properties. <IMAGE>

Description

The invention relates to a new process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno - [2,3-e] -l, 4-diazepines of the formula VII

wherein Halj represents a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb 40 thus formed

CH2-Hal2

(Vb),

(VII)

wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of

Formula VI

50

and their acid addition salts.

In this formula:

Rj and R2, which may be the same or different, are hydrogen * or halogen atoms, lower alkyl groups having 1 to 55 2 carbon atoms or together, connected via an alkylene chain, a 5- or membered ring;

R3 is a hydrogen atom, a straight-chain or branched alkyl group having 1 to 3 carbon atoms, a w-hydroxyalkyl group having 1 to 3 carbon atoms, a cycloalkyl-60 group having 3 to 6 carbon atoms or a 5- or membered group, an oxygen, sulfur or or a saturated heterocyclic ring containing nitrogen atom, it being possible for the nitrogen-containing ring to be optionally substituted on the nitrogen atom by a lower alkyl group; and

65

R4 and R5, which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom.

The compounds of the formula VII are prepared according to the following reaction scheme:

IIA

II

x "

"

0 = N

y

0 — HO

'H

'HO

\

, 0 M S UH

0 "" H

91

17th

630630

The usual process for the preparation of thieno-tri-azolo-diazepine leads, if one starts from the same starting product, namely a 2-haloacetylamino-3-benzoylthiophene of the formula I, via the corresponding amine, ring closure to the diazepinone, activation of the carbonyl Function and implementation with a hydrazine derivative to the end product. Although this synthesis involves two steps less than the process according to the invention, the latter - based on the overall synthesis - yields a yield which is almost twice as high. The formation of the triazole ring was found to be the critical step in the synthesis of the final product. This ring closure on the oxazepine molecule - presumably for steric reasons - occurs spontaneously and in almost quantitative yield, while the corresponding reaction on the diazepine molecule requires a longer treatment, usually with heating.

A ketone of the formula I is first used to synthesize the thienotriazolo-diazepines

(II),

(I),

wherein the radicals Rj to R5 have the meaning given above and X represents a halogen atom, an amino group or an acyloxy group, to the corresponding carbinol of the formula Ia

(the radicals Rj to R5 and X have the meaning given above), optionally converting the amino group into a halogen atom or splitting off the acyl group and then subjecting it to a ring closure reaction.

Thieno-oxazepines of the formula II are obtained

15

wherein the radicals Rt to R5 have the meaning given.

The ketone of the formula I is reduced to the carbinol of the formula Ia according to the invention by means of sodium borohydride in dimethylformamide or dimethylacetamide at a temperature of between 0 and 10 ° C. Surprisingly, there is hardly any reductive cleavage of the radical X or hydrolytic cleavage of the radical -CO-CH2-X, while in other solvents, e.g. in a lower alcohol, the cleavage reactions outweigh the carbinol formation.

The reduction of a compound of the formula I in which X represents an amino group is expediently carried out using a starting material in which Rx does not represent hydrogen; otherwise, a nitro group is simultaneously introduced in the subsequent reaction of the aminocarbinol to the halocarbinol, which is carried out with the aid of nitrous acid in a solution strongly acidified with hydrochloric acid.

If X is an acyloxy group, this is cleaved off with strong alkali after reduction with sodium borohydride.

The detour via a functional derivative of the aminoketone proved to be necessary in the present case, because it surprisingly turned out that in contrast *

sentence to the easily reducible 2-aminobenzophenones 40 (see e.g. DE-OS 15 45 639) the corresponding 2-amino-benzoylthiophenes cannot be reduced directly to the carbinols.

In contrast to the hydrolysis-sensitive keto compounds of the formula I, the carbinols of the formula Ia obtained in the manner described above are surprisingly extremely stable to alkali, a circumstance which determines the high yields in the sodium borohydride reduction described above.

In the case of X = halogen, the ring closure of the 50 carbinol of the formula Ia to the oxazepine of the formula II which follows the reduction is generally carried out with a suitable alkali metal alcoholate or with sodium hydride; sodium isopropylate and sodium tert-butoxide are preferred for the ring closure. Alko-55 hole, tetrahydrofuran, dioxane, dimethylformamide or inert solvents such as benzene and its homologues can be used as solvents. The reaction temperature depends on the starting material used and is between 0 ° C and the boiling point of the solvent used in each case.

In the case of X = OH, the ring can be closed with the usual water-releasing agents, such as thionyl chloride, sulfuric acid, polyphosphoric acid or dicyclohexylcarbodiimide.

The radicals Rj and / or R2 can be introduced in different reaction stages. If Rt and / or R2 represent a lower alkyl group or together form an alkylene chain, the residues are expediently brought along when the thiophene ring is built up.

630630

18th

In contrast, halogen atoms can be introduced both at the acylaminoketone stage of the formula I or into a compound of the formula II. In both cases, the halogenation takes place within a short time by reaction with the equivalent amount of the halogen or a suitable halogen compound, such as a sulfuryl halide or a halogen succinimide or the like, in solvents such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally with the addition of a tertiary organic base, for example pyridine. The reaction temperature in the halogenation is - depending on the starting material used and the method used - between room temperature and the reflux temperature of the reaction mixture.

In this way, a halogen atom can also be introduced next to an existing alkyl group. If desired, a second halogen atom can also be introduced using conventional methods (Ri and R2 = halogen).

The starting materials of formula I are known from the literature and can e.g. can be obtained by the method given in Monthly Journals of Chemistry, Volume 104, (1973) page 704.

The compounds of formula II are intermediates for the preparation of therapeutically valuable substituted thieno- [2,3-e] -triazolo- [3,4-c] -1,4-diazepines of the formula VII, as are described, for example, in US Pat CH-PS 611 900 and in DE-OS 22 29 845.

These end products are obtained from the above-mentioned intermediates by reaction with a carboxylic acid hydrazide, the corresponding thieno [2,3-e] tri-azolo [3,4-c] -4, l-oxazepine being formed, Opening the oxaze pin ring with hydrohalic acids, conversion of the 4- (3-phenylhalomethyl) thienyl- (2) -5-hy-hydroxymethyl-l, 2,4-triazoles thus formed into the corresponding 5-halogenomethyl compounds, Ring closure with ammonia and dehydration.

The thieno-triazolo-diazepines mentioned in the protective rights mentioned above have been shown to be effective in the use of various pharmacological test methods as an anxiolytic, tension-relieving and muscle-relieving effect and, moreover, have shown an intensive anticonvulsant effect. They also have the property of significantly increasing feed intake in mammals. Their remarkably low toxicity is also remarkable.

The compounds of the formula II obtained as described above are subjected to treatment with phosphorus pentasulfide in general in a solvent such as dimethylformamide, diglyme or tetrahydrofuran, for example with the addition of an alkali metal carbonate, pyridine or their mixtures. The temperatures t5 used here can be between the room temperature and the reflux temperature of the reaction mixture. Such compounds of the formula III are obtained

(III),

wherein the radicals Rx to R5 have the meaning given and X represents an SH group.

35 In addition, X in formula III can also mean a lower alkoxy or alkyl mercapto group or a halogen atom.

They are in tautomeric equilibrium with the corresponding thiono compounds:

R,

R.

These compounds, after having been reacted in a solvent to give the corresponding 60 salts with the aid of a metalating agent such as sodium methylate or sodium amide, can be separated in a conventional manner with alkylating agents, e.g. Methyl or alkyl iodide, to be reacted to those compounds of the formula III in which X denotes a lower thioalkyl group.

Compounds of the formula III in which X denotes a lower alkoxy group are obtained from compounds of the formula II by reaction with a trialkyloxonium fluoroborate. This connection, which is based on a method by H. Meerwein et al. in J. pr. Chem. (2), 147 (1937) 257 and 154

19th

630630

(1939) 83 described process from boron trifluoride etherate and epichlorohydrin is reacted in situ with a compound of formula II. In particular, ether or halogenated hydrocarbons, e.g. Carbon tetrachloride, suitable. The reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

Compounds of formula III with X = halogen are prepared by treating a compound of formula II with a phosphorus pentahalide, preferably with phosphorus pentachloride, suitably in an anhydrous organic solvent, such as dioxane or tetrahydrofuran, at temperatures between -50 and + 50 ° C. The imide chloride obtained can be reacted in situ with compounds of the formula IV to give the triazolo-thieno-oxazepine of the formula V. In special cases, however, the halogen compound can also be isolated.

Compounds of formula III are now with a compound of formula IV

R3-CO-NH-NH2 (IV),

wherein R3 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 3 carbon atoms, a 03-hydroxyalkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a 5- or membered saturated atom containing an oxygen, sulfur or nitrogen atom Ring, where the nitrogen-containing ring may optionally be substituted on the nitrogen atom by a lower alkyl group, is reacted, wherein a compound of formula V

R.

1

"2

wherein the radicals Rt to R5 have the meaning given, is obtained.

This reaction can be carried out at temperatures between 100 and 250 ° C both without solvent and in solvents such as methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene, or mixtures of these solvents, without or in the presence of an acidic catalyst (e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, poly-phosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid) are carried out; the intermediate of formula IIIc formed in the reaction

IH-HH-COR

R

1

R

2nd

(IIIc);

in which the radicals Rj to R5 have the meaning given is not isolated here.

Starting from thieno- [2,3-e] -triazolo- [3,4-c] -4, l-oxazepinene of the formula V, the thieno-triazolo-diazepines of the formula VI are obtained in accordance with the following scheme:

î

io

15

20th

25th

30th

35

40

45

50

55

60

65

630630

20th

(V)

R,

R,

Rr- ^ f N

s5 V "

■ CH2-Hal2

R5-r ^

(Va)

CH-Hal,

Rr

R /

R.

(Vb)

R-,

R,

InL N - (/

-CH-NH

Rr

■ R /

(VI)

Here, the oxazepine ring of a compound of formula V is first split by treatment with preferably strong hydrochloric acid or hydrobromic acid on the oxygen atom.

For this purpose, it is generally sufficient to leave a compound of the formula V in a strongly hydrochloric or hydrobromic acid solution for a few minutes to a few hours at room temperature. The hydrohalide of a compound of the formula Va which forms in this reaction is generally extracted from the reaction solution in the cold with a water-immiscible solvent, preferably a chlorinated hydrocarbon such as chloroform or methylene chloride, and - expediently after evaporation of the extraction solution - with a phosphorus or

55 sulfur halide, such as thionyl chloride or phosphorus tri-bromide. The reaction temperature here is advantageously between 0 and 40 ° C - preferably about 20 ° C.

In general, after the excess halide and optionally the solvent still present have been distilled off, the residue, consisting of a dihalide of the formula Vb, is reacted with substances which provide ammonia or ammonia, such as urotropin. Lower alcohols are suitable as solvents for the reaction with ammonia, e.g. Methanol or ethanol, ethyl acetate, dioxane, 65 tetrahydrofuran or inert hydrocarbons, such as benzene and its homologues; but liquid ammonia can also be used for the reaction. The reaction temperature is advantageously between 0 ° C and the boiling point of the

21st

630630

applied solvent; however, the reaction is preferably carried out in an autoclave. The compounds of formula VI are obtained in excellent yield.

The dehydrogenation of the compounds of formula VI to the end products of formula VII is generally carried out using suitable dehydrating agents, e.g. of halogens, or also of compounds of the higher oxidation levels of chromium or manganese, for example a chromate, a bichromate or a permanganate. Chlorinated hydrocarbons, such as chloroform, are suitable solvents for the reaction with a halogen.

or called methylene chloride; In this reaction, a tertiary organic base, for example pyridine, is expediently added to scavenge the hydrohalic acid formed.

The oxidation with the chromium or manganese compounds mentioned takes place in solvents such as acetone, tetrahydrofuran or dioxane.

Depending on the type of oxidizing agent, the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

If in a compound of the formula VI R3 is a hydrogen atom, both the end product of the formula VII with R3 = hydrogen and, if an excess of the halogen in question is used, an end product of the formula VII with R3 in the reaction with chlorine or bromine = Chlorine or bromine can be obtained.

The end products of formula VII can be converted into their physiologically tolerated acid addition salts in a conventional manner. Acids suitable for salt formation are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane or toluenesulfonic acid and the like.

The end products of formula VII and their acid addition salts have a pronounced anticonvulsant, anxiolytic and antiagressive effect in the dose range from 0.1 to 3 mg / kg with very low toxicity.

The following examples illustrate the invention:

example 1

8-bromo-6- (o-chlorophenyl) -l-methyl-4H-s-triazolo- [3,4-c] - thieno- [2,3-e] -l, 4-diazepine a, a) 1 mol = 314 g of 2-chloroacetylamino-3- (o-chloro-benzoyl) thiophene are dissolved in 500 ml of dimethylformamide and 36 g of powdered sodium borohydride are added at 0 ° C. with vigorous stirring for one hour. Then poured into 2 1 of ice water, whereby a greasy precipitate is formed. The water phase is decanted off, the grease is washed 2-3 times with water and taken up in methylene chloride. After drying the methylene chloride phase and evaporation, 300 g of oil are obtained, which gradually solidifies and is recrystallized from methanol ether.

294 g (93.1% of theory) of 2-chloroacetylamino-3 - [(o-chlorophenyl) hydroxymethyl] thiophene, melting point 118 to 120 ° C., are obtained.

The oil can also be used directly to close the ring.

β) 0.8 mol = 253 g of 2-chloroacetylamino-3 - [(o-chlorophenyl) hydroxymethyl] thiophene, dissolved in 200 ml of isopropanol, are dissolved in a boiling solution of 52 g (2.25 mol ) Sodium in 1.8 1 isopropanol and boiled under reflux for 5 minutes. The brownish suspension is then poured into 1.5 l of ice water and acidified with concentrated hydrochloric acid. The precipitated crystals are filtered off and washed with water. Then the moist residue is dissolved in 2 1 of methylene chloride, dried with magnesium sulfate, evaporated and the residue is recrystallized from methanol.

242 g (87% of theory) of 5- (o-chlorophenyl) thieno - [2,3-e] -4, l-oxazepinon- (l) of mp 175-176 ° C. are obtained.

b) 0.1 mol = 27.9 g of 5- (o-chlorophenyl) thieno- [2,3-e] - 4, l-oxazepinon- (l) in 300 ml of chloroform and 8.5 ml of io Pyridine dissolved. A solution of 5.5 ml of bromine in 50 ml of chloroform is added over 10 to 15 minutes at room temperature. Decolorization occurs immediately. The title link fails. It is suctioned off and washed with ether.

15 The yield of 7-bromo-5- (o-chlorophenyl) thieno- [2,3-e] - 4,1-oxazepinon is 30 g (83% of theory), mp. 178 to 180 ° C (dec.).

c, a) 0.1 mol = 35.8 g of 7-bromo-5- (o-chlorophenyl) thieno - [2,3-e] -4, l-oxazepinon with 350 ml of diglyme, 24 g

20 P2S5 and 19 g NaHC03 heated to 60 ° C for 30 minutes. The mixture is then poured onto about 11 ice water, a crystalline precipitate being formed which is filtered off, washed with water and dried.

37 g = 99% of theory are obtained 7-bromo-5- (o-chlorophenyl) -25-thieno- [2,3-e] -4, l-oxazepin-2-thione, mp from 200 ° C (dec.).

β) -0.1 l mol = 37.5 g of 7-bromo-5- (o-chlorophenyl) thieno - [2,3-e] -4, l-oxazepine-2-thione are dissolved in 370 ml of tetrahydrofuran and mixed with 10 ml hydrazine hydrate. The reaction is complete after 30 5 minutes at room temperature. The solution is evaporated, the residue is taken up in methylene chloride, washed several times with water, the separated methylene chloride phase is dried and evaporated. The residue is taken up in 200 ml of ethanol 35 and mixed with 50 ml of tri-ethyl acetate. The mixture is boiled under reflux for 30 minutes, evaporated in vacuo and the residue is crystallized using ether.

Yield of 8-bromo-6- (o-chlorophenyl) -l-methylthieno - [2,3-e] -triazolo- [3,4-c] -4, l-oxazepine: 34.5 g = 87% of theory 40 m.p. 146-148 ° C.

d, a) 0.1 mol = 39.6 g of 8-bromo-6- (o-chlorophenyl) -l-methyl-thieno- [2,3-e] -triazolo- [3,4-c] -4, l-oxazepine of mp. 146 to 148 ° C are concentrated in 250 ml. Hydrobromic acid suspended. As soon as a clear solution has been reached (after

4S 15-20 minutes), diluted with 300 ml of ice water and shaken out with methylene chloride. The methylene chloride phase is dried and evaporated, and the residue is crystallized using ether. 52 g of 3-methyl-4- [3 - (o-chlorophenyl-bromomethyl) -5-bromothienyl (2)] - 5-hydroxy-50 methyl-l, 2,4-triazole hydrobromide ( 94% of theory) of mp. 200 ° C (dec.).

β) 0.05 mol = 27.9 g of the hydrobromide are stirred with 100 ml of thionyl chloride for 30 minutes at room temperature. The excess thionyl chloride 55 is then distilled in vacuo, the residue is taken up in methylene chloride and washed with ice water and dilute ammonia. The dried methylene chloride phase is evaporated and the residue is triturated with ether.

Yield: 24.2 g of 3-methyl-4- [3- (o-chlorophenyl-bromo-60-methyl) -5-bromothienyl (2)] - 5-chloromethyl-l, 2,4-triazole, mp. 167-169 ° C.

Y) 12.4 g of this compound are dissolved in 270 ml of methanol and 100 ml of liquid ammonia are added. The mixture is then heated to 100 ° C. in an autoclave for 30 minutes. The 65 reaction mixture is evaporated, the residue taken up in methylene chloride, washed with water, the methylene chloride phase dried, evaporated and the residue recrystallized from methanol.

630630

22

Yield of 8-bromo-6- (o-chlorophenyl) -l-methylthieno - [2,3-e] -triazolo- [3,4-cl-5,6-dihydro-1,4-diazepine: 9.0 g = 91% of theory m.p. 160-162 ° C.

e) 39.5 g = 0.1 mol of 8-bromo-6- (o-chlorophenyl) -l-methyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e ] -5,6-dihydro-l, 4-diazepine, mp 162 ° C., are dissolved in 500 ml of methylene chloride and 15 ml of pyridine, and 10 ml of bromine in 50 ml of methylene chloride are added to the solution within 10 minutes while stirring at room temperature. The immediately decolorising solution is stirred for 30 minutes, then shaken out several times with water, dried, evaporated and the residue recrystallized from ethanol.

Yield of 8-bromo-6- (o-chlorophenyl) -l-methyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepine: 36 , 9 g = 94% of theory m.p. 208-210 ° C.

Very good yields are also obtained if the dehydrogenation with potassium permanganate is carried out analogously to Example 3.

Example 2

8-bromo-6- (o-chlorophenyl) -l- [tetrahydropyranyl- (4)] - 4H-s - triazolo- [3,4-c] -thieno- [2,3-e] -l, 4 -diazepine

0.01 mol = 3.74 g of the 7-bromo-5- (o-chlorophenyl) thieno [2,3-e] -4, l-oxazepine-2-thione obtained according to Example 1 c, a) boiled under reflux with 100 ml of dioxane and 1.5 g of tetrahydropyran-4-car-bonsäurehydrazid for 30 minutes. The mixture is then worked up as in Example 1 (c, β).

Yield of 8-bromo-6- (o-chlorophenyl) -l- [tetrahydro-pyranyl- (4)] -thieno- [2,3-e] -triazolo- [3,4-c] -4,1- oxazepine: 2.7 g (58% of theory) of melting point 182-184 ° C.

Analogously to the procedures described in Example 1 d) and 1 e), 8-bromo-6- (o-chlorophenyl) -l-- [tetrahydropyranyl- (4)] -thieno- [2,3-e] - triazolo- [3,4-c] -5,6 - dihydro-1,4-diazepine, mp. 174-175 ° C the title compound in a yield of 98% of theory (Mp 257-258 ° C).

Example 3

8-bromo-6- (o-chlorophenyl) -l-cyclohexyl-4H-s-triazolo - [3,4-c] thieno- [2,3-e] -l, 4-diazepine

4.65 g = 0.01 mol of 8-bromo-6- (o-chlorophenyl) -l-cyclo-hexyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -5,6-dihydro-l, 4 - diazepine, mp 192 ° C, made from 7-bromo-5- (o-chlorophenyl) thieno- [2,3-e] -4, l- oxazepin-2-thione (Example 1 c, a),

Mp 200 ° C) over 8-bromo-6- (o-chlorophenyl) -l-cyclohexyl-thieno- [2,3-e] -triazolo- [3,4-c] -4,1-oxazepine ( Analogously to Example 1 c, β), mp. 172-174 ° C) in the way described in Example 1 d, a) - y), are dissolved in 100 ml of KMn04 distilled acetone. 3 g of sodium bichromate in 15 ml of water and then 2 ml of 20% sulfuric acid are first added with stirring at the boil and the mixture is left to boil for 30 minutes. The solvent is distilled off, the residue is diluted with a little water, made ammoniacal and shaken with methylene chloride. After washing, drying and evaporating the solvent, a crude product remains, which is recrystallized from ethanol.

Yield: 4.1 g = 88% of theory m.p. 190-192 ° C.

Instead of sodium bichromate, potassium permanganate can also be used for dehydration. Then proceed as follows:

4.65 g = 0.01 mol of 8-bromo-6- (o-chlorophenyl) -l-cyclo-hexyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -5,6-dihydro-1,4 - diazepine are dissolved in a mixture of 50 ml acetone and 2o 50 ml methylene chloride. 1.4 g of finely powdered KMn04 are added in one portion and the mixture is stirred for 6 hours at room temperature. He separates from Braunstein. After suction filtration over diatomaceous earth, the light yellow filtrate is evaporated and the residue is triturated with ether. 25 4 g = 86% of theory are obtained the title compound of mp 190-192 ° C.

Example 4

1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4-c] thieno-30 - [2,3-e] -l, 4-diazepine

3.8 g = 0.01 mol of 8-bromo-6- (o-chlorophenyl) -4H-s-tri-azolo- [3,4-c] thieno- [2,3-e] -5,6 dihydro-l, 4-diazepine, mp 178 ° C, made from 7-bromo-5- (o-chlorophenyl) -thieno-35 - [2,3-e] -4, l-oxazepine-2-thione the 8-bromo-6- (o-chlorophenyl) thieno [2,3-e] triazolo [3,4-c] -4,1-oxazepine (mp. 182 ° C.) as in Example 1 d, a) - y)> are dissolved in 50 ml methylene chloride and 1 ml pyridine. 1.5 ml of bromine in 15 ml of methylene chloride are added over the course of 10 minutes, and 40 are then boiled under reflux for 30 minutes.

The reaction solution is washed with water, dried and evaporated. The concentrate is placed on a SiO 2 column and eluted with methylene chloride, to which 2% methanol has been added.

45 The first main fraction contains 4.2 g of the title compound of mp 209-210 ° C = 92% of theory

23 630630

Analogously to the examples listed, the following end products were prepared using the intermediates indicated:

Mp. ° C Mp. ° C Mp. ° C Mp. ° C

Ri R2 R3 R4 R5 intermediate-intermediate-intermediate end product VII

Product II product V product VI

Br h

ch3

Br h

176 (dec.)

137-139

171-173

205-206

cl h

ch3

Cl h

223-225

124-126

131-133

204-206

Br h

ch3

F

H

145-150 (dec.)

170-171

180-182

208-210

c2h5

h ch3

Cl h

148-150

90

120-122

144-146

ch2-ch2

-ch2-ch2

ch3

Cl h

263-264

189-190

219-220

203-205

Br h

ch3

Cl h

178-180

146-148

160-162

208-210

Br h

Cl h

178-180

172-1774

190-192

190-192

Br h

O

Cl h

178-180

182-184

174-175

257-258

Br h

■ A

Cl h

178-180

169-170

156-158

212-214

Br h

H

Cl h

178-180

182

176-178

198-200

Br h

-ch2-oh

Cl h

178-180

198

205-206

224-225

Br h

Br

Cl h

178-180

135-137

135-137 (dec.)

209-210

v

Claims (18)

630630 2nd PATENT CLAIMS 1. Process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII (VII), 15 reduced, then split off the acyl group and with a cyclizing agent in a compound of formula II wherein Rj and R2, which are the same or different, are each hydrogen, halogen or lower alkyl having 1 to 2 carbon atoms or together, connected via an alkylene group, a 5- or 6-membered ring; Rs is hydrogen, straight-chain or branched alkyl having 1 to 3 carbon atoms, w-hydroxyalkyl having 1 to 3 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or a 5- or 6-membered, saturated heterocyclic ring containing an oxygen, sulfur or nitrogen atom, where the nitrogen-containing ring is optionally substituted on the nitrogen atom by a lower alkyl group; and R4 and R5, which are the same or different, each represent hydrogen, fluorine, chlorine or bromine, and of their physiologically acceptable acid addition salts, characterized in that a compound of the formula I (II) converted this by treatment with phosphorus pentasulfide in a compound of formula III (HI), (I), wherein Xt represents a group -SH, the compound thus obtained is converted with a compound of formula IV 50 R3-CO-NH-NH2 (IV) to a compound of formula V where X is an acyloxy group, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to give the corresponding carbinol of the formula Ia (V) 3rd 630630 converts the compound thus obtained with a strong hydrohalic acid at the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va mei la sodium isopropylate or sodium tert-butoxide used. 3. Process for the preparation of substituted 6-aryl-4H-s-triazoIo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII -OH (Va), wherein Halj represents a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb thus formed (VII), CH2-Hal2 (Vb), wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of formula VI wherein 25 R 1 and R 2, which are the same or different, are each hydrogen, halogen or lower alkyl having 1 to 2 carbon atoms or together, connected via an alkylene group, a 5 or membered ring; R3 is hydrogen, straight-chain or branched alkyl 3o having 1 to 3 carbon atoms, w-hydroxyalkyl having 1 to 3 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or a 5- or ole-membered, saturated heterocyclic ring containing an oxygen, sulfur or nitrogen atom, the nitrogen-containing ring Ring is optionally substituted on the nitrogen atom by a lower alkyl group; and R4 and R5, which are the same or different, each represent hydrogen, fluorine, chlorine or bromine, and of their physiologically acceptable 40 acid addition salts, characterized in that a compound of the formula I R, in which X denotes an amino group, using sodium borohydride in dimethylformamide or dimethylacetamide at 60 temperatures in the range from 0 to 10 ° C. to convert the corresponding carbinol of the formula Ia, dehydrate it to the corresponding compound of the formula VII and, if appropriate, subsequently process the products into their physiologically acceptable acid addi 65 ion salts transferred. 2. The method according to claim 1, characterized in that that as a cyclizing agent for the connection of the 630630 4th N - CO - CH, wherein Xi denotes a group -SH, the compound thus obtained is transferred with a compound of the formula IV R, —CO — NH — NH, to a compound of formula V (IV) (Ia) 10th reduced, then converting the amino group with the help of nitrous acid in a solution strongly halogenated into a halogen atom and the compound obtained with a cyclizing agent into a compound of formula II 15 rows 20th 25th (V) converts the compound thus obtained with a strong hydrohalic acid at the oxygen atom of the oxazepine ring (II), the hydrohalide of the formula Va obtained converted this by treatment with phosphorus pentasulfide in a compound of formula III -OH (Va), (HI), 45 wherein Halj is a halogen atom, extracted with a water-immiscible solvent, the residue is mixed with a phosphorus or sulfur halide, the dihalogen compound of the formula Vb thus formed CH2-Hal2 (Vb), -CH-Hal1 65 wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI 5 630630 R-, R, (I), 15 wherein X represents a halogen atom, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to give the corresponding carbinol of the formula Ia, dehydrating it to the corresponding compound of the formula VII and, if appropriate, subsequently converting the process products into their physiologically acceptable acid addition salts. 4. The method according to claim 3, characterized in that there is used as the cyclizing agent for the compound of formula Ia sodium isopropylate or sodium tert-butoxide. 5. Process for the preparation of substituted 6-aryl-4H-s-triazolo-t3,4-c] -thieno [2,3-e] -l, 4-diazepines of the formula VII '). N V 35 reduced, then with a cyclizing agent into a compound of formula II (VII), wherein Rj and R2, which are the same or different, are each hydrogen, halogen or lower alkyl having 1 to 2 carbon atoms or together, connected via an alkylene group, a 5- or 6-membered ring; R3 is hydrogen, straight-chain or branched alkyl having 1 to 3 carbon atoms, w-hydroxyalkyl having 1 to 3 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or a 5- or 6-membered saturated heterocyclic ring containing an oxygen, sulfur or nitrogen atom, the nitrogen-containing ring being the nitrogen-containing ring is optionally substituted on the nitrogen atom by a lower alkyl group; and R4 and Rä, which are the same or different, each represent hydrogen, fluorine, chlorine or bromine, and their physiologically acceptable acid addition salts, characterized in that a compound of the formula I (II) converted this by treatment with phosphorus pentasulfide in a compound of formula III (III), 630630 6 where X! represents a group -SH, the compound thus obtained is converted with a compound of formula IV R3-CO-NH-NH2 (IV) to a compound of formula V 5 R, io R, (V) «5 (VI) converts the compound thus obtained with a strong hydrohalic acid at the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va obtained 20 is implemented, dehydrated to the corresponding compound of formula VII and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 6. The method according to claim 5, characterized in that 25 is used as the cyclizing agent for the compound of formula Ia sodium isopropylate or sodium tert-butoxide. 7. Process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII 30th -OH (Va), wherein Halj represents a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb thus formed 40 R (VII), 45 where the symbols R1; R2, R3, R4 and R5 have the meaning given in patent claim 50, as well as their physiologically acceptable acid addition salts, characterized in that a compound of the formula I CH2-Hal2 55 (Vb), wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI 60 65 7 630630 in which X denotes an acyloxy group, by means of sodium boron wherein X2 denotes a group O-alkyl, which is hydrided in dimethylformamide or dimethylacetamide in the compound obtained with a compound of the formula IV, temperatures in the range from 0 to 10 ° C. to the corresponding carbinol of the formula Ia ®-s CO NH NH2 (IV) 5 H to a compound of formula V (V) reduced, then split off the acyl group and by treatment with a cyclizing agent in a compound of formula II 25, the compound thus obtained splits with a strong hydrohalic acid on the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va obtained converted this into a compound of the formula purple by treatment with a trialkyloxonium fluoroborate -OH (Va), 45 where Halj is a halogen atom, extracted with a solvent which is not water-resistant, the residue is mixed with a phosphorus or sulfur halide, the dihalogen compound of the formula Vb thus formed (purple), 50 55 , N N .N- // CH2-Hal2 R, CH-Hal, (Vb), 60 65 wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI 630630 8th Rh in which X represents an amino group, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to give the corresponding carbinol of the formula Ia CO - CH. (VI) OK (Ia) reacted, dehydrated this to the corresponding compound of formula VII and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 8. The method according to claim 7, characterized in that sodium isopropylate or sodium tert-butoxide is used as the cyclizing agent. 9. Process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII 20th reduced, then converting the amino group with the aid of nitrous acid in a solution strongly halogenated into a halogen atom and the compound 25 obtained with a cyclizing agent into a compound of the formula II (VII), (II) converted by treatment with a trialkyloxo-45 nium fluoroborate into a compound of the formula purple in which the symbols R1: R2, Rs, R4 and R5 have the meaning given in claim 1, and from their physiologically acceptable acid addition salts, characterized in that that a compound of formula I (purple), wherein X2 represents an O-alkyl group, the compound thus obtained is converted with a compound of the formula IV R3-CO-NH-NH2 (IV) to a compound of formula V 9 630630 5 R-, (V) converts the compound thus obtained with a strong hydrohalic acid at the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va io R0 ^ i; (VI) * x R ~ 15 20 is implemented, dehydrated to the corresponding compound of formula VII and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 10. Process for the preparation of substituted 6-aryl-4H-25 -s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII (Va) wherein Halt means a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb thus formed (VII), CH2-Hal2 (Vb). 45 wherein the symbols Rx, R2, R3, R4 and R5 have the meaning given in claim 1, and of their physiologically acceptable acid addition salts, characterized in that a compound of formula I. N _ CO - CH, wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI (I), 65 wherein X represents a halogen atom, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to the corresponding carbinol of the formula Ia 630630 10th N - CO - CH. wherein X2 is a Grappe O-alkyl, the compound thus obtained is converted with a compound of the formula IV R "-CO-NH-NH, to a compound of formula V (IV) (Ia) reduced and then with a cyclizing agent in a compound of formula II (V) 25, the compound thus obtained splits with a strong halo (II) hydrochloric acid at the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va obtained 30th converted this into a compound of the formula purple by treatment with a trialkyloxonium fluoroborate 40 -OH (Va), (Illa), 45 where Halt means a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of the formula Vb thus formed 50 .N R-, N N 55 60 CH2-Hal2 (Vb), CH-Hal, R, 65 wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI 11 630630 R. R, (VI) 10 15 reacted, dehydrated to the corresponding compound of formula VII and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 11. Process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII 25 reduced, then split off the acyl group and by treatment with a cyclizing agent in a compound of formula II (II) (VII), 35 transferred this by treatment with a phosphorus penta-halide into a compound of the formula Illb in which the symbols Rt, R2, R3, R4 and R5 have the meaning given in claim 1, and from their physiologically acceptable acid addition salts, characterized in that a compound of formula I. (Illb), wherein X3 represents a group of sharks, the compound thus obtained is converted with a compound of the formula IV R3-CO-NH-NH2 (IV) to a compound of formula V wherein X represents an Äeyloxygruppe, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range of 0 to 10 ° C to the corresponding carbinol of formula Ia 65 630630 12th (V) io R, R, converts the compound thus obtained with a strong hydrohalic acid at the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va obtained (VI) -OH (Va), 15 converts them to the corresponding compound of formula VII 20 dehydrated and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 12. The method according to claim 11, characterized in that the cyclizing agent is sodium isopropylate or 25 sodium tert-butoxide used. 13. The method according to claim 11, characterized in that one uses in the reaction of a compound of formula II to a compound of formula IIIb as phosphorus pentahalide phosphorus pentachloride. 30 14. Process for the preparation of substituted 6-aryl-4H-s - triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII wherein Halx represents a halogen atom, extracted with a water-immiscible solvent, the residue mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb thus formed Rz— N CH2-Hal2 R £ CH-Hal, - <y (Vb), (VII), 50 wherein the symbols Rw R2, Rs, R4 and R5 have the meaning given in claim 1, and their physiologically acceptable acid addition salts, characterized in that a compound of formula I. wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI (I), 13 630630 wherein X represents an amino group, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to the corresponding carbinol of the formula Ia CH. X R 10th (Ia) 15 (V) the compound thus obtained is split with a strong hydrohalic acid on the oxygen atom of the oxazepine ring 20, the hydrohalide of the formula Va is reduced, then the amino group is converted into a halogen atom with the aid of nitrous acid in a solution strongly halogenated with hydrochloric acid and this compound is converted into a compound with a cyclizing agent of formula II 25 30 pounds. (II) 35 (Va), wherein Hali is a halogen atom, extracted with a water-immiscible solvent, the residue is mixed with a phosphorus or sulfur halide, the dihalo compound of formula Vb thus formed converted this by treatment with a phosphorus penta-halide into a compound of the formula Illb R, 45 5oR2 s? ! n .N N CH2-Hal2 (Vb), CH-Hal, (iiib), 55 wherein Hal2 represents a halogen atom, with ammonia or an ammonia-providing substance to a compound of Formula VI 60 wherein X3 represents a group of sharks, the compound thus obtained is converted with a compound of the formula IV 65 R3 — CO — NH — NH2 (IV) to a compound of formula V 630630 14 R-, wherein X represents a halogen atom, using sodium borohydride in dimethylformamide or dimethylacetamide at temperatures in the range from 0 to 10 ° C. to the corresponding carbinol of the formula Ia (VI) io, dehydrogenated to the corresponding compound of formula VII 20 and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 15. The method according to claim 14, characterized in that sodium isopropylate 25 or sodium tert-butoxide is used as the cyclizing agent. 16. Process for the preparation of substituted 6-aryl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -l, 4-diazepines of the formula VII / N. reduced, then with a cyclizing agent into a compound of formula II (VII), (II) 40 converted this by treatment with a phosphorus penta-halide into a compound of the formula Illb 45 where the symbols R1; R2, R3, R4 and R5 have the meaning given in claim 1, and of their physiologically acceptable acid addition salts, characterized 50 in that a compound of the formula I CO - CH2 - X 55 (I), 60 (Illb), wherein X3 represents a group of sharks, the compound thus obtained is converted with a compound of the formula IV 65 R, —CO — NH — NH, (IV) to a compound of formula V 15 630630 R-, (V) io R, 15 implemented, the compound thus obtained split with a strong hydrohalic acid on the oxygen atom of the oxazepine ring, the hydrohalide of the formula Va 20 obtained (VI) 25th -OH reacted, dehydrated to the corresponding compound of formula VII and the process products optionally subsequently converted into their physiologically acceptable acid addition salts. 17. The method according to claim 16, characterized in that sodium isopropylate or sodium tert-butoxide is used as the cyclizing agent. (Va), 30th