NO792319L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE TRIAZOLO-TIENO-DIAZEPINES - Google Patents

Description

"Analog process for the production of therapeutically active triazolo-thieno-diazepines"

This invention relates to the preparation of compounds of the general formula

where

1*2 means hydrogen, fluorine, chlorine or bromine,

R-. means chlorine or bromine or an alkyl radical of 1 to 3 carbon atoms, and

R4°9R5'which may be Uke or different, means hydrogen,

an alkyl residue with 1 to 4 carbon atoms or a hydroxyalkyl residue with 2 to 3 carbon atoms, or both residues together form a 4- or 5-membered alkylene chain which may optionally be substituted with one or two methyl groups, and where the 6-membered ring may also contain an oxygen atom.

The new compounds of the general formula I are prepared according to the invention

a) when selling a connection with the general

formula

where R 2 and R 3 have the meanings given above, with an amine of the general formula where R 4 and R 3 have the meanings given above, or b) by dehydrogenation of a compound of the general formula

where R 2 , R 2 /R 2 and R 2 have the above meanings, in a manner known per se.

The reaction of compounds of the general formula II with an amine of formula III is carried out either without a solvent1 or in solvents such as benzene, toluene, dioxane, tetrahydrofuran, chlorohydrocarbons such as carbon tetrachloride or methylene chloride, preferably at the boiling temperature of the solvent used. When reacting with lower amines

(dimethylamine, diethylamine etc.) the reaction is preferably carried out in an autoclave. The duration of the reaction depends on the starting material used, and can range from a few minutes to several hours.

The dehydrogenation of compounds with the general formula IV is carried out using suitable dehydrogenating agents, e.g. halogens or also compounds of the higher oxidation stages of chromium or manganese, e.g. a chromate, a bichromate or a permanganate. Chlorohydrocarbons such as chloroform or methylene chloride can be mentioned as suitable solvents for the reaction with halogen. The oxidation with the aforementioned compounds of chromium or manganese is carried out in solvents such as acetone, tetrahydrofuran or dioxane, possibly with the addition of phase transfer catalysts. Depending on the nature of the oxidizing agent, the reaction temperature is usually between 0°C and the boiling temperature of the solvent used.

The 1-amino compounds (R^ and R,- = hydrogen) are obtained

by reacting a 2-hydrazino-thieno[2,3e]-1,4-diazepine with cyanogen bromide according to the following scheme:

See in this context: K.T. Potts and C. Hirsch, J. Org. Chem.

33, 143 (1968).

Suitable solvents are alcohols, benzene, toluene and halogenated hydrocarbons.

These compounds can optionally be alkylated in the usual way. Alkyl halides, dialkyl sulfates or esters of toluenesulfonic acid are preferably used as alkylating agents. Solvents such as tetrahydrofuran, dimethylformamide or lower alcohols are used here, but the alkylation can also be carried out without the addition of a solvent. When introducing a hydroxyalkyl residue, it is recommended to carry out the reaction with an alkylene oxide.

According to the methods described above

can e.g. the following final compounds are prepared: 8-bromo-6-(o-chlorophenyl)-1-amino-4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepine,

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

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

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

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

8-bromo-6-(o-chlorophenyl)-1-(N-methyl-N-ethylamino)-4H-s-triazolo-[3,4c]thieno[2,3e]-1,4-diazepine,

8-bromo-6-(o-chlorophenyl)-1-n-propylamino-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine,

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

8-bromo-6-(o-chlorophenyl)-1-di-n-butylamino-4H-s-triazolo[3,4c]-thieno[2,3e]-1,4-diazepine,

8-bromo-6-(o-chlorophenyl)-1-N-methyl-N-(O-hydroxyethyl)-amino-4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepine ,

8-bromo-6-o-chlorophenyl)-1-di-(O-hydroxyethyl)-amino-4H-s-triazolo-[3,4c]thieno[2,3e]-1,4-diazepine,

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

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

8-bromo-6-phenyl-1-dimethylamino-4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepine,

8-bromo-6-(o-bromophenyl)-1-dimethylamino-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine,

8-bromo-6-(o-chlorophenyl)-1-piperidino-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine, 8-bromo-6-(o-chlorophenyl )-1-(2<1>,4<1->dimethylpiperidino)-4H-s-triazolo-[3,4c]thieno[2,3e]-1,4-diazepine,

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

8-bromo-6-(o-chlorophenyl)-1-(2<1->methylmorpholino)-4H-s-triazolo-[3,4c]thieno[2,3e]-1,4-diazepine,

8-bromo-6-(o-chlorophenyl)-1-(4<1->methylpiperidino)-4H-s-triazolo-[3,4c]thieno[2,3e]-1,4-diazepine,

8-Bromo-6-(o-chlorophenyl)-1-pyrrolidino-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine.

The starting compounds of the general formula II

is known from the literature. The starting compounds with the general formula IV are obtained by reacting compounds with the formula

where R 2 and R 1 have the meanings given above and Hal means a halogen atom, with an amine of the general formula III under the conditions indicated in a) and subsequent replacement of the ring oxygen atom with a nitrogen atom, which e.g. described in German patent application P 25 31 678.

The final products of the general formula I exhibit valuable therapeutic properties. Thus, in various pharmacological investigations, they were found to have calming, anxiety-reducing and tension-relieving properties. In dressage trials, it also turns out that the new compounds have a distinct neuroleptic effect. This effect was found on the basis of the signaled active avoidance relationship (discriminated active avoidance) following a modified study by Dobrin, P.B., Rhyne, Arch, Int. Pharmacodyn. 178, 351-356

(1969).

It then turned out in particular that the new connections

they only suppress timely avoidance actions, while, on the other hand, the reaction to immediate shocks is kept completely intact. Such a selective effect is considered for the commercially available neuroleptics, e.g. chlorpromazine, as a strong indication of neuroleptic action properties (Cook, L., Sepinwall, J., Proceedings of the sixth international congress of pharmacology, vol. 3 - Central Nervous system and behavioral pharmacology. Oxford: Pergamon 1976 b).

It is also noteworthy that this selection in the present case is particularly strong and is far better than for the commercial products.

The new compounds are thus particularly suitable for

eliminate psychomotor tension and anxiety states, such as e.g. appears' in schizophrenia, as this calming and relaxing effect does not cause any disturbance in the level of alertness.

Particularly active compounds of the general formula I

are found to be those where R 2 is chlorine, FU is bromine and R 2 and R 1 - are lower alkyl groups or a 3-hydroxyethyl 1 group.

The single dose of the new compounds is from 0.05 to 50, preferably 0.1 to 25 mg (oral) and 5 to 150 mg as a daily dose.

The new compounds produced according to the invention can be used alone or in combination with other compounds produced according to the invention, possibly also in combination with other pharmacologically active substances such as spasmolytics or 3-receptor blockers. Suitable forms of ice are e.g. tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Suitable tablets can e.g. is produced by mixing the active substance or active substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents which cause a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl -acetate. The tablets can also consist of several layers.

Similarly, dragees can be produced by coating cores produced analogously to the tablets with agents that are usually used in dragee coatings, e.g. collidon or shellac, gum arabic, talc, titanium dioxide or sugar.

To achieve a depository effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragé coating can also consist of several layers to achieve a depot effect, as the excipients mentioned above for tablets can be used.

Juices of the new compounds or combinations thereof may also contain a sweetener such as saccharin, cyclamate, glycerol or sugar, as well as a taste enhancing agent, e.g. flavoring substances such as vanillin or orange extract. They may also contain suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, especially condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions can be prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates, or stabilizers such as alkali salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.

Capsules containing an active ingredient or a combination of active ingredients can e.g. are produced by mixing the active substances with inert carriers such as milk sugar or sorbitol and encapsulating in gelatin capsules. Suitable suppositories can e.g. are produced by mixing with suitable carriers, such as neutral fats or polyethylene glycol or derivatives thereof.

Example 1

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

0.01 mol = 4.5 g of 1,8-dibromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepine is heated together with 50 ml dimethylamine in 150 ml dioxane for 1 hour at 100°C in an autoclave. The solvent is distilled off, the residue is distributed between water and methylene chloride, the methylene chloride phase is separated, washed with water and dried over magnesium sulfate. The residue" is placed on a SiO2_column and the product is eluted with methylene chloride/methanol 98:2: After distilling off the solvent, 2.2 g' = 52% of the theoretical amount of the title compound with m.p. 166-168°C is obtained from ethyl acetate.

Example 2

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

4.2 g = 0.01 mol 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno[2,3e]-5,6-dihydro-1, 4-diazepine is dissolved in 50 ml of methylene chloride, and after adding 0.2 g of triethyl-N-benzylammonium chloride at 0-5°C, a solution of 2 g of potassium permanganate in 20 ml of acetone. After 15 minutes, a sodium bisulphite solution is added and the reaction mixture is acidified with dilute sulfuric acid. The title compound is obtained from the organic phase. The yield amounts to 3.1 g = 73% of the theoretical with m.p. 165-167°C.

The 5,6-dihydro compound was prepared as follows:

a) 53 mmol = 20 g 7-bromo-5-(o-chlorophenyl)-thieno[2,3e]-4,1-oxazepine-2-thione (prepared analogously to the procedure

according to Belgian patent 844,170) is stirred in 600 ml of methylene chloride with 12 g of formyl hydrazide and 80 ml of pyridine for 45 minutes at room temperature. 10 g of POCl3 are then added dropwise in 50 ml of methylene chloride at a maximum of 35°C and stirred for 5 hours under reflux cooling. After cooling, the organic phase is shaken out with 200 ml of 2N hydrochloric acid and washed with water. After drying, the organic phase is evaporated and the residue taken up in hot ethyl acetate. Upon cooling, 15 g = 73% of the theoretical 8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno[2,3e]-4,1-oxazepine with m.p. . 176-178°C.

b) 28 g of this compound in 280 ml of methylene chloride and 8.9 ml of pyridine are added to 5.4 ml of bromine. You cook for 3 hours under

reflux cooling, decant with water after cooling, dry the organic phase with magnesium sulfate, evaporate and add the residue to a SiO2 column. From methanol you get 19.2 g =

57% of the theoretical 1,8-dibromo-6-(o-chlorophenyl)-4H-s-triazolo-[3,4c]thieno[2,3e]-4,1-oxazepine with m.p. 138°C.

c) 9.2 g = 0.02 mol of the dibromo compound is heated together with 300 ml of dioxane and 100 ml of dimethylamine for 1 hour at 100°C

in an autoclave. After distilling off the solvent, the residue is taken up in methylene chloride, washed with water, the organic phase is dried over magnesium sulfate and the residue 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c] is obtained thieno[2,3e]-4,1- . oxazepine as an oil (7.0 g = 82% of theoretical).

d) 8.5 g = 0.02 mol of the oxazepine obtained according to c) is stirred with 50 ml of concentrated hydrobromic acid for 1 hour at

room temperature. Dilute with 200 ml of water, make the solution alkaline with ammonia and decant with 100 ml of methylene chloride. The methylene chloride solution is stirred for 1 hour with 4 ml of thionyl chloride. The excess of thionyl chloride is carefully split with water and dilute ammonia, the organic phase is separated and after evaporation and addition of ether, 4.8 g = 92% of the theoretical 3-dimethylamino-4-[3-(o-chlorophenyl-bromomethyl)-5 are obtained -bromothienyl-(2)]-5-chloromethyl-1,2,4-triazole with m.p. 203°C.

e) 5.3 g = 0.01 mol of the triazole compound are heated together with 100 ml of ammonia-saturated methanol in an autoclave for 30 minutes to

60°C. One evaporates and works up in a suitable way. The yield is 2.8 g = 66% of the theoretical 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno[2,3e]-5,6-dihydro -1,4-diazepine with m.p. 155-157°C.

Example 3

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

0.013 mol = 5 g of 2-hydrazino-5-(o-chlorophenyl)-7-bromo-thieno[2,3e]-1,4-diazepine is heated together with 100 ml of ethanol,

1.4 g of cyanogen bromide and 1.4 g of sodium carbonate for 30 minutes at 60°C. Evaporate, take up the residue in methylene chloride and chromatograph

>

over SiC^. The yield is 1.5 g = 29% of the theoretical with m.p. 251-252°C (from ethanol).

Example 4 i

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

395 mg 1-amino-8-bro.i-6-(o-chlorophenyl)-4H-s-triazolo~

[3,4c]thieno[2,3e]-1,4-diazepine is boiled under reflux for 15 hours together with 5 ml of 85% formic acid and 2 ml of 30% formalin solution. After cooling, the reaction product is decanted with methylene chloride. The organic phase is evaporated,

and the residue is chromatographed over a silica gel column. From the eluates, 250 mg of the title compound with m.p. 164-166°C (= 60% of the theoretical).

Analogous to examples 1-4, the following end products are produced:

Claims (4)

1. Analogous process for the preparation of therapeutically active, substituted 4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepines of the general formula where R2 means hydrogen, fluorine, chlorine or bromine, R., means chlorine or bromine or an alkyl radical of 1 to 3 carbons atoms, and R^ and R,., which may be the same or different, mean hydrogen, an alkyl radical of 1 to 4 carbon atoms or a hydroxyalkyl radical of 2 to 3 carbon atoms, or the two radicals together form a 4- or 5-membered alkylene chain which may optionally be substituted with one or two methyl groups, and where the 6-ring may optionally contain an oxygen atom as an additional heteroatom, characterized by ata) compounds of the general formula where R^ and R., have the above meaning, and Hal means a halogen atom, are reacted with amines of the general formula where R^ and R^- have the meanings given above, orb) compounds with the general formula where R^ , R^ , R^ and Rj. has the meanings given above, is dehydrogenated. 2. Process as stated in claim 1 for the production of 1-dimethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine , characterized in that starting materials are used where means chlorine, R^ means bromine, R^ means methyl and R^ means methyl. 3. Process as stated in claim 1 for the production of 1-diethylamino-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3,4c]thieno-[2,3e]-1,4-diazepine , characterized in that starting materials are used where R^ means chlorine, R^ means bromine, R^ means ethyl and R,, means ethyl. 4. Process as stated in claim 1 for the production of 1-[N-methyl-N-((3-hydroxyethyl)-amino]-8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[3 ,4c]thieno[2,3e]-1,4-diazepine, characterized in that starting materials are used where R2 means chlorine, R^ means bromine, R^ means methyl and R^ means 3-hydroxyethyl.