DD144777A5 - METHOD FOR THE PRODUCTION OF NEW SUBSTITUTED 4H-S-TRIAZOLO SQUARE BRACKET TO 3.4C SQUARE BRACKET TO THIENO SQUARE BRACKET TO 2.3E SQUARE BRACKET TO-1.4-DIAZEPINE - Google Patents

Abstract

The invention relates to the preparation of novel substituted 4H-s-triazolo [3,4c] thienol 2,3e] 1,4-diazepines of general formula I in which El ·? R3 is chlorine or bromine or an alkyl radical having 1 to 3 carbon atoms and R4 and R5, which may be identical or different, denote hydrogen, an alkyl radical having 1 to 4 carbon atoms or a hydroxyalkyl radical having 2 to 3 carbon atoms or both radicals together form a 4- or 5-membered alkylene chain which may optionally be substituted once to twice by methyl and. Wherein the 6-ring may optionally contain an oxygen atom as another heteroatom. The new compounds have excellent pharmaceutical properties; In addition to anxiolytic, tranquilizing and hypnotic, they also have a neuroleptic effect

Description

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Process for the preparation of novel substituted 4H-sl'riazolo [314c] thieno £ 2, 3e [] 1,4-diazepines

Field of application of the invention

The invention relates to processes for the preparation of compounds of the general formula

(DR ₃

in the . , , '·.

R "is hydrogen, fluorine, chlorine or bromine,

R is chlorine or bromine or an alkyl radical having 1-3 carbon atoms and. ..

R. and Rj-, which may be the same or different, are hydrogen, an alkyl radical having 1-4 carbon atoms or a hydroxyalkyl radical having 2-3 carbon atoms or both radicals together form a 4- or 5-membered alkylene chain, optionally one to may be substituted twice by methyl and wherein the

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(55 667/18) ..,.

6- ^ ing may optionally contain an oxygen atom as another heteroatom.

Object of the invention

The aim of the invention was to find new compounds with good pharmacodynamic properties.

Explanation of the essence of the invention

It was an object of the invention to provide a process for the preparation of novel compounds with good anxiolytic, tranquilizing, hypnotic and also neuroleptic effects. "

The novel compounds of general formula 1 can be obtained

a) by reacting a compound of the general formula

(ID

in the

R ₂ and Ε-, which have the abovementioned meaning, with an amine of the general formula

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^l 4 ^l 5

(in)

in which R and Rp have the abovementioned meaning, or

b) by dehydration of a compound of the general formula

(IV)

in the

R ₂ , R, R and Re have the abovementioned meaning, in a manner known per se.

The reaction of compounds of general formula II with an amine of formula III is carried out either without solvent or in solvents such as benzene, toluene, dioxane. Tetrahydrofuranj chlorinated hydrocarbons such as carbon tetrachloride or methylene chloride, preferably

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at the boiling point of each solvent used. In the reaction with lower amines (dimethylamine, diethylamine, etc.), the reaction is preferably carried out in an autoclave.

The reaction time depends on the starting material used and can be between a few minutes and several hours.

The dehydrogenation of compounds of general formula IV is carried out using suitable dehydrating agents, e.g. As halogens or compounds of higher oxidation states of chromium or manganese, for example, a chromate, a bichromate or a permanganate. Chlorinated hydrocarbons such as chloroform or methylene chloride may be mentioned as suitable solvents for the reaction with a halogen. The oxidation with the mentioned compounds of chromium or manganese is carried out in solvents such as acetone, tetrahydrofuran or dioxane, if desired with the addition of phase transfer catalysts. Rt depending ^A of the oxidant, the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

The 1-amino compounds (R, and R ₁ - = hydrogen) are obtained by reaction of a 2-hydrazino-thieno [2,3e11,4-diazepine with cyanogen bromide according to the following scheme;

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See: K.T. Potts and G, Hirsch, J. Org. Chem, 13, 143 (1968).

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

If desired, these compounds can be alkylated in the usual way. The alkylating agents used are preferably alkyl halides, dialkyl sulfates or esters of toluenesulfonic acid; In this case, solvents such as tetrahydrofuran, dimethylformamide or lower alcohols are used, but the alkylation can also be carried out without addition of a solvent. In the case of the introduction of a hydroxyalkyl radical, the reaction with an alkylene oxide is recommended,

After the above? For example, methods may include the following final specifications; to be obtained:

ö -bromo-6- (o-chlorophenyl) -1-amino-4H-s-triazolo [ _i 3,4c] thieno [2,3ej1,4-diazepine,

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8-bromo-6 ~ (o-chlorophenyl) -1-methylamino ^ H-s-triazoyl Γ3, 4cJ thieno J2, 3ej 1,4-diazepine,

-o (o-chlorophenyl) -1-ethylamino-4H-s-triazolo f3, 4c] thieno [2,3e | 1,4 ~ diazepin,

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

8 ~ 3 _ro m -6 (o-chlorophenyl) -1-diethylamino ^ Hs-triazolo [3, 4c] thieno (2,3e] 1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1 - (isiamethyl-N-ethylamino) -4 H -striazolo [3,4,4] thieno [2,3-l, 1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1-n-propylamino-4H-s-triazolo [3 , thieno J2,3e] 1,4-cLiazepine,

8-bromo-6- (o-chlorophenyl) -1-diisopropylamino-4H-s-triazolo _f 4c] thieno {^ 2,3e11,4-diazepine,

8-> rom-6- (o -chlorophenyl) -1-di-n-butylamino-4H-3-triazolo [314c] thieno [2-, 1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1-D-methyl-N- (β-hydroxyethyl) -aiino-4H-s-triazolo [3, thieno] 2,3eJ 1,4-diazepine,

B-bromo-ö- (o-chlorophenyl) -1-di- (β-hydroxyethyl) amino-4H-striazoloJ3,4c3 thieno [2,3ej 1,4-diazepine, .. _if

8-ethyl-6- (o -chlorophenyl) -1-dimethylamino-4H-s-triazolyl f3,4c] thienoJ2,3ej1,4-diazepine, "

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8-> h-chloro-6- (o-chlorophenyl) -1-dimethylamino-4H-s-triazolor3,4c3 thieno [2, 3 e] i, 4-diazepine,

8-bromo-6-phenyl-1-dimethylamino ~ 4H-s-triazoloQ3,4c] thieno [2,3eJ 1,4-diazepiii,

-O- (o-bromophenyl) -1-dimethylamino-4H-s-t-riazone [3, 4c] thieno [2,3e] 1,4-diazepine,

8-bromo-6- (o-chlorodrphenyl) -1-piperid ± no-4H-s-triazolo [3,4-thieno [2,3e] 1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1- (2 ', 4'-dimethylpiperidino) -4H-striazolor3,4cl thieno / 2,3,3-diene, 4-diazepine,

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

8-Bromo-6- (o -chlorophenyl) -1- ( ^2f -methylmorpholino) -4H-s-triazolo [3,4c | thieno Γ2,3βΊ 1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1- (4'-methylpiperidino) -4H-striazolof3,4c-thienof2,3el1,4-diazepine,

8-bromo-6- (o -chlorophenyl) -1-pyrrolidino-4H-s-triazolo [3,4-ci thienoJ2,3e] 1,4-diazepine

The starting compounds of the general formula II are known from the literature. Starting compounds of general formula IV are obtained by reaction of compounds of the formula. ί'- ^τ . · '·' ^::: .''.- · ''

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(V)

in the

IU and Ro have the abovementioned meaning and Hai represents a halogen atom, with an amine of the general formula III under the conditions specified under a) and subsequent replacement of the ring oxygen atom by a nitrogen atom, as described, for. B. in German Patent Application P 25 31 678 has been described.

The end products of general formula I have valuable therapeutic properties. Thus, when performing various pharmacological test methods, damping, anxiolytic and stress-relieving properties were found. In dressage experiments it was also shown that the new compounds have a pronounced neuroleptic effect. This effect was measured by the signaled active avoidance behavior according to a modified test of Dobrin, P.B., Rhyne, Arch. Int. Pharmacodyn. V78, 351-356 (1969)> found.

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It showed in particular that the new substances suppress only the timely avoidance treatment, the reaction to the immediate shock, however, completely intact. Such a selective effect is found in the commercial uteroleptics, such as, e.g. Chlorpromazine, regarded as a strong indication of neuroleptic action properties. (Cook, 1, Sepinwall, J., Proceedings of the Sixth International Congress of Pharmacology., Vol. 3- Central Nervous Syndrome of Behavioral Pharmacology, Oxford: Pergamon 1976 b).

It is also noteworthy that in the present case this selection is particularly pronounced and significantly exceeds that of the commercial products.

The new compounds are therefore particularly suitable for repairing motor and anxiety states, such as occur in schizophrenia, but this sedation and relaxation effect does not disturb the wakefulness (vigilance) causes.

Particularly effective are those end products of general formula I have proven in which Rp is chlorine, R ^ bromine and R. and R ^ lower alkyl groups or a ß-hydroxyethyl.

., The single dose of the substances according to the invention is 0.05 to 50, preferably 0.1 to 25 mg (orally) and 5 to 150 mg as a daily dose.

The compounds obtainable according to the invention can be used alone or in combination with other active compounds according to the invention.

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optionally, in combination with other pharmacologically active agents v / ie Spasmolytika or ß-receptor blocker used. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be prepared, for example, by mixing the active ingredient (s) with known excipients, for example 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 Achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers »

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cycamate, glycerol or sugar, and a

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taste-improving.the means, ζ. Β. Flavorings such as vanillin or orange extract. They may also contain suspending agents or thickening agents such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide or protective agents such as p-hydroxybenzonates.

Injection solutions are prepared in a customary manner, for example with the addition of preservatives, such as p-hydroxybenzonates or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.

The one or more active substances or capsules containing active ingredient combinations can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and. encapsulated in gelatine capsules ·

Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral or polyethylene glycol or derivatives thereof. *

Ausführun, ^ y SExample Example ^1:

1-dimethyl- amino-B - bromo ^ - (o-chlorophenyl) -4-Hs-triazolo [3,40! thien o (2 »3e] 1, 4-dia zepi n

0.01 mol = 4.5 g of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3 _f 4cl thieno [2 _t 3 © Ί 1,4-diazepine are mixed with 50 ml of dimethylamine

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in 150 ml of dioxane for 1 hour at 100 ⁰ C in an autoclave. The solvent is distilled off, the residue is partitioned between water and methylene chloride, the methylene chloride phase is separated off, washed with water and dried over magnesium sulfate. The residue is added to a SiO _? Column and elutes the substance with methylene chloride / methanol 98: 2. After distilling off the solvent is obtained from ethyl acetate 2.2 g = 52 % d. Th. The title compound of the PP.

166 - 168 ⁰ C.

Example 2

1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolof3 _; 4o4 thieno f2 «3e) 1» 4-diazepine

4.2 g = 0.01 mol of 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazoloQ3,4cT} thienoj_2,3e] 5,6-dihydro-1,4-diazepine are incorporated in Dissolved 50 ml of methylene chloride and treated after addition of 0.2 g of triethyl-IT-benzylammonium chloride at 0 - 5 ⁰ C with a solution of 2 g of potassium permanganate in 20 ml of acetone. After 15 minutes, a solution of bis-bisulphite is added, and the reaction mixture is acidified with dilute sulfuric acid. From the organic phase gives the title compound »The yield is 3.1 g = 73 % d. Th. From Pp. 165 -

167 ^0G .

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

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

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Belgian patent Ur. 844 170) are stirred in 600 ml of methylene chloride with 12 g of formylhydrazide and 80 ml of pyridine at room temperature for 45 minutes. Then added dropwise 10 g of POCl ₃ in 50 ml of methylene chloride at a maximum of 35 ⁰ C and stirred for 5 hours under reflux. After cooling, the organic phase is extracted by shaking with 200 ml of 2N hydrochloric acid and washed with water. After drying, the organic phase is evaporated and the residue is taken up in hot ethyl acetate. On cooling, 15 g = 73% d. Th. 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4cJthieno [2,3eJ4,1-oxazepine, mp. 176 178 ⁰ C.

b) 28 g of this compound are mixed in 280 ml of methylene chloride and 8.9 ml of pyridine with 5.4 ml of bromine. The mixture is refluxed for 3 hours, shaken out after cooling with water, the organic phase is dried with magnesium sulfate, evaporated and 'gives the residue over SiO ₂ . From methanol, 19.2 g = 57% d. Th. 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolor3,4c] thieno [2,3-e] 4,1 ~ · oxazepine from Pp. 138 ⁰ C.

c) 9.2 g = 0.02 mol of the dibromo compound are heated with 300 ml of dioxane and 100 ml of dimethylamine for 1 hour at 100 ⁰ 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 obtained is 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3 , 4c] thieno [2,3e]] 4,1-oxazepine as an oil (7.0 g = 82 % of theory)

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α) 8.5 g = 0.02 mol of oxazepine obtained according to c) are stirred with 50 ml of concentrated hydrobromic acid for 1 hour at room temperature. It is diluted with 200 ml of water, made alkaline with ammonia and extracted with 100 ml of methylene chloride. The methylene chloride solution is stirred with 4 ml of thionyl chloride for 1 hour. The excess of thionyl chloride is carefully decomposed with water and dilute ammonia, the organic phase is separated off and, after evaporation and addition of ether, 4.8 g = 92% of theory. Th 3-dimethylamino-4 -. [^ - (o-chlorophenyl-bromomethyl) -5-bromo-thienyl- (2) J-5-chloromethyl-1, 2,4 -triazol * Pp from 203 ⁰ G..

e) 5.3 g = 0.01 mol of the triazole are heated for 30 minutes at 60 ⁰ C with 100 ml of ammonia-saturated methanol in an autoclave. It is evaporated and worked up accordingly. The yield is 2.8 g = 66 % d. Th. 1-Dimethylamino-8-bromo-6- (o -chlorophenyl) -4H-s-triazolo {β, 4c] thieno [2,3e] 5,6-dihydro-1,4-diazepine from pp. 155 - 157 ⁰ C.

Example 3

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

0.013 mol = 5 g of 2-hydrazino-5- (o-chlorophenyl) -7-bromo-thieno JJ2,3eji, 4-diazepine are brought to 60 with 100 ml of ethanol, 1.4 g of cyanogen bromide and 1.4 g of sodium carbonate for 30 minutes ⁰ G heated. It is evaporated, the residue is taken up in methylene chloride and chromatographed on SiO.sub.2. The yield is 1.5 g = 29% d. Th. From Pp. 251 - 252 ⁰ G (from ethanol). '

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Example 4

1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-3-triazolo

3el 1,4-diazepine

395 mg of 1-amino-8-bromo-6- (o-chlorophenyl) -4H-s-triazoloJ3,4c [] thienoj2,3ej 1,4-diazepine are together with 5 mml of 85% formic acid and 2 mml of 30% Pormaliril solution refluxed for 15 hours. After cooling, the reaction product is extracted by shaking with methylene chloride. The organic phase is evaporated and the residue chromatographed on a silica gel. (Th = 60% d..) 166 ⁰ G - is obtained from the eluates 250 mg of the title compound Pp 164th.

The following end products were obtained analogously to Examples 1-4:

Example Mr. -HKT-CH ₃ 5 -HN-C ₂ H ₅ 6 -N (C ₂ H ₅ ) 7 -O 6 -N 0 9

Cl br 166-168 Cl br 224-226 Cl br 143-145 Cl br 224-226 Cl br 205-207

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R Example ^ 4

Cl Br 175 - 176

CH ₂ -CH ₂ -OH

11 -Ν'λ-CH ₀ Cl Br 180

12 ~ ^N yy dragees Cl br 209-210 13 -N (CH ₃ ), Cl C ₂ H ₅ 130 - 132 14 TiT ι / " ¹ TT ^ -.u \ ViXl-, ) f. Cl Cl 154 - 155 15 -N (CH ₃ ) ₂ H br 216 - 217 16 -N (CH ₃ ) 2 br br 171 17 -NH- (CH ₂ ) ₂ -CH ₃ Cl br 148 - .150 formulation Examples a)

1 drag core contains:

Active ingredient according to the invention Milk sugar Corn starch Gelatin

magnesium stearate

50.0 mg

1.0 mg 28.5 mg. 19.0 mg 1.0 mg 0.5 mg

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manufacture;

The mixture of the active substance with lactose and corn starch is granulated with a 1Obigen aqueous gelatin solution through a sieve with 1 mm mesh size, dried at 40 ⁰ C and again driven through a sieve. The granules thus obtained are mixed with magnesium stearate and pressed. The cores thus obtained are coated in the usual way with a shell which is applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragees are polished with beeswax

 Dragee final weight: 100 mg.

b) tablets

Active ingredient according to the invention Milk sugar Corn starch Soluble starch. magnesium stearate

Production: *.

Active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and intimately mixed with milk sugar von'Maisstärke, The mixture is then compressed into tablets of 100 mg weight, each containing 0.5 mg 'active ingredient.

0.5 mg 50.0 mg 43.5 mg 5.0 mg 1.0. mg 100.0 mg

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c) Suppositories

1 suppository contains:

Active ingredient according to the invention 5.0 mg

Suppository mass 1 »695,0 mg

production:

The finely powdered substance is stirred with the aid of an immersion homogenizer in the molten and cooled to 40 ⁰ O suppository mass. The mass is poured at 35 ⁰ C in slightly pre-cooled molds.

d) ampoules (injection solutions)

Composition:

Active ingredient according to the invention 0.5 parts by weight

JTatriumpyrosulfit .1,0 ^G ew. parts

Disodium salt of ethylenediamine 0.5 parts by weight of tetraacetic acid

Sodium chloride 8.5 parts by weight

double distilled water ad 1000.0 parts by weight

Production:.

The active ingredient and the excipients are dissolved in a sufficient amount of water and brought to the desired concentration with the necessary amount of water. The solution is filtered and bottled under aseptic conditions in 1 ml ampoules. Finally, the ampoules are sterilized and sealed. Each ampule contains 0.5 mg of active ingredient.

Claims (2)

invention claim A process for the preparation of novel substituted 4H-s-triazolo £ 3,4c / thieno £ 2,3ej 1,4-diazepines of the general formula (D in the Rp is hydrogen, fluorine, chlorine or bromine, R-3 is chlorine or bromine or an alkyl radical having 1-3 carbon atoms and R. and R ₁ -, which may be identical or different, are hydrogen, an alkyl group having 1-4 carbon atoms or hydroxyalkyl of 2 - 3 are carbon atoms, or form two radicals together form a 4- or 5-membered alkylene chain which is optionally mono- may be substituted up ζγ / eifach by methyl and wherein the 6-membered ring optionally containing as a further heteroatom an oxygen atom can _t characterized in that a) Connections of the general formula 21 4,271 25/10/1979 AP C 07 D / 214 (55 667/18) Hal (ID in which Rp and R-3 have the abovementioned meaning and Hai represents a halogen atom with amines of the general formula (III) in the R. and Rc have the abovementioned meaning, or implements or b) compounds of the general formula 25/10/1979 AP C 07 D / 214 271 (55 667/18) (IV) in which Rp, Ro, R, and R, have the abovementioned meaning, dehydrogenates in a manner known per se.