IE43694B1

IE43694B1 - Thieno-4,1-oxazepinones

Info

Publication number: IE43694B1
Application number: IE1583/76A
Authority: IE
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1975-07-16
Filing date: 1976-07-16
Publication date: 1981-05-06
Also published as: NL186008B; IE43694L; IL50032A; NL186008C; AU506140B2; PT65374A; NL7607871A; PT65374B; YU175376A; CH627181A5; GR60819B; DD126744A5; FR2318165B1; HU172620B; YU40458B; CH630630A5; MX4246E; FR2318165A1; AU1591376A; CA1077475A

Abstract

The invention relates to a process for the preparation of substituted 6-ary-4H-s-triazolo-3,4-c!-thieno-2,3-e!-1,4-diazepines having anxiolytic, tensiolytic, muscle relaxant, antiaggressive and anticonvulsive activity and to intermediates useful in the preparation of such compounds. Examples of the new process are also given.

Description

This invention, relates to a process for the preparation of substituted 6-aryl-4H-s-tria2olo-[3,4-c]-thieiio-[2,3-e]1,4-diazepines and to intermediates useful in the preparation of such compounds.

According to one feature of the present invention there are provided compounds of general formula II, v/herein either R^ and which may be the same or different, each represents a hydrogen or halogen atom or an alkyl group containing 1 or 2 carbon atoms or, together with the two carbon atoms to which they are attached, they represent a 5or 6-membered ring; and R^ and R^, v/hich may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom; and acid addition salts thereof.

The compounds of general formula II may be prepared, for example, by cyclising a compound of formula Ia, S R.

H N - CO - CH2 - X (Ia) (wherein R^, R2, R^ and Rg are as hereinbefore defined and X represents a halogen atom or a hydroxy group).

When, in the compound of formula la, X represents a 5 halogen atom, the cyclisation is conveniently effected with an alkali metal alcoholate or sodium hydride, preferably with sodium isopropylate or sodium tert.butylate. Preferred solvents for the cyclisation include, for example, alcohols, tetrahydrofuran, dioxan, dimethylformamide or inert solvents such as benzene and its homologues. Preferred reaction temperatures are from 0°C to the boiling point of the reaction mixture depending upon the particular starting materials employed.

When, in the compound of formula Ia, X represents a hydroxy group then the cyclisation may be effected in the presence cf conventional dehydrating agents such as, for example, thionyl chloride, sulfuric acid, polyphosphoric acid or dicyclohexylcarbodiimide.

Compounds of general formula la wherein X represents a hydroxy group may, if desired, be obtained by reaction of a (wherein Rp R2, R^ and R$ are as hereinbefore defined and W represents an acyloxy group) with a strong alkali.

Compounds of general formula la wherein R^ is other than a hydrogen atom and X represents a halogen atom may, for example, be obtained by reaction of a compound of formula la, as hereinbefore defined other than a hydrogen atom) with a concentrated hydrohalic acid solution in the presence of nitric acid. Such a reaction is not desirably effected with - 4 4 3 6 3 a compound of formula Ia wherein R. represents a hydrogen atom due to the simultaneous addition under the reaction conditions employed, of a nitro group in this position.

The compounds of general formula la wherein X repre5 sents a halogen atom and the compounds of general formula la’ and la may all be obtained, If desired, by reduction of a (wherein R, . R.,. R, and R_ are as hereinbefore defined and Z represents a halogen atom or an amino or acyloxy group).

The reduction may, for example, be effected by means of sodium borohydride in dimethylformamide or dimethylacetamide at low temperatures, preferably of from 0° to 10oC. It will be appreciated that in certain solvents, such as those des15 cribed above, this reduction of the carbonyl group to a carbinol group proceeds with little simultaneous reductive cleavage of the group X or hydrolytic cleavage of the radical - CO - CiL - X. However, in some solvents, for example lower z alcohols, the cleavage reactions will exceed the carbinol formation reaction, hence leading to lower yields of the desired carbinol.

We have surprisingly found that 2-am.inobenzoyl-thiophenes are not themselves easily reduced as are the corres5 ponding 2-aminobenz©phenones (see e.g. German Offenlegungsschrift 15 45 639) thus necessitating a detour via a functional derivative thereof before reduction of the keto group to a carbinol can take place.

The carbinols of general formula Ia are, unlike the ι corresponding keto compounds of general formula I which are sensitive to hydrolysis, extremely stable under alkaline conditions which accounts for the high yields obtained when the above reduction is effected with compounds such as sodium borohydride.

When Rj and/or P2 represent substituents other than a hydrogen atom then these substituents may be introduced at various stages during the processes described above. Thus when R^ and/or represent lower alkyl groups or together with the two carbon atoms to which they are attached represent a 5- or 6-membered ring then they are advantageously already present before formation of the thiophene ring. However, when R^ and/or R2 represent halogen atoms then they may be introduced either into a compound of formula I or into the 3 6 3 <5 compound of formula II itself by halogenation of the corresponding compound therein the said groups R^ and/or R? represent hydrogen atoms. In either case the halogenation may, for example, be effected by means of the appropriate halogen, sulfuryl halide or halosuccinimide, preferably in the presence of carbon tetrachloride, chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide or a hydrocarbon as solvent. The halogenation is also preferably effected in the presence of a tertiary organic base e.g. pyridine. Preferred temperatures for the halogenation are from ambient temperature to the boiling point of the reaction mixture depending on the reagents used. As will be appreciated, either one or two halogen, atoms may be introduced depending on the reaction conditions and the quantities of the reagents employed. Appropriate methods for either mono- or di-halogenation are well known in the art. Thus, in order to introduce a single halogen atom, the reactants are preferably employed in equimolar quantities.

The compounds of general formula I are known from the literature and may be obtained according to the method described in Monatsheften der Chemie Vol. 104, p. 704 (1973).

The compounds of general formula II are useful intermediates in the production of therapeutically active substituted thieno-[2,3-e]-triazolo-[3,4-c]-l,4-diazepines as described in detail hereinafter. The following is a summary of a reaction sequence whereby such compounds may be obtained from compounds of formula II.

VII The compounds of general formula JI may, for example, he reacted with phosphorus pentasulfide to give a compound of formula Ilia (wherein Rp Rp R^ and R^ are as hereinbefore defined), this compound being a tautomeric equilibrium with the corresponding thione compound of formula Ilia '.

(Hla) (ma ’) The reaction is preferably effected in the presence of a solvent such as dimethylformamide, diglyme or tetrahydrofuran and preferably in the presence of an alkali metal bicarbonate, pyridine or mixtures thereof. Preferred reaction temperatures are from ambient temperature up to the boiling point of “ 10 4363 the reaction mixture.

The compounds of general formula Ilia may themselves be converted, if desired, into compounds of general formula (Illd) (wherein Rp R2, R^ and are as hereinbefore defined and X3 represents a lower thioalkyl group) by forming a salt of the compound of formula Ilia by reaction with sodium methylate or sodamide in the presence of a solvent and subsequent reaction of the salt thus formed with an appropriate alkylating agent e.g. an alkyl halide, preferably the iodide.

The compounds of general formula II may if desired, alternatively be reacted with an appropriate trialkyloxoniumfluoroborate to give a compound of formula Illb (Illb) (v/herein R^, Ry, R^ and R^ are as hereinbefore defined and X^ represents a lower alkoxy group). The trialkyloxoniumfluoroborate, obtained, for example, according to the process described by H„ Meerwein et al in J. pr. Chem. (2), 147. 257 (1937) and 154. 83 (1939) from a borotrifluoride etherate and epichlorohydrin, is desirably prepared in situ.

Preferably the reaction is effected in the presence of an ether or halogenated hydrocarbon, e.g. carbon tetrachloride, as solvent and preferably at temperatures of from 0°C to the boiling point of the reaction mixture.

Alternatively compounds of general formula II may, if desired, be reacted with an appropriate acidic inorganic halide, preferably a phosphorus pentahalide, to give a compound of formula IIIc (wherein R^, Ry, R^ and R^ are as hereinbefore defined and Xy represents a halogen atom). Such a reaction is preferably effected in the presence of an anhydrous organic solvent such 'ΐ. ο 51 j as, for example, dioxan or tetrahydrofuran and preferably at temperatures of from -50 to 50°C.

The compounds of general formulae Illa-d may collect- (wherein Rp R9, R^ and R. are as hereinbefore defined and X represents a halogen atom or a lower alkoxy, thio or lower alkylthio group).

The compounds of general formula III may, for example, be reacted, with a compound of formula IV, R * - CO - NH - NH, (IV) (wherein R^' represents a hydrogen atom, a straight or branched chain alkyl or ω -hydroxyalkyl group containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms or a 5- or 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl, group) to form a compound of formula V, (wherein Rp R2, R^ and Rg are as hereinbefore defined and Rg represents a hydrogen atom, a straight and branched chain alkyl or o-hydroxyaikyl'group containing from 1 to 3 carbon atoms, a cyeloalkyl group containing from 3 to 6 carbon atoms or a 5- or 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group)· The reaction is preferably effected at temperatures of from 100 to 250°C and may be carried out either in the presence or in the absence of a solvent, suitable solvents including, for example, methanol, ethanol, dioxan, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures thereof. The reaction may also, if desired, be carried out in the presence of an acid catalyst e.g. hydrochloric, sulfuric, phosphoric, polyphosphoric, acetic, propionic, benzenesulfonic or toluenesulfonic acid. - 14 The intermediate product formed during the reaction, having the formula: is not isolated.

When the above compounds of general formula V are prepared from a compound of formula III in which X represents a halogen atom, then the compound of formula III is preferably prepared in situ.

The above compounds of general formula V wherein 10 represents a hydrogen atom, a straight or branched chain alkyl or ω-hydroxyalkyl group containing from 1 to 3 carbon atoms, a eycloalkyl group containing from 3 to 6 carbon atoms or a 5- or 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group may, if desired, be converted by chlorination or bromination into further compounds of general formula V wherein R., represents a chlorine or bromine atom. The chlorination or bromination is preferably effected in the presence of a solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide or a hydrocarbon and preferably at temperatures of from ambient temperature to the boiling point of the reaction mixture. Chlorination or bromination may, for example, be carried out by means of chlorine or bromine or by means of N-chloro- or N-bromo-succinimide and is desirably effected in the presence of a tertiary organic base.

The compounds of general formula V (wherein Rg represents a chlorine br bromine atom or represents a hydrogen atom, straight or branched chain alkyl or to-hydroxyalkyl group containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms or a 5- or 6membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group are themselves novel compounds and constitute a further feature of the present invention.

According to a still further feature of the present invention there are provided compounds of general formula VI, (wherein R^, R^, , R^ and R^ are as hereinbefore defined).

The compounds of general formula VI are novel compounds also useful as intermediates in the preparation 5 of substituted 6-aryl-4H-s-triazolo-[3,4-c]-thieno-[2,3-e]1. ,4-diazepines. They may, for example, be prepared by reaction of a compound of formula VI', 4 a o a it (wherein Rp Rg, Rg, R^ and Rg are as hereinbefore defined and Hal^ and Haig, which may be the same or different, each represents a halogen atom) with ammonia or an ammonia precursor such as, for example, urotropine.

The reaction is preferably effected in the presence of a solvent such as liquid ammonia, a lower alcohol, e.g. methanol or ethanol, ethyl acetate, dioxan, tetrahydrofuran or an inert hydrocarbon e.g. benzene or a homologue thereof. Preferred reaction temperatures are from 0°C to the boiling point of the reaction mixture. It is particularly preferred that the reaction is effected in an autoclave.

The compound of formula VI’ may itself be obtained, if desired, by reaction of a compound of formula V’, (wherein R. , R„, R„, R. and R.. are as hereinbefore defined 1’ 2’ 3’ 4 o and Y represents a halogen atom or a hydroxy group) with a phosphorus or sulfur halide e.g. a thionyl halide or phos5 phorus trihalide. The reaction is preferably effected at temperatures of from 0 to 40 C, most preferably about 20nC.

As will be appreciated, if, in the compound of formula V1 Y represents a hydroxy group, then, on reaction with the phosphorus or sulfur halide, a compound of formula VI* wherein Hal^ and Hal? are identical will be obtained.

The compound of formula V’ may, for example, be obtained from a compound of formula V as hereinbefore defined. Thus, when it is desired to obtain a compound of formula V* wherein Y represents a halogen atom, the compound of formula V is 15 treated with concentrated hydrohalic acid, preferably by allowing the two reagents to stand together for from several minutes up to several hours at ambient temperature. When it - 19 3 δ © 4 is desired to obtain a compound of formula V' where Y represents a hydroxy group then preferably the compound of formula V is heated in a concentrated acid solution. In either case the compound of formula V’ is preferably isolated from the reaction mixture by extraction with a solvent immiscible with water, preferably a chlorinated hydrocarbon e.g. chloroform or methylene chloride.

The compounds of general formula VI may, if desired, be directly converted into compounds of general formula VII, (wherein R^, Ry, R^, R^ and R^ are as hereinbefore defined) by dehydrogenation. Suitable dehydrogenating agents include, for example, the halogens or reagents containing chromium or manganese in a high oxidation state.

When the dehydrogenation is effected by means of a halogen then the dehydrogenation is preferably effected in the presence of a chlorinated hydrocarbon e.g. chloroform or methylene chloride, as solvent. Advantageously the dehydrogeneration will be carried out in the presence of a tertiary organic base e.g. pyridine, the said base serving as a binding agent for the hydrogen halide formed during the dehydrogenation. If, in the compound of formula VI Rg represents a hydrogen atom, then it will be appreciated that the use of excess halogen in the dehydrogenation may lead to some replacement of the said hydrogen atom by the halogen. If it is desired to obtain a compound of formula VII wherein Rg represents a chlorine or bromine atom from a compound of formula VI wherein Rg represents a hydrogen atom then the dehydrogenation should be effected with an excess of chlorine or bromine.

The dehydrogenation of the compound of formula VI may also be effected, if desired, using a reagent containing chromium or manganese in a high oxidation state e.g. Mn with a valence of 7 or Cr with a valence of 6. Suitable reagents include, for example, chromates, dichromates and permanganates.

In this case the dehydrogenation is preferably effected in solvents such as acetone, tetrahydrofuran or dioxan, and preferably at temperatures of from 0nC to the boiling point of the reaction mixture. 3 ® 0 d The compounds of general formula VII may, if desired, be -converted into their physiologically compatible acid addition salts by reaction with an appropriate acid such as, for example, sulfuric, phosphoric, nitric, succinic, cyclo5 hexylsulfaminic, citric, tartaric, ascorbic, maleic, formic, salicylic, methanesulfonic, toluenesulfonic or a hydrohalic acid.

The compounds of general formula VII have previously been described in German Patent Applications Nos. P 24 10 030 ) P 24 35 041, P 24 45 430 and P 24 60 776 as well as In German Offenlegungsschrift No, 2,229,845. By various pharmacological test methods these compounds, together with their physiologically compatible acid addition salts, have been shown to possess anxiolytic, tensiolytic, muscle relaxant, ί antiaggressive and anticonvulsive activity, particularly in a dosage of from 0.1 to 3 mg/kg, whilst having a low toxicity. They also have the ability to considerably increase the uptake of food in warm-blooded animals.

Thus, according to a yet still further feature of the present invention we provide pharmaceutical compositions comprising, as active ingredient, a compound of formula VII as hereinbefore defined prepared by a process according to the present invention, or a physiologically compatible acid - 22 4 3 6 8 Λ addition salt thereof, in association with a pharmaceutical carrier or excipient. - 23 ώ 3 68 d The following non-limiting examples serve to illustrate the present invention: Example 1 8-Bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4-c]5 thieno-[2,3-e]-l,4-diagepine a,a) 314 g(l mol) of 2-chloroacetylamino-3-(o-chlorobenzoyl)thiophene are dissolved in 500 ml of dimethylformamide and the solution obtained is mixed at 0°C while stirring vigourously for one hour with 36 g of pulverised sodium borohydride.

LO The resultant mixture is subsequently poured into 2 Itr. of ice-water, whereupon a smeary precipitate forms. The aqueous phase is decanted off and the grease is washed 2 or 3 times with water and then taken up in methylene chloride. After drying of the methylene chloride phase and evaporation, 300 g of an oil are obtained, which soldifies gradually and is then recrystallized from methanol-ether. 294 g (93,1% of theory) of 2-chloroacetylamino-3-[(o-chlorophenyl)-hydroxymethyl]-thiophene of m.p. 118 - 120°C are obtained.

This oil may be used directly in the cyclisation reaction. β) 253 g(0„8 mo}) of 2-chloroacetylamino-3-[(o-chlorophenyl)hydroxymethyl]-thiophene, dissolved in 200 ml of isopropanol, are added to a boiling solution of 52 g (2.25 mol) of sodium in 1.8 ltr. of isopropanol. The resultant mixture is refluxed for 5 minutes. Subsequently, tbe brownish suspension thus formed is poured into 1.5 ltr. of ice-water and the solution obtained is acidified with concentrated hydrochloric acid. A precipitate is formed which is filtered off with suction and washed with water. The moist residue is then dissoved in 2 ltr. 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-ej4,1-oxazepin-l-one of m.p. 175 - 176°C are obtained, b) 27.9 g (0.1 mol) of 5-(o~chlorophenyl)-thieno-[2,3-e]4,1-oxazepin-l-one are dissolved in 300 ml of chloroform and 8.5 ml of pyridine. A solution of 5.5 ml of bromine in 50 ml of chloroform is added thereto over a period of 10 to minutes at room temperature. Decoloration takes place immediately. The title compound precipitates and is filtered off with suction and washed with ether.

Yield of 7-broino-5“(o-chLorophenyl)-t’nieno-[2,3-e]-4,120 oxazepinone: 30 g (83% of theory) of m.p. 178 - 180°C (decomp.). c,(i) 35.8 g ¢).1 mol) of 7-bromo-5~(o-chlorophenyl)-thieno[2,3-e]-4,l-oxazepinone are heated with 350 ml of diglyme, 24 g of ?2®5 an<3 ·*·9 S °f NaHCOg for 30 minutes at 60°C. The mixture thus obtained is subsequently poured into approx.

Itr. of ice-water, whereupon a crystalline product precipitates out. The precipitate is filtered off with suction, washed with water and dried. g = 99% of theory of 7-bromo-5-(o-chlorophenyl)-thieno[2,3-e]-4,l-oxazepine-2-thione are obtained.

M.p. from 200°C (decomp.). β) 37.5 g(0.1 moi) of 7-bromo-5-(o-chlorophenyl)-thieno[2,3-e]“4,l“Oxazepine-2-thione are dissolved in 370 ml of tetrahydrofuran and the solution obtained is mixed with 10 ml of hydrazine hydrate. After 5 minutes at room temperature reaction is complete and the solution is subsequently evaporated. The residue is taken up in methylene chloride and the resultant solution is washed several times with water. The methylene chloride phase is then separated and evaporated. The residue is taken up in 200 ml of ethanol and mixed with 50 ml of o-triethyl acetate. The mixture obtained is refluxed after 30 minutes and then evaporated in vacuo. The residue is crystallized with ether.

Yield of 8-bromo-6-(o-chlorophenyl)-l-methyl-thieno-[2,3-e]triazolo-[3,4-c]-4,l-oxazepine: 34.5 g = 87% of theory of m.p. 146 - 148°C. - 26 d,oc) 39.6 g(0.1 mol) of 8-bromo-6-(o-chlorophenyl)-l-methylthieno-[2,3-e]-triazolo-[3,4-cj-4,l-oxazepine of m.p. 146 148°C are suspended in 250 ml of cone, hydrobromic acid. As soon as a clear solution has formed (after 15 to 20 minutes), it is diluted with 300 ml of ice-water and the resultant solution is shaken with methylene chloride. The methylene chloride phase is separated, dried and evaporated. The residue is crystallized with ether. 52 g of 3-methyl-4-[3(o-chlorophenyl-bromome thyl)-5-bromo-thienyl-(2)]-5-hydroxy10 methyl-1,2,4,-triazole hydrobromide (94% of theory) of m.p. 200°C (decomp.) are obtained. β) 27.9 g(0.05 moi of the hydrobromide obtained above are stirred with 100 ml of thionyl chloride for 30 minutes at room temperature. Excess thionyl chloride is then distilled off in vacuo and the residue is taken up in methylene chloride. The solution obtained is washed with ice-water and then a dilute ammonia solution. The dried methylene chloride phase is subsequently evaporated and the residue is triturated with ether.

Yield: 24.2 g of 3-methyl~4-[3-(oj-chlorophenyl]-bromomethyl)5-bromo-thienyl(2)]-5-chloromethyl“l,2,4-triazole of m.p. 167 - 169°C. y) 12.4 g of the compound obtained in the previous stage are - 27 43694 dissolved in 270 ml of methanol and 100 ml of liquid ammonia are added thereto. The solution thus formed is heated for 30 minutes at 100°C in an autoclave and then evaporated. The residue is taken up in methylene chloride and the solution obtained is washed with water, dried and evaporated. The residue is recrystallized from methanol. Yield of 8-bromo6-(o-chlorophenyl)-l“tnethyl-thieno“[2,3-e]-tria2olo-[3,4“c]5,6-dihydro-l,4-diazepine: 9.0 g = 91% of theory of m.p. 160 - 162°C. e) 39.5 g(0.1 mol) of 8-bromo-6-(o-chlorophenyl)-l-methyl4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-5,6-dihydro-l,4-diazepine of m.p. 162°G are dissolved in 500 ml of methylene chloride and 15 ml of pyridine. The solution obtained is mixed, within 10 minutes while stirring at room temperature, with 10 ml of bromine in 50 ml of methylene chloride. The solution, which decolours immediately, is stirred for 30 minutes and then extracted several times with water. The organic phase is dried and evaporated and the residue is recrystallized from ethanol.

Yield: 32 g = 81% of theory of m.p. 208 - 210°G.

Very good yields are also obtained if the dehydrogenation is effected with potassium permanganate, as described - 28 hereinafter in Example 3.

Example 2 S-Bromo-S-(o-chlorophenyl)-1-Ctetrahydropyranyl-(/Q ]-4H-strlazolo-[3,4-c]-thieno-[2,3-ej-1,4-diazepine 5 3.74 g (0.01 mol) of the 7-bromo-5-(o-chlorophenyl)-thieno[2,3-ej-4,l-oxazepine-2-thione (obtained in accordance with Example 1 c,u) are refluxed with 100 ml of dioxan and 1.5 g of tetrahydropyrano-4-carbonic acid hydrazide for 30 min.

The mixture obtained is then processed further as in Example 1 c,p).

Yield of 8-brotno-6-(o-chlorophenyl)-l-[terahydropyranyl(4)]-thieno~L2,3-e]-triazolo-[3,4-c]-4,l-oxazepine: 2,7 g (58% of theory) of m.p. 182 - 184°C.

Analogously to the processes described in Examples 1 d) and 15 1 e); the title compound is obtained via 8-bromo-6-(ochlorophenyl)-1-[tetrahydropyranyl-(4)]-thieno-[2,3-ejtriazolo-[3,4-c]-5,6-dihydro-l,4-diazepine of m.p. 174 175°C.

Yield: 98% of theory; m.p. 157 - 158'JC.

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-cyclohexyl- 29 4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-5,6-dihydro-1,4-diazepine of m.p. 192°C [obtained from 7-bromo-5-(o-chlorophenyl)thieno-[2,3-e]-4,l-oxazepine-2-thione (Example 1 c,«), m.p. 200pC via 8-bromo=6-(o-chlorophenyl)-1-cyclohexyl-thieno[2,3-e]-triazolo-[3,4-c]-4,l-oxazepine (see Example 1 c,p), m.p. 172 - 174*C according to the process described in Example 1 d,a) -Ϊ)] are dissolved in 100 ml of acetone distilled via ICMnO^. While boiling the solution thus obtained there are added thereto vzith stirring, first 3 g of sodium ) dichromate in 15 ml of water and then 2 ml of 20% sulfuric acid. Boiling is continued for 30 minutes and then the solvent is distilled off. The residue is diluted with some water and the solution obtained is made ammoniacal and then extracted with methylene chloride. After washing and drying the organic phase is evaporated to leave a crude product, which is recrystallized from ethanol.

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

Instead of sodium dichromate, potassium permanagnate may be used for the dehydrogenation. In this case the procedure is as follows: 4.65 g (0,01 mol) of 8-bromo-6-(o-chlorophenyl)-l-cyclohexyl4H-s-triazolo-[3,4-c]-thieno-[2,3-e]-5,6-dihydro-l,4-diaz- 30 4 8 6 9 <ί epine are dissolved in a mixture of 50 ml of acetone and 50 ml of methylene chloride. 1.4 g of finely divided KMnO^ are added thereto in one portion and the solution obtained is stirred for 6 hours at room temperature. Manganese dioxide separates out. The solution is filtered with suction over kieselguhr and the light-yellow filtrate thus obtained is evaporated. The residue is triturated with ether. g “ 86% of theory of the title compound of m.p. 190 - 192°C are obtained.

Example 4 1,8-Dibromo-6-(o-ch]orophenyl)-4H-s-triazolo-[3,4-c]-thieno[2.3-e]-l,4-diazepine 3.8 g (0.01 mol) of 8-bromo-6-(£-chlorophenyl)-4H-s-triazolo[3,4-c]-thieno-[2,3-e]-5,6-dihydro-l,4-diazepine of m.p. 178°C [obtained from 7-bromo-5-(o-chlorophenyl)-thieno-[2,3-e]-4,loxazepin-2-thione via 8-bromo-6-(o-chlorophenyl)-thieno-[2,3e]-triazolo-[3,4-cJ-4,l-oxazepine (m.p. 182°C) analogously to Example 1 d,,z)-O] are dissolved in 50 ml of methylene chloride and 1 ml of pyridine. Over a period of 10 minutes are added thereto 1.5 ml of bromine in 15 ml of methylene chloride. The mixture thus obtained is then refluxed for 30 minutes, washed with water, dried and evaporated. The resultant concentrate is applied on a SiOyColumn and eluted 3 δ 9 & with methylene chloride containing 2% methanol.

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

Analogously to the procedure described above the following products were obtained via the named intermediates: - 32 4 3 6 0 4 h-ί w kO ffl o ffl in o CM 00 -d © in o Η O O r-H © r-H 05 m i-H o CM rH O 0 o a CM CM 1 CM —4 CM 1 CM 9 rH CM 3 CM CM CM CM . Ό m CO cn OO o CM CO © ft 0 o © O © o 05 in rH 05 CM O • Jh g IX CM CM CM i-H CM CM r-H CM CM rH CM CM 1 Jh Φ !u H C > l*rt cn cn CM CM o Cm CM m 00 CO ffl r- · ¢1 cn CO CM CM ffl 05 r* m r-. O cn ϋ Q U f—t H r-H rH nj H rH rH i-H r-i CM rH Q) o I 3 3 I 3 g J 3 XJ • -H rH H O o <7· O O ffl ffl tn m &Ό r* m Cd CM rH ffl O' m n- O m • Φ <—1 H rH rH CM lH iH rH pH pH CM rH e e it 4J 1 C > •rH ffl rH O 00 O C-- ! cn CM r* © Γ» co P- cn Q P »—I rH r-H rH rH rH rH r-H CM 00 rH !0 fij I 1 © , 1 1 00 © 1 : · >rH Γ* © o © ffl CM CM 05 rH r-H in ftO cn CM !^- CO r- co ffl cn • Φ rH rH r-H rH r-H rH rH rH rH ε e Jh Φ zs J Φ 4J IH • β w o •rH 0 in o o O O O © © © T3 CM in in ffl CO 00 CO CO 00 00 co CJ P o flj \»z CM 1 rH 1 rH 1 CM rH 3 rH pH 1 rH r-H i-H pH 3 • ·ιΗ ffl cn in 00 cn 00 CO 00 00 co CO 00 ftX r- CM Mt ffl r^· r~- r- ΓΗ, r^. P- 3*- 1 . Φ rH CM rH rH CM rH i-H rH pH i-H pH <—H jE B in ffl aj X SE 33 ffl X X X X X X X r-H rH i-H rH r-H i-H rH i-H r-H rH ffl ffl U ft o ϋ ϋ ϋ o © ϋ ϋ u j X o o. 1 CO cn m m cn cn cn T CM Jh as X ffl ffl ffl ffl ffl fxl kJ X X ffl o a o o Q υ τ T © — CM X a CM CM * 33 κ X 33 ffl © 2 X X X ffl X X X ^CM in a JH i-H 3h ffl 1 M Jh Jh Jh Jh μ M I r*H CQ o CQ CM CM ffl ω ffl ffl ffl ffl ffl j# ϋ ffl 1 £J

Claims

1. Compounds of general formula II R. R, ‘2 I (II) R, '5 wherein either R^ and R£, which may be the same or different, each represents a hydrogen or halogen atom or an alkyl group containing 1 or 2 carbon atoms or, together with the two carbon atoms to which they are attached, they represent a 5- or 6-membered rings and R^ and R^, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom; and acid addition salts thereof.

2. Compounds as defined in claim 1 as herein specifically disclosed in Example la or lb.

3. A process for the preparation of compounds of general formula II as defined in claim 1 which comprises cyclising a compound of formula Ia, 34 4 3 6 G a (wherein R^, Rg, R^ and R^ are as defined in claim 1 and X represents a halogen atom or a hydroxy group).

4. A process as claimed in claim 3 wherein, in the compound of formula la, X represents a halogen atom.

5. A process as claimed in claim 4 wherein the cyclisation is effected by means of an alkali metal alcoholate or sodium hydride,

6. A process as claimed in claim 5 wherein the cyclisation is .0 effected by means of sodium isopropylate or sodium t.-butylate.

7. A process as claimed in any of claims 4 to 6 wherein the cyclisation is effected in an alcohol, tetrahydrofuran, dioxan, dimethylformamide or benzene as solvent.

8. A process as claimed in any of claims 4 to 7 wherein the cyclisation is effected at temperatures of from 0 n C to the boiling point of the reaction mixture.

9. A process as claimed in claim 3 wherein, in the compound of formula la, X represents a hydroxy group. - 35 e 4i ci V iZ ii

10. A process as claimed in claim 9 therein the cyclisation is effected by means of thionyl chloride, sulfuric acid, polyphosphoric acid or dicyclohexylcarbodiimide.

11. A process as claimed in claim 9 or claim 10 wherein the compound of formula Ia wherein X represents a hydroxy group is obtained by reaction of a compound of formula la’, represents an acyloxy group) with a strong alkali.

12. A process as claimed in any of claims 3 to 10 wherein a compound of formula Ia wherein R^ is other than a hydrogen atom and X represents a halogen atom is obtained by reaction of a compound of formula la, - 36 (wherein R„, R, and R c are as defined in ciaim 1 and R, is z. 4 o i as defined in claim 1 other than a hydrogen atom) with a concentrated hydrochloric acid solution in the presence of nitric acid.

13. A process as claimed in any of claims 4 to 8, 11 and 12 wherein the compound of formula la wherein X represents a halogen atom, or the compound of formula la* or la is obtained by reduction of a compound of formula I, R. - CO - CH 0 - Z if (I) io (wherein R^, Rg, R^ and Rg are as defined in claim 1 and Z represents a halogen atom or an amino or acyloxy group) whereby the desired compound of formula la, la’ or la is obtained.

14. A process as claimed in claim 13 wherein the reduction is effected by means of sodium borohydride in dimethylformamide 5 or dimethylacetamide at low temperatures.

15. A process as claimed in claim 14 wherein the reduction is effected at temperatures of from 0° to 10°C.

16. A process as claimed in any of claims 13 to 15 for the - 37 <£ ϋ <3 <» preparation of compounds of general formula II wherein R^ and/or R£ represents a halogen atom vzherein the compound of formula I wherein R^ and/or R£ represents a halogen atom is obtained by halogenation of a compound of formula I as defined in claim 13 wherein the said R^ and/or represents a hydrogen atom.

17. A process for the preparation of compounds of general formula II as defined in claim 1 wherein R^ and/or represents a halogen atom which comprises halogenating a compound of formula II as defined in claim 1 wherein the said R^ and/or R2 represents a hydrogen atom.

18. A process as claimed in claim 16 or claim 17 wherein the halogenation is effected by means of a halogen, sulfuryl halide or halosuccinimide.

19. A process as claimed in any of claims 16 to 18 wherein the halogenation is effected in the presence of carbon tetrachloride, chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide or a hydrocarbon as solvent.

20. A process as claimed in any of claims 16 to 19 wherein the halogenation is effected in the presence of a tertiary organic base.

21. A process as claimed in claim 20 wherein the tertiary organic base comprises pyridine. - 38 4 363/}

22. A process as claimed in any of claims 16 to 21 wherein the halogenation is effected at temperatures of from ambient temperature to the boiling point of the reaction mixture.

23. A process for the preparation of compounds of general 5 formula II as defined in claim 1 substantially as herein described.

24. A process for the preparation of compounds of general formula II as defined in claim 1 substantially as herein described in Example la or lb. 10

25. Compounds of general formula II as defined in claim 1 whenever prepared by a process as claimed in any of claims 3 to 24.

26. , A process ibr the preparation of compounds of general formula Ilia, 39 (wherein R^, R 2 , R^ and Rg are as defined in claim 1) or the thione tautomer thereof which comprises reacting a compound of formula II, as defined in claim 1, with phosphorus pentasulfide.

27. A process as claimed in claim 26 wherein the reaction is carried out in the presence of dimethylformamide, diglyme or tetrahydrofuran as solvent. I

28. A process as claimed in claim 26 or claim 27 wherein the reaction is effected in the presence of an alkali metal bicarbonate, pyridine or mixtures thereof.

29. A process as claimed in any of claims 26 to 28 wherein the reaction is effected at temperatures of from ambient temperature to the boiling point of the reaction mixture.

30. A process for the preparation of compounds of general (Illb) (wherein R^, Rg, R^ and R^ are as defined in claim 1 and X^ represents a lower alkoxy group) which comprises reacting a compound of formula II as defined in claim 1 with an appropriate trialkyloxoniumfluoroborate.

31. A process as claimed in claim 30 wherein the trialkyloxoniumf luoroborate is formed in situ from a borotrifluoride 40 4 3 6 3 4 etherate and epichlorohydrin.

32. A process as claimed in claim 30 or claim 31 wherein the reaction is effected in the presence of an ether or halogenated hydrocarbon as solvent.

33. A process as claimed in claim 32 wherein the reaction is effected in the presence of carbon tetrachloride.

34. A process as claimed in any of claims 30 to 33 wherein the reaction is effected at temperatures of from 0°C to the boiling point of the reaction mixture. io

35. A process for the preparation of compounds of general (wherein R^, Ry, R^ and R^ are as defined in claim 1 and Xy represents a halogen atom) which comprises reacting a 15 compound of formula II as defined in claim 1 with an appropriate acidic inorganic halide.

36. A process as claimed in claim 35 wherein the acidic inorganic halide comprises a phosphorus pentahalide.

37. A process as claimed in claim 35 or claim 36 wherein the reaction is effected in the presence of an anhydrous organic solvent.

38. A process as claimed in claim 37 wherein the solvent comprises dioxan or tetrahydrofuran.

39. A process as claimed in any of claims 35 to 38 wherein the reaction is effected at temperatures of from -50° to 50°C.

40. A process for the preparation of compounds of formula represents a lower thioalkyl group) which comprises forming a salt of a compound of formula Ilia as defined in claim 26 by reaction with sodium methylate or sodamide in the presence of a solvent and reacting the salt thus obtained with an appropriate alkylating agent.

41. A process as claimed in claim 40 wherein the alkylating agent is an alkyl halide.

42. 4 ΰ 6 S j

42. A process as claimed in claim 41 wherein the alkylating agent is an alkyl iodide.

43. A process as claimed in any of claims 40 to 42 wherein the compound of formula Ilia is obtained by a process as claimed in any of claims 26 to 29.

44. A process as claimed in any of claims 26 to 39 and 43 wherein the compound of formula II is obtained by a process as claimed in any of claims 3 to 25.

45. A process for the preparation of compounds of general io formula III, represents a halogen atom or a lower alkoxy, thio or lower alkylthio group) substantially as herein described. 15

46. A process for the preparation of compounds of general formula III as defined in claim 45 substantially as herein described in Example lc.

47. Compounds of general formula III as defined in claim 45 whenever prepared by a process as claimed in any of claims 26 2rto 46.

48. Compounds of general formula V, R. ‘2 R OH—0 R (V) wherein Rp Rg, R^ and Rg are as defined in claim 1 and Rg represents a hydrogen, chlorine or bromine atom, a straight or branched chain alkyl or to-hydroxyalkyl group containing from 1 to 3 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms or a 5- or 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group and acid addition salts thereof.

49. Compounds of general formula V as defined in claim 48 as herein specifically disclosed in Example lc or 2a.

50. A process for the preparation of compounds of general formula V as defined in claim 48 wherein Rg represents a hydrogen atom, a straight or branched chain alkyl orO-hydroxyalkyl group containing from 1 to 3 carbon atoms, a cyclo· alkyl group containing from 3 to 6 carbon atoms or a 5- or 44 4 ii 3 3 ¢1 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group, which comprises reacting a compound of formula III as defined in claim 45 with a compound of formula IV, R 3 ’ -CO-NH - NHy (IV) (wherein K^' represents a hydrogen atom, a straight or branched chain alkyl or ¢0-hydroxyalkyl group containing from i to 3 carbon atoms, a cycloaikyl group containing from 3 to lo 6 carbon atoms or a 5- or 6-membered saturated ring containing an oxygen or a sulfur atom or a nitrogen atom optionally substituted by a lower alkyl group).

51. A process as claimed in claim 50 wherein the reaction is effected at temperatures of from 100 to 250°C. 15

52. A process as claimed in claim 50 or claim 51 wherein the reaction is effected in the presence of a solvent.

53. A process as claimed in claim 52 wherein the solvent comprises methanol, ethanol, dioxan, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures thereof. .,

54. A process as claimed in any of claims 50 to 53 wherein the reaction is effected in the presence of an acid catalyst.

55. A process as claimed in claim 54 wherein the acid - 45 catalyst comprises hydrochloric, sulfuric, phosphoric, polyphosphoric, acetic, propionic, benzenesulfonic or toluenesulfonic acid.

56. A process for the preparation of compounds of general formula V as defined in claim 48, wherein Rg represents a chlorine or bromine atom, which comprises chlorinating or brominating a compound of formula V as defined in claim 48 (wherein Rg represents a hydrogen atom) whereby ths desired compound of formula V is obtained.

57. A process'as claimed in claim 56 wherein the chlorination or bromination is effected by means of chlorine or bromine.

58. A process as claimed in claim 56 wherein the chlorinat ion or bromination is effected by means of N-chloro- or N-bromosuccinimide.

59. A process as claimed in claim 57 or claim 58 wherein the chlorination or bromination is effected in the presence of a tertiary organic base.

60. A process as claimed in any of claims 56 to 59 wherein the chlorination or bromination is effected in the presence of carbon tetrachloride, chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide or a hydrocarbon as solvent.

46. 4 3 6 3 4 bl. A process as claimed in any of claims 56 to 60 wherein the chlorination or bromination is effected at temperatures of from ambient temperature to the boiling point of the reaction mixture. 5

62. A process as claimed in any of claims 56 to 62 wherein the compound of formula V in which R, represents a hydrogen atom is obtained by a process as defined in any of claims 50 to 55.

63. A process .as claimed in any of claims 50 to 55 and 62 0 wherein the compound of formula III is obtained by a process as defined in any of claims 26 to 46.

64. A process as claimed in any of claims 50 to 55 and 62 wherein the compound of formula III is obtained by a process as defined in any of claims 26 to 43.

65. A process for the preparation of compounds of general foi'mula V as defined in claim 48 substantially as herein described.

66. A process for the preparation of compounds of general formula V as defined in claim 48 substantially as herein 20 described in Example lc or 2a.

67. Compounds of general formula V whenever prepared by a process as claimed in any of claims 50 to 63, 65 and 66. -

47. 68. Compounds of general formula VI, wherein Rp Rg, R^ and Rg are as defined in claim 1 and Rg is as defined in claim 48 and acid addition salts thereof.

69. Compounds of general formula VI as defined in claim 68 as herein specifically disclosed in Example Id or 2b.

70. A process for the preparation of compounds of general formula VI as defined in claim 68 which comprises reacting a (wherein R^, Rg, R^ and Rg are as defined in claim 1, Rg is

48. 4 3 S S 4 as defined tn claim lib and Halj, and Haig, which may be the same or different, each represents a halogen atom) with ammonia or an ammonia precursor.

71. A process as claimed in claim 70 wherein the compound of formula VI' is reacted with urotropine.

72. A process as claimed in claim 70 or claim 71 wherein the reaction is effected in the presence of liquid ammonia, a lower alcohol, ethyl acetate, dioxan, tetrahydrofuran or an inert hydrocarbon as solvent.

73. A process as claimed in claim 72 wherein the reaction is effected in the presence of methanol, ethanol or benzene. 7/j.

A process as claimed in any of claims 70 to 73 wherein the reaction is effected at temperatures of from 0°C to the boiling point of the reaction mixture.

75. A process as claimed in any of claims 70 to 74 wherein the compound of formula VI' is obtained by reaction of a compound of formula V* (V) (wher irein Rp Rg, R^ and Rg are as defined in claim 1, Rg is as defined in claim 48 and Y represents a halogen atom or a hydroxy group) with a phosphorus or sulfur halide.

76. A process as claimed in claim 75 wherein the phosphorus or sulfur halide is a thionyl halide or phosphorus trihalide. 5

77. A process as claimed in claim 75 or claim 76 wherein the reaction is effected at temperatures of from 0 to 40°C.

78. A process as claimed in claim 77 wherein the reaction is effected at temperatures of about 20°C.

79. A process as claimed in any of claims 75 to 78 wherein io a compound of formula V wherein Y represents a halogen atom is used and is obtained by treatment of a compound of formula V as defined in. claim 48 with a concentrated hydrohalic acid.

80. A process as claimed in claim 79 wherein the treatment 15 is effected at ambient temperature.

81. A process as claimed in any of claims 75 to 78 wherein a compound of formula VI 1 wherein Y represents a hydroxy group is used and is obtained by heating a compound of formula V as defined in claim 48 in a concentrated acid 2o solution.

82. A process as claimed in any of claims 79 to 81 wherein the compound of formula V’ is isolated from the reaction mixture by extraction with a solvent immiscible with water.

49. 50 83. A process as claimed in claim 82 wherein the solvent immiscible with water comprises chloroform or methylene chloride.

84. A process as claimed in any of claims 79 to 83 wherein 5 the compound of formula V is obtained by a process as defined in any of claims 50 to 63, 65 and 66.

85. A process for the preparation of compounds of general formula VI as defined in claim 68 substantially as herein described. io

86. A process for the preparation of compounds of general formula VI as defined in claim 68 substantially as herein described in Example Id.

87. Compounds of general formula VI as defined in claim 68 whenever prepared by a process as claimed in any 15 of claims 70 to 83 and 86.

88. Compounds of general formula VI as defined in claim 68 whenever prepared by a process as claimed in claim 84 or claim 85.

50. 51 89. A process for the preparation of compounds of general formula VII, (wherein Rp Rg, R^ and Rg are as defined in claim 1 and Rg is as defined in claim 48) which comprises dehydrogenating a compound of formula VI as defined in claim 68 whereby the desired compound of formula VII is obtained.

90. A process as claimed in claim 89 wherein the dehydrogenation is effected by means of a halogen.

91. A process as claimed in claim 90 wherein the dehydrogenation is effected in the presence of a chlorinated hydrocarbon as solvent.

92. A process as claimed in claim 91 wherein the dehydrogenation is effected in the presence of chloroform or

51. 52 43 804 or methylene chloride.

93. A process ns claimed in any of claims 90 to 92 wherein the dehydrogenation is effected in the presence of a tertiary organic base. 5

94. A process as claimed in claim 93 wherein the tertiary organic base comprises pyridine.

95. A process as claimed in any of claims 90 to 94 for the preparation of compounds of general formula VII, wherein R 3 represents a chlorine or bromine atom, in which a compound of io formula VI (wherein R^ represents a hydrogen atom) is dehydrogenated with an excess of chlorine or bromine.

96. A process as claimed in claim 89 wherein the dehydrogenation is effected by means of a reagent containing chromium or manganese in a high oxidation state. 15

97. A process as claimed in claim 96 wherein the reagent comprises a chromate, dichromate or permanganate.

98. A process as claimed in claim 96 or claim 97 wherein the dehydrogenation is effected in acetone, tetrahydrofuran or dioxan as solvent. 20 99. A process as claimed in any of claims 89 to 98 wherein the dehydrogenation is effected at temperatures of from 0°C to the boiling point of the reaction mixture.

52. 53 ί δ 9 <3

100. A process as claimed in any of claims 89 to 99 wherein the compound of formula VI is obtained by a process as defined in any of claims 70 to 86,

101. A process for the preparation of compounds of general formula VII as defined in claim 89 substantially as herein described.

102. A process for the preparation of compounds of general formula VII as defined in claim 89 substantially as herein described in any one of Examples le, 3 and 4.

103. Compounds of general formula VII as defined in claim 89 whenever prepared by a process as claimed in any of claims 89 to 102.

104. Compounds of general formula VII as defined in claim 89 whenever prepared by a process as claimed in any of claims 89 to 99 and 102.

105. A process for the preparation of physiologically compatible acid addition salts of compounds of general formula VII as defined in claim 89 which comprises reacting a compound of formula VII as defined in claim 103 with an appropriate acid.

106. A process as claimed in claim 105 wherein the acid comprises sulfuric, phosphoric, nitric, succinic, cyclohexy lsulf aminic, citric, tartaric, ascorbic, maleic, formic, salicylic, methanesulfonic, toluenesulfonic or a hydrohalic

53. 54 4 3SS.J acid.

107. Compounds of general formula III as defined in claim 45 and acid addition salts thereof. 1.08. Pharmaceutical compositions comprising, as active ingredient, a compound of formula VII as defined in claim 89, or a physiologically compatible acid addition salt thereof, in association with a pharmaceutical carrier or excipient, tthh—Each and-every-nove-1-ittefchod-;’ proc-as»·; compound-ana