IE42565B1 - Thieno (1,5) benzodiazepine intermediates - Google Patents

Description

This invention relates to intermediates which are useful in the preparation of the compounds described in Patent Specification No. 42564.

According to the present invention there is 5 provided a compound of formula (V): 2 wherein R and R independently represent hydrogen, C-^4 alkyl, C2_4 alkenyl, C3_g cycloalkyl, halogen, haloalkyl, nitro, amino, C2_^ alkanoyl amino, hydroxyl, alkoxy, alkylthio or a group of formula -S02N(R^)2 or SO2R^, where R^ is alkyl; wherein the group represents an optionally substituted thiophene ring fused to the diazepine nucleus; and where Q is hydroxyl, thio, Cj._4 alkoxy, C^_4 alkylthio, halogen or amino.

Preferably, in the compounds of formula (V) R^ and R independently represent hydrogen, C1-4 alkyl, halogen, C-L_4 haloalkyl, nitro, amino, C, 4 alkoxy, C1-4 alkylthio or a group of formula -SO2N(R4)2 where R4 is Cx_4 alkyl.

Those skilled in the art will appreciate that the compounds of the invention can exist in three forms which can be represented by the following structures; N Ii (XV) .-4In the above structural formulae, for ease of representation, the thiophene ring is shown as unsubstituted but it is to be understood that the thiophene ring may be substituted, for instance, by one or two groups selected from C^_g alkyl, typically C^_g alkyl, C2_^ alkenyl, C-^_^ haloalkyl, C2_^ alkanoyl, nitro, halogen and optionally substituted phenyl. In addition, in the structures of formulae (II) and (IV), the thiophene ring may be fused to a Cg_g cycloalkyl ring.

Preferred compounds falling within the scope of compounds defined in any of formulae (I) to (IV) above are those having one or more of the following characteristics: (A) R1 is a 6 or 7-halo substituent, such as chlorine or fluorine; (B) R is a 7-halo substituent such as chlorine or • fluorine and R is hydrogen; T 2 (C) R is a 7-fluoro substituent and R is hydrogen; (D) R is hydrogen; (E) R^ or R^ is trifluoromethyl; (F) R·*· is a 6- or 7-trifluoromethyl substituent and R is hydrogen; 2 (G) R or R is methylthio or methoxy; 2 (H) R and R both represent halogen atoms, for example fluorine; (I) the compound of formula (V) has the structure (II) ; (J) the thiophene ring is substituted by a C^_4 alkyl group, such as ethyl; (K) the thiophene ring is unsubstituted; (L) Q is hydroxyl or thiol; - 5 The method by which the intermediates of formula (V) can be prepared and the processes by which they can be converted into pharmacologically active final products is described in detail in Patent Specification No. 42564. However, the following Preparation and Examples are given to illustrate how specific compounds of formula (V) can be prepared.

PREPARATION 1 a' - Carboxymethyl - β' - carboxyethyl -a - ethylethyl” methylsulphide Ethyl pent - 3 - enoate (12.6 g, 0.1 mol) J. Org. Chem. 12, 138-154, was added dropwise to a solution of methyl thioglycolate (10.6 g, 0.1 mol) and piperidine (0.1 ml) which were stirred together in a three-necked 100 ml flask equipped with a dropping funnel, thermometer and condenser. The temperature of the reaction was kept between 40-50°C, piperidine (0.6 ml) being added in 0.05 ml amounts over a period of 45 minutes. After the addition of pentenoate, the reaction was maintained at 50°C for 10 minutes. The reaction mixture was then cooled, washed with water, dried over MgSO^, filtered and the filter pad washed with ether. The combined filtrate was evaporated to dryness and the title compound obtained as a yellow liquid.

EXAMPLE 1 (a) Ethyl 5 - ethyl - 2 - (2 - nitroanilino) thiophene - 3 - carboxylate Ethyl 2 - amino - 5 - ethyl - thiophene - 3 carboxylate (Ber. 99, 94-100) (40 g, 0.2 mol) in dry tetrahydrofuran (150 ml) was stirred under nitrogen and cooled to -40°C. n - Butyl lithium (125 ml of 10.2% w/v solution in hexane, 0.2 mol) was added keeping the temperature below -30°C. The mixture was then stirred at -6 -30°C for a further 15 minutes. This solution was blown by nitrogen through an inverted 0 tube into'a solution of o - fluoro - nitrobenzene (28 g, 0.2 mol) in dry tetrahydrofuran (100 ml) maintained at 15-3O°C. The mixture was stirred overnight. The resulting ink-blue solution was poured into three volumes of ice water, extracted with ether (3x500 ml), washed with water (2x500 ml), dried and then evaporated to dryness. The deep red oil was dissolved in ethanol (200 ml) and chilled over10 night. Crystals of the title compound were filtered off and dried in vacuo at 50°C.

Recrystallisation from ethanol gave pure product having a m.p. of 66-68°C. (b) , Ethyl 5 -,ethyl - 2 --(4 - fluoro - 2 - nitro15 anilino - thiophene - 3 -carboxylate The title compound was similarly prepared but using 2,5 - difluoro - nitrobenzene in place of the o fluoronitrobenzene used in Example 1(a) above, m.p. 90°C (after recrystallisation from ethanol).

Anal. Calc, for ci5Hx5E’N2°4S C: 53.24; H: 4.45; N: 8.28; F: 5.61; S: 9.47% Found C: 53.45; H: 4.75; N: 8.15; F: 5.71; S: 9.75% Similarly/ using'the procedure described in Example 1(a), the following compounds were prepared. In each case, the nitrobenzene Used in place of the o - nitrobenzene of Example 1(a) is given, as is the melting point of the title compound, together with recrystallisation solvent-indicated in parenthesis. (e) Ethyl 2 - (3,5 - difluoro - 2 - nitroanilino) 5 - ethyl - thiophene - 3 - carboxylate 2,4,6 42565 - 7 Trifluoro - nitrobenzene, m.p. 74-75°C (EtOH). (d) Ethyl 5 - ethyl - 2 - (5 - fluoro - 2 - nitroanilino) - thiophene - 3 - carboxylate 2,4 Difluoro - nitrobenzene, m.p. 87-88°C (EtOH). (e) Ethyl 2-(4- chloro - 2 - nitroanilino) - 5 ethyl - thiophene - 3 - carboxylate 5 - Chloro 2 - fluoro - nitrobenzene, m.p. 75-76°C (EtOH). (f) Ethyl 2 - (2,4 - dinitroanilino) - 5 - ethyl thiophene - 3 - carboxylate 2,4 - Dinitro fluorobenzene, 148°C (EtOH). (g) Ethyl 2-(4- fluoro - 2 - nitroanilino) 4,5,6,7 - tetrahydrobenzo/b/thiophene - 3 carboxylate The title compound was similarly prepared using the process of Example 1(a) but using as starting materials 2,5 - difluoro - nitrobenzene and ethyl 2 - amino 4,5,6,7 - tetrahydrobenzo/b/thiophene - 3 - carboxylate, m.p. 140-142°C (EtOH). (h) Ethyl 2-(4,5- difluoro - 2 - nitroanilino) 5 - ethyl - thiophene - 3 - carboxylate 2,4,5 Trifluoro - nitrobenzene, m.p. 105°C (EtOH). (i) Methyl 3-(2- nitroanilino) - thiophene - 2 carboxylate The title compound was prepared using the process of Example 1(a) but with 2 - fluoro - nitrobenzene and methyl 3 - aminothiophene - 2 - carboxylate (British Peitent Specification No. 837,086) as starting materials, m.p. 184°C, (toluene/MeOH, 2:1). - 8 (j) Methyl 3 - (4 - fluoro - 2 - nitroanilino) thiophene - 2 - carboxylate The title compound was prepared using the process of Example 1(a) but with 2,5 - difluoronitrohenzene and methyl 3 - aminothiophene - 2 - carboxylate as starting materials, m.p. 172-175°C (benzene).

Similarly prepared were: (k) Ethyl 5-i. - propyl -2-(4- fluoro - 2 nitroanilino) - thiophene - 3 - carboxylate (l) Ethyl 5 - n - hexyl -2-(4- fluoro - 2 nitroanilino) - thiophene - 3 - carboxylate (m) Ethyl 4 - methyl - 2 - (4 - fluoro - 2 nitroanilino) - thiophene - 3 - carboxylate (n) Ethyl 4 - methyl - 5 - ethyl -2-(4- fluoro 2 - nitroanilino) - thiophene - 3 - carboxylate EXAMPLE 2 (a) Ethyl 5 - ethyl - 2 - (2 - nitroanilino) thiophene - 3 - carboxylate - Fluoronitrobenzene (56.4 g, 0.4 mol) and ethyl 2 - amino - 5 - ethylthiophene - 3 - carboxylate (100 g, o mol) were dissolved in dry dimethylsulphoxide (320 ml).

The stirred solution, under nitrogen, was heated in an oil bath. When the internal temperature reached 60°C, potassium carbonate (55 g, 0.4 mol) Was added and the mixture stirred at 100°C until GLC indicated that all the o - fluoronitrobenzene had been consumed (6.5 hours). The mixture was then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO^) and the solvent evaporated to give a red semi-solid which was recrystallised from ethanol to give the title product as a solid (m.p. 6642565 68°C).

The following compounds were similarly prepared using the process of Example 2(a). In each case, the melting point of the title compound, the recrystallisation solvent-indicated in parentheses-and the starting materials (when different from those of Example 2(a) are given. (b) Ethyl 2-(4- chloro - 2 - nitroanilino) - 5 ethyl - thiophene - 3 - carboxylate 5 - Chloro 2 - fluoro - nitrobenzene, m.p. 75-76°C (EtOH). (c) Ethyl 2 - (2,4 - dinitroanilino) - 5 - ethyl thiophene - 3 - carboxylate 2,4 - Dinitro fluorobenzene, m.p. 146-148°C (EtOH). (d) Ethyl 5 - ethyl - 2 - (2 - nitro - 4 - trifluoromethy lanilino) - thiophene - 3 - carboxylate 4 Fluoro - 3 - nitrobenzofluoride, m.p. 1O2°C (EtOH). (e) Ethyl 5 - ethyl - 2 - (5 - methyl - 2 - nitroanilino) - thiophene - 3 - carboxylate 3 - Fluoro 4 - nitrotoluene, m.p. 55-57°C (EtOH). (f) Ethyl 2-(4- difluoromethyl - 2 - nitroanilino) 5 - ethyl - thiophene - 3 - carboxylate 5 Difluoromethyl - 2 - fluoro - nitrobenzene, m.p. 88-9O°C (EtOH). (g) Methyl 2-(4- N,N - dimethylsulphonamido - 2 nitroanilino) - 5 - ethyl - thiophene - 3 carboxylate - N,N - Dimethylsulphonamido - 2 - fluoro nitrobenzene and methyl 2 - amino - 5 - ethyl - thiophene - 3 - carboxylate, m.p. 166-168°C (EtOH). 43565 - 10 (fi) Methyl 5 - athyl - 2 - (4 - methoxy - 2 ni troanilino) - thiophene - 3 - carboxylate - Fluoro - 5 - methoxy - nitrobenzene and methyl 2 - amino - 5 - ethyl - thiophene - 3 - carboxylate, m.p. 125-127°C (EtOH). (i) Ethyl 2-(4- fluoro - 2 - nitroanilino) thiophene - 3 - carboxylate 2,5 - Difluoro - nitrobenzene and ethyl 2 - amino thiophene - 3 - carboxylate, m.p. 125°C (EtOH). (j) Ethyl 5 - ethyl - 2.- (4 - methylthio - 2 nitroanilino) - thiophene - 3 - carboxylate - Fluoro - 3 - nitro - thioanisole and ethyl 2 amino - 5 - ethyl - thiophene - 3 - carboxylate. (k) Ethyl 2-(2- chloro - 6 - nitroanilino) - 5 15 ethyl - thiophene - 3 - carboxylate Ethyl 2 - amino - 5 - ethyl - thiophene - 3 carboxylate and 3 ~ chloro - 2 - fluoronitrobenzene, m.p. 67-7O°C (EtOH). (l) Ethyl 5 - ethyl - 2 - (2 - trifluoromethyl 20 6 - nitroanilino) - thiophene - 3 - carboxylate Ethyl 2 - amino - 5 - ethylthiophene - 3 carboxylate and 2 - fluoro - 3 - trifluoromethylnitrobenzene, m.p. 72-73°C (EtOH). (m, Methyl 3-(4- chloro - 2 - nitroanilino) 25 thiophene - 2 - carboxylate - Chloro - 2 - fluoro - nitrobenzene and methyl 3 - amino - thiophene - 2 - carboxylate, m.p. 2O7-2O8°C (EtOAc/Hexane). (n) Methyl 5 - methyl -2-(2- nitro - 4 - fluoro30 anilino) - thiophene - 3 - carboxylate 2 5 6 5 - 11 Methyl 2 - amino - 5 - methyl - thiophene - 3 carboxylate and 2,5 - difluoronitrobenzene, m.p. 149151°C (IitOH) . (o) Ethyl 2-(4- bromo - 2 - nitroanilino) - 5 ethyl - thiophene - 3 - carboxylate Ethyl 2 - amino - 5 - ethyl - thiophene - 3 carboxylate and 5 - bromo - 2 - fluoronitrobenzene, m.p. 76-78°C (EtOH). (p) Methyl 2-(4- fluoro - 2 - nitroanilino) - 5 phenyl - thiophene - 3 - carboxylate Methyl 2 - amino - 5 - phenyl - thiophene - 3 carboxylate and 2,5 - difluoronitrobenzene, m.p. 150°C (ch2ci2). (q) 5 - Ethyl - 2 - (2 - nitroanilino) - thiophene 3 - carboxylic acid Ethyl 5 - ethyl - 2 - (2 - nitroanilino) - thiophene - 3 - carboxylate (6.0 g) dissolved in ethanol (100 ml) and water (50 ml) and heated to 60°C with stirring.

Sodium hydroxide (5N, 50 ml) was then added and the temperature maintained for 16 hours. The reaction mixture was cooled and diluted with water (500 ml), and solid title product filtered off, m.p. 189-191°C (EtOAc). (r) 5 - Ethyl - 2 - (4 - fluoro - 2 - nitroanilino) thiophene - 3 - carboxylic acid The title compound was similarly prepared from ethyl 5 - ethyl -2-(4- fluoro - 2 - nitroanilino) thiophene 3 - carboxylate but using a reaction temperature of 25°C, m.p. 198-2OO°C (EtOAc). (s) Methyl 5 - Ethyl - 3 - (4 - fluoro - 2 - nitroanilino) - thiophene - 2 - carboxylate - 12 EXAMPLE 3 (a) Methyl 3-(4- fluoro - 2 - nitroanilino) thiophene - 4 - carboxylate - Carhoxymethyl - 4 - aminothiophene hydrochloride 5 /£·*·£·;>· 2232 (1946) (48.5 g, 0.25 mol]7 was dissolved in a minimum of water and shaken in the presence of saturated sodium bicarbonate solution and ether. The ether extract was dried with MgSO^, filtered and evaporated to an oil, dissolved in dimethylformamide (DMF), 2 - (DMSO) (anhydrous), preferably the latter (100 ml). To this stirred solution at 100°C, under nitrogen, was added 2,5 - difluoronitrobenzene (40 g, 0.25 moi) and triethylamine 35 ml), the reaction mixture was then refluxed under nitrogen for an hour and more triethylamine (35 ml) added. The reaction mixture was then heated, with stirring under nitrogen for a further 40 hours.

The chilled mixture was poured into saturated brine (1¼ litres) with stirring, in the presence of ethyl acetate, and the two-phase mixture was filtered.

The organic phase was run off, washed with brine, dried with MgSO^, filtered and evaporated to a brown gum. This gum was dissolved in a minimum of ethyl acetate and vacuum-filtered through a pad of Florisil (trade mark) contained in a sintered funnel, the pad was washed with ethyl acetate until all the product had been removed, the filtrates bulked, evaporated to an oil, dissolved in cold ethanol (250 ml) and left at 0°C for 24 hours. The red-orange crystalline product occasionally contained traces of brown tar, but it was found that this could be removed by adding a little ethyl acetate and triturating. The crystals so obtained were filtered, washed with ethanol, 4O-6O°c petrol, and then dried under yacuo to give the title compound as a solid product, m.p. 164°C. - 13 (b) Methyl 3-(2- nitro - 4 - trifluoromethylanilino) - thiophene - 4 - carboxylate The title compound was similarly prepared using the process described in Example 3(a) above, m.p. 175°C (EtOH). (c) 2-(4- Fluoro - 2 - nitroanilino) - 4,5,6,7 tetrahydrobenzo/b7thiophene - 3 - nitrile A mixture of 2 - amino - 4,5,6,7 - tetrahydrobenzo/b/thiophene - 3 - nitrile (3.6 g, 0.02 mol) and 2,5 difluoronitrobenzene (3.2 g, 0.02 mol) in dry DMSO (20 ml) was stirred and heated on an oil bath. When the internal temperature reached 60°C, potassium carbonate (2.76 g, 0.02 mol) was added and the mixture was then stirred at 100°C for 5 hours. The reaction mixture was poured onto ice-water, acidified and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO^) and the solvent removed in vacuo, m.p. 137-139°C (EtOAc).

Similarly, the following compounds were prepared using 2 - amino - 5 - ethyl - thiophene - 3 - nitrile. (d) 5 - Ethyl - 2 - (4 - fluoro - 2 - nitroanilino) thiophene - 3 - nitrile (e) 5 - Ethyl 2-(4- methoxy - 2 - nitroanilino) thiophene - 3 - nitrile (f) 5 - Ethyl - 2 - (4 - methylthio - 2 - nitroanilino) - thiophene - 3 - nitrile (g) 5 - Ethyl - 2 - (2 - nitro - 4 - trifluoromethylanilino) - thiophene - 3 - nitrile - 14 EXAMPLE 4 (a) 3-(4- Chloro - 2 - nitroanilino) - 2,5 dihydrothiophene - 4 - nitrile - Cyanotetrahydrothiophen - 4 - one (Dutch Patent 5 Application No. 66,04742) (38.1 g, 0.25 mol) and 4 chloro - 2 - nitroaniline (51.8 g, 0.28 mol) were dissolved in refluxing toluene (~200 ml) in a threenecked flask (500 ml) fitted with a Dean and Stark apparatus, A few drops of boron trifluoride etherate were added and the reaction was left to reflux for 4 hours, the water formed being tapped off.

The reaction mixture was left to cool whereupon a brown solid precipitated and was filtered off. The solid was recrystallised from absolute ethanol using activated charcoal as a decolouriser, and the orange crystalline solid which was obtained was filtered,washed with ethanol and then dried at 50°C under vacuum. The dried solid so obtained was the title compound which had a melting point of 154-155°C. (b) 3 - (4 - Methylthio - 2 - nitroanilino) - 2,5 dihydrothiophene - 4 -.- nitrile The title compound was obtained using a similar procedure to that outlined in Example 4(a) above, m.p. 141-142°C (EtOH). (c) 4-(4- Fluoro - 2 - nitroanilino) - 2 - ethyl 2,5 - dihydrothiophene - 3 - nitrile EXAMPLE 5 (a) 3-(4- Chloro - 2 - nitroanilino) - thiophene 4 - nitrile 3-(4- Chloro - 2 - nitroanilino) - 2,5 - dihydrothiophene - 4 - nitrile (14.09 g, 0.05 mol) dissolved in xylene (150 ml) was added to a solution of chloranil (12.3 g, 0.05 mol) in hot xylene (100 ml). The mixture was allowed to reflux for two hours. After cooling, the - 15 xylene was evaporated off under vacuum to leave a redbrown solid which was triturated with methanol to give a brick-red solid. The solid was recrystallised from hot methanol to give red crystals which were filtered off, washed with methanol and dried at 50°C under vacuum. The dried product so obtained was the title compound, m.p. 214°C. (b) 3-(4- Methylthio - 2 - nitroanilino) - thiophene - 4 - nitrile was similarly prepared, m.p. 167-169°c (MeOH). (c) 4-(4- Fluoro - 2 - nitroanilino) - 2 - ethyl thiophene - 3 - nitrile EXAMPLE 6 (a) Ethyl 2-(2- aminoanilino) - 5 - ethyl - thiophene - 3 - carboxylate Ethyl 5 - ethyl - 2 - (2 - nitroanilino) - thiophene - 3 - carboxylate (20.7 g) in ethanol (150 ml) was catalytically reduced over 10¾ palladium on charcoal (2.0 g) at 60 p.s.i. The catalyst was removed by filtration and the solvent removed by distillation in vacuo. The title product so obtained had a melting point of 5O-52°C (hexane).

The following compounds were similarly prepared. (b) Ethyl 2-(2- amino - 4 - fluoroanilino) - 5 ethyl - thiophene - 3 - carboxylate m.p. 82-84°C (hexane). (c) Ethyl 2-(2- amino - 3,5 - difluoroanilino) 5 - ethyl - thiophene - 3 - carboxylate m.p. 1O6°C (EtOH). (d) Ethyl 2-(2- amino - 5 - fluoroanilino) - 5 ethyl - thiophene - 3 - carboxylate m.p. 100— 1O1°C (EtOH). (e) Ethyl 2-(2- amino - 4 - chloroanilino) - 5 ethyl - thiophene - 3 - carboxylate m.p. 119121°C (EtOH). (f) Ethyl 2 - (2,4 - diaminoanilino) - 5 - ethyl thiophene - 3 - carboxylate, m.p. 152-5°C (hexane). (g) Ethyl 2-(2- amino - 4 - trifluoromethylanilino) - 5 - ethyl - thiophene - 3 - carboxylate (h) Ethyl 2-(2- amino - 5 - methylanilino) - 5 ethyl - thiophene - 3 - carboxylate (i) Ethyl 2-(4- difluoromethyl - 2 - nitroanilino) - ethyl - thiophene - 3 - carboxylate (j) Methyl 2-(2- amino - 4 - N,N - dimethylsulphonamidoanilino) - 5 - ethyl - thiophene - 3 carboxylate (k) Methyl 2-(2- amino - 4 - methoxyanilino) - 5 ethyl - thiophene - 3 - carboxylate (l) Ethyl 2 - (2.- amino - 4 - fluoroanilino) - 4,5,6, - tetrahydrobenzo/b/thiophene - 3 - carboxylate (m) Ethyl 2-(2- amino - 4 - fluoroanilino) - thiophene - 3 - carboxylate (n) Ethyl 2 - (2 - amino - 4 - methylthioanilino) 5 - ethyl - thiophene - 3 - carboxylate (o) Methyl 3 - (2 - aminoanilino) - thiophene - 2 carboxylate m.p. 102°C.

The title compound was prepared by the reduction of methyl 3-(2- nitroanilino) - thiophene - 2 carboxylate. (p) Methyl 3-(2- amino - 4 - fluoroanilino) thiophene - 2 - carboxylate ι - 17 The title compound was similarly prepared by the reduction of methyl 3-(4- fluoro - 2 - nitroanilino) - thiophene - 2 - carboxylate. (q) Methyl 3-(2- amino - 4 - chloroanilino) - thiophene - 2 - carboxylate (r) Methyl 2-(2- amino - 4 - fluoroanilino) - 5 methyl - thiophene - 3 - carboxylate m.p. 116-118°C. (s) Ethyl 5 - i - propyl - 2 - (4 - fluoro - 2 aminoanilino) - thiophene - 3 - carboxylate (t) Ethyl 5-n - hexyl - 2 - (4 - fluoro - 2 - aminoanilino) - thiophene - 3 - carboxylate (u) Ethyl 4 - methyl - 2 - (4 - fluoro - 2 - aminoanilino) - thiophene - 3 - carboxylate (v) Ethyl 4 - methyl - 5 - ethyl - 2 - (4 - fluoro 2 - aminoanilino) - thiophene - 3 - carboxylate (w) 2-(2- Aminoanilino) - 5 - ethyl - thiophene 3 - carboxylic acid - Ethyl -2-(2- nitroanilino) - thiophene - 3 carboxylic acid (8.0 g, 0.027 mol) in ethanol (150 ml) was catalytically reduced over 10% palladium on charcoal (900 mg) at 60 p.s.i. The catalyst was removed by filtration and the solvent removed by distillation in vacuo to give the title compound. (x) Methyl 5 - ethyl -3-(2- amino - 4 - fluoroanilino) - thiophene - 2 - carboxylate EXAMPLE 7 Ethyl 2-(2- amino - 4 - nitroanilino) - 5 ethyl - thiophene - 3 - carboxylate Ethyl 2 - (2,4 - dinitroanilino) - 5 - ethyl thiophene - 3 - carboxylate (0.5 g) in 6N ammonia (25 ml) - 18 and ethanol (10 ml) was stirred at reflux temperature and hydrogen sulphide gas passed in over a period of 2 hours. The reaction mixture was cooled to room temperature and the title compound obtained as a yellow precipitate filtered off, washed with water, and dried in vacuo, m.p. 174-176°C (EtOAc).

EXAMPLE 8 Ethyl 2-(2- amino - 4 - bromoanilino) - 5 ethyl - thiophene - 3 - carboxylate Ethyl 2-(4- bromo - 2 - nitroanilino) - 5 - ethyl - thiophene - 3 - carboxylate (0.4 g, 0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride (0.4 g) in water (10 ml) and stirred at 50°C for 24 hours. The reaction mixture was filtered and the recovered solid washed successively with water and ethyl acetate.

The organic phase was separated, washed with water, dried (MgSO^) and evaporated in vacuo to give the title compound.

EXAMPLE 9 (a) Methyl 3-(2- Aminoanilino) - 2,5 - dihydrothiophene - 4 - carboxylate - Carboxymethyltetrahydrothiophen - 4 - one (48.06 g, 0.3 m) and o -phenylenediamine (32.4 g, 0.3 m) were dissolved in boiling ethanol (500 ml), to which a few drops of acetic acid had been added. The solution was then heated under reflux, in a nitrogen atmosphere for four hours and left to cool. The crystalline material so obtained Was filtered off, washed with ethanol and dried under vacuum. The product was recrystallised from absolute ethanol using activated charcoal as a decolouriser, a yellow solution being obtained from which white needles crystallised out. The white crystalline solid was filtered off, washed with ethanol and dried under vacuum to give the title product, m.p. 101°C. 2 5 6 5 - 19 (b) Methyl 3-(2- amino - 4,5 - dichloroanilino) 2,5 - dihydrothiophene - 3 - carboxylate The title compound, m.p. 152°C, was obtained by a process similar to that of Example 9(a).

EXAMPLE 10 (a) Methyl 3-(2- aminoanilino)thiophene - 4 carboxylate Methyl 3-(2- aminoanilino) - 2,5 - dihydrothiophene - 4 - carboxylate (25.03 g, 0.1 mol) and chloranil (24.6 g, 0.1 mol) were refluxed together in xylene (900 ml) for two hours. The solvent was then evaporated off, under vacuum to leave a dark brown solid which was triturated with ethyl acetate to give a light brown solid, which was filtered, washed with ethyl acetate and dried under vacuum to give the title product, melting point 12O-122°C.

Similarly prepared was :(b) Methyl 3-(2- amino - 4,5 - dichloroanilino) thiophene - 4 - carboxylate m.p. 162-163°C.

EXAMPLE 11 Methyl 3-(2- aminoanilino) - thiophene - 4 carboxylate Methyl 3-(2- aminoanilino) - 2,5 - dihydrothiophene - 4 - carboxylate (2.5 g, 0.001 mol) was added to a flask containing palladium on charcoal catalyst (5%, 200 mg) in cyclohexene (or norbornadlene or norbornylene) (50 ml) and the reaction was heated at reflux with stirring for 4 hours, the reaction being followed by t.l.c.

The reaction mixture was then cooled, the solvent evaporated off under vacuum to leave a dark brown oil which was column chromatographed using a Florisil column and chloroform to give the title product as an 42365 - 20 orange solid, m.p. 12O-122°C.

EXAMPLE 12 (a) 3-(2- Amino - 5 - trifluoromethylanilino) 2,5 - dihydro - thiophene - 4 - nitrile 4 - Trifluoromethyl - o - phenylenediamine (24 g, 0.136 mol) and 3 - keto - 4 - organo - 2,5 - dihydrothiophene (17.3 g, 0.136 mol) were dissolved in 200 ml of warm ethanol, acetic acid (3 ml) was added and the solution heated under reflux for 24 hours, then left to cool. The title product was thus obtained as a white solid which was filtered off and combined with solid obtained from evaporating the filtrate to small bulk, and cooling, m.p. 189°C.

Similarly prepared were:15 (b) 3 - (2 - Amino - 5 - chloroanilino) - 2,5 dihydrothiophane - 4 - nitrile m.p. 164~165°C. (c) 3-(2- Aminoanilino) - 2,5 - dihydrothiophene 4 - nitrile - Keto - 4 - cyanotetrahydrothiophene (80 g, 0.629 mol) and o - phenylenediamine (68 g, 0.629 mol) were dissolved by heating in 1.5 litres of industrial methylated spirit. To the solution, glacial acetic acid (3 ml) was added, the solution then being heated under reflux with mechanical stirring for 24 hours. The solution was then chilled and filtered to give the title product as a solid, m.p. 163°C.

EXAMPLE 13 (a) 10 - Amino - 7 - chloro - 4H - thieno/3,4 - £//1,5/benzodiazepine 3 - (4 - Chloro - 2 - nitroanilino) - thiophene - 4 nitrile (17.18 g, 0.06 mol) was hydrogenated in ethanol (300 ml) and ethyl acetate (100 ml) using a palladium/ 2 5 6 5 - 21 charcoal catalyst (3.5 g, 10%) in a Parr hydrogenator to give 3-(4- Chloro - 2 - aminoanilino) - thiophene - 4 - nitrile. After two hours, the reaction was complete, the catalyst was filtered off and the solution was evaporated to dryness under vacuum.

The light brown solid obtained was redissolved in absolute ethanol (100 ml) in a three-necked flask (500 ml). Concentrated hydrochloric acid (12 ml) was added dropwise carefully to the stirred solution. The alcoholic solution was then allowed to reflux for approximately 24 hours. Sodium hydroxide solution (10%, 60 ml) was then added dropwise to the cooled solution until the solution was slightly basic. During addition, a precipitate of the title compound was formed, which was filtered off to give a pale yellow/brown solid, which was washed with water and dried at 50°C under vacuum, m.p. 239-24O°C.

Similarly prepared were:(b) 10 - Amino - 7 - methylthio - 4H - thieno/3,4 - b//1,5/benzodiazepine, m.p. 195°-7°C. (c) 12 - Amino - 9 - fluoro - 6H - 1,2,3,4 - tetrahydrobenzothieno/J, 3 - bf/ΐ, 5/benzodiazepine (d) 10 - Amino - 2 - ethyl - 7 - fluoro - 4H - thieno/2,3 - 1//1,57benzodiazepine (e) 10 - Amino - 2 - ethyl - 7 - methoxy - 4H - thieno/2,3 - b//l,57benzodiazepine (f) 10 - Amino - 2 - ethyl - 7 - methylthio - 4H thieno/2,3 - b//T,57benzodiazepine (g) 10 - Amino - 2 - ethyl -7.- trifluoromethyl 4H - thieno/2,3 - S7/I,5/benzodiazepine (h) 10 - Amino - 1 - ethyl - 7 - fluoro - 4H - th.ieno/7,4 - 57/1, 5/benzodiazepine 43565 - 22 EXAMPLE 14 (a) 10 - Amino - 4H - 1,3 - dihvdrothieno/3.4 - h//l,57benzodiazepine hydrochloride 3-(2- Aminoanilino) - 2,5 - dihydrothiophene 5 4 - nitrile (84.5 g, 0.39 mol) was suspended by mechanical stirring in hot industrial methylated spirit (1.5 litres). Concentrated hydrochloric acid (57 ml, 0.66 mol) was added dropwise, the solution was stirred at reflux temperature for 1 hour then chilled, and the solid so obtained filtered, washed with a little industrial methylated spirit, petrol (4O-6O°C) and dried at 50°C under vacuum. The title compound so obtained had a melting point of 292°C . (decomp.). (h) 10 - Amino - 4H - 1,3 - dihydrothieno/3, 4 - £715 /1 ,_57benzodiazepine The hydrochloride of (a) above (54.5 g) was suspended in 1 litre of chloroform with mechanical stirring and 500 ml. of 10% w/w sodium hydroxide was added in one portion. The suspension was stirred for two hours where20 upon the title compound was obtained as a white solid.

This was filtered off, washed with water, ethanol, ether and dried under vacuum to give the free base, m.p. 240250°C (decomp.). (c) 9,10 - Dihydro - 4H - 1,3 - dihydro - thieno25 /5,4 - b7/li5/l>enzodiazepine - 10 - one Methyl 3 (2 - aminoanilino) - 2,5 - dihydrothiophene - 4 - carboxylate (0.5 g, 0.002 mol) in dry DMSO (2 ml) was added to a solution of 50% w/w sodium hydride/ oil suspension (300 mg) in dry DMSO at 90° under nitro30 gen. When effervescence had ceased, the solution was stirred for two hours and poured onto 300 ml. of icebrine. The solutioh was then extracted into ethyl acetate, the extract dried with magnesium sulphate, filtered and evaporated to small bulk. Ether was added to the 3 5 6 5 - 23 suspension and this was filtered. The filtrate was evaporated to dryness and triturated with chloroform to yield the title compound as a yellow solid, m.p. 210°C (decomposition).

EXAMPLE 15 (a) 10 - Amino - 4H - 1,3 - dihydrothieno/3,4 - b//T,S/~ benzodiazepine - Cyanotetrahydrothiophen- 4 - one (80 g, 0.629 mol) and o - phenylenediamine (68 g, 0.629 mol) were dissolved in 1.5 litres of industrial methylated spirit by heating under reflux with stirring, acetic acid (3 ml) was then added and the mixture heated under reflux with stirring for 5 hours. To the cooled solution there was carefully added concentrated hydrochloric acid (92 ml, 1.08 mol) with stirring. The solution was then heated under reflux for one hour and to the chilled, stirred solution of hydrochloride there was added 10% w/w sodium hydroxide (500 ml) dropwise, keeping the temperature below 40°C. The solution was then stirred for one hour, the solid filtered off, washed with water, ethanol, acetone, ether, dried under vacuum. The dried product, which was the title compound, had an m.p. of 230-240°C (decomp.). (b) 10 - Amino - 4H - thieno/J,4 - S/benzodiazepine - Amino - 4H - 1,3 - dihydrothieno/3,4 - b7/l,57~ benzodiazepine (43 g, 0.198 mol) was suspended with mechanical stirring in boiling xylene (1 litre). To this was added chloranil (49 g), the suspension being stirred at reflux temperature for 2-6 hours and then left to stand overnight at room temperature. The suspension was then filtered, and the solid washed with xylene until the washings were colourless. It was then dried on a filter funnel. The dried black solid thus obtained was suspended 43565 - 24 in hot water (200 ml) and 5M hydrochloric acid (36 ml) was added to form a red solution which was boiled for 10 minutes.

The solution was then filtered and residual tar 5 extracted with another 36 ml of 5M HCl in water (200 ml) and refiltered. The collected hot filtrates were added dropwise to an ice-cooled solution of sodium hydroxide (14.4 g, 0.36 mol) in water (100 ml) at such a rate that the temperature of 40°C was not exceeded. The solution was stirred for 1 hour, filtered, the solid being washed with water and dried under vacuum at 50°C. The dried title compound thus obtained had a melting point of 190°C (decomp.).

EXAMPLE 16 (a) 10 - Amino - 6 - trifluoromethyi - 4H - 1,3 dihydrothieno/T, 4 - b7/l,57benzodiazepine 3-(2- Amino - 5 - trifluoromethylanilino) - 4 cyano - 2,5 - dihydrothiophene (10.5 g, 0.368 mol) was dissolved in industrial methylated spirit (100 ml) by heating, and to this stirred solution, a solution of concentrated hydrochloric acid (3.2 ml, 0.0368 mol) was carefully added. The red solution so formed was heated under reflux for 1 hour. To the chilled, stirred solution, a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise, the temperature being kept below 40°C. The buff amidine thus formed was filtered off, washed with water, ethanol, 4O-6O°C petrol, and then dried at 50°C under vacuum. The filtrate was diluted with an excess of water and the solid so produced was filtered off and dried and included with the other solid. The title compound thus produced had a melting point of 2OO-21O°C (decomp.).

Similarly prepared was:4 2 5 6 5 - 25 (b) 10 - Amino - 6 - chloro - 4H - 1,3 - dihydrothieno/3,4 -_b//l,5/benzodiazepine EXAMPLE 17 The product of Examples 16(a) and 16(b) were aromatised to (a) 10 - Amino - 6 - trifluoromethyl - 4H - thieno/J,4 - b7/jL,5/benzodiazepine, m.p. 178°C (dec); and (b) 10 - Amino - 6 - chloro - 4H - thieno/3-, 4 - b//l,57benzodiazepine, using the process of Example 15(b).

EXAMPLE 18 (a) 9,10 - Dihydro - 2 - ethyl - 4H - thieno/2,3 - b7~ /J,57benzodiazepin - 10 - one Sodium methyl sulphinyl carbanion was generated by stirring sodium hydride (7.2 g, 0.15 mol) in dry dimethylsulphoxide (loo ml) at 70°C until gas evolution ceased. Ethyl 2-(2- aminoanilino) - 5 - ethyl thiophene - 3 - carboxylate (14.5 g, 0.05 mol) in dry dimethylsulphoxide (50 ml) was added and stirred for 15 minutes. The mixture was poured onto ice-water (600 ml) and stirred for fifteen minutes. The solid was filtered off, washed well with water, dried, washed with carbon tetrachloride and dried in vacuo at 60°C. The dried product which was the title compound had a melting point of 218~220°C (CHC13). (b) 2 - Ethyl - 7- fluoro - 9,10 - dihydro - 4H thieno/2,3 -b7,/T,^/benzodiazepin - 10 - one The title compound, m.p. 210-212°C, was similarly prepared from ethyl 2-(2- amino - 4 - fluoroanilino) - ethyl - thiophene - 3 - carboxylate. The title compound was reerystallised from ethanol. - 26 The following compounds were also similarly prepared using the process of Example 18(a). Xn each case, the starting thiophene material, melting point of title product, and recrystallisation solvent are indicated. (c) 6,8 - Difluoro - 9,10 - dihydro - 2 - ethyl - 4H thieno/2]3 - U//T,^/benzod.iazepin - 10 - one Ethyl 2 - (2 - amino - 3,5 - difluoroanilino) - 5 ethyl - thiophene - 3 - carboxylate, m.p. 23O-232°C (CHC13). (d) 9,10 - Dihydro - 2 - ethyl - 6 - fluoro - 4H thieno/2,3 - b//l,5/benzodiazepin - 10 - one Ethyl 2-(2- amino - 5 - fluoroanilino) - 5 ethyl - thiophene - 3 - carboxylate, m.p. 255-257°C (EtOAc). (e) 7 - Chloro - 9,10 - dihydro -2.- ethyl - 4H thieno/2,3 - b7/l,57benzodiazepin - 10 - one Ethyl 2 - (2 - amino - 4 - chloroanilino) - 5 ethyl - thiophene - 3 - carboxylate, m.p. 216-218°C (EtOAc). (f) 7 - Amino - 9,10 - dihydro - 2 - ethyl - 4H thieno/2,3 - b//l,5/benzodiazepin - 10 - one Ethyl 2 - (2,4 - diaminoanilino) - 5 - ethyl - thiophene - 3 - carboxylate, m.p. 23O°C (decomp.) (CHC13/ MeOH). (g) 9,10 - Dihydro - 2 - ethyl - 6 - methyl - 4H thieno/2,3 - bZ/l/S/benzodiazepin - 10 - one 2-(2- Amino - 5 - methylanilino) - 5 - ethyl thiophene - 3 - carboxylate m.p. 205-207°C (EtOAc). (h) 9,10 - Dihydro - 7 - N,N - dimethylsulphonamido 2 - ethyl - 411 - thieno/T,3 - b7/I,£7benzodiazepin - 10 - one - 27 Methyl 2-(2- amino - 4 - Ν,Ν - dimethylsulphonamidoanilino) - 5 - ethyl - thiophene - 3 - carboxylate, m.p. 258-260°C (EtOAc). (i) 9,10 - Dihydro - 2 - ethyl - 7 - nitro - 4H thieno/2,3 - b7/l,57benzodiazepin - 10 - one Ethyl 2-(2- amino - 4 - nitroanilino) - 5 - ethyl - thiophene - 3 - carboxylate, m.p. 264-266°C (EtOAc). (j) 9,10 - Dihydro - 7 - fluoro - 4H - thieno/2,3 - b//1,5/benzodiazepin - 10 - one Ethyl 2-(2- amino - 4 - fluoroanilino) - thiophene - 3 - carboxylate, m.p. 235-24O°C (CCl^/hexane). (k) 9 - Fluoro - 6H - 1,2,3,4,11,12 - hexahydrobenzothieno/2,3 - b7/J,§7benzoazepin - 12 - one Ethyl 2-(2- amino - 4 - fluoroanilino) - 4,5,6,7 tetrahydrobenzo/B/thiophene - 3 - carboxylate m.p. 238°C (EtOAc). (l) 9,10- Dihydro - 2 - ethyl - 7 - trifluoromethyl 4H - thieno/2,3 - b//?,5/benzodiazepin - 10 - one Ethyl 2-(2- amino - 4 - trifluoromethylanilino) 5 - ethyl - thiophene - 3 - carboxylate. (m) 9,10 - Dihydro - 2 - ethyl - 7 - methoxy - 411 thieno/2,3 -_b//l,5/benzodiazepin - 10 - one Ethyl 2-(2- amino - 4 - methoxyanilino) - 5 ethyl - thiophene - 3 - carboxylate. (n) 9,10 - Dihydro - 2 - ethyl - 7 - methylthio - 4H thieno/2,3 - _B7/1,57benzodiazepin - 10 - one Ethyl 2-(2- amino - 4 - methylthioanilino) - 5 ethyl - thiophene - 3 - carboxylate. (o) 6,7 - Difluoro - 9,10 - dihydro - 2 - ethyl - 4H thieno/2,3 - Β//Ί,5/benzodiazepin - 10 - one •42565 - 28 Ethyl 5 - ethyl - 2 - (4,5 - difluoro - 2 - aminoanilino) - thiophene - 3 - carboxylate, m.p. 290°C. (p) 9,10 - Dihydro - 7 - fluoro - 2 - phenyl - 411 thieno/2~,3 - £//1,57benzodiazepin - 10 - one m.p. 250°-252°C (dec.) (EtOAc). (q) 9,10 - Dihydro - 7 - fluoro - 2 - methyl - 4H thieno/2,3 - b7/l,57benzodiazepin - 10 - one m.p. 25O-252°C (EtOAc). (r) 9,10 - Dihydro - 4H - thienq/β,2 - b7/T,S/benzo10 diazepin - 10 - one Methyl 3-(2- aminoanilino) - thiophene - 2 carboxylate, m.p. 226°C (CCl^). (s) 9,10 - Dihydro - 7 - fluoro - 4H - thieno/3,2 - b//1,67benzodiazepin - 10 - one Methyl 3-(2- amino - 4 - fluoroanilino) - thiophene .-2- carboxylate, m.p. 225-23O°C (EtOAc). (t) 7 - Chloro - 9,10 - dihydro - 4H - thieno/3,2 - bj/T, 57benzodiazepin - 10 - one Methyl 3-(2- amino - 4 - chloroanilino) - thio20 phene - 2 - carboxylate, m.p. 255-256°C (EtOAc). (u) 9,10 - Dihydro - 4H - thieno/3,4 -_b//T,ybenzodiazepin - 10 - one, m.p. 233-234°C. (v) 9,10 - Dihydro - 7 - fluoro - 4H - 10 - one.

Melting point 238°C (decomposition). (w) 6,7 - Dichloro - 9,10 - dihydro - 4H - thieno/3,4 -_b//L,57benzodiazepin - 10 - one. Melting point 284-287°C. (x) 2 - i - Propyl - 7 - fluoro - 9,10 - dihydro - 4H thieno/2, 3 - jy/T, 5/benzodiazepin - 10 - one - 29 XO (y) 2 - n ·- Hexyl - 7 - fluoro - 9,10 - dihydro ~ 4H thieno/2,3 “ _b72l/5/t>enzodiazepin -· 10 - one (z) i - Methyl - 7 - fluoro - 9,10 - dihydro - 4U thieno/2,3 - j£7/l,5/benzodiazepin - 10 - one (aa) 1 - Methyl - 2 - ethyl - Ί - fluoro - 9,10 dihydro - 4H - thieno/2,3 - b//I,5/benzodiazepin 10 - one (bb) 2 - Ethyl - 7 - fluoro - 9,10 - dihydro - 4H thieno/3,2 ~ b7/I,57henzodiazepin - 10 - one (cc) 2 - Ethyl - 9,10 - dihydro - 4H - thieno/Σ, 3 - b//T, 5/benzadiazepin - 10 - one - Ethyl - 2 - (2 - aminoanilino) - thiophene - 3 carboxylic acid was dissolved in tetrahydrofuran (distilled from lithium aluminium hydride)(200 ml) and solid dicyclohexylcarbodiimide (5.7 g, 0.027 mol) added. The mixture was stirred under a nitrogen atmosphere for 16 hours and the solution thus formed filtered and evaporated to dryness. The residue was boiled with carbon tetrachloride and allowed to crystallise to yield the title compound, m.p. 218-22O°C (CHCl^).

EXAMPLE 19 (a) 7 - Chloro - 9,10 - dihydro - 4H - thieno/3,4 - bf/T,57bensodiazepin - 10 - one - Amino - 7 - chloro - 4H - thieno/3,4 - //7),3/25 benzodiazepine (4 g, 0.15 mol) was dissolved in the minimum of water (100 ml) to which was added potassium carbonate ¢13.0 g) in water (20 ml). Absolute ethanol (40 ml) was then added to redissolve the amidine and the reaction mixture gently refluxed for 17 hours, during the last hour of which, the ethanol was slowly distilled off.

The reaction mixture was then allowed to cool, and concentrated hydrochloric acid added dropwise to the - 30 solution, in the presence of ethyl acetate, until the solution was slightly acidic. The aqueous phase was extracted with ethyl acetate, dried over MgSO^ and the bulked extracts evaporated to dryness under vacuum, the title product being obtained as a light brown solid.

The solid was triturated with ether, filtered and dried at 50°C under vacuum to give a yellow solid, m.p. 212213°C.

Using the hydrolytic procedure of Example 19(a) the following other amides were obtained :(b) 9,10 - Dihydro - 4H - thieno/T/4 - Jb72T,57benzodiazepin - 10 - one. Melting point 234°C (decomp). (c) 9,10 - Dihydro - 7 - methylthio - 4H - thieno- by//?, S/benzodiazepin - 10 - one (d) 9,10 - Dihydro - 6 - trifluoromethyl - 4H thieno/T, 4 - b7/r,5/benzodiazepin - 10 - one, m.p. 213°C. (e) 9,10 - Dihydro - 2 - ethyl - 7 - fluoro - 4H thieno/2,3 - 6///,57benzodiazepin - 10 - one m.p. 211°C. (f) 9,10 - Dihydro - 2 - methyl - 7 - fluoro - 411 thieno/J,3 - b7/T,57benzodiazepin - 10 - one (g) 9,10 - Dihydro - 2 - ethyl - 7 - methylthio - 4H thieno/y, 3 - b7/T,57benzodiazepin - 10 - one (h) 9,10 - Dihydro - 2 - ethyl - 7 - trifluoromethyl 4H - thieno/?, 3 - bf/I, 57benzodiazepin - 10 - one (i) 9 - Fluoro - 6H - 1,2,3,4,11,12 - hexahydrobenzothieno/Σ, 3 - ΐ£7/ΐ,57benzodiazepin - 12 - one (j) 9,10 - Dihydro - 2 ethyl - 6 - trifluoromethyl 4H - thieno/2,3 - bjB-,57benzodiazepin - 10 - one - 31 (k) 1 - Ethyl - 7 - fluoro - 4H - thieno/3,4 - b//1.5/~ benzodiazepin - 10 - one EXAMPLE 20 9,10 - Dihydro - 4H - thieno/3, 4 - BJ/ΐ, 5/benzodiazepin - 10 - one 9,10 - Dihydro - 4H - 1,3 - dihydrothieno/374 - b//T,57benzodiazepin - 10 - one (0.33 g) was stirred in cyclohexene (norbornadiene or norbornylene) at reflux temperatures in the presence of a palladium on charcoal catalyst (o.l g, 5%), the reaction being followed by t.l.c. meiisurements. 'l’he reaction mixture was then cooled, and the solvent evaporated off under vacuum to leave dark brown solid which was column chromatographed using a Florisil column and 5% methanol in chloroform to give the title compound as a pale yellow solid, m.p. 23O-232°C.

EXAMPLE 21 - N - Acetylamino - 9,10 - dihydro - 2 - benzodiazepin - 10 - one - Amino - 9,10 - dihydro - 2 - ethyl - 4H - thieno/2,3 - b//I,57benzodiazepin - 10 - one (100 mg) was suspended in methylene chloride (5 ml) and triethylamine (0.1 ml). Acetic anhydride (10.1 ml) was added and the reaction mixture stirred for 18 hours. The precipitate was filtered off, washed with water, dried in vacuo at 60°C to give the title compound as a solid, m.p. 264°C.

EXAMPLE 22 - Chloro - 9,10 - dihydro - 4H - thieno/3,4 - K//1,5/benzodiazepin - 10 - one 4H - Thieno/3-, 4 - b/ΖΓ,^benzodiazepin - 10 - one (4.32 g, 0.02 mol) in hot dichloromethane was reacted - 32 with stirring, with N - chlorosuccinimide (3.0 g, 0.025 mol) in the presence of a trace of benzoyl peroxide. After refluxing for 1 hour the hot solution was filtered. The blue residue was washed with three portions of hot ethyl alcohol which were combined and bulked with the dichloromethane filtrate and evaporated to a brown solid. Soxhlet extraction with benzene and subsequent washing with I^COg solution, drying and evaporation yielded the title compound as a buff solid m.p. 229°C.

EXAMPLE 23 - Acetyl - 9,10 - dihydro - 2 - ethyl - 7 fluoro - 4H - thieno/2,3 - b7/T,57benzodiazepin 10 - one To a stirred solution of 9,10 - dihydro - 2 - ethyl - 7 - fluoro - 4H - thieno/Σ, 3 - ib7/T,57benzodiazepine (0.26 g, 0.001 mol) in acetyl chloride (3 ml) was added, with stirring, stannic chloride (2 drops). The reaction mixture was diluted with benzene (5 ml)‘ and stirred for 18 hours at room temperature. The reaction mixture was diluted with water and extracted into chloroform, the chloroform extracts were washed with water, dried (MgSO^) and evaporated in vacuo to give the title product as a solid, m.p. 215-218°C (MeOH/hexane).

EXAMPLE 24 (a) 9,10 - Dihydro - 2 - ethyl - 7 - fluoro - 4H thieno/2,3 - b7/I,57benzodiazepin - 10 - throne 9,10 - Dihydro - 2 - ethyl - 7 - fluoro - 4H thieno/Σ) 3 - 57/J-,57benzodiazepin - 10 - one (20 g, 0.076 mol) was added to a stirred solution of phosphorus pentasulphide (17 g, 0.076 mol) in dry pyridine (400 ml). The solution was stirred at gentle reflux for 1.5 hours, poured onto ice-water, stirred for 1 hour, filtered, washed with cold water and dried. Recrystallisation from ‘3 ίί 6 5 EtOH/water gave the title compound as bronze plates m.p. 2O3-2O6°C. (b) 9,10 - Dihydro - 2 - ethyl ~ 4H - thieno/T,3 - Jof/1,5/benzodiazepin - 10 - thione The title compound was similarly prepared using the process of Example 24(a) with 9,10 - dihydro - 2 - ethyl 411 - thieno/?, 3 - b7/T,5/benzodiazepin - 10 - one as starting material, m.p. 233~236°C (EtOH-H^O).

Similarly prepared were:10 (c) 9,10 - Dihydro - 2 - ethyl - 7 - nitro - 4H thieno/_2,3 - b//l,5/benzodiazepin - 10 - thione (d) 9,10 - Dihydro - 4H - thieno/3,4 - b7/T,5/benzodiazepin - 10 - thione, m.p. 221°C.

Other amides of Example 18 were similarly converted into their thioamide derivatives using the procedure of Example 24(a). In each case, the identification and confirmation of the final product was effected by means of t.l.c. and microanalytical evidence.

Claims (3)

1. A compound of formula: R' ,1 Q (I) 1 2 wherein R and R independently represent hydrogen, 5 c i-4 alky 1 / C 2-4 alkenyl, C 3_g cyeloalkyl, halogen, C^_ 4 haloalkyl, nitro, amino, C 2 _^ alkanoyl amino, hydroxyl, alkoxy, alkylthio or a group of formula -SO 2 N(R^) 2 or SO 2 r4, where R^ is Cy_^ alkyl wherein the group represents an optionally substituted thiophene ring fused to the diazepine nucleus? and where Q is hydroxyl, thiol, alkoxy, C^_^ alkylthio, halogen or amino.

2. A compound as claimed in Claim 1 wherein Q is 15 hydroxyl.

3. A compound as claimed in Claim 1 substantially as hereinbefore described with reference to any one of the foregoing Examples 13, 15(b) and 17 to 24.