SE429045B - INTERMEDIATE FOR USE IN THE PREPARATION OF TIENOBENZODIAZEPINES - Google Patents

Description

The present invention relates to intermediates of the following formula V, which are useful in the preparation of novel thieno [1,5] benzodiazepines of formula (I) 1 and R 2 each represent a hydrogen atom, C 1-4 alkyl group, halogen atom, C 1-4 and acid addition salts thereof, wherein R is haloalkyl group, hydroxyl group, C 1-4 alkoxy group or C 1-4 alkylthio group or -SO 2 NR 2, wherein R 4 represents a C 1-4 alkyl group P | R 5 represents a group of the formula 'wherein R 6 represents a hydrogen atom, a C 1-4 alkyl, C 3-6 cycloalkyl, benzyl or C 1-4 carbalkoxy group or - (CH 2) n OX, where n is 2 or 3 and X represents a hydrogen atom or an ester radical, and the symbol 7812194-4 means a thiophene ring fused to the diazepine nucleus.

In the compounds of formula I and their acid addition salts, R 1 and R 2 represent a hydrogen atom or a halogen atom or a C 1-10 alkyl, C 1-10 haloalkyl, C 1-8 alkoxy or C 1-10 alkylthio group or -SO NRH, where R represents a C 1-8 alkyl alkyl group, and R 5 is preferably a group of the formula preferably each one wherein R 5 is carbalkoxy group or - (CH 2) n OH, where n is 2 or 3.

The novel thieno [1,5] benzodiazepines can, of course, mean that a hydrogen atom, a C1-6 alkyl group, a C1_u- can have three different forms, which can be represented by the formulas ï 1 R _ / N-C G N s R H 5 R RT | N = C (::> S (III) N R 2 'H 7812194-4' (IV) In the above structural formulas, the thiophene ring is shown to be unsubstituted for simplicity, but it may of course be substituted, for example with one or two identical or different substituents, which may be C 1-6 alkyl groups.

In addition, in the structures of formulas II and IV, the thiophene ring may be fused to a cycloalkyl ring having 3 to 8 carbon atoms.

By "C 1-4 alkyl group having not more than 4 carbon atoms, i.e. methyl, ethyl, n- -alkyl group" is meant a straight or branched propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl group. By "C 1-4 haloalkyl group" is meant such an alkyl group substituted by one or more halogen atoms, eg trifluoromethyl group. By "-alkoxy group" or C thiophene ring.

With "C 3-6 cyclic group having not more than 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

As stated above, the novel thieno [1,5] benzodiazepines-cycloalkyl group "is intended to be a saturated carbon useful both as free bases and as acid addition salts. These salts are preferably pharmaceutically acceptable additive salts with suitable acids. , such as inorganic acids, eg hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acids, and organic acids, such as carboxylic acids, eg glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, salicylic acid, o-acetoxybenzoic acid, nicotinic acid and isonicotinic acid, and organic sulfonic acids, eg methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid and naphthalene-2-sulfonic acid. salts with picric acid and oxalic acid, which may serve as intermediates in the purification of the compounds or in the preparation of other acid addition salts, for example pharmaceutically ac acceptable salts, or they are useful for identifying, characterizing or purifying the bases.

The compounds of formula I can be prepared by a process which consists in reacting an amine of formula RSH with a compound of formula (V) R 2 H where R 1, R 2 and R 5 have the meanings given above, the symbol means an optionally substituted fused thiophene ring as well as above and Q represents a radical which can be cleaved with the hydrogen atom of the amine RSH, and when R 5 represents 781ZÉ94-f4 '10 and R6 represents a C1-4 carbalkoxy group, optionally hydrolysed to the amine, wherein R6 represents a hydrogen atom.

The radical Q may be a hydroxyl or thiol group, an amino group or a mono- or dialkyl substituted amino group, wherein each alkyl group has at most 4 carbon atoms.

Preferably Q represents a hydroxyl or thiol group, d wherein the intermediates of formula V are predominantly in amide or thioamide form, i.e.

S H 'U NH: C or C' \ iWhen Q represents a hydroxyl group PP, i.e. the compound of formula V is an amide, the reaction a can be carried out in the presence of titanium tetrachloride. This compound is capable of reacting with the amine of the formula RSH to form a metal amine complex. Other metal chlorides, such as chlorides of zirconium, hafnium and vanadium, also have this property. The reaction is conveniently carried out in the presence of an acid-binding agent, such as a tertiary amine, e.g. triethylamine. Alternatively, the reaction may be carried out with excess of the amine R 5 H as an acid scavenger.

Any suitable solvent, such as toluene or chlorobenzene, may be used, although it has been found particularly convenient to use anisole, at least as an auxiliary solvent, in view of its ability to form a soluble complex with titanium tetrachloride.

To speed up the reaction, you can use an elevated temperature (up to 14000). A suitable temperature range for carrying out the reaction is 50 - 100 ° C.

The amidines of formula V, i.e. Q is NH 2, can likewise be condensed with the amine of the formula RSH, although the yield of this reaction may be rather low. In fact, it is generally most convenient to convert the amidine to the corresponding amide by alkaline hydrolysis and use the amide formed for the condensation reaction.

Thioamides of formula V (Q is SH) can be prepared by treating a solution of the corresponding amide in an anhydrous basic solvent, such as dry pyridine, with phosphorus pentasulfide. Likewise, the amides can be converted to iminothioethers, iminoethers or iminohalides or other derivatives with active radicals Q as above by treatment with conventional reagents, e.g. phosphorus pentachloride for an imino chloride. These derivatives of the amides are usually more reactive with the amine R5H and can generally be reacted with the need to use titanium tetrachloride.

The compounds of formula I prepared by the above procedure can be isolated as such or converted to the corresponding acid addition salts by conventional methods. The amides of formula V can be prepared by a new process which involves intramolecular cyclization of an amino ester of formula 2 g (v11) R 2 N where R 9 represents a C 1-10 alkyl group, e.g. ethyl group, and R 1, R 2 and have the meanings given above. The reaction may be carried out with dimethyl sodium in a suitable solvent, preferably dimethyl sulfoxide.

Alternatively, amides of formula V may be prepared by intramolecular cyclization of an amino acid of formula _: <1 2 NH 2 I * A 3 _N: <2 .H by means of dicyclohexylcarbodiimide in a suitable solvent (VIII) such as tetrahydrofuran. The amino acids can be obtained from the esters by basic hydrolysis, for example with NaOH / EtOH.

A suitable method of preparing amides of formula V involves, as mentioned above, the reaction. .-._-, ._.__._._._..._._._ 1 7812194-4 1 NH2 RN = C (IX) N Rz H 1 hydrolysis O 1 HRN NC / 2 NRH The hydrolysis can be performed under alkaline hydrolytic conditions, for example with KQCO3 / H2O / EtOH.

A suitable method for preparing amidines of formula IX is set forth below.

R R1 + DMS1_, _ \ 1 <co F 2 3 2 NRRH H2 / Pd ~ C R1 N fl g N 2 H IHCl / ethanol R 7: 8 'IïiZ 1914- 4 16 l R1 ïfHz mig, N 122 H Alternatively, amidines can i [S fi-bl system is prepared with the reaction sequence given below. _ 1 - R1 X V R1 N02 CN 'NO CN ßFs-Etzü /' toluæn 2 \ + S värme åå- NHZ o * a N Rz R2 H '2 X Chloranil / xylene värm R1 X1 R1 X1 ma? t: l a N02 CN _ QS H2 PdC. S N í N RQ H X2 R? - H X2 (IX) 7812194-4 11 where X1 and X2 denote possible substituents on the thiophene ring. The above reaction involves an "aromatization" with chloranil and xylene.

Alternatively, the above reaction can be performed with o-phenylenediamines instead of the nitroanilines.

The esters of formula VII are new compounds which can be prepared by condensation of a thiophene compound of formula R CO HZN where RQ has the meaning given above, with an orthofluoronitrobenzene of formula R2 in the presence of an n-butyllithium derivative or in the presence of a base, such as sodium hydride, sodium amide, triethylamine or potassium carbonate in dimethyl sulphoxide, to a nitro ester of the formula 121 co ZRQ NO2 TN Rz H which can then be reduced to the amino ester of formula VII by catalytic , ammonium polysulfide or Fe / HCl. 7812194-4 -12 For example, HH-thieno [2,3-b] [1,5] benzodiazepines can be prepared according to the following exemplary reaction scheme.

CO Et 1 2 X Ü \ HZN 'SX 121- NO2 H2 / EtOH FR 10% PdC NaOH / EtOH R1 1 X NH2 CO2Et I 2 R2 \\\\ ~ g ///// SXNH H2 / EtOH DMSO Pd / C Other thieno [1,5] benzodiazepine-10-ones can be similarly prepared over the amino ester route outlined above.

The thiophones used in the process as starting material are either known (see, for example, Chem. Berichte 99, QH-100 (1966), J. Am. Chem. Soc. 68, 2,232 (19U6) and Dutch patent application 7812194-4. 66 (7H7H2) or can be prepared by conventional methods from known compounds. The orthofluoronitrobenzene intermediates are commercially available or can be readily prepared from commercially available substances.

The intermediates of formula V are novel compounds which are the subject of the present invention.

The compounds of formula I have useful activity on the central nervous system. This activity has been demonstrated in extensive animal testing using conventional methods, such as inducing catalepsy, blocking the conditioned escape reaction, and abolishing amphetamine-induced stereotyped behavior in rats. More specifically, the compounds of formula I and their acid addition salts are potent centrally acting compounds having neuroleptic, sedative or relaxing or antiemetic properties. Together with their high therapeutic index, these properties make them useful for the treatment of mild anxiety disorders and certain types of psychotic conditions, such as schizophrenia and acute mania.

The invention is illustrated by the following preparation and examples. When the melting point is not specified, the structure of the final product has usually been confirmed by thin layer chromatography and / or spectral data.

Preparation 1 12.6 g (0.1 mol) of ethyl pent-3-enoate (J. Org. Chem. 12, 138-154) were added dropwise to a solution of 10.6 g (0.1 mol) of methyl thioglycolate and 0, 1 ml of piperidine, which was stirred together in a three-necked 100 ml flask with a dropping funnel, thermometer and condenser. The reaction temperature was maintained between 40 and 5000, while 0.6 ml of piperidine was added in 0.05 ml portions over H5 min. After addition of the pentenoate, the reaction mixture was kept at 50 ° C for 10 minutes. The reaction mixture was cooled, washed with water, dried over magnesium sulfate and filtered, and the filter cake was washed with ether. The combined filtrates were evaporated to dryness, and α'-carboxymethyl-β'-carboxyethyl-α-ethylethylmethyl sulfide was obtained as a yellow liquid. 81.12 194- 4- 14 Example 1 (a) 40 g (0.2 mol) of ethyl 2-amino-5-ethylthiothene-3-carboxylate (Ber. 99, QH - 100) in 150 ml of dry tetrahydrofuran were stirred under nitrogen and cooled to -HOOC. 125 ml, 2% (w / v) hexane solution of n-butyllithium (0.2 mol) was added, keeping the temperature below -3000.

The mixture was stirred for an additional 15 minutes at -30 ° C. The solution was purged with nitrogen through an inverted U-tube into a solution of 28 g (0.2 mol) of orthofluoronitrobenzene in 100 ml of dry tetrahydrofuran, which was kept at 15-3000.

The mixture was stirred overnight. The resulting ink blue solution was poured into three volumes of ice water, extracted with 3 X 500 ml of ether, washed with 2 X 500 ml of water, dried and evaporated to dryness. The dark red oil was dissolved in 200 ml of ethanol and cooled overnight. Crystals of ethyl 5-ethyl-2- (2-nitroanilino) -thiophene-3-carboxylate were filtered off and dried in vacuo at 50 ° C. Recrystallization from ethanol gave pure product, m.p. 66-68 ° C. (h) Ethyl 5-ethyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate, m.p. 9000 (after recrystallization from ethanol), was prepared in the same manner using the 2,5-difluoronitrobenzene instead of the orthofluoronitrobenzene used in Example 1a.

Ber. for C 15 H 15 FN 2 O 2 S C 53.24; H 4, H 5; N 8.28; F 5.61; S 9.47% C 53.5 H5; H 4.75; N 8.15; F 5.71; s 9.75% In the same manner, the following Found compounds were prepared by the procedure set forth in Example 1a.

In each particular case, the nitrobenzene used instead of the orthofluoronitrobenzene in Example 1a and the melting point of the final product together with the solvent for recrystallization are given in parentheses. (c) Ethyl 2- (3,5-difluoro-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 7U - 75 ° C (BtOH), was obtained from 2,4,6-trifluoronitrobenzene. (d) Ethyl 5-ethyl-2- (5-fluoro-2-nitroanilino) thiophene-s-carboxylate, m.p. av - ss ° c (Bron), was obtained from 24 + - difluoronitrobenzene. 7812194-4 (e) Ethyl 2- (4-chloro-2-nitroanilino) -5-ethylthiophen-3-2-fluoronitrobenzene. (f) Ethyl 2- (2,4-dinitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 148 ° C (EtOH), obtained from 2,4-dinitrofluorobenzene. (g) Ethyl 2- (4-fluoro-2-nitroanilino) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate, m.p. 140 DEG-142 DEG C. (EtOH), were also prepared using the procedure of Example 1a from 2,5-difluoronitrobenzene and ethyl 2-amino-4,5,6,7-tetrahydrobenzofb] thiophene-3-carboxylate as starting material. (h) Ethyl 2- (4,5-difluoro-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 105 ° C (EtOH), was obtained from 2,4,5-trifluoronitrobenzene. (i) Methyl 3- (2-nitroanilino) thiophene-2-carboxylate, m.p. 18400 (toluene / MeOH 2: 1), was prepared by the method of Example 1a, but using 2-fluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate (British Patent Specification 837,086) as starting material. (j) Methyl 3- (4-fluoro-2-nitroanilino) thiophene-2-carboxylate, m.p. 172 DEG-175 DEG C. (benzene), were prepared by the procedure of Example 1a, but using 2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate as starting material.

Example 2 (a) 56.4 g (0.4 mol) of orthofluoronitrobenzene and 100 g (0.5 mol) of ethyl 2-amino-5-ethylthiophene-3-carboxylate were dissolved in 320 ml of dry dimethyl sulfoxide. The solution stirred under nitrogen was heated on an oil bath. When the internal temperature reached 6000, 55 g (0, H mol) of potassium carbonate were added, and the mixture was stirred at 100 ° C until the GLC showed that all the orthofluoronitrobenzene had been consumed (6.5 h). The mixture was poured onto ice water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO 4) and evaporated to a red semi-solid residue, which was recrystallized from ethanol to give ethyl 5-ethyl-2- (2-nitroanilino) thiophene-3-carboxylate in solid form (m.p. 66 - ss ° c).

The following compounds were also prepared by the method of Example 2a. In each particular case, the melting point of the final product, the solvent pre-crystallization in parentheses and the starting materials are indicated to the extent that they differ from those given in Example 2a. (b) Ethyl 2- (H-chloro-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 75-7,600 (EtOH), was obtained from -chloro-2-fluoronitrobenzene. (c) Ethyl 2- (2,4-dinitroanilino) -5-ethylthiophene-3-carboxylate m.p. 1H6 - 148 ° C (EtOH), obtained from 2,4-dinitrofluorobenzene. (d) Ethyl 5-ethyl-2- (2-nitro-4-trifluoromethyl-anilino) thiophene-3-carboxylate, m.p. 102 ° C (EtOH), was obtained from U-fluoro-3-nitrobenzotrifluoride. (e) Ethyl 5-ethyl-2- (5-methyl-2-nitroanilino) -thiophene-3-carboxylate, m.p. 55-57 ° C (EtOH), obtained from 3-fluoro-4-nitrotoluene. (f) Ethyl 2- (4-difluoromethyl-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 88-90 ° C (EtOH), was obtained from -difluoromethyl-2-fluoronitrobenzene. (g) Methyl 2- (H-N, N-dimethylsulfonamido-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 166 DEG-168 DEG C. (EtOH), obtained from 5-N, N-dimethylsulfonamido-2-fluoronitrobenzene and methyl 2-amino-5-ethylthiophene-3-carboxylate. (h) Methyl 5-ethyl-2- (α-methoxy-2-nitroanilino) -thiophene-3-carboxylate, m.p. 125 DEG-127 DEG C. (EtOH), was obtained from 2-fluoro-5-methoxynitrobenzene and methyl 2-amino-5-ethylthiophene-3-carboxylate. (i) Ethyl 2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylate, m.p. 12500 (EtOH), was obtained from 2,5-difluoronitrobenzene and ethyl 2-aminothiophene-3-carboxylate. (k) Ethyl 2- (2-chloro-6-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 67-70 ° C (EtOH), was obtained from ethyl 2-amino-5-ethylthiophene-3-carboxylate and 3-chloro-2-fluoronitrobenzene. (1) Ethyl 5-ethyl-2- (2-trifluoromethyl-6-nitroanilino) thiophene-3-carboxylate, m.p. 72-73 ° C (EtOH), was obtained from ethyl 2-amino-5-ethylthiophene-3-carboxylate and 2-fluoro-3-trifluoromethylnitrobenzene. (m) Methyl 3- (4-chloro-2-nitroanilino) thiophene-2-carboxylate, m.p. 207-20800 (EtOAc / hexane), was obtained from -chloro-2-fluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate. (n) Methyl 5-methyl-2- (2-nitro-4-fluoroanilino) -thiophene-3-carboxylate, m.p. 149 DEG-151 DEG C. (EtOH), was obtained from methyl 2-amino-5-methylthiophene-3-carboxylate and 2,5-difluoronitrobenzene. (0) Ethyl 2- (4-bromo-2-nitroanilino) -5-ethylthiophene-3-carboxylate, m.p. 76-78 ° C (EtOH), was obtained from ethyl 2-amino-5-ethylthiophene-3-carboxylate and 5-bromo-2-fluoronitrobenzene. (p) Methyl 2- (4-fluoro-2-nitroanilino) -5-phenylthiophene-3-carboxylate, m.p. 150 ° C (CH 2 Cl 2), was obtained from methyl 2-amino-5-phenylthiophene-3-carboxylate and 2,5-difluorohitrobenzene. (q) 6.0 g of ethyl 5-ethyl-2- (2-nitroamino) thiophene-3-carboxylate were dissolved in 100 ml of ethanol and 50 ml of water and heated to 60 ° C with stirring. 50 ml of SN sodium hydroxide were added, and the temperature was maintained for 16 hours. The reaction mixture was cooled and diluted with 500 ml of water, and solid-ethyl-2- (2-nitroanilino) thiophene-3-carboxylic acid was filtered off, m.p. 189-119 ° C (EtoAc). (r) 5-ethyl-2 - (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid, m.p. 198 - 20,000 (EtQAc), was prepared in the same manner from ethyl 5-ethyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate, but with a reaction temperature of%.

Example 2 (a) 48.5 g (0.25 mol) of 3-carboxymethyl-4-amino-thiophene hydrochloride (JACS, 68,. and ether. The ether extract was dried over magnesium sulfate, filtered and evaporated to an oil which was dissolved in 160 ml of dimethylformamide (DMF), 2-methoxyethanol or anhydrous dimethylsulfoxide (DMSO), preferably the latter. To this stirred solution was added at 100 ° C under nitrogen 40 g (0.25 mol) of 2,5-difluoronitrobenzene and ml of trimethylamine. The reaction mixture was kept under reflux for one hour under these conditions, and 35 ml of triethylamine was added. The reaction mixture was heated with stirring under nitrogen for 40 hours. The cooled mixture was poured into 1.5 l of saturated brine with stirring in the presence of ethyl acetate, and the two-phase mixture was filtered. The organic phase was removed, washed with brine, dried over magnesium sulphate, filtered and evaporated to a brown gum.

This was dissolved in the least possible amount of ethyl acetate and vacuum filtered through a pad of "Florisil" (trademark) in a sintered funnel. The pad was washed with ethyl acetate until all product was discarded, the filtrates were combined, evaporated to an oil, dissolved in 250 ml of cold ethanol and allowed to stand at 0 ° C for 24 hours. The organic crystalline product sometimes contained traces of brown tar, but this could be disposed of by adding a small amount of ethyl acetate and triturating.

The resulting crystals were filtered, washed with ethanol and 40 DEG-60 DEG C. gasoline and dried in vacuo to give methyl 3- (4 + fluoroa2-nitroanilino) thiophene-4-carboxylate as a solid product, m.p. 164 ° C. 7812194-4 19, (b) Methyl 3- (2-nitro-4-trifluoromethylanilino) -thiophene-4-carboxylate, m.p. 175 ° C (EtOH) was prepared by the method of Example 3a. (c) 3.6 g (0.02 mol) of 2-amino-4,5,6,7-tetrahydrobenzofb] thiophene-3-nitrile and 3.2 g (0.02 mol) of 2,5-difluoronitrobenzene in 20 ml of dry DMSO was stirred and heated on an oil bath. When the internal temperature reached 60 ° C, 2.76 g (0.02 mol) of potassium carbonate were added, and the mixture was 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 and dried (MgSO 4), and the solvent was evaporated in vacuo to give 2- (4-fluoro-2-nitroanilino) -4,5,6,7-tetrahydrobenzofb] thiophene-annitrile, m.p. 137 DEG-139 DEG C. (EtoAc), obtained.

Example 4 (a) 38.1 g (0.25 ml) of 3-cyanotetrahydrotiophen-3-one (Dutch patent application 6,604,742) and 51.8 g (0.28 mol) of 4-chloro-2-nitroaniline were dissolved in approx. 200 ml under reflux boiling toluene in a 500 ml three-necked flask equipped with Dean-Stark apparatus. A few drops of boron trifluoride etherate were added, and the mixture was refluxed for 4 hours, separating the water formed. The reaction mixture was allowed to cool, whereupon a brown substance precipitated and was filtered off.

This was recrystallized from absolute ethanol with activated charcoal as decolorizing agent, and the resulting orange crystalline substance was filtered, washed with ethanol and dried at 50 ° C in vacuo. The dried solid was 3- (4-chloro-2-nitroanilino) -2,5-dihydrotiophene-4-nitrile, m.p. 154 DEG-155 DEG. 7812194-4 A a f (b) 3- (4-methylthio-2-nitroanilino) -2,5-dihydro-thiophene-4-nitrile, m.p. 141 DEG-142 DEG C. (EtOH) was prepared by a procedure similar to that of Example 4a.

A (c) 4- (4-fluoro-2-nitroanilino) -2-ethyl-2,5-dihydrotiophene-3-nitrile.

Example 5 14.09 g (0.05 mol) of 3- (4-chloro-2-nitroanilino) -2,5-dihydrotiophene-4-nitrile dissolved in 150 ml of xylene was added to a solution of 12.3 g (0, 05 mol) chloranil in 100 ml of hot xylene. The mixture was refluxed for 2 hours. After cooling, the xylene was evaporated in vacuo to give a red-brown solid which was triturated with methanol to give a brick-red substance. This was recrystallized from hot methanol, and the red crystals thus formed were filtered off, washed with methanol and dried at 50 ° C under vacuum. The dried product was 3- (4-chloro-2-nitroanilino) thiophene-4-nitrile, m.p. 214 ° C. (b) 3- (4-Methultio-2-nitroanilino) thiophene-4-nitrile, m.p. 167-169 ° C (MeOH), was prepared in a similar manner. (c) 4- (4-fluoro-2-nitroanilino) -2-ethylthiophene-3-nitrile.

Example gel 6 (o) 20.7 g of ethyl 5-ethyl-2- (2-nitroamino) thiophene-3-carboxylate in 150 ml of ethanol was catalytically reduced over 2.0 g of 10% palladium on charcoal at 4.2 kp / cm . The catalyst was separated by filtration, and the solvent was distilled off in vacuo. The ethyl 2- (2-aminoanilino) -ethylthiophene-3-carboxylate thus obtained had a melting point of 50-52 ° C (hexane); The following compounds were prepared in the same manner. (b) Ethyl 2- (2-amino-4-fluoroanilino) -5-ethylthiophene-3-carboxylate, m.p. 82-84 ° C (hexane). (c) Ethyl 2- (2-amino-3,5-difluoroanilino) -5-ethylthiophene-3-carboxylate, m.p. 106 ° C (EtOH). (d) Ethyl 2- (amino-5-fluoroanilino) -5-ethylthiophene α-carboxylate, m.p. : Loo - 1o1 ° c (Ewa). (e) Ethyl 2- (2-amino-4-chloroanilino) -5-ethylthiophene-3-carboxylate, m.p. 119-112 ° C (EtOH). __. . (-) Ethyl 2- (2,4-diaminoanilino) -5-ethylthiophene-s-carboxylate, m.p. 152 DEG-1.5 DEG C. (hexane). (g) Methyl 3- (2-aminoanilino) thiophene-2-carboxylate, m.p. 10 ° C, was prepared by reduction of methyl 3- (2-nitroanilino) thiophene-2-carboxylate. (h) Methyl 2- (2-amino-4-fluoroanilino) -5-methylthiophene-α-carboxylate, m.p. 116 _ 11s ° c. (i) 8.0 g (0.027 mol) of 5-ethyl-2- (2-nitroanilino) -thiophene-3-carboxylic acid in 150 ml of ethanol were catalytically reduced over 900 mg of 10% palladium on charcoal at 4.2 kp / cm 2. The catalyst was separated by filtration and the solvent by vacuum distillation to give 2- (2-aminoanilino) -5-ethylthiophene-3-carboxylic acid.

Example 7 0.5 g of ethyl 2- (2,4-dinitroanilino) -5-ethylthiophene-3-carboxylate in 25 ml of 6N ammonia and 10 ml of ethanol were stirred at reflux temperature, and hydrogen sulfide gas was introduced for 2 hours. The reaction mixture was cooled to room temperature. , and ethyl 2- (2-amino-4-nitroanilino) -5-ethylthiophene-3-carboxylate was obtained as a yellow precipitate, which was filtered off, washed with water and dried in vacuo, m.p. 174-176 ° C (EtOAc). Example 8 0.4 g (0.001 mol) of ethyl 2- (4-bromo-2-nitroanilino) -ethylthiophene-3-carboxylate was added to 0.4 g of zinc powder and 0.4 g of ammonium chloride in 10 ml water, and the mixture was stirred at 50 ° C for 24 hours. The reaction mixture was filtered, and the recovered solid was washed successively with water and ethyl acetate. The organic phase was separated, washed with water, dried (MgSO 4) and evaporated in vacuo to give ethyl 2- (2-amino-4-bromoanilino) -5-ethylthiophene-3-carboxylate.

Example 9 (a) 48.06 g (0.3 mol) of 3-carboxymethyltetrahydro-thiophen-4-one and 32.4 g (0.3 mol) of orthophenylenediamine were dissolved in 500 ml of boiling ethanol to which a few drops of acetic acid had been added. The solution was heated at reflux in a nitrogen atmosphere for 4 hours and allowed to cool. The resulting crystalline material was filtered off, washed with ethanol and dried in vacuo.

The product was recrystallized from absolute ethanol with activated charcoal with decolorizing agent to give a yellow solution, from which white needles crystallized. The white crystalline substance was filtered off, washed with ethanol and dried in vacuo to give methyl 3- (2-aminoanilino) -2,5-dihydrotiophene-4-carboxylate, m.p. 10 ° C, was obtained. (b) Methyl 3- (2-amino-4,5-dichloroanilino) -2,5-dihydrotiophene-3-carboxylate, m.p. 162 ° C, was obtained by a procedure similar to that of Example 9a. Example 23 10.03 g (0.1 mol) of methyl 3- (2-aminoanilino) -2,5-dihydrotiophene-U-carboxylate and 24.6 g (0.1 mol) of chloranil were boiled together in 900 ml of xylene with reflux for 2 hours.

The solvent was evaporated in vacuo to leave a dark brown solid, which was triturated with ethyl acetate. This gave a light brown substance which was filtered, washed with ethyl acetate and dried in vacuo to give 3- (2-aminoanilino) thiophene-4-carboxylate, m.p. 120 - 122 ° C, obtained. (b) In a similar manner, methyl 3- (2-amino-1,5-dichloroanilino) thiophene-4-carboxylate was prepared, m.p. 162-163 ° C.

Example 11 2.5 g (0.001 mol) of methyl 3- (2-aminoanilino) -2,5-dihydrotiophene-H-carboxylate were introduced into a flask containing 200 mg of cyclohexene (or norbornadiene or norbornylene). Reaction% palladium on charcoal as catalyst in 50 ml of the mixture was heated H h at reflux and stirring, during which the reaction was monitored by thin layer chromatography. The reaction mixture was cooled, and the solvent was evaporated in vacuo leaving a dark brown oil. This was chromatographed on a Florisil column and chloroform to give methyl 3- (2-aminoanilino) thiophene-H-carboxylate as an orange solid, m.p. 120 - 12200.

Example gel 12 (a) 2 H g (0.136 mol) of U-trifluoromethylorthophenylenediamine and 17.3 g (0.136 mol) of 3-keto-2,5-dihydrotiophene-U-nitrile were dissolved in 200 ml of hot ethanol. 3 Acetic acid was added, and the solution was heated at reflux for 2% h and then allowed to cool. 3- (2-Amino-5-trifluoromethylanilino) -2,5-dihydrotiophene-U-nitrile was obtained as a white solid, which was filtered off and combined with solid obtained by evaporation of the filtrate to a small volume and cooling, m.p. 189 ° C. (b) In a similar manner, 3- (2-amino-5-chloroanilino) -2,5-dihydrotiophene-H-nitrile was prepared, m.p. 164-165 ° C. (c) 80 g (0.629 mol) of 3-keto-4-cyanotetrahydrotiophene and 68 g (0.629 mol) of orthophenylenediamine were dissolved by heating in 1.5 l of technically denatured alcohol. To the solution was added 78 ml of glacial acetic acid, after which the solution was heated at reflux and mechanical stirring for 24 hours. Upon cooling the solution and filtering, 3- (2-aminoanilino) -2,5-dihydrotiophene-4- was obtained. nitrile as a solid, m.p. 163 ° C. Example 13 (a) 17.18 g (0.06 mol) of 3- (4-chloro-2-nitroanilino) thiophene-4-nitrile were hydrogenated in 300 ml of ethanol and 1000 ml of ethyl acetate to 3- (4-chloro -2-aminoanilino) thiophene-4-nitrile. The hydrogenation was carried out with 3.5 g of 10% palladium on charcoal as catalyst in a Parr hydrogenator. After 2 hours the reaction was complete, after which the catalyst was filtered off and the solution was evaporated to dryness. The resulting light brown solid was dissolved in 100 ml of ethanol in a 500 ml three-necked flask, 12 ml of concentrated hydrochloric acid was added dropwise to the stirred solution. The alcohol solution was refluxed for about 24 hours. 60 ml of 10% sodium hydroxide solution was added dropwise to the cooled solution until it was slightly basic. During the addition, a precipitate of 10-amino-7-chloro-4H-thieno 3,4-b 1,5-benzodiazepine formed, which was filtered off as a pale yellow to brown solid, which was washed with water and dried at 50 ° C. in vacuum, m.p. 239-240 ° C.

The following compound was prepared in a similar manner. (b) 10-amino-7-methylthio-4H-thieno [3,4-b] [1,5] benzodiazepine, m.p. 195 - 19700. 7812194-4 Example 14 (a) 8u, 5 g (0.39 mol) of 3- (2-aminoanilino) -2,5-dihydrotiophene-H-nitrile were suspended by mechanical stirring in 1.5 l technically denatured spirits. 57 ml (0.66 mol) of concentrated hydrochloric acid were added dropwise, the solution was stirred for 1 hour at reflux temperature and cooled, and the solid thus obtained was filtered off, washed with a small amount of technically denatured alcohol and gasoline (40-60 ° C) and dried at SOOC in vacuo. The resulting 10-amino-4H-2,5-dihydrotieno [3, H-b] melting point of 292 ° C (dec.). (b) 54.5 g of the hydrochloride according to a was suspended [1.5] the benzodiazepine hydrochloride had one in 1 l of chloroform with mechanical stirring, and 500 ml of 10% (w / w) sodium hydroxide was added in one portion. The suspension was stirred for 2 hours, then 10-amino-HH-2,5-dihydrotieno- [3, H-b] [1,5] benzodiazepine was obtained as a white solid.

This was filtered off, washed with water, ethanol and ether and dried under vacuum to give the free basener, m.p. (c) 0.5 g (0.002 mol) of methyl 3- (2-aminoanilino) -2,5-dihydrotiophene-H-carboxylate in 2 ml of dry DMSO was added to a solution of 300 mg 50% (w / w) oil suspension of sodium hydride in dry DMSO at 90 ° C under nitrogen After cessation of effervescence, the solution was stirred for 2 hours and poured onto 300 ml of ice and brine. The solution was extracted with ethyl acetate and the extract was dried over magnesium sulphate, filtered. and evaporated to a small volume, ether was added to the suspension, which was filtered, the filtrate was evaporated to dryness and triturated with chloroform to give 9,10-dihydro-HH-2,5-dihydrotieno [3,1H-b1 [1,5] benzodiazepine -10-one was obtained as a yellow solid, mp 210 ° C (dec.).

Example 15 80 g (0.629 mol) of 3-cyanotetrahydrotiophen-H-one and 68 g (0.629 mol) of orthophenylenediamine were dissolved in 1.5 l of technically denatured alcohol by heating under reflux with stirring.

Then 3 ml of acetic acid were added, and the mixture was heated at reflux with stirring for 5 hours. To the cooled solution was carefully added, while stirring, 92 ml (1 = Û3 ml) of concentrated hydrochloric acid. The solution was then heated to reflux for 1 hour, and to the cooled stirred solution of the hydrochloride was added 500 ml of 10% (w / w) sodium hydroxide dropwise, while maintaining the temperature below 0 ° C. The solution was stirred for 1 hour, the solid was filtered off, washed with water, ethanol, acetone and dried under vacuum. The dried product, 10-amino-HHH-2,5-dihydrotienol-3,4-b] [1,5] benzodiazepine, had m.p. 230 - 2 ° C.

In (b) Q3 g (0.198 mol) of 10-amino-HH-2,5-dihydrotieno- [3,1-b] [1,5] benzodiazepine was suspended under mechanical stirring in 1 l of boiling xylene. To this was added 49 g of chloranil, and the suspension was stirred for 2-6 hours at reflux temperature and then allowed to stand overnight at room temperature. The suspension was filtered, and the solid was washed with xylene until the wash was colorless. It was then dried on a filter funnel. The resulting dried black substance was suspended in 200 ml of hot water, and 36 ml of SM hydrochloric acid was added. A red solution formed, which was boiled for 10 minutes. The solution was then filtered, and the tar residue was extracted with 36 ml of SM hydrochloric acid in 200 ml of water and filtered again. The collected hot filtrates were added dropwise to an ice-cold solution of 14.4 g (0.36 mol) of sodium hydroxide in 100 ml of water at such a rate that the temperature did not exceed 4000. The solution was stirred for 1 hour and filtered, the solid was washed with water and dried in vacuo at 50 ° C. There was thus obtained dry 10-amino-HH-thieno [3,4-b] [1,5] benzodiazepine, m.p. 19 ° C (Sun.).

Example gel 16 (a) 10.5 g (0.0368 mol) of 3- (2-amino-5-trifluoromethylanilino) -4-cyano-2,5-dihydrotiophene were dissolved in 100 ml of technically denatured alcohol by heating and to this To a stirred solution was carefully added a solution of 3.2 ml (0.0368 mol) of concentrated hydrochloric acid. The resulting red solution was heated at reflux for 1 hour. To the cooled and stirred solution was added dropwise a solution of 1.6 g of sodium hydroxide in 10 ml of water, while maintaining the temperature under HOOC. The matte yellow amidine was filtered off, washed with water, ethanol and gasoline (H0-6000), and then dried at 5000 under vacuum. The filtrate was diluted with excess water, and the The solid formed was filtered off and dried and combined with the other solid.The resulting 10-amino-6-trifluoromethyl-UH-2,5-dihydrotoeno [3, Mb] [1,5] -benzodiazepine had a melting point of 200 - 21000 (Sun.) (b) In the same manner, 10-amino-6-chloro-HH-2,5-dihydrotieno [S, Hb] [1,5] benzodiazepine was prepared.

Example 17 The products of Examples 16a and 16b were "aromatized" to 10-amino-6-trifluoromethyl-HH-thieno [3, H-b] [1,5] -benzodiazepine, m.p. 178 ° C (Sun.), and 10-amino-6-chloro-UH-thieno [3,4-b] [1,5] benzodiazepine by the method of Example 15b.

Example 18 (a) Sodium ethylsulfinylcarbanion was prepared by stirring 7.2 g (0.15 mol) of sodium hydride in 100 ml of dry dimethylsulfoxide at 7006 until gas evolution ceased. 5.5 g (0.05 mol) of ethyl 2- (2-aminoanilino-5-ethylthiophene-3-carboxylate in 50 ml of dry dimethyl sulfoxide were added and stirred for 15 minutes. The mixture was poured onto 600 ml of ice water and stirred for 15 minutes. the solid was filtered off, washed well with water, dried, washed with carbon tetrachloride and dried in vacuo at 6000. The dried product, which was 9,10-dihydro-2-ethyl-HH-thieno [2,3-b] [1, 5] benzodiazepin-10-one, had melting punctures 218 - 220 ° C (cncig). W (b) 2-ethyl-7-fluoro-9,10-dihydro-HH-thieno [2,3-b] - [1 , 5] benzodiazepin-10-one, mp 210-21200, was prepared in the same manner from ethyl 2- (2-amino-4-fluoroanilino) -5-ethylthiophene-3-carboxylate, the compound was recrystallized from ethanol.

The following compounds were also prepared by the procedure of Example 18a. For each compound, the melting point, the solvent for recrystallization and the starting thiophene material are given. (c) 6,8-difluoro-9,10-dihydro-2-ethyl-HH-thieno [2,3-b] [1,5] benzoiazepin-10-an, m.p. 230 DEG-232 DEG C. (cHCl3) from ethyl 2- (amino-3,5-difluoroanilino) -5-ethylthiophene-3-carboxylate. (d) 9,10-dihydro-2-ethyl-6-fluoro-4H-thienophea, 3-b] -El, 5] benzodiazepin-10-one, m.p. 255 DEG-257 DEG C. (EtOAc), from ethyl 2- (2-amino-5-fluoroanilino) -5-ethylthiophene-3-carboxylate. (e) 7-chloro-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] -fl, Slbenzodiazepin-10-one, m.p. 216-218 ° C (EtOAc), from ethyl 2- (2-amino-4-chloroanilino) -5-ethylthiophene-3-carboxylate. (f) 7-amino-9,10-dihydro-2-ethyl-4H-thieno [e, 3-Q] -E1, Slbenzodiazepin-10-one, m.p. 23000 (Sun.) (CHCl 3 / MeOH), from ethyl 2- (2,4-diaminoanilino) -5-ethylthiophene-3-carboxylate. (9) 9,10-Ahydro-2-ethyl-6-methyl-4H-thieno [2,3-b] -1.5] benzodiazepin-10-one, m.p. 205 DEG-207 DEG C. (EtOAc), from 2- (2-amino-5-methylanilino) -5-ethylthiophene-3-carboxylate. (h) 9,10-dihydro-7-N, N-dimethylsulfonamido-2-ethyl-4H-thieno [α, 3-b] E1.5] benzodiazepin-10-one, m.p. 258 DEG-260 DEG C. (EtOAc), from methyl 2- (2-amino-5-N, N-dimethylsulfonamidoanilino) -ethylthiophene-3-carboxylate. (1) 9,10-amino_2_ethyl-7-nitro-4H-thienophea, 3_b] - E1, 5] benzodiazepin-10-one, m.p. 264 DEG-266 DEG C. (EtOAc), from ethyl 2- (2-amino-4-nitroanilino) -5-ethylthiophene-3-carboxylate.

(J) 9,10-Hydro-7-fluoro-4H-thieno [2,3-b] [1,5] -benzoiazepin-10-one, m.p. 235 DEG-24 DEG C. (c14 / hexane), from ethyl 2- (2-amino-4-fluoroanilino) thiophene-3-carboxylate. (k) 9-fluoro-6H-1,2,3,4,11,12-hexahydrobenzothienophe, 3-b] E1, Sibenzodiazepin-12-one, m.p. 238 ° C (EtOAc), from ethyl 2- (2-amino-4-fluoroanilino) -4,5,6,7-tetrahydrobenzo [b] -tisphen-3-carboxylate. 7312194-4 29 (l) 6,7-difluoro-9,10-dihydro-2-ethyl-4H-thieno- [zß-b] [L] benzodiazepin-lo-one, m.p. 29 ° C, from ethyl s-ethyl 2- (4,5-difluoro-2-nitroanilino) thiophene-3-carboxylate. (m) 9,10-dihydro-7-fluoro-2-phenyl-4H-thieno- [La-b] Ll, fl benzoiazepin-10-one, m.p. 250 DEG-252 DEG C. (m.p.) (EtOAC). (n) 9,10-dihydro-7-fluoro-2-methyl-4H-thieno- [Ls-b] fl, silbenzodiazepin-10-one, m.p. 250 DEG-252 DEG C. (EtoAc). (o) 9,10-dihydro-4H-thieno [3,2-t] [1,5] benzodiazepin-10-one, m.p. 226 ° C (CCl 4), from methyl 3- (2-aminoanilino) thiophene-2-carboxylate. (p) 9,10-Dihydro-γ-fluoro-Lzn-thieno [s, z-b] [1, s] -benzodiazepin-10-one, m.p. 225 DEG-230 DEG C. (EtOAc), from methyl 3- (2-amino-4-fluoroanilino) thiophene-2-carboxylate. (q) v-chloro-Q, 10-dihyaro- 4H-thieno [3,2-b] [1, s] -benzodiazepin-10-one, m.p. 255 DEG-255 DEG C. (EtOAc), from methyl 3- (2-amino-4-chloroanilino) thiophene-2-carboxylate. (r) 9,10-dihydro-fln-thienofs, 4-b] [1,1-benzodiazepin-10-one, m.p. 233 ~ 234 ° C. (s) 9,10-dihydro-7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 238 ° C (dec.). (t) s, Dichloro-Q, 10-ahydride <> _ 4f1_thiophene [3,4-b] - (1,1-benzodiazepin-10-one, mp 284 - 28700. (u) 5-ethyl-2- (2-aminoanilino) thiophene- 3-Carboxylic acid was dissolved in 200 ml of tetrahydrofuran (distilled from lithium aluminum hydride), and 5.7 g (0.027 mol) of solid dicyclohexylcarbodiimide were added, the mixture was stirred under nitrogen for 16 hours, and the resulting solution was filtered and evaporated to 78 ° C. The residue was boiled with carbon tetrachloride and crystallized to give 2-ethyl-9,10-dihydro-4H-thieno 2,3-b 1,5-benzodiazepin-10-one, mp 218-222000 (CHCl 3).

Example Gel 19 (a) 4 g (0.15 mol) of 10-amino-7-chloro-4H-thieno- [3,4-5] [1,5] benzolaazepine were dissolved in 100 ml of water, to which was added 13.0 g potassium carbonate in 20 ml of water. 40 ml of absolute ethanol were added to redissolve the amidine, and the reaction mixture was slowly refluxed for 17 hours. During the last hour, the ethanol was slowly evaporated. The reaction mixture was allowed to cool, and concentrated hydrochloric acid was added dropwise to the solution in the presence of ethyl acetate, until the solution was slightly acidic. The aqueous phase was extracted with ethyl acetate, and dried over magnesium sulfate. The combined extracts were evaporated to dryness in vacuo to give 7-chloro-9,10-dihydro-4H-thieno-3,4-b solid. This was triturated with ether, filtered and 1.5 benzodiazepin-10-one was obtained as a light brown dried at SOOC under vacuum to give a yellow substance, m.p. 212 _ 213 ° C.

Using the hydrolytic process of Example 19a, the following amides were also prepared. (b) 9,10-dihydro-4H-thieno- [3,4-b] [1,5] benzodiazepin-10-one, m.p. 2340C (Sun.). (c) 9,10-dihydro-6-trifluoromethyl-4H-thieno- [§, 4-b] K1, Sjbenzodiazepin-10-one, m.p. 21300. (d) 9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno- [ε, 3-b] fl, Benzodiazepin-10-one, m.p. 2llOC. 7812194-4 31 Example 20 0.33 g of the mio-ahyla-: zn-z, s-ayyarethiene [all-b] - [1,5] benzodiazepin-10-one was stirred in cyclohexane (or norbornadiene or norbornylene) at reflux temperature in the presence of 0.1 g of palladium on charcoal (5%), the reaction being monitored by thin layer chromatographic measurements. The reaction mixture was then cooled, and the solvent was evaporated in vacuo. This gave a dark brown solid which was column chromatographed with "Florosil" and 5% methanol in chloroform to give 9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one as a biekguit party, m.p. 230 ° C 232 ° C.

Example 21 100 mg of 7-amino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] - [1,5] benzodiazepin-10-one was suspended in 5 ml of methylene chloride and 0.1 ml of triethylamine . 10.1 ml of acetic anhydride were added, and the reaction mixture was stirred for 18 hours. The precipitate was filtered off, washed with water and dried in vacuo at 60 ° C, whereby 7-N-acetylamino-9,10-dihydro-2-ethyl-4H- thieno [2,3-b] I: 1,5] -benzodiazepin-10-one was obtained in solid form, m.p. 26400.

Example 22 4.32 g (0.2 ml) of the element 3,4-b] [1,5] benzediazepin-10-one in the hot dichloromethane were reacted with stirring with 3.0 g (0.025 mol) of N-chlorosuccinimide in presence of traces of benzoyl peroxide. After 1 hour at reflux, the hot solution was filtered. The blue residue was washed with three quantities of hot ethyl alcohol, which was combined with the dichloromethane filtrate and evaporated to a brown solid residue.

Soxhlet extraction and evaporation gave 3-chloro-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one as a pale yellow solid, m.p. 22900.

Example 23 To a stirred solution of 0.26 g (0.001 mol) of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,51-benzodiazepine in 3 ml of acetyl chloride was added two drops of stannous chloride while stirring. The mixture was diluted with 5 ml of benzene and stirred for 18 hours at room temperature. The reaction mixture was diluted with water and extracted with chloroform. The chloroform extracts were washed with water, dried (MgSO 4) and evaporated in vacuo. There was obtained 1-acetyl-9,10-dihydro-2-ethyl-7-fluoro-4H-thieno- [2,3-b] [1,5] benzodiazepin-10-one in solid form, m.p. 215 DEG-21 DEG C. (meon / hexane).

Example 24 (a) 20 g (0.076 mol) of 9,10-dihydro-2-ethyl-7-fluoro-4H-thienoE2,3-b] [1,5] benzodiazepin-10-one were added to a stirred solution of 17 g (0.076 g mol) of phosphorus pentasulfide in 400 ml of dry pyridine. The solution was stirred at slow reflux for 1.51L, poured onto ice water, stirred for 1 hour, filtered, washed with cold water and dried. Recrystallization from EtOH / water gave 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno (β, 3-b] Cl, 5] benzodiazepine-10-thione as bronze colored plates, mp 203-206 (B) 9,10-Dihyaro-2-ethyl-4H-thienofz, 3_b] [1, s] -benzodiazepination, mp 233-236 ° C (EtOH-H 2), was prepared by the method of Example 24a with 9 ° C. 10-dihydro-2-ethyl-4H-thieno [2,3-b] fl, 5] benzodiazepin-10-one.

Other amides of Example 18 were similarly converted to thioamide derivatives by the procedure of Example 24a. The final product was identified and confirmed in each individual case by thin layer chromatography and microanalysis.

Claims (1)

Claim intermediate for use in the preparation of thienobenzodiazepines, characterized by the formula N = C (V) wherein Q represents a hydroxyl group, thiel group or amino group, R1 and R2 each represent a hydrogen atom, C1-4 alkyl group, halogen atom, C 1-4 haloalkyl group, hydroxyl group, C 1-4 alkoxy group or C 1-4 alkylthio group or -SO 2 NR 2, where R 4 represents a C 1-4 alkyl group, and the symbol 1 .. means a thiophene ring-fused, optionally C 1-6 alkyl-substituted thiophene nucleus.