CS236753B2 - Processing of thieno (1,5) benzodiazepine derivatives - Google Patents

Abstract

Thieno1,5!benzodiazepines having useful CNS activity containing the novel tricyclic ring system : the 10-position being substituted by an amino, preferably a piperazino, group.

Description

The present invention relates to a process for the preparation of thieno [1,5] benzodiazepine derivatives, i.e., a novel class of compounds having significant central nervous system activity (hereinafter abbreviated as "CNS") and / or useful as intermediates in the manufacture of the compounds of the aforementioned compounds. efficiency. The invention further relates to a process for the preparation of acid addition salts of said novel compounds.

Said novel compounds have a hitherto unwritten thieno [1,5] benzodiazepine system of the general formula

wherein R 6 represents · a hydrogen atom, Ci_4alkyl, C3-Ocycloalkyl, C ₂ -4alkenyl, 'C | _aalkanoyl, benzyl, C1-4karboxyškupinu or - (CH2 I _n OX where n is 2, .or 3 and X represents a hydrogen atom or an ester residue, and a group

O denotes a thiophene ring attached to a diazepine core, optionally substituted with C 1-4 alkyl, and their acid addition salts.

It will be appreciated by those skilled in the art that the novel thieno [1,5] benaodiazepines of formula I may exist in three different forms, which may be represented by the following structural formulas II-IV:

in which the group

indicates a thiophene ring.

Recently, intensive attention has been paid to the field of pharmaceutical chemistry concerning tricyclic and benzodiazepine systems and a large number of patents have been published. Typical examples include British Patent Nos. 980 853, 1 291 684, 1 380 242, 1380, 243, 1 380 244, and US Patent Nos. 2,893,992, 3,102,116, 3,109,843, 3 136 815, 3 474 099

654 286, 3,749,786 and 3,842,082,

The present invention relates to a process for the preparation of novel thieno [1,5] benzodiazepine derivatives of the general formula I

in which

R ¹ and R ² represent, individually, hydrogen, Cl-C4alkyl, (^ - "alkenyl, C3 _'cycloalkyl, halogen, Ci_4halogenalkyl, nitro, amino, C ₂ -4acylaminoskupinu hydroxy, Ci_4alkoixyskupinu, C ^ alikylthioškupinu or a group of the formula - SO 2 N '(R 4) 2 or -SO 2 R 4, wherein R 4 is C 1-4 alkyl,

R @ ⁵ denotes a group of the formula --T @ 1 R @ ⁶

In the above structural formulas II-IV, the thiophene ring is shown for convenience as unsubstituted, but is understood to be substituted, for example, by one or two substituents selected from the group consisting of C 1 -C 8 alkyl, especially C 1 -C 8 alkyl. 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkanoyl of 2-4 carbon atoms, nitro, atom. halogen, phenyl or substituted phenyl. In the structures represented by formulas II and IV, the thiophene ring may additionally be fused to a 3-8 cycloalkyl ring.

Preferred compounds included within the scope of the compounds of Formulas I-V are those having one or more of the following characteristics:

''^'·: _(A], R ^1st is a halogen atom such as _ chloro _ or fluorine at position 6 or 7, (B] R, represents, hydrogen.. A halogen such as chlorine or fluorine at the 7-position , and R2 represents. hydrogen, ^hydrogen, (C] R represents fluorine atom in position 7, and R ² represents. a hydrogen. atom, (D] .. R ² represents, a hydrogen.. H (e] Ri. or R 2 represents trifluoromethyl, (F 1; R 1; denotes; trifluoromethyl in the 6-position, or 7 when R 2 denotes hydrogen, (G) R 1 or; R 2; denotes methylthio or methoxy, (H) both R @ 1 and R @ 2 denote halogen atoms, for example fluorine, (I) R @ ⁵ denotes a group of the general formula:

CH,

-N '- N - R wherein R ⁶ represents an atom; hydrogen, alkyl of up to 4 carbon atoms, benzyl or. (CH2) GX, (J); R5 denotes a group of the formula - ΝN1-7 (K) the compound of formula I has the structural formula II, (L) the thiophene ring is substituted with an alkyl group with I —4 carbon atoms, for example ethyl, (M) thiophene ring is not substituted, (N) thiophene, the ring is substituted with an electron withdrawing group, for example halogen, nitro, trifluoromethyl or C2-4 alkanoyl.

The most preferred group of compounds of the formula; I consist of those compounds which contain in the molecule the characteristic 'substituents given' in (A) to (E), [J] and (L ')!

Especially; the active compound in this group is 2-ethyl-7-fluoro-10- [4'-methyl-1'-piperazinyl] -4H-thieno [2,3-b] -1,5,5-benzodiazepine; both in the free base form and in the form of the corresponding pharmaceutically acceptable salts.

As used herein, the term "C 1 -C 4 alkyl" refers to an alkyl group having also a running or branched chain containing from 1 to 4; 4 carbon atoms, for example methyl, ethyl, isopropyl, n-butyl, secondary butyl, isobutyl and n-butyl. The term "C 1-4 haloalkyl" refers to the above-mentioned alkyl groups substituted with one or more halogen atoms, for example trifluoromethyl. The terms "C 1-4 alkoxy"; and "alkythio; 1-4 carbon atoms' means the above-mentioned alkyl groups attached via an oxygen or sulfur atom to a benzene or thiophene ring ^:

The term "alkenyl * 2-4" alkoxy "represents groups such je- ha chloride as example vinyl, allyl and 'butenyl.'^''; *

The term "amino" as used herein refers to a group of formula -NH 2, and also substituted; amino groups such as; monoalkylatogroup containing

1-4 carbon atoms and a dialkyl alcohol containing 1-4 carbon atoms in each alkyl. The term "C 2-4 acylamino" refers to an amine substituted by an acyl group containing 2-4 carbon atoms, for example, an acetyl group. The term 'halka-hoyl having 1-4 carbon atoms' denotes, for example, formyl or acetyl.

The term "cycloalkyl having 3--6 'carbon atoms"denotes; a saturated ring having 3 to 6 carbon atoms in the ring, for example cyclopropyl, cyclobutyl, cyclopentyl ^; or cyclohexyl. The term "substituted phenyl" represents a phenyl group-substituted or once * · 'more groups such "halogeno, trifluoromethyl, methyl, or meťhoxy'Skupinou - ^{níťróséupihó:} u.

Examples of compounds of formula I include the following sloučéíítóy ⁴

2-Ethyl-11- (4R, 4-methyl-11H-piperidinyl) -4H-

-thi-noj 2,3-b] [1,5] benzodiazepine,

7-chloro-ε-Ethyl-10-1H-1-methyl-1 '(piperazin-1-yl) -dH-thieno [2,3-b] [1,5] benzodiazepine, ethyl-7'-fluoro-10- [H4-methyl] -1- -eipe.-nyl] -4H-thiynO [2,3-b] [1,5] benzodiazepine,

2-ethyl-7-trifluoromethyl-10- (1H-methyl-

-1 ‘(pi.prrazinyl) -4H-tertiary [2,3-b] [1,5] benzodiazepine;

Zmmmo -1-ethyl-1,0- (H '(methyl) (piperazin-4-yl) -4H-thiide [2,3-H] [1,5] benzodiazepine, ethylthi-n-nolyl-10- ( 4'4] methyl-1'1

4-thieno [2,3-b] [1,5] benzodiazepine ^; ethylthyl (6'-fluoro-10- (4 '(methyl))

piperazinyl] -4H-thieno ^d [2,3-b] [, 5] benzodiazepine,

2-mУthlΊ (7 · -ΓNN-dimhthslsulnonnmid1-110-

- (1H-methyl-Γ-pl-propynyl) -4H-thihydro [2,3-b] [1,4] benzodiazepine,

Z-Peylyl-trans-10- (4'-methyl-Γ-piperazinyl) -4H-thiopheno [2,3-b] [1,5] benzodiazepine, ethyl-n-mythyl- 10- (4'-methyl-.'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodizzepine,

2-mythyl (n-methyl: boxes-00- [4 ‘(methyl-Γ-)

-piperazinyl] -4H-hieneb [2,3-b] [1,5] benzodiazepine,

6.7- difluoro-l-trifluoro-2 · (rťhyl IO ((N-methyl-l / piperazinyl] HH-t ·] thieno Уí ⁱ '[2,3-b] [, 5] benzodiazepine;

eťУth-7-7-myththtO-1-10- (44 ^^ 71-1 / j-piperazinyl 4Hthirno [ '2,3-b] [I, 5] - benžodizzrpin ¹

6,8-difluoro-2-methyl-1,3- [4-methyl-1H-piperidin] -4H-thieno [2,3-b] [1,5] benzodiazepine, * ^; '

7-Fluoro-10 ^: - (4'-methyl-1'-piperazinyl) -4H-thienoyl 2,3-b] [1,5] benzodiazepine, 7-chloro-10- [4'-methyl-1 ' -piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine, 7-chloro-1-methyl-10- (4) -methyl-1'-piperazinyl) -4H-thien [2,3-b] [1,5] benzodiazepine,

1,2-dimethyl-7-ch-or-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b]] 1,5 [benzodiazepine,

7-ch-or-2-methyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno] 2,3-b] [1,5] benzodiazepine,

6-Trifluoromethyl-2-ethyl-10- (4‘-methyl-1‘-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine,

2iVyi- ^ l-l-7lfhiO10L'O4 4'Lmethyl ^{<-pipirazlnyl]} -4H-thieno [2,3-b] [[1,5] benzodiazepine,

2-ninol-71-trifluoromethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine,

7-chloro-2-ethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine, ethyl-7-phosphor-4-yl 4'-methyl-4'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine, ethyl-4'-N- [4'-methyl]. 1'-piperazinyl) -4H-thieno [3,2-b] [[1,5] benzodiazepine, ethers 1-7-trifluoromethyl-10- [4 (611111-1) -terazinyl] -4H-thieno ^: [ 3,2-b] [1,5] benzodiazepine,

7-Amino-2-ethyl-10- [4,6,6-l-4-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine, ethyl-7-nit-1-10- (4'-Methyl-Γ-piperazinyl) -1-411-1: 1,4- [3,2-b] [1,5] benzodiazepine, 11'-10 '(4'-methyl-1') Lpiperazines - - L-4H-thieno [3,2-b] [[1,5] benzodiazepine,

2-Methyl-7-N, N-dimethylsulfanyl-1-O-

- (4'-Methyl-4'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazeein, ethyl-6-methyl-O- (4'-methyl-11'-piperazinyl)] -4H-thieno- [3,2-b] [1,5] benzodiazepine,

2L-Ethyl-7-methyl-1-O- (4‘-methyl-1‘-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine,

6,7-difluoro-2-ethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine, ethyl 17-methylthi-1-ol- 1-methyl-1-piperazinyl) -4H-theno [3,2-b] [1,5] benzodiazepine,

6,8-Difluoro-2-ethyl-10- (4‘-methyl-1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine,

7-Fluoro-TO- [4'-Methyl-1'-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine, 7-celor-10- (4 'methyl-l-eipirazmy'l) -4H-thieno ^[3,2-b] [1,5] benzodiazepine,

2,3-dimethyl-7-celor-11 '- (4‘-methyl-Γ-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine,

7-ch-or-2L-methyl-10L [4'-methyl-1'-pipirazinyl) -4H-thieno [3,2-b]. [1,5] benzodiazepine, hfor-12- [4'-Methyl-Γ-piperazinyl) -64-1,2,3,4--6-ahydrobenzo [b] thieno [3,2-b] [1] 5] binzodiazipine, 2-ethyl-7-fluoro-10- [4'- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine, ethyl- 7-Fluoro-10- [4'- (3-hydroxyproeyl) L 1 -piperazinyl] -4 H -thieno [2,3- b] [1,5] benzodiazepine,

2-okl-7-7fluoro-10- (4'-meteyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine, ethyl-7fluoro-10- (Γ) -piperazinyl) L4H-thieno [2,3-b] [1,5-benzodiazepine, ethyl-7-fluoro-10- [N- (N, N-dimethylaminoethyl) amino] -4H-thieno [2,3] -b] [1,5) · diaziei'n Binz, etethyl-7-f ^ -10 -uoi ¹ - (2'-N-Pip-piperidine uh yl) amino-4H-thieno [ '2,3-b] [1,5] binzodiazipine, luor-10- (4,711,111,111,111,11,14) -4H-hiino [2,3-b] [[1,5] benzodiazepine, itethole-C- chloro-10- [3'L [4L-ynyl-1-piperazinyl] propyl] amino-4H-thiino [2,3-b] [1,5] benzodiazepine,

2-Ethyl-7-ce-or-10- [3'- [4-hydroxyethyl-1-piperazinyl] -propyl] amino-4H-hieno [2,3-b] [1,5] binzodiazepine,

3-Methyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine,

3-Methoxy-7-oxo-110- (4‘-methyl-1'-eiperazinyl) -4H-4-yeno [3,4-b] [1,5] benzodiazepine,

7-fluoro-4H- [4'-ac'-ityl-4'-nitrazyl] -4H-thieno [3,4-b] [1,5] benzodiazepine,

7-Trifluoromethyl-11L [4'-methyl-piperazinyl] -4H-thieno [3,4-b] [1,5] benzodiazepine,

7-Amino-11- [4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine, 7-acetylamino-10- (4'-methyl-1'-methyl) -1H-thieno [3,4-b]; piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazine, 7-mithylamino-11- (4'-methylpiperazinyl) -4- [1, 1,10] -4,3-b] [1 5] binzodiazepine, 7-dimethylamino-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine,

7-nitro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine,

G-fluoro-H- (4‘-methyl-e-eiperazinyl) -4β-thienol 3,4-b] [1,5] binzodiazipine,

3-methyl-17-N, N-dimethylsulphonamino-10- (4‘-methyl-Γ-pleerazinyl) -4,4-thieno 3,4-b] [1,5] benzodiazepine,

2-ethyl-7-hydroxy-10- (4'-biphenyl-4-etrazrazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine,

6-methyl-N- [4'-methyl-l'-eieio ^гaz i'nyl) -4'И-Teien [3,4-b] [[1,5] benzodiazepine,

3LmethylL7Lmethoxyl-10L (4‘-methyl-β-piperazinyl) L4β-thieno [3,4-b] [1,5] benzodiazepine,

6,7-Naphloro-10- (4L, 4'-chloro-4'-chlorobazinyl) -4H-1: hieno [3,4-b] [1,5] benzodiazepine;

7-Meteylthio-11- (4'-methyl-1'-pipirazinyl) -4H-: hieno [3,4-b] [1,5] benzodiazipine,

6,8-difluoro-10- (4'-methyl-4'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine, 7-c01oi-10- [4'-т1е1Ьу1- 1'-ргрегаг1пу1]

-thieno · [3,4-b] [1,5] benzodiazepine,

7-fluoro-10- (4-methyl-1- (piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine,

Hthyl 2-7-fluoro-10- [4 ^'N- (2-hydroxyethyl] -Γ-piperazinyl] - 4H-thieno [3,2-b] [1,5] benzodiazepine.

As already mentioned, the new thieno [1,5] benzodiazepines. They can be used either in the form of the free bases or in the form of acid addition salts. Particularly preferred as said addition salts are the pharmaceutically usable nonolic salts with suitable acids, such as inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic carboxylic acids, for example glycolic, maleic, hydroxymaleinic acids. , fumaric, cider, tartaric, lemon, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic, or; with organic sulfonic acids, for example methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid or naphthalene-4-sulfonic acid. In addition to these pharmaceutically acceptable acid addition salts, other acid addition salts such as picric acid or oxalic acid are included within the scope of the invention. The latter salts may serve as intermediates in the purification of the compounds of the invention, or may be used to prepare other, for example pharmaceutically acceptable, acid addition salts, or may be used for identification, characterization or purification. base according to the invention.

The process according to the invention for the preparation of thieno [1,5] benzodiazepine derivatives of the formula I is characterized in that the amine of the formula R5H, in which R5 is as defined above, is reacted with a compound of the formula V

And R ⁶ carries a C 1-4 carbalkoxy group, hydrolyzes to an amine in which R 6 represents a hydrogen atom.

It should be noted that the above process is based on analogous procedures previously described in the literature (see, for example, British Patent 1,216,532). Therefore, on. due to the nature of the starting materials and end products, a suitable Q substituent as well as suitable reaction conditions can be readily determined.

Particular preference is given to the substituent Q. a hydroxyl or thiol group; in this case, the intermediates of formula V exist predominantly in the corresponding amide or amide. thioamide form:

⁰ with Ш-Q

When Q represents a hydroxyl group and a starting compound of general formula. Thus, the reaction of formula (V) is an amide, preferably in the presence of titanium tetrachloride. The latter agent has the ability to form a metal amnocamplex with an amine of formula R5H. Other metal chlorides, such as zirconium chloride, hafnium or vanadium tetrachloride, also have this ability. The reaction is preferably carried out in the presence of an agent. tying. acid, such as tertiary. an amine such as triethylamine. Alternatively, the reaction may be carried out using an excess of an amine of formula R 5 H as an acid binding agent.

The reaction can be carried out in any suitable manner. an organic solvent such as benzene or toluene, but it has been found that an especially preferred solvent is anisole, at least as a cosolvent, since it has the ability to form a soluble complex with the chloride. titaničitým.

If desired, the reaction may be carried out at elevated temperature (up to 140140 ° C) to expedite the reaction.

The Arnidines of Formula V, i.e. compounds of Formula V in which Q is NH 2, can similarly be condensed with amines of Formula R 5 H, although the yield of this reaction is rather low. It is usually preferable to convert the amidine. by alkaline hydrolysis to the corresponding amide and then to use the compound for the condensation reaction with the above. amine.

Thioamides of formula V, i.e. compounds of formula V wherein Q is

SH can be prepared by treatment with phosphorus pentasulphide · 'to a solution of the corresponding amide in an anhydrous basic solvent, such as crack in which R 1, R ^2, and

O is as defined above and Q is hydroxy, thiol or amino, and the compound obtained is optionally, when R ^{5 is a water} group. pyridine. Similarly, the amides can be converted to iminothioethers, iminoethers or iminohalides, or to other derivatives containing the above-mentioned activated radical Q. Said reactions are carried out by treatment with conventional reagents, for example in the preparation of iminochloride by treatment with phosphorus pentachloride. The latter amide derivatives are more reactive and can usually be reacted with. amines of the general, formula ^R5 H such as, without the presence of titanium tetrachloride.

Compounds of formula (I) in which R @ ⁵ is a radical of the formula can advantageously be prepared by hydrolysis of the corresponding carbalkoxy derivative having 1 to 4 carbon atoms.

The compounds of formulas (I) to (V) may optionally be subjected to an electrophilic substitution reaction in the manner customary to aromatic compounds to obtain derivatives having electronegative groups on the thiophene ring.

The acetylation of the amide (V) can be carried out. · An example of mixtures of acetyl chloride with tin (II) chloride. Said amide can also be halogenated, for example with N-chlorosuccinimide, to give the corresponding chlorinated derivative. · Compounds .obecného formula I wherein R 1 · R ² .or represents amino, can be conventional manner · · · acylated or alkylated to give the corresponding N-acylamino · ·, and N-alkylaminoderivátů. The N-hydroxyalkylpiperazines, i.e. the compounds of formula (I) in which R @ ⁶ represents a group of formula - (CH2) _rt OH, can be esterified with fatty acid chlorides to the corresponding esters, such as decanoates or enanthates.

The compounds of formula (I) produced by the above methods can be isolated by methods known per se or can be converted into the corresponding acid addition salts by conventional methods.

The amides of formula (V) may be prepared by a novel process consisting in the intramolecular ring closure of an amine-ester of formula (VII)

wherein R ⁹ is alkyl of 1 to 4 carbon atoms, for example ethyl, and R 1, R ² and a group of the formula

are as defined above. Said reaction may be carried out by treating the methylsulfinyl carbanion sodium in a suitable solvent, preferably dimethylsulfoxide.

Alternatively, the amides of formula (V) may be produced by an intramolecular ring closure of the amino acid of formula (VIII)

in the presence of dicyclohexylcarbodiimide (DCC) in a suitable solvent such as tetrahydrofuran. The starting amino acids can be obtained by alkaline hydrolysis of the respective esters, for example by treatment with sodium hydroxide in ethanol.

As mentioned above, appropriate. The method for the preparation of amides of formula V is hydrolysis of amidines of formula IX according to the following reaction scheme:

The hydrolysis can be carried out in an alkaline medium, for example by treatment with potassium carbonate in an aqueous-ethanolic medium.

One suitable process for the preparation of amidines of formula IV is shown in the following reaction scheme:

Alternatively, the amidines of the [3,4-b] system can be prepared by the following reaction sequence:

fix) wherein X ¹ and X ² denote optional substituents on the thiophene ring. As will be appreciated, the process comprises an &quot; aromatizing &quot;

Alternatively, o-phenylenediamines may be used in place of the nitroanilines in the above condensation reaction.

Esters of formula VII are novel compounds which can be prepared by condensing a substituted thiophene of the formula wherein R ⁹ is as defined above with o-fluoronitrobenzene of the formula

in the presence of n-butyllithium or in the presence of another base such as sodium hydride, sodium amide, triethylamine or potassium carbonate in dimethylsulphoxide, and the nitroester of formula

VII either catalytically, for example with hydrogen in the presence of palladium on activated carbon as catalyst, or chemically, for example with zinc in ammonium chloride, ammonium polysulfide or iron in hydrochloric acid.

4-H-thieno [2,3-b] [1,5] benzodiazepin-10-ones can be prepared, for example, by the following illustrative reaction sequence:

is reduced to the aminoester of the general formula

R

N

H n / E L 10% Pd / C _N H _Z COOH

EtOOC

NaOH / EtOH

H ₂ / EtOH

10% Pd-C (*) (-)

Na.sub.2CH.sub.2 (.alpha. ₎

Similarly, other thieno [1,5] benzodiazepin-10-ones can be prepared via the amino ester route as described above.

The thiophene derivatives used as starting materials in the processes of the invention are either known compounds [see, for example, Chem. Berlchte 99, 94-100 '(1966), J. Am. Chem. Soc. 68, 2232 (1946) - and Dutch patent application 66 04742], or can be prepared by known techniques from known compounds. The required o-fluoronitrobenzenes are either commercially available or can be readily prepared from commercially available substances.

As mentioned above, the compounds of the invention have significant central nervous system activity. Such efficacy has been demonstrated by extensive testing of substances on experimental animals using methods known per se, such as inducing catalepsy, preventing conditional reflex avoidance, and reversing amphetamine-induced stereotyped rat behavior. The novel thieno [1,5] oenzzdiazepines of the formula I and their acid addition salts are compounds with a strong central effect, with neuroleptic, sedative or relaxing or animic properties. These properties, together with the high therapeutic index of the compounds, allow their use in the treatment of mild anxiety and some types of psychotic conditions such as schizophrenia and acute mania.

The compounds of formula (I) are effective over a wide dosage range, the size of the dose being administered depending on many factors, such as the type of active compound used, the type of disease being treated - and the type and size of mammal being treated. Usually, the required dose is in the range of 0.1 to 20 mg of active ingredient per kg of weight per day; for example, doses of from 0.1 to 10 mg / kg may be used in the treatment of adults.

The thieno [1,5] benzoeiazhpizaes of the formula I and their salts can normally be administered orally or by injection; these substances are usually administered in the form of pharmaceutical preparations. Said preparations may be prepared by methods known per se in the pharmaceutical industry, and usually comprise at least one active compound of the formula I - or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. In the manufacture of the pharmaceutical compositions according to the invention, the active ingredient is usually mixed with a carrier, or diluted with a carrier, or enclosed in a carrier, which in this case may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, a solid, semi-solid, or liquid material may be used as a vehicle, excipient or medium for the active ingredient. Suitable carriers include, for example, lactose, glucose, saeharose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, syrups, methylcellulose, methyl ester and propyl ester of hydroxybenzoic acid, layman, magnesium stearate or mineral stearate. The pharmaceutical preparations may be formulated as known to those skilled in the art to permit rapid or sustained (sustained) release of the active ingredient after administration to the patient.

According to the envisaged mode of administration, said preparations may be formulated for oral use, for example as tablets, capsules or suspensions, or for parenteral use, as injectable solutions. The pharmaceutical preparations are preferably produced in such a form as to permit the administration of single doses and that each dose contains 1 to 200 m 2, most often 5 to 100 mg of active ingredient.

The invention is illustrated by the following examples. In the examples in which the melting points of the compounds are not given, the basis for the structure of the final (in the respective title) products was obviously obtained by thin-layer chromatography and / or based on spectral data.

Examples

Starting compound .alpha.-carboxymethyl-.beta.-carboxyethyl .alpha.-ethylethylmethylsulfide

In a 100 ml three-necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, pent-3 ethyl ester was added dropwise to the mixture of methyl thioglycolic acid (10.5 g, 0.1 mol) with piperidine (0.1 mL) with stirring. - ene (12.6 g, 0.1 mol) (for the preparation of the ester see J. Org. Chem. 12, 138-154), maintaining the temperature of the mixture at 40-50 ° C. Simultaneously, additional piperidine (0.6 mL) was added in portions of 0.05 mL over 45 minutes. After the pentenoate was added dropwise, the reaction mixture was heated at 50 ^° C for 10 minutes, then cooled, washed with water, dried over anhydrous magnesium sulfate, filtered and washed with ether. The combined filtrates, after distilling off the solvents, gave the title compound as a yellow liquid.

Example 1 (a) 5-Ethyl-2- (2-nitroanilino) -thiophene-3-carboxylic acid ethyl ester

To ethyl acetate solution. 2-amino-5-ethylthiophene-3-carboxylic acid (Ber. 99, 94-100) (40 g, 0.2 mole) in anhydrous tetrahydrofuran (150 mL) cooled to -40T was stirred, under a nitrogen atmosphere, a solution of n-butyllithium in hexane [125 mL of a 10.2% (w / v) solution, 0.2 mol] was added dropwise while maintaining the temperature below -30 ° C. The reaction mixture was stirred for an additional 15 minutes at -30 ^° C, and then the resulting solution was pushed through a nitrogen U-tube to a solution of o-fluoronitrobenzene (28 g, 0.2 mol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred overnight at 15-30 ° C and the resulting inky blue solution was poured into 3 times the volume of ice water. The mixture was shaken with ether (3 x 500 mL), ethereal extracts washed with water (2 x 500 mL), dried and the solvents evaporated. The dark red oil was dissolved in ethanol (200 mL) and cooled overnight. The separated crystalline substance was filtered and dried under vacuum at 50 ^{C 1} C. After recrystallization from ethanol gave pure ethyl 5-ethyl-2- (2-nitroanilino) thiofе'П-3-carboxylic acid of mp 66-68 ^C C.

(b) 5-Ethyl-2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester

The title compound was prepared in a similar manner to that described in Example K a) but using 2,5-difluoronitrobenzene instead of o-fluorobenzene as starting material. Mp 90 ° C (after recrystallization from ethanol).

Calcd for C15H15FN2O4S:

% C, 53.24;% H, 4.45;% N, 28.21;

9.47% S, found:

C 53.45, H 4.75, N 8.15, F 5.71,

9.75% S.

Similarly, the following compounds were prepared as described in Example 1 (a); for each compound, the starting substituted nitrobenzene is used, instead of the O-fluoronitrobenzene used in Example 1 (a), the melting point of the title compound and the solvent used for crystallization (indicated in parentheses).

(C)

2- (3,5-Difluoro-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

2,4,6-trifluoronitrobenzene, mp 74-75 ^° C (ethanol).

(d)

5-Ethyl-2- (5-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

2,4-difluoronitrobenzene, m.p. 87-88 ° C (ethanol).

(E)

2- (4-Chloro-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

5-chloro-2-fluoronitrobenzene, m.p. 75-76.5 ° C (ethanol).

(F)

2- (2,4-Dinitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

2,4-dinitrofluorobenzene, 148 ° C (ethanol).

(G)

2- (4-Fluoro-2-nitroanilino) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylic acid ethyl ester.

The title compound was prepared as described in Example 1 (a), but using 2,5-difluoronitrobenzene and 2-amino-4,5,6,7-tetrahydrobenzo [b] 1'-γ-β-3-carboxylic acid ethyl ester as starting material. . Mp 140-142 ° C (ethanol).

(h)

2- (4,5-Difluoro-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester. 2,4,5-trifluoronitrobenzene, mp 105 ^q C (ethanol).

(and)

3- (2-Nitroanilino) thiophene-2-carboxylic acid methyl ester.

The compound was prepared as described in Example 1 (a) but using 2-fluoronitrobenzene and 3-aminothiophene-2-carboxylic acid methyl ester (British Patent No. 837,086) as starting materials. Mp 184 ° C (toluene / methanol 2: 1).

(and)

3- (4-Fluoro-2-nitroanilino) thiophene-2-carboxylic acid methyl ester.

The title compound was prepared as described in Example 1 (a) but using 2,5-difluoronitrobenzene and 3-amino-thiophene-2-carboxylic acid methyl ester as starting material. Mp. 172 to 175 ³ C (benzene).

Similarly, the following compounds were prepared:

(kj

5-Isopropyl-2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

(1)

5-n-Hexyl-2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

(m)

4-Methyl-2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

(n)

4-Methyl-5-ethyl- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

Example 2 (a) 5-Ethyl-2- (2-nitroanilino) thiophene-3-carboxylic acid ethyl ester

A solution of o-fluoronitrobenzene (56.4 g, 0.4 mol) and 2-amino-5-ethylthiophene-3-carboxylic acid ethyl ester (100 g, 0.5 mol) in anhydrous dimethylsulfoxide (320 mL) was stirring and heated in an oil bath under a nitrogen atmosphere. When the internal temperature of the solution reached 60 ^° C, potassium carbonate (55 g, 0.4 mol) was added and the mixture was heated to 100 ^° C with stirring until all o-fluoronitrobenzene had been reacted (ca. 6.5 hours). The reaction mixture was poured into ice water, the solution acidified with concentrated hydrochloric acid, and the tracts were washed with water, dried with magnesium sulfate, and the solvent was distilled off. The red colored semi-solid residue was recrystallized from ethanol to give 5-ethyl-2- (2-nitroanilino) thiophene-3-carboxylic acid ethyl ester as a crystalline solid, mp 66-68 ° C.

The following compounds were prepared analogously to Example 2 (a). For each compound, the starting materials [if different from the starting materials given in Example 2 (a)], the melting point of the title compound and the solvent used to crystallize it (indicated in parentheses) are shown.

(b)

2- (4-Chloro-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

5-chloro-2-fluoro-nitro-benzene, m.p. 75-76 ° C (ethanol).

(C)

2- (2,4-Dinitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

2,4-dinitrofluorobenzene, m.p. 146-148 ° C (ethanol).

(d)

5-Ethyl-2- (2-nitro-4-trifluoromethylanilino) thiophene-3-carboxylic acid ethyl ester.

fluoro-3-nitrobenzotrifluoride, m.p. 102 ° C (ethanol).

(E)

5-Ethyl-2- (5-methyl-2-nitroanilino) -thiophene-3-carboxylic acid ethyl ester.

3-fluoro-4-nitrotoluene, m.p. 55-57 ° C (ethanol).

(F)

2- (1-Difluoromethyl-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

^5-L-i diftuΌrmetllo 2lfluornitrobenuen, mp 88-90 ° C (ethanol).

(G)

2- (4-N, N - [(4'-Dimethylsulfonamido-4-nitroamino) -5-ethylthlophene-3-carboxylic acid methyl ester].

5-N, N-dimethylfulfunnmido-2-fluoronitrobenzene and 2-amino-5-ethylthiophene-3-carboxylic acid methyl ester, mp 1668-168 cc (ethanol).

(h).

5-Ethyl-2- (4-methoxy-2-pentanediol) thiophene-3-carboxylic acid methyl ester.

2-fluoro-5-methoxuititrobenuene and 2-amino-5-ethyl-thiophene-3-carboxylic acid methyl ester, m.p. mp 125-127 ° C (ethanol).

(and)

2- (1-Fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

2,5-difluoronitro-benzene and 2-amino ^, thiophene-3-carboxylic acid ethyl ester, mp 125 ° C (ethanol). - (j)

5-Ethyl-2- (1-methylthio-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester.

4-fluoro-3-nitro-thioauisole and 2-amino-15-ethylthiophene-3-carboxylic acid ethyl ester.

(to)

2- (2-Chloro-6-nitroamino) -5-ethylthiofluoro-3-carboxylic acid ethyl ester. 2-Amino-5-ethylthiophene-3-carboxylic acid ethyl ester and 3-chloro-2-fluoro-uitrobenzene, mp 67-70 ° C (ethanol).

(l)

Ethyl 5-ethyl-2- ^{(2-trifluoromethyl-6-ethyl-ι} uitroa uiliuo) thiophene EU-3-carboxylic acid. 2-Amino-5-ethylthiophene-3-carboxylic acid ethyl ester and 2-fluoro-3-trifluoromethyltrobenzene, mp 72-73 ° C (ethanol).

(m)

3- (1-Chloro-2-nitroamino) -thiophene-2-carboxylic acid methyl ester.

5- chlorinating · r 2 fluoгnitrobeuzen and 3-methyl-2-aminothiofe'n the carboxy mp 207-208 ^q C (ethyl acetate-hexane).

(n)

5-Methyl-2- (2-nitro-Φ-piperidin) thiophene-3-carboxylic acid methyl ester.

2-Aromo-5-methylthiophene-3-carboxylic acid methyl ester and N, S-dinomethylbenzene, m.p. 149-151 ° C (ethanol).

(O)

2- (1-Bromo-2-nitro-amino) -4-ethylthiophene-3-carboxylic acid ethyl ester.

2-Amino-5-ethylthiophene-3-carboxylic acid ethyl ester and 5-bromo-2-fluoronitrobenzene, m.p. 76-78 ° C (ethanol).

(P)

2- (1-Fluoro-2-nitroan-6-enyl-hiophene-3-carboxylic acid methyl ester).

2-Amino-5-phenylthiophene-3-carboxylic acid methyl ester and 2,1,14- (1,1,3,4-trimethyl) -benzene, m.p. 150-T (dichloromethane).

(q)

5-Ethyl-2- (2-nitroanilino) thiophene-3-carboxylic acid.

5-Ethyl-2- (2-nitroamino) -thiophene-3-carboxylic acid ethyl ester (6.0 g) was dissolved in a mixture of ethanol and water (100 mL: 50 mL) and the solution was heated to 60 ° C with stirring. To the solution was added 5 N sodium hydroxide solution (50 ml) and the mixture was heated to the above temperature for 16 hours. The reaction mixture was cooled, diluted with water (500 ml) and the precipitated 5-ethyl-2- (2-nitroamino) thiophene-3-carboxylic acid filtered off. Mp 189-191 ° C (ethyl acetate).

(r)

5-Ethyl-2- (1-floor-2- (4-nitro) -thiophene) -thiophene-3-carboxylic acid.

The compound was prepared from 5-ethyl-2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylic acid ethyl ester in a similar manner to Example 2 (q), but at 25 ° C. . Mp 198-200 ° C (ethyl acetate).

(with)

5-Ethyl-3- (1-fluoro-4-nitroamino) thiophene-2-carboxylic acid methyl ester.

EXAMPLE 3 (a) Methyl 3- (4- (4-Fluoro-2-nitroanilino) thiophene-1-carboxylic acid methyl ester)

3-Carbmethoxy-1-aminothiophene hydrochloride [J. Am. Chem; Soc. 68, 2232 (1946)] (48.5 g, 0.25 mol) was dissolved in a minimum amount of water, saturated sodium bicarbonate solution and ether were added, and the mixture was shaken. The ether was separated, dried over anhydrous magnesium sulfate, The oily residue was dissolved in dimethylsulfoxide (DMSO) (10 ° C · 0 mL) and can also be dissolved in dimethylformamide (DMF) or 2-methoxyethanol, but DMSO is most preferred. heated to 100 ° C and with stirring, under nitrogen, was added 2,5-difluornitrobenze n ⁱ (40 g, 0.25 mol) and triethylamine (35 mL). the reaction mixture was heated under these conditions for one hour (under reflux) triethylamine (35mL) was added and the mixture heated under stirring and under nitrogen for a further 40 hours.

After cooling, the reaction mixture was poured into a mixture of saturated aqueous sodium chloride solution (1.5 L) with ethyl acetate with stirring. The biphasic mixture was filtered, the organic portion separated, washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off. The brown gum was dissolved in a minimum amount of ethyl acetate, filtered under vacuum through a layer of "Florisil" (protected trademark) silica gel placed in a porous filter funnel, washed with ethyl acetate until all product was removed, the filtrates combined and the solvent evaporated. The oily residue was dissolved in cold ethanol (250 mL) and the solution was allowed to stand at 0 ^{° C for} 24 hours. The precipitated red-orange-colored crystalline product sometimes contained traces of brown tarry impurity; it has been found that this impurity can be separated by mixing the product with a little ethyl acetate. ¹ thus obtained crystalline substance was filtered, washed with ethanol, then with petroleum ether b.p. 40-60 ° C and dried in vacuo. 3- (4-fluoro-2-nitroanilino) thiophene-4-carboxylic acid methyl ester was obtained as a crystalline solid, mp 164 ^° C.

(b)

3- (2-Nitro-4-trifluoromethylanilino) thiophene-4-carboxylic acid methyl ester.

The title compound was prepared in a similar manner to that described in Example 3 (a) above. Mp 175 ° C (ethanol).

(C)

2- (4-fluoro-2-nitroanilino) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-nitrile.

It was added to anhydrous DMSO (20 mL)

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) and the mixture heated with stirring n, and an oil bath. When the temperature reached 60 ^Q C was added potassium carbonate (2.76 g, 0.02 mole) and the mixture stirred for 5 hours at 100 ^Q C. The reaction was poured into ice water, acidified, and vytřeipán methylene chloride. The organic extracts were combined, washed with water, dried over magnesium sulfate and the solvent distilled off in vacuo. The title nitrile, mp 137-139 ° C (ethyl acetate), was obtained.

In a similar manner, starting from 2-amino-15-ethylthifen-3-nitrile, the following compounds were prepared:

(d)

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.

Example 4 (a) 3- (4-Chloro-2-nitroanilino) -2,5-dihydrothiophene-4-nitrile

In a three-necked flask (500 ml) equipped with a Dean-Stark attachment for azeotropic distillation of water, 3-cyantetrahydrothiophen-4-one (see Dutch patent application 66 04742) (38.1 g, 0.25 mol) and 4-chloro-2-nitroaniline (51.8 g, 0.28 mol). A few drops of boron trifluoride etherate were added to the solution, and the mixture was heated to boiling for 4 hours while distilling off the water formed.

The reaction mixture was cooled and the precipitated brown solid was filtered off. The crude product was recrystallized from absolute ethanol, using activated carbon to decolorize the solution. The separated orange colored crystalline material was filtered off, washed with ethanol. and dried under vacuum at 50 ° C. The 3- (4-chloro-2-nitroanilino) -2,5-dihydrothiophene-4-nitrile thus obtained had a m.p. of 154-155 ° C.

(b)

3- (4-methylthio-2-nitroanilino) -2,5-dihydrothiophene-4-nitrile.

The title compound was obtained in a similar manner to that described in Example 4 (a) above. Mp 141-142 ° C (ethanol).

(C)

4- (4-fluoro-2-nitroanilino) -2-ethyl-, 5-dihydrothiophene-3-nitrile.

Example 5 (a) 3- (4-chloro-2-nitroanilino) thiophene-4-nitrile

A solution of 3- (4-chloro-2-nitroanilino) -2,5-di-.

hydrothiophen-4-nitrile (14.09 g, 0.05 mol) in xylene (150 mL) was added to a solution of chloranil (12.3 g, 0.06 mol) in hot xylene (100 mL) and the mixture was heated with After cooling, xylene was distilled off under reduced pressure and a reddish brown colored solid red brick was recrystallized from boiling methanol to give a crystalline red colored 3- (4-chloro-2-nitroamilino) thiophene-4 The nitrile was filtered off, washed with methanol and dried under vacuum at 50 ° ^C, 214 ^° C.

(b)

3- (4-methylthio-2-nitroanilino) thiophene-4-nitrile was prepared in a similar manner; mp 167-169 ° C (methanol).

(C)

4- (4-fluoro-2-nitroanilino) -2-ethylthiophene-3-nitrile.

Example 5 (a) 2- (2-Aminoanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester

A solution of 5-ethyl-2- [2-nitroanilino) thiophene-3-carboxylic acid ethyl ester (20.7 g) in ethanol (150 mL) was catalytically reduced, with hydrogen at 4 atmospheres (60 µL).

i.) in the presence of 10% palladium on charcoal (2.0 g). The catalyst was filtered off and the solvent was distilled off under reduced pressure. The obtained 2- (2-aminoanilino) -5-ethylthioien-3-carboxylic acid ethyl ester had

mp 50-52 ° C (hexane).

The following compounds were prepared in a similar manner:

(b)

2- (2-Amino-4-fluoroanilino-5-ethylthiophene-3-carboxylic acid ethyl ester, m.p. 82-84 ° C (hexane)).

(C)

2- (2-Amino-3,5-difluoroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester. Mp 106 ° C (ethanol).

(d)

2- [2-Amino-5-fluoroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester. Mp 100-101 ° C (ethanol).

(E)

2- (2-Amino-4-chloroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester. Mp 119-121 ^° C (ethanol).

{F)

2- (2,4-Diaminoanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

Mp 152-155 ^° C (hexane).

(G)

2- (2-Amino-4-trifluoromethyl-anilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

(h)

2- (2-Amino-5-methylanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

if)

2- (4-Difluoromethyl-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

(and)

2- (2-amino-4-N, N-dimethylsulfonamidoanilino) -5-ethylthiophene-3-carboxylic acid methyl ester.

(to)

2- (2-Amino-4-methoxyanilino) -5-ethylthiophene-3-carboxylic acid methyl ester.

2- (2-Amino-4-fluoroanilino) -4,5,6, y-tetrahydrobenzo [b] thiophene-3-carboxylic acid ethyl ester.

(m)

2- (2-Amino-4-fluoroanilino) thiophene-3-carboxylic acid ethyl ester.

(n)

2- (2-Amino-4-methylthioanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

(O)

3- (2-Aminoanilino) thiophene-2-carboxylic acid methyl ester.

Mp 102 ° C. The title compound was prepared by reduction of 3- (2-nitroanilino) thiophene-2-carboxylic acid methyl ester.

(P)

3- (2-Amino-4-fluoroanilino) thiophene-2-carboxylic acid methyl ester.

The title compound was prepared similarly by reduction of 3- (4-fluoro-2-nitroanilino) thiophene-2-carboxylic acid methyl ester.

(q)

Methyl 3- (2-amino-4-chloranilinoj thiophene-2- carboxylic acid ^J.

. (r)

2- (2-α, amino-4-fluoroamino) -5-methylthiophene-3-carboxylic acid methyl ester, mp 116-118 ° C.

(with)

5-Isopropyl-2- (4-fluoro-2-amino-amino) -thiophene-3-carboxylic acid ethyl ester.

(t J

5-n-Hexyl-2- (4-fluoro-2-aminoanilino) thiophene-3-carboxylic acid ethyl ester.

(at)

4-Imthyl-2- [44-fluoro-2-amino-anilino) -thiophene-3-carboxylic acid ethyl ester.

(in)

4-Methyl-5-ethyl-2- (4-fluoro-2-aminoanilino) thiophene-3-carboxylic acid ethyl ester.

(w)

2- (2-Amino-amino) -5-ethylthiophene-3-carboxylic acid.

A solution of 5-ethyl-2- [2-nitroanilino) thiophene-4-carboxylic acid (8.0 g, 0.027 mol) in ethanol (150 ml) was catalytically hydrogenated with hydrogen at 4 atmospheres in the presence of 10% palladium on charcoal (900 mg) After filtration of the catalyst and distilling off the solvent under reduced pressure, the title compound was obtained.

(x)

5-Ethyl-3- (2-amino-4-fluoroanilino) thiophene-2-carboxylic acid methyl ester.

Example 7

2- (2-amino-4-initroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester

A solution of 2- (2,4-dinitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester (0.5 g) in a mixture of 6N ammonia (25 ml) and ethanol (10 ml) was heated to boiling under stirring. · The mixture · hydrogen sulfide was introduced for 2 hours. After cooling the reaction mixture to room temperature, 2- (2-amino-4-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester precipitated in the form. The yellow precipitate was filtered off, washed with water and dried in vacuo. Mp. 174-176 ^C C (ethyltcetát).

Example 8

2- (2-Amino-4-bromoanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester

2- (4-Bromo-2-nitroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester (0.4 g, 0.001 mol) was added to a suspension of zinc powder (0.4 g) in ammonium chloride solution (0). , 4 g) in water (10 mL), and the mixture was mixed at 50 ° C for 24 hours. The reaction mixture was filtered, the solid washed sequentially with water and ethyl acetate, the organic layer was • separated, washed with water and dried over ^sodium: sulfate. After distilling off the solvent, the title ester was obtained.

Example 9 (a) 3- (2-Aminoanilino) -2,5-dihydrothiophene-4-carboxylic acid methyl ester

3-Carbmethoxytetrahydrothiophen-4-one (48.06 g, 0.3 mole) and o-phenylenediamine (32.4 g, 0.3 mole) were dissolved in boiling ethanol (500 mL). acetic acid was added and the mixture was refluxed under nitrogen for 4 hours. Upon cooling of the reaction mixture, a crystalline material precipitated, which was filtered off, washed with absolute ethanol and dried in vacuo After dissolving the crude product in absolute ethanol and decolourising the solution with activated charcoal, a yellow solution was obtained from which the product crystallized in colorless needles. The precipitated 3- (2-aminoanilino) -2,5-dihydrothicene-4-carboxylic acid methyl ester was filtered off, washed with ethanol and dried in vacuo; mp 101 ° C.

(b)

3- _{(2-amino-4,5-1} dichloranlli amino) -2,5-dihydrothio1 ene-3-carboxylic acid.

Said compound was obtained in a similar manner to that described in Example 9 (a); mp 162 ° C.

Example 10 (a) S-4-Aminoanilino) thiophene-4-carboxylic acid methyl ester

A mixture of 3- (2-aminoanilino) -2,5-dihydrothiophene-4-carboxylic acid methyl ester (25.03 g, 0.1 mol) and chloranil (24.6 g, 0.1 mol) was heated for two hours. hours to boil. under reverse. · Condenser in xylene (900 · ml). The solvent was distilled off under reduced pressure, the dark brown residue was triturated with ethyl acetate and the resulting light brown product was filtered off, washed with ethyl acetate and dried in vacuo. 3- (2-Ethyl-amino) -thiophene-4-carboxylic acid methyl ester of melting point 120 DEG-122 DEG C. was obtained.

(b)

3- (2-Amino-4,5-dichloroanilino) -toluene-4-carboxylic acid methyl ester.

It was prepared in a similar way; mp 162-163 ° C.

Example 11

3- (2-Aminoanilino) thiophene-4-carboxylic acid methyl ester

In a flask containing a slurry of palladium catalyst on activated carbon (5%, · 200 milligrams) in cyclohexane (or in norbor236753 nadiene, or in norbornylene) (50 ml, 3- (2-aminoa: nilino) methyl ester was added - The 2,5-chlorophen-4-carboxylic acid (2.5 g, 0.001 mol) was added and the reaction mixture was heated to reflux for 4 hours with stirring, followed by TLC.

The reaction mixture was cooled, the solvent was evaporated under reduced pressure and the dark brown oily residue was chromatographed on a column of silica gel "Florisil" using chloroform to elute the substances. The title ester was obtained in the form of an orange-colored solid, mp 120-122 ° C.

Example 12 (a) 342-Amino-5-trifluoromethylanilino) -2,5-dihydrothiophene-4-nitrile

4-trifluoromethyl-n-phenelenediamine.n (24 g, 0.136 mol) -and 3-keto-2,5-dl-thiothiophene-4-nitrile (17.3 g, 0.136 mol) were dissolved in 200 ml of warm ethanol, acetic acid (3 mL) was added to the solution, and the mixture was heated to reflux for 24 hours. Upon cooling of the solution, the desired compound precipitated as colorless crystals, which were filtered off and combined with a further fraction which formed after the filtrate had concentrated to a small volume and after cooling. Mp 189 ° C.

(b)

3- (2-Amino-chloro-chloro) -5,5-trimethylthin-4-yltril.

It was prepared in a similar way; t. t.

164 to 165 cc.

(C)

3- (2-Dloinoanilino) -2,5-dihydrothiophene-4-nitrile.

3-Ke-o-4-oxa-tetramethylthiothene (80 g, 0.629 mol) and o-phenylenediamine (68 g, 0.629 mol) were dissolved in 1.5 liters of technical · denatured ethanol with heating. (3 ml) was added and the mixture was heated under reflux for 24 hours under mechanical stirring, after cooling the solution to give the title compound, which was filtered off and dried, m.p.

Example 13 (a) 10-Amino-7-chloro-4H-thiello [3,4-b] - [1,5] benzodidzepine

A solution of 3- (4-chloro-2-miroainilino) thiophene-4-nitrile (17.18 g, 0.06 mol) in a mixture of ethanol (300 mL) and ethyl acetate [100 mL] was hydrogenated in the presence of palladium on active Coal catalyst (3.5 g, 10%) in a Parr-hydrogenation apparatus. After two hours, the reaction was complete, the catalyst was filtered off and the solvent was distilled off under reduced pressure. 3- [4-Chloro-2-amino-amino) -thiophene-4-nitrile was obtained.

The latter light brown product was dissolved in a three-necked flask (500 ml) in absolute ethanol, concentrated hydrochloric acid (12 ml) was added dropwise gently with stirring, and the mixture was heated under reflux for about 24 hours. The reaction mixture was cooled and sodium hydroxide solution (10%, 60 mL) was added dropwise until the reaction was slightly alkaline. During alkalization, a precipitate of pale yellow-brown colored 10-amino-7-chloro-4H-thieno [3,4-b-i] precipitated. [1,5] Benzodiazepine, which was filtered off, washed with water and dried under vacuum at 50 ° C. Mp 239-240 ° C.

Similarly, the following compounds were prepared:

(b) 10-amino-7-methylthio-4H-hieno [3,4-b] [-1,5] benzodiazepine.

Mp 195-197 ° C.

(c) 12 < 10 &gt; 10oo-9-fluoro-6H-1,2,3,4-tetrahydro-benzothienof 2,3-b] [1,5] benzodiazepine.

(d) d 10 -Amino-2-yl-7-fluoro-4H-thleno [2,3-b] [1,5] benzodiazepine.

(e) d-α-ω-2-e-7-O-methoxy-4-thieno [2,3-b1 [1,5] benzodiazepine.

(f) d (4-Amino-1-eth-7-O-methylthio-4H-trifluoro- [2,3-b] [1,5] benzodiazepiin).

(G)

10-amino-2-ethanol-7-trifluoromethyl-4H-

-thieno- [2,3-b] [1,5] -benzodiazepine.

(h)

10-amino-ethyl-7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepine.

EXAMPLE -1a -d 14 (a) Hydrochloride 10-O-amino-H-2,5,5-dihydro-thieno [3,4-b-] [1,5] benzodiazepine

3- (2-dimananilino) -2,5-dihedrothiophene-4-nitrile (84.5 g, 0.39 mol) was added with mechanical stirring to hot denatured technical ethanol (1.5 L) to the resulting suspension. Concentrated hydrochloric acid (57 ml, -0.66 mol) was added dropwise, and the mixture was heated under stirring for 1 hour at reflux, and upon cooling a solid product precipitated which was filtered off, washed with some ethanol, then with petroleum ether at temperature. boiling 40-60 ° C and dried under vacuum at 50 ^° C. The obtained 10-amino-4H-2,5-dihydrothieno [3,4-b] [1,5] benzodiazepine hydrochloride had mp 292 ° C (with decomposition). ).

(b) 10-amino-4H-2,5-dihydrothieno [3,4-b] [1,5] benzodiazepine.

The hydrochloride prepared as described above (a) (-4.5 g) was added with stirring to 1 liter of chloroform and 500 ml of a 10% (w / v) sodium hydroxide solution was added in one portion to the suspension. The suspension was stirred for two hours to give the title compound as a colorless solid. The free base was filtered, washed with water, ethanol and ether, and dried in vacuo; mp 240-250 ° C (dec.).

(C)

9,1O-dihydr-4H-2,5-dihydrothio [3,4-b] [1,5] benzodium ^, zeipin-10-one.

A solution of 3- (2-aminoanilino) -2, i ^ - (^ ^ d ^ ^iihy, of: thiophene-4-carboxylic acid (0.5 g, 0.002 mol) in anhydrous DMSO (2 mL) at 90 ° C, under a nitrogen atmosphere, was added to a sodium hydride dispersion (50% w / v suspension in mineral oil, 300 milligrams) in anhydrous DMSO. When gas evolution ceased, the solution was stirred for two more hours and then poured into 300 ml of brine / ice. The solution was shaken with ethyl acetate, and the extract was dried over anhydrous sulfate. magnesium, the desiccant filtered, and the filtrate concentrated to a small volume. Ether was added to the suspension, the solid was filtered off, the filtrate was evaporated to dryness and the residue was stirred with chloroform. 9,10-dihydro-4H-2,5-dihydro.Lieno [3,4-b] [1,1,5] -benzodiazepin-10-one was obtained as a yellow solid, mp 210 ° C (dec.).

Example 15 (a) 10-O-Amino-4- (4H-2,5-dihydrotrimidine) (3 [3,4-b] [1,5] benzodiazepine

3-yttrarahrdroonophen-one (80 g, 0.629 mol) and o-phenylenediamine (68 g, 0.629 mol) were dissolved in 1.5 liters of technical denatured ethanol while stirring and heating to reflux. acetic acid (3 mL) was added and the mixture was heated to reflux with stirring for 5 hours. After cooling, concentrated hydrochloric acid (92 ml, 1.08 mol) was carefully added to the solution with stirring, and the solution was heated under reflux for one hour. After cooling, 10% (w / v) sodium hydroxide solution (500 ml) was added dropwise to the rydrochloride solution while stirring, maintaining the temperature below 40. The mixture was stirred for one hour, the precipitate filtered off, washed with water, ethanol, acetone and ether and dried in vacuo. The title product of m.p. 230 DEG-240 DEG C. (dec.).

(b)

10-amino-1H-thieno [3,4-b] [1,5] benzodiazepine.

The 10-amino-1H-dihydrothiono [3,4-b]] 1,5] bonzodiazopine (43 g, 0.198 mol) obtained above was introduced into boiling xylene (1 liter) with mechanical stirring, added to the suspension. chloranil (49 g) and the mixture was heated under reflux for 2 to 6 hours.

The reaction mixture was allowed to stand overnight at room temperature, then the suspension was filtered, the solids washed with xylene until the wash liquid was colorless, and then dried in a filter funnel. The dried black product was taken up in hot water (200 ml), a 5 M hydrochloric acid solution (36 ml) was added to the suspension, and the resulting red solution was heated to boiling for 10 minutes.

The solution was filtered, the tar residue on the filter was extracted with a solution of an additional 36 mL of 5M hydrochloric acid in water (200 mL), and the mixture was filtered again. The combined 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 the mixture did not exceed 40 ^° C. The solution was stirred for 1 hour. The product was filtered off, washed with water and dried under vacuum at 50 ° C. The obtained 10-amino-4 H -11160 o {3,4-b] [1,5] benzodiazolepin had a mp of 190 ° C (with decomposition).

Example 16 (a) 10-Amino-6-difluoromethyl-1H-dihydro-thieno [3,4-b] [1,5] benzodiazepine

3- (2-Amino-5-trifluoromethylanilino) -n-cyano-N -dihydrothiophene (10.5 g, 0.0368 mol) was dissolved in technical denatured ethanol (100 ml) with heating, with stirring concentrated hydrochloric acid (3.2 mL, 0.0368 mol) was added carefully, and the resulting red colored solution was heated under reflux for 1 hour. The reaction mixture was cooled, a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring at a temperature below 40 ° C and the precipitated amidine was filtered off, washed with water, ethanol and boiling potrolotherm 40. to 60 ° C and dried under vacuum at 50 ° C. The filtrate was diluted with an excess of water and the further product fraction was filtered off, dried and combined with the first crop. The title product thus obtained had a melting point of 200-210 ° ^C. C (dec.).

(b) 10-a, mino-6-chloro-4H-2,5-dihydroihieno [3,4-b] 1,5] benzodiazepine was prepared in a similar manner.

Example 17

The products obtained in the manner described in Examples 16 (a) and 16 (b) were "flavored" in the manner described in Example 15 (b) and were obtained by (a)

10-amino-6-trifluoromethyl-4H-thieno [3,4-b] [1.5. Jbenzoidiazepine,

tt 178 ^Ci C (dec.), and (b)

10-amino-6-chloro-4H-thieno [3,4-b] [1,5] benzodiaisepine.

Example 18 (a) 9,10-Dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepine-10-o.n

To a solution of methylsulfmyl carbanyl sodium salt, prepared by heating sodium hydride (7.2 g, 0.15 mol) in anhydrous dimethylsulfoxide (100 mL) to 70 ^° C with stirring until evolution was complete? gas was added a solution of 2- (2-ami.noanili'no) ^-5-e thylthiofen-3-carboxylate (14.5 g, 0.05 mol) in anhydrous dimethylsulfoxide (50 ml) and the mixture was stirred Fifteen minutes. The solution was poured into ice water (600 ml), stirred for 15 minutes, the precipitated product was filtered off, washed well with water, dried, washed with carbon tetrachloride and dried under vacuum at 60 ^° C to give 9-10-dihydro-2-ethyl-4H. -thiono [2,3-b] [1,5] benzodiazepine, m.p. 218 DEG-220 ^DEG C. (chloroform).

(b)

2-Ethyl-7-fluoro-9,10-dihydro-4 H -thieno [2,3- b] [1,5] benzodiazepin-10-one.

The title compound was prepared in a similar manner using 2- (2-amino-4-fluoroanilimo) -5-ethylthiophene-3-kcriboxylic acid ethyl ester as the starting material. After recrystallization from ethanol, mp 210-212 ^° C.

Similarly, the following compounds were prepared as described in Example 18 (a). For each compound, the starting substituted thiophene, the melting point of the title compound and the solvent used to recrystallize it are shown.

(c) 6,8-Difluoro-9,10-dihydro-2-ethyl-4H-

-thieno [2,3-b] [1,5] benzodiazepin-10-one.

Ethyl 2- (2-amino-3,5-difluoroanilino) -5-ethylthiophene-3-carboxylic acid, mp 230-323 ^{O C} (chloroform).

(d)

9,10-dihydro-2-ethyl-6-fluoro-4H-thieno- [2,3-b3 [1,5] benzodiazepin-10-one.

2- (2-Amino-5-fluoroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester, mp 255-257 ° C (ethyl acetate).

(e) 7-chloro-9,1-O-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

2- (2-Amino-4-chloroanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester, mp 216-218 ^° C (ethyl acetate).

(f) 7-Amino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

2- (2,4-Diaminoanilino) -5-ethylthiazine-3-carboxylic acid ethyl ester, m.p. 230 ° C (from a to 1 to d) (chloroforme / chloro).

(AND

9.10- Ь1Ьу0.го-2-еМ1у1-6-п1е1Ьу1 · 4Η-1ο1οηο- [2,3-b] [1,5] b enzod i a z ep in -10-on.

2- (2-Amino-5-methylanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester, mp 205-207 ^° C (ethyl acetate).

(h)

9.10-dihydro-7, N, N-methylsulfonamido-2-ethyl-4 H-thieno [2,3-b] [1,5] benzodiazepin-1-one.

2- (2-Amino-4-N, N-dimethylsulfonamidoanilino) -5-ethylthioene-3-carboxylic acid methyl ester, mp E 258-260 ° C (ethyl acetate).

(and)

10-dihydroc-2-ethyl-7-nitro-4H-eieno [2,3-b] [1.51] benzodiazepin-10-one.

Eihylest.r 2- (2-amino-4nitroa. iilino) -5-el: hylithiofen-3-carboxylic acid, mp 264-266 ^r C (ethyl acetate).

(and)

9, N-dihydro-7-fluoro-4H-thieno [2,3-b [1,5] benzodiazepin-19-one.

Ethyl 2- {2-amine thus obtained 4-fluoroanilino) -thiophene-3-carboxylic acid, mp 235-240 ^C ° C (carbon tetrachloride / hexane).

(to)

9-fluoro-6H-1,2,3,4,11,12-hexahydro-enzolineieno; 2,3-b! [1.5] Benzodiazejine-12-ene.

2- (2-Amino-4-fluoro-2,3,6,7,5-anilino) -4,5,6,7-tetramyl-benzo [b] thiophene-3-carboxylic acid ethyl ester, m.p. 238 ° C (ethyl acetate).

(1)

9.10-8 [eta] &lt; 2 &gt; -ethyl] -1H-difluoromethyl-1H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

Z-N-amino-4-trifluoromethylanilino-5-ethylthiophene-3-carboxylic acid ethyl ester.

(m)

9,10-dihydroxy-1,2-ethyl-4- (7-methyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one).

2- (2-Amino-4-methoxyanilino) -5-ethylthiophene-3-carboxylic acid ethyl ester.

(n)

9.10-dihydroc-2-ethyl-7-methylthic-4Ht

- thieno [2,3-b] [1,5] beidinodiazepin-10-one.

2- (2-Amino-4-methyl-thioanilino) -4-ethylthiophene-4-carboxylic acid ethyl ester.

(o) ϋ 17,11,19,19,19-Ethyl-2-ethyl-4-cyclo-4-thieno [2,3-b] [1] benzodiazepin-10-one.

5-Ethyl-2- (4,5-difluoro-2-nitroanilino] thiophen-3-carboxylic acid ethyl ester, mp 290 ^{° C |}

(P)

9.10-Dihydro-7-fluoro-2-phenyl-4H-trifluoro [2,3-b] [1,5] benzodiazepin-10-one.

Mp 250-252 ° C (dec.) (Ethyl acetate).

(q) 9,10-Dihydroth-7-fluoro-2-methyl-4H-thienol [2,3-b] [1,5] benzodiazepin-10-one.

Mp 25 0-252 ° C (ethyl acetate).

(r)

9,10-dihydro-4H-thieno [3,2-b] [1,5] benzodiazepin-10-one.

Methyl 3- (2-aminoanilino] thiophene-2 t-ka.rboxylo'vé, mp 226 ^C 'C (tetrachloro-lormeíhan).

(with)

9.10-Dihydro-7-fluoro-4H-thieno [3,2-b] -

11.5] benzodiazepin-10-one.

3- (2-Amino-4-fluoro-amino) -thiophene-2-carboxylic acid methyl ester, m.p. 225-230 ° C (ethyl acetate).

(t) 7-Chloro-9,10-di-phenyl-4-thieno [3,2-b] [1,5] benzodiazepin-10-one.

3- (2-Amino-4-chloroanilino) _-1 -thlofent-2-carboxylic acid methyl ester, m.p.

256 ° C (ethyl acetate).

(at)

9,1Otdihydroc-4H-thieno [3,4-b] [1,5] benzodiazeipin-10-one.

Mp 233-234 ° C.

(in)

9.1O-dihydro-7-fluoro-4H-thieno [3,4-b] [1,5] azaziaziazine-10-ene.

238 ° C (dec.).

(w)

6,7-trans-9,10-trans-4,10-4Η + 1-methyl- [3,4-b] [1,5] benzothiazepin-10-one.

Mp 284-287 ° C.

(x)

2-Isopropyl-7-fluoro-9,10-dihydro-4H-

-thieno [2,3-b] [1,5] benzodiazepin-10-one.

(s)

2-n-hexyl-77-fluoro-^-,, ^ΐΰΐΰΠ ^ ^ ^ΓΗΗ-

-thieno [2,3-b] [1,5] benzodiazepin-10-one.

(of)

1- [eta.-thienyl] -thi-or-9,10-dihydro-4H-pyrrolo [2,3-b]] 1,5] benzodiazepin-10-ol.

(aa) 1-Methyl-2-ethyl-7-fluoro-9,1O-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepine-10-сп.

(bb)

2-ethyl-7-lucyl-1,1-dihydric-4H-hien [3,2-0] [1,5] benzodiazepin-10-one.

(cc) ethoxy-4,10H-indol-4H-1-yl [2,3-b] [1,5] benzodiazepine-O-o-oine.

5-Ethyl-2- (2-amino-aniline) thiophene-3-carboxylic acid was dissolved in tetrahydrofuran (distilled from lithium aluminum hydride) (200 mL) and solid dicyclohexylcarbodiimide (5.7 g, 0.027 mol) was added to the solution. The mixture was stirred under nitrogen for 16 hours, the precipitate was filtered off and the filtrate was evaporated to dryness. Recrystallization of the residue from boiling acetonitrile gave 2-ethyl-9,1O-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepint-10-one, m.p. 218-220 ° C (chloroform).

Example 19 (a) 7-chloro-9,10-dihydro-4H-theno [3,4-b] [1,5] benzodiazepin-10-one and 0-amino-7-chloro-3-nitro [3,4-b] ] [1,5] benzodiazepine (4 g, 0.15 mol) was dissolved in a minimum amount of water (100 ml), a solution of potassium carbonate (13.0 g) in water (20 ml) was added, the amidine precipitated dissolved ethanol (40 ml) was added and the reaction mixture was heated at reflux for 17 h 2 S 7 5 3 din, ethanol was slowly distilled off over the last hour of the reaction time.

The reaction mixture was allowed to cool, added and concentrated hydrochloric acid was added to the mixture until a slightly acidic reaction. The aqueous phase was extracted with ethyl acetate, the organic extract dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The light brown residue was triturated with ether, filtered off and dried under vacuum at 50 ° C. 7-Chloro-9,10-dihydro-4H-thieno [3,4-b) (1,5) -benzediophenyl-10-one was obtained as a yellow solid, mp 212-213 ^° C.

In the manner described in Example 19 (a), the following amides were prepared by hydrolysis of the respective amidines:

(b)

9,10-dihydro-4 H -1-thieno [3,4- b] (1,5-) benzodiazepin-10-one.

234 ° C (dec.).

(C)

9,10-dihydro-7-methylthio-4H-thieno- (3,4-b] [1,5-] benzodiazepHi-10-one.

9.10-dihydro-6-trifluoromethyl-4H-thieno- (d).

[3,4-b) - (: 1,5] -benzoedazepin-10-one.

Mp 213 ° C.

(E)

9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [1,2,3-b] [1,5] benzediazep-n-10-ene.

Melting point 211%.

(F)

9.10-dihydro-2-ethyl-7-fluoro-4H-thieno- [2,3-b] [1,5] benzyl [2,3-b] [eta] &lt; 4 &gt; he.

(G)

9.10-Dihydro-2-ethyl-7-methylthio-4H-

-thieno [2,3-b] [1,5] benzodiazepin-10-one.

(h)

9,10-dihydro-4-ethyl-4-trifluoromethyl-1H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

(i) 9-feuor-6H-l, 2,3,4,1l, Mount Heha 12 · ₁ h.ydrebZle taken into thieno [2,3-b] [1,5] benzodiazepin-10-one.

(j)

9.10- ^{dihydro-2-ett-yl-6-ones} IFH ORMET ^ ^ ^ LiY J ^ - ^ 4 ^ Hthieno [2,3-b] [l, 5] benzodiazepin-10-one.

(k) Ethyl-7-fluoro-4H-thieno (3,4-b) (1,5) -benzodiazepin-10-one.

Example 20

9,10-dioydro-4N4 hieno [3,4 ·· -]] [1,5] benzodiazepine-10-one

A solution of 9,10-dihydro-4H-2,5-dihydrothieno [3,4-b] [1,5] lbenzorazepin-10-ene (0.33 g) ^! in cyclohexane (or in norbornylene or norbornylene) was heated to reflux with stirring in the presence of palladium on activated carbon catalyst (0.1 g, 5%). The course of the reaction was followed by thin-layer chromatogy.

After completion of the reaction, the reaction mixture was cooled, the catalyst was filtered off and the solvent was distilled under reduced pressure. The dark brown residue was chromatographed on a Florisil silica gel column. Using a mixture of chloroform and 5% methanol to elute the substances. 9,10-01-fluoro-4H-thieno [3,4-b ((1.5) benzodiazepin-10-one) was obtained as a light brown solid, m.p. 230-232 ° C.

Example 21

7- (4-Ethyl) amino-9,10-dihydro-2-methyl-4H-trifluoro [2,3-b] (1,5) benzoriazepin-10-one

To a suspension of 7-amino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] (1,5) benzorothoren-10-one (100 mg) in methylene chloride (-5 ml) Acethanhyrrir (10.1 ml) was added with triethylamine (0.1 ml) and the reaction stirred for 18 hours The precipitate was filtered off, washed with water and dried in vacuo at 60 ^° C. -ethyl derivative, mp 1. 264 ° C.

EXAMPLE 22 E-Co-9,10-Dihydro-4H-thio [3,4-b] [1,51 bzz] zepin-10-one

To a solution of 4H-thieno [3,4-b] [1,5] bemzodiazepin-10-one (4.32 g, 0.02 mol) in hot methanol was added with stirring N-chlorosuccin-3-one (3, 3, 4, 2, 2, 3). 0.02 g (0.025 mol) and a catalytic amount of benzeylperoxir, the mixture was heated under reflux for 1 hour and filtered while hot. The blue-colored portion of the filter was washed three times with hot ethanol, the ethanol portions were combined with the diatomaceous filtrate, and the solvents were distilled off. The brown-colored residue was extracted with benzene in a Soxblet apparatus, washed with potassium carbonate solution and dried. After removal of the solvent by distillation, the title 3-chloro-derivative was obtained as a pale yellow solid, mp 229 ° C.

Example 23 1-Acce-γ-9,10-dihydro-2-ethyl-7-fluoro236753

-4H-thieno [2,3-b] [1,5] benzodlazepin-10-one

To a solution of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine (0.26 g, 0.001 mol) in acetyl chloride (3 The reaction mixture was diluted with benzene (5 mL) and stirred at room temperature for 18 hours, diluted with water, extracted with chloroform, washed with water, dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title 1-acetyl derivative, mp 215-218 ^° C (methanol / hexane).

Example 24 (a) 9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b-1 [1,5] benzodiazepine-

-10-thione

9,10-il-2 - [(4-yl-1- [1- (1-yl) -7- (4-yl) -H] -H-11-ieno [2,3-b] | Zepin-10-one (20 grams, 0.076 mol) was added with stirring to a solution of phosphorus pentasulfide (17 g, 0.076 mol) in anhydrous pyridine (400 mL) and the solution was heated to reflux under stirring for 1.5 hours. The reaction mixture was then poured into ice-water, stirred for one hour, the precipitated product was filtered off, washed with cold water and dried, and recrystallized from ethanol-water to give 9,10-dihydio-2-ethyl-7-fluoro. -4H-thieino [2,3-b] - [1,5] bdiazzepine-10-thione in the form of bronze-colored plates · mp 203-206 ° C (b)

9.10-Dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepine-10-thione

The title compound was prepared in a similar manner to that described in Example 24 (a) using 9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] henzodiazepine-10. -one as starting material. Mp 233-236 ° C (ethanol-water).

In a similar manner, the following compounds were prepared:

(C)

9,10-di-cyclro-2-ethyl-7-methyl-4-thieno [2,3-b] [1,5] benzodiazeipin-2-ol.

Jd)

9,10-dihydro-4H-thieno [* 3,4-b] [1,5] benzodiazepine-10-thio.

Mp 221 ° C.

The other amides of Example 18 were similarly converted to the corresponding thioamides as described in Example 24 (a).

In all cases, the identification and confirmation of the structure of the end products was carried out by thin-layer chromatography and elemental analysis.

Example 25 (a) 2-ethyl-6-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

A mixture of 9,10-dihydro-12-ethyl-6-fluoro-4H-thieino [2,3-b] [1,5] benzothiazepin-10-one (0,4g), phosphorus oxychloride (4 ml and N, N) Dimethyl amine (0.15 mL) was heated at reflux for 3 hours, the reaction mixture was evaporated under reduced pressure and the residue evaporated again twice with xylene.The crude iminochloride was dissolved in absolute dioxane (1 mL), added to the solution. N-methylpiperazine (3 ml) was added and the mixture was refluxed for 4 hours, the volatiles were distilled off under reduced pressure, the residue was partitioned between aqueous ammonia and ether and the ether was shaken with 1N hydrochloric acid. The product was washed with ether, washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product, mp 175-177 ° C (ethyl acetate / hexane).

(b) Ethyl-β-β-β- (1-piperazinyl) -4H-

- [2,3-b] [1,5] benzodiazepine

It was prepared in a similar way. Mp 138-140 ° C (carbon tetrachloride / hexane).

Example 26 (a) 2-ethyl-10- (4-methyl-11-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

To a suspension of 9,10-dihydro-12-ethyl-4H-thieno [2,3-h] -1,5,5-benzodiazole-10-one (2.4 g, 0 · 0 · 1 mol) in N- A solution of titanium tetrachloride (1.2 mL, 0.011 mol) in anhydrous anisole (5 mL) was added to methylptperazine (10 mL) and the mixture heated to 120 ° C with stirring for 2 hours. The reaction mixture was poured into ice-water and the solution was shaken until an off-white precipitate formed. The suspension was extracted with methylene chloride until the lumps were yellow. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The yellow residue was triturated with ether, the product filtered off and recrystallized from hexane; mp 195-197 ° C.

The free base was converted to the corresponding maleic acid; mp 186-188 ° C (ethanol-ol / ether).

(b)

2-ethyl-7-fluoro-10- (4-106- [1,1-beta] -1- [10,7] -4H-thieno [2,3-b] [1,5] benzodiazepine.

The title compound, mp 161-163 ° C (hexane), was prepared as described in Example 26 [a) using 9,10-dihydro-2-ethyl-7-fluoro-4 H -thieno [2,3-b] [ 1,5] benzodiazepin-10-one as starting material.

For C18H21FN4S calculated:

% C, 62.76;% H, 6.14;% N, 16.26;% F, 5.51 °;

% C, 62.99;% H, 5.87;% N, 16.06;% F, 6.67.

The free base was converted to the appropriate maleic acid, m.p. 125-127 ° C (ethanol-ether).

For C 24 H 27 FNUO 1 S calculated:

% C, 57.37;% H, 5.47;% N, 12.16;

6.96% S, found:

57.53% C, 5.54% II, 11.99% N, 4.16% F, 6.93% S.

The following benzodiazepines were similarly prepared by the method of Example 26 (a). For each compound, the title amide, the melting point of the title compound, and. solvent used to recrystallize the product (indicated in parentheses).

(C)

2-ethyl-6-fluoro-10- (4-methyl-4-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

9,10-dioydro-2-ethyl-o-fluoro-4-e-thieno [2,3-b] [1,5-benzodiazepin-10-one, m.p. 206-208 ° C (hexane); maleate, mp 125-127 ° C (ethanol-ether).

(d) 1,8-Ditluoro-2-ethyl- [Ώ- (4-methyl) -L-piperazazinyl [2,3-b] [1,5] benzodiazepine.

6.alpha.-U1-oxo-e.90-dihodrot-1H-1-4H-thieno [2,3-b] [1,51] benzodiazepin-10-one. mp 243-246 ° C (tetrachloraethanhexain); maleate, mp 12.2-124 ° C (ethanol-ether).

[θ]

7-chloro-2-ethyl-10f (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

7-chloro-9,10- 9 -hydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepidin-10-one, mp 235-240 ° C; maleate, mp 119-121 ° C (ethanoelher).

(f) 2 - [(6-methyl-4-methyl-4-methyl-4-methylsulfonyl) -4H-thleno [2,3-b] [1,5] benzodiazepine.

9.10-dihydro-2-ethyl-1-methyl-4H-thieno] 2,3-b] [1,5] benzodiazepin-10-one, m.p. 177-179 T [dichloromethane / hexain].

(G)

7-N, N-dimethylsulfonamyl-9-ethyl-10- (4-methyl-11-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

9,10-dihydropyridine-N, N-N-methylsulfonamido-2-ethyl-4H-1H-halo [2,3-b] [1,5] benzodiazepin-10-one, m.p. mp 225-227 ° C (ethyl acetate / hexane).

(h)

7-Fluoro-10- (4-methyl-1-piperazinyl) -4-thieno [2,3-b], [1,5] benzodiazepine.

9.10- dihydro-7-fluoro-4H-thieno [2,3-b] [l ^ jodnzodiazepin-lo-one, mp 228-230 ° ^C c [dichloromethane / ha. ran).

(and)

9-11-fluoro-12I (4-m-11-llyl-4-piperidinyl) -6H-1,2,3,4-fluorohydrobenzothiezlo [2,3-b] [1,5] benzodiazepine.

9-phthalene-1 H, 1,3,4,4,11, 2-thynyldrodiazole [2,3-b] [1,51. beloodiz.zeρin-12-one, m.p. 196-199 ° C (9-chloromethyl-hexane).

7-fluoro-2-methyl-10- (4-110-7,11-piperazinyl) -1H-pheno [2,3-b] [1,5] benzodiazepine.

^7-fluoro-1 l-2fmethy 9,10f9ihydrOf4Hfthieno [2,3-b] [1,5] benzodiazepine; pin-10-one, mp 160-165 ° CC (dec) (ethyl acetate / hexane).

(k) -Fluoro-2-phenyl-10- (4-methyl) -yl-1-piperzoilyl) -4H-thieno [2,3-b] [1,5] benzoepine, dihydrochloride.

The free base of the above chloride was prepared in vacuo. using 7-fluoro-2-methyl-9,10-9,11,9-trifluoro-4'-thieno [2,3-b] ¹ ) 1,5 ° benzodizil-10-ol as starting material. Field base was converted to the hydrochloride salt, mp 240- 235 DEG ^C DEG C. (with decomposition) (meOhzlol / hexane).

(IJ

7-Trifluoromethyl-2-ethyl-10- (4-methyl-1-pipexazinyl) -4H-thieno [2,3-b] [1,5] beloodiazole.

7-Trifluoromethyl-2-ethyl-9,10-dihydro-4H-thieno [2,3-b] [1,5] -benzoylpin-10-ene.

(m)

10- (4-methyl- ¹ H -piperidine) -yl-N-oxo [3,2-b] [1,5] benzodiazepine.

236

9,10-dihydro-4H-thieno [3,2-b] (1,5) benzodiazepine-10-cinine, 202-206 ° C (carbon tetrachloride).

(n)

7-Fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine.

7-Fluoro-9,10-dihydro-4H-thieno [3,2-b] [1,5] benzodiazepin-10-one, mp 206-208 ° C.

(O)

7-Chloro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine.

7-chloro-9,10-dihydro-4H-thieno [3,2-b] benzodiazepin-10-one, mp 225-226 ° C (chloroform).

(> P)

7-chloro- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine.

7-chloro-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, mp 169-170 ° C.

(0)

7-methylthio-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine.

(r)

101 (4-Methyl-1-piperazinyl) -7-trifluoromethyl-4H-thieno [3,4-b] [1,5] benzodiazepine.

6-Trifluoromethyl-9,10-dihydro-4H-

-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p.

202 ° C (carbon tetrachloride / petroleum ether m.p.

to 60 ^° C).

(with)

3-Chloro-10- (4-methyl-1-piperazinyl) -4H-

-thieno [3,4-b] [1,5] benzodiazepine.

[1,5] benzodiazepin-10-one.

(t)

10- (4-methyl-1-piperazinyl) 4 H -thieno [3,4- b] [1,5] benzodiazepine.

Melting point 200 - 201 ° C.

(at)

7-Fluoro-10- (4-methyl-1-piperazinyl) -4H-

-thienoph 3,4-b] [1,5] benzodiazepine.

Mp 190.5-191.5 ° C.

(in)

6,7-dichloro-10- (4-methyl-1-piperazinyl) -4H-

thieno [3,4-b] [1,5 | benzodiazepine.

Melting point 200-202 ° C.

(w)

2-Isopropyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

(X)

2-n-hexyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

(У) 1-Methyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

(of)

1-Methyl-2-ethyl-7-fluoro-10- [4-imethyl-

-1-piperazinyl] -4H-thiino [2,3-b] [1,5] benzodiazepine.

(aa)

6,7-difluoro-2-ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

Melting point 172 ° C (carbon tetrachloride / hexane).

(bb)

7-Fluoro-10- (4-ethyl-1-piperazinyl) -1-ethyl-4H-thieno [3,4-b] [1,5] benzodiazepine.

(cc)

2-ethyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine.

Example 27

Using the methods of Example 26, but using the thioamides produced by the method of Example 24 instead of the amides, the benzodiazepines specified in Examples 2-6 were prepared (a) to (cc).

Example 28

10- (4-Methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

Titanium tetrachloride (0.04 ml) was added to a solution of 4H-2,5-dihydrothieno [3,4-b] [1,5] beinzodiazepin-10-one (10 g) in anhydrous anisole (5 ml). and N-methylpiperazine and simes were heated to 120 ° C with stirring. After 1.5 hours, the reaction mixture was cooled, shaken with ethyl acetate, the ethyl acetate portion was separated, and the solvent was distilled off under reduced pressure at 70 ^° C. The residue was chromatographed on a silica gel column of "Flarisi" using 5% chloroform. of methanol as eluent. The fractions containing the desired product were combined, the solvents evaporated and the residue dried. The title compound was obtained as a yellow solid, mp 200-201 ° C.

Example 29

10- (4-Methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

In a 100 ml round-bottom flask, N-methylpiporazine (10 g) was added to the solution of 10-amino-4H-2,5-dihydro-thieno [3,4-b] [1,5] benzodiazepine (2.17 g) in anisole. The complex obtained by the addition of titanium tetrachloride (2.6 ml) to anisole (15 ml) was slowly added dropwise with stirring at room temperature. After addition of the complex reaction mixture was stirred and heated at 120 C in ⁿ an atmosphere of nitrogen ipřes night. The course of the reaction was followed by thin-layer chromatography, which showed formation of the aromatized intermediate prior to condensation with N-methylpiperazine. The reaction mixture was cooled, poured into water, basified with dilute sodium hydroxide solution and shaken with chloroform. The organic extract was washed with water, dried and the solvent distilled off under reduced pressure. The oily residue was chromatographed on a silica gel column using 5% methanol in chloroform as eluent and the fractions containing the desired material were combined and the solvents evaporated.

Example 30

10- (4-Methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

To a solution of 10-amino-4H-thieno [3,4-bj- [1,5] benzodiazepine (215 mg) in anisole (1 mL) was added N-methylipiperazine (2.5 mL) and added dropwise to the mixture with stirring Titanium tetrachloride complex (0.12 mL) with anisole (1 mL) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 110 ^{° C} with stirring under nitrogen atmosphere with stirring.

The mixture was cooled, poured into water, basified with dilute sodium hydroxide solution and shaken with chloroform. The organic portion was separated, washed with water, dried and the solvent was evaporated under reduced pressure. The oily residue was chromatographed on a silica gel column using chloroform / 5% methanol to elute the title compound as a pale yellow solid, mp 206-203;

Similarly, the benzodiazepines specified in Examples 26 (a) to 26 (cc) were prepared from the corresponding 10-amino derivatives, although in many cases the yields were extremely low.

Example 31 (a) 10- (4-Carbethoxy-1-piperazinyl) -2-ethyl-7-fluoro-4H-thieno [2,3-h] [1,5] benzodiazepine

To a suspension of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one (2.6 g, 0.01 mol) in anisole mixture ( 5 ml) of toluene (10 ml) β-N-ethoxycyclonylpiperazine (9.6 g, 0.06 mol) was added a solution of titanium tetrachloride (1.2 ml, 0.011 mol) in anhydrous anisole (5 ml) -toluene (10 ml). ml). The reaction mixture was heated at reflux for 3 hours and then poured into ice-water (20b mL). The aqueous solution was washed with methylene chloride, the organic extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The gummy residue (5 g), triturated with ether and filtered off the solid to give the desired product as a yellow solid, mp 168-171 ^° C (dichloromethane / hexane); maleate, mp 149-151 ° C (ethanol-ethyl ether).

The following compounds were prepared in a similar manner:

(b)

N- (4-carbethoxy-1-piperazinyl) -2-ethyl-4H-thieno [2,3-b] [1,51] benzodiazepine.

Melting point 169 ^DEG C. (dichloromethane / carbon tetrachloride / n-hexane).

(C)

10- (4-Carbethoxy-1-piperazinyl) -7-chloro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepine.

The title compound was prepared in a similar manner using 7-chloro-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one as starting material. Mp 155-158 ^° C (ethyl acetate / hexane).

(d)

10- (4-carbethoxy-1-piperazinyl) -2-ethyl-6-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine.

M.p. 176-178 ° C (ethyl acetate / hexane).

( ^e )

10- (4-carbethoxy-1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine. 166 DEG C. (chloroform).

(F)

10- [4-carbethoxy-1-piperazinyl) -7-fluoro-4H-thieno [3,2-b] [1,5] benzodiazepine.

Mp 162-164 ° C (ethyl acetate).

(G)

10- (4-Carbethoxy-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine.

Melting point 186-187 ° C.

(h)

10- (4-Carbethoxy-1-piperazinyl) -7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepine. Melting point 197-199 ° C.

10- (4-carbethoxy-1-piperazinyl) -6,7-dichloro-4H-thieno [3,4-b] [1,5] benzodiazepine.

Mp 213-214 ° C.

(!)

10- (4-carbethoxy-l-piperazinyl) -7-chloro-4H-thieno ^[3.4-b] [1,5] benzodiazepine.

Mp 195-196 ^° C.

Example 32 (a) 2-ethyl-7-fluoro-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

A mixture of 10- (4-carbethoxy-T-piperazinyl) -2-ethyl-7-fluoro-4H-thieno [2,3-b] (1,5) benzodiazepine [1.0 g] and stearic potassium hydroxide (6). 1.0 g] in 96% ethanol (50 ml) was refluxed for 16 hours, the solvent was distilled off and the residue was partitioned between water and chloroform, washed with water, dried over anhydrous magnesium sulfate and evaporated The title 1-piperazinyl derivative was obtained as a yellow solid, mp 138-140 ° C (carbon tetrachloride / hexane).

The following benzodiazepines were produced in a similar manner:

(b)

2-methyl-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

Melting point 170-171 ° C (ethyl acetate / hexane).

(C)

7-chloro-2-ethyl-10- (1-piperazinyl) -4H-thienof 2,3-b] [1,5] benzodiazepine.

Melting point 167-169 ° C.

(d)

10- (1-piperazinyl) -411-thiorio [3,2-b] [1,5] benzodiazepine.

Mp 203-206C (ethyl acetate).

(E)

Fluoro-10- (1-piperazinyl) -4H-hieno [3,2-b] [1,5] benzodiazepine.

Melting point 165-167 ° C (carbon tetrachloride).

(F)

10- (1-piperazinyl) -4H-thieno (3,4-b) [1,5] benzodiazepine.

Mp 233-235 ° C.

(G)

7-f) -4H-thieno [3,4-b] [1,5. Jhenzodiažepin.

Melting point 19.2-193 ° C.

(h)

6,7-di-10-10- (1-piperazinyl 1 H-thieno [3,4-b]. [1,5] benzodiazepine.

Mp 213-214 ° C.

(and)

7-chloro-10- (1-piperazinyl) -4H-thieno [3,4-b) (1,5) benzodiazepine.

Melting point: 178-179 ° C.

EXAMPLE 33 (a) 10- (4-Chloro-2-Chloro-3-yl) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine

A mixture of 2-ethyl-7-fluoro-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazole; (1.0 g, 0.003 mol), p-chlorobenzyl chloride (0.038 mL) , 0.0033 mol) and triethylamine (1.0 ml) in 90% ethanol (25 ml) was refluxed for 16 hours, the ethanol was distilled off and the residue was partitioned between water and methylene chloride. washed with water, dried over anhydrous magnesium sulfate and the solvent · distilled under reduced pressure. This was obtained the title product, which upon -překrystalizování from dichloromethane-hexane had mp 166-168 ^o C.

The following compounds were prepared in a similar manner:

(b)

10- (4-benzyl-11β-prazrazinyl) -2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepine.

Benzyibramide was used as the alkylating agent in this case. Mp 79-80 ° C.

(C)

10- (4'-benzylll'- pipe2aziιnyl ₁₎ -4H-thieno [3,2-b] [1,5] benzodiazepine.

Mp 198-200 cg (ethyl acetate).

(d)

7-Fluoro-10- (4'-benzyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine.

180 DEG-182 DEG C. (chloroform).

(e) 10- (4-Benzyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine.

Mp 221-222.5 ° C.

(f) 2-ethyl-7-fluoro-10- (4-cyclopropyl-1-

-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

Example 34 (a) 2-ethyl-7-fluoro-10- [4- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine

A mixture of 2-ethyl-7-fluoro-10- (1-piperazinyl) -4-thieno [2,3-] [1,5] benzodiazepine (1.65 g, 0.005 mol), ethylene bromide (1.25) g, 0.01 mol) and triethylamine (2.02 g, 0.0 / 2 mol) in 90% ethanol (150 ml) was heated under reflux for 16 hours under nitrogen. The R-solvent was evaporated to dryness, the residue was partitioned between water and methylene chloride, the methylene chloride extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The title product was obtained as a solid, m.p. 173-175 (dichloromethane / hexane).

The following compounds were prepared in a similar manner:

(b)

7-Fluoro-10-14- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine.

Melting point: 205 to 210 ^g C (chloroform).

(C)

2-ethyl 1-7-fluoro-10-1 4- (3-hydroxypropyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine.

145 DEG-148 DEG C. (dichloromethane / hexane).

(d)

2-ethyl-10- [4- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine.

Melting point 175 ^DEG- 176 ^DEG C. (ethyl acetate / hexane).

(θ)

10- [4- (3-hydroxypropyl) -1-piperazinyl] -4H-thieno [3,2-b H 1,5 | benzodiazepine.

M.p. 172 ^DEG- 173 ^DEG C. (ethyl acetate / hexane).

(F)

7-fluoro-10 ' -4- (3-hydroxypropyl) -1'-piperazinyl. -4H-thieno [3,2-b] [1,5] benzodiazepine.

M.p. 138-140 ° C (chloroform).

(G)

10- [4- (3-hydroxypropyl) -1-piperazinyl] -4H-thieno [3,4-b] [1,51] benzodiazepine.

Melting point 184 ° C.

Example 35 (a) 2-ethyl-7-fluoro-10- [3-N- (4-methyl-1-piperazinyl) propylamino-1-4H-thieno [2,3-b] [1,5] benzodiazepine

A mixture of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,51] benzodiazepine-10-thione (2 g, 0.0072 mol), 1- (3-armopropyl) (l) -4-phenylpiperazine (1.3 mL and triethylamine (8 mL) in anhydrous dimethylformamide (10 mL) was heated under nitrogen at 65 ° C until it was assessed by thin layer chromatography (in ether) The reaction mixture was poured into an excess of a molar solution of maleic acid, shaken twice with ether, basified with 0.88 N ammonia solution and shaken with ethyl acetate, and the combined organic extracts were washed with water, dried without aqueous magnesium sulfate and Semi-solids, yellow-colored residue, after recrystallization from ethyl acetate-n-hexane gave the title compound, mp 181 ^° C.

The following compounds were prepared in a similar manner:

(b)

10- (3-N, N-dimethylamino-propylamino) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine.

Mp 193-195 ^° C (isopropanol / hexane).

(C)

2-ethyl-7-fluoro-10- (3-N-morpholinopropylamino) -4H-thieno [2,3-b] [1,5] benzodiazepine climaleate.

Melting point. Mp 182-186 ° C (isopropanol / n-hexane).

(d)

2-Ethyl-7-fluoro-10- (2-hydroxyethylamino) -411-thieno [2,3-b] [1,5] benzodiazepine, maleic acid.

Melting point 196-198 ^° C (ethanol-ethyl acetate-n-hexane).

(E)

10- (2-N, N-dimethylaminoethylainino) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine, maleic.

183 DEG-184 DEG C. (ethanol-ethyl acetate-n-hexane).

(F)

2-ethyl-7-fluoro-10- (3-hydroxypropylamino) -4H-thieno [2,3-b [1,5] benzodiazepine maleic acid.

174 DEG-175 DEG C. (ethanol-ethyl acetate-n-hexane).

(G)

2-ethyl-7-fluoro-10- (2-N-piperidinoethylamine) -4H-thieno [2,3-b] [1,5] benzodiazepine, sesquifumaran.

184 DEG-185 DEG C. (ethanol-ethyl acetate-n-hexane).

(b)

2-ethyl-7-fluoro-10- (2-N-morpholinoethylamino) -4H-thieno [2,3-b] [1,5] benzodiazepine fuinaran.

Melting point 189 ^DEG- 203 ^DEG C. (ethanol-ethyl acetate-n-hexane).

2-ethyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine. Mp 153-155 ^° C (ethyl acetate n-hexane).

2-ethyl-7-fluoro-10- (4-phenyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.

23S753

Melting point 154-156 ° C (dichloromethane-hexane).

W 10- _(4-be-l nzylll'piperazmyl) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine.

Melting point hydrochloride: 265-270 ° C (ethanol-ethyl ether).

(1)

10- [4- (t-chlorophenyl) -1-piperazinyl] -2-ethyl-7-fluoro-4H-thieno [2,3-b] (1,5) benzodiazepine hydrochloride.

Melting point (hydrochloride) 250-260 ° C.

(m)

2-ethyl-7-fluoro-10- [4- (m-trifluoromethylphenyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride.

Melting point (hydrochloride) 184-187 ° C.

(n)

10- (2-N-piperidinoethylamino) -4H-thieno [3,4-b] [1,5] benzodiazepine.

Mp 183 ° C.

Example 36 (a) 10- (4- (3-decanoyloxypropyl) -1-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine hydrochloride

To a solution of 10- [4- (3-hydroxypropyl) -1-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine (1.71 g, 0.005 mol) in anhydrous benzene mL) was added dropwise with stirring a solution dekanoyíchloridu (1.42 g, 0.0075 mole) and benzene (10 mi) and the mixture heated to 75 C and ^three reaction was complete by thin layer chromatography complete evaluation. After the reaction mixture was washed with water and the solvent was evaporated, the title decanoate was obtained.

In a similar manner, using the above procedure of Example 36 (a), the other hydroxyalkyl derivatives described in Example 34 were esterified to the corresponding decanoates and enanthates.

In following . The following examples illustrate the preparation of pharmaceutical preparations containing thieno (1,5) benzodiazepines of the general formula I as an active ingredient. 1.5 J benzodiazepine; however, it may be replaced by any other active compound of formula I.

Example 37

Tablets containing 10 mg of active ingredient were prepared as follows:

active ingredient 10 mg

potato starch 45 mg lactose 35 mg polyvinylpyrrolidone (in the form of 10% solution in water) 4 mg sodium salt. starch glycol ether 4,5 mg magnesium stearate 0.5 mg talc 1 mg Total 100 ALIGN! mg

Active substance, starch and lactose. were screened; No. 44 mesh B, S. (number of meshes per inch, i.e. per 2.54 cm according to the British Standard) and the ingredients were thoroughly mixed. The resulting powdery mass was mixed with a polyvinylpyrrolidone solution and sieved through a 12 mesh B sieve. the granules were dried at 50-60 cc and passed through a 16 mesh screen

B. S. Sodium starch glycol ether sodium stearate was then added to the granules. Magnesium and talc, previously sieved through a No. 60 mesh B.S. sieve, blended perfectly and compressed in a tabletting machine into 100 mg tablets.

Example 38

Capsules containing 20 mg of active ingredient each were prepared as follows:

active substance . 20mg starch 89. mg lactose 89 .mg magnesium stearate 2mg

Total 200 mg

The active ingredient, lactose, starch and magnesium stearate were sieved through a No. 44 mesh B.S. sieve and the resulting pulverulent mass was filled into. hard gelatin capsules of 200 milligrams each.

Example 39

Suppositories containing 25 mg of active ingredient each were prepared as follows:

active substance 2.5 mg saturated fatty acid glycerides 2000 mg

Active substance . and was suspended in molten fatty acid glycerides (the glycerides were pre-heated to melt). The mixture was poured into suppository molds with a nominal capacity of 2 g each and allowed to cool.

Example 40) '

A suspension containing 5 mg of active ingredient in 5 ml (single dose) was produced as follows:

active substance 5 mg The active substance was sieved through sieve number sodium carboxymethyl- 44 mesh B.S. and the sieved mass mixed with cellulose 50 <50 mg sodium carboxymethylcellulose 50 and si- syrup 1,25 ml rupem on a smooth paste. Acid solution. benzoic acid solution 0.10 ml benzoic, flavoring and coloring agents were flavoring substances q. with. Dilute with a little chloroform water and add (as needed) mixing is added to the above paste. dyes q. with. The required amount was then added chloroform water chloroform water to the desired volume. to the total volume 5 ml

SUBJECT OF THE INVENTION

Claims (2)

A process for the preparation of thieno [1,5] benzodiazepine derivatives of the general formula I wherein R ¹ and R ^{2 are} each independently hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-8 haloalkyl, halogen, C 1-4 haloalkyl, nitro, amino, C 2-4 acylamino, hydroxy, C 1-4 alkoxy, C 1-4 alkylthio or a group of the formula -SO 2 'N (R ⁴ ) 2 or -SO ² R ⁴ , wherein R ⁴ is C ^1-4 alkyl, R ⁵ denotes a group of the general formula \ ______! wherein R ⁶ is hydrogen, C ₄ alkyl, C ₃ _ _cycloalkyl, C ₂ _ ₄ alkenyl, C ₄ alkamoyl, benzyl, C-carboxy group or - (CHzjnOX wherein n is 2 or 3 а X is hydrogen or an ester residue, and a group O denotes a thiophene ring attached to a diazepine ring, optionally substituted with C _1-4 alkyl, and acid addition salts thereof, characterized in that the amine of formula R ⁵ H, wherein R ⁵ is as defined above, is reacted with a compound of the formula of formula V, wherein R ¹ and R ² and the group are as defined above and Q is hydroxy, thiol or amino, and the compound obtained is hydrolyzed to an amine if R ⁵ and R ⁶ denote a C _1-4 carboxyl group wherein R ⁶ is hydrogen. 2. Method according to claim 1, characterized in that using the corresponding starting compounds of the formula R @ ⁵ H and of the formula V with the abovementioned meanings for the substituents to give 2-methyl-7-fluoro-10- (4-methyl- -1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine.