SU629879A3 - Method of obtaining thieno(1,5)-benzodiazepines or salts thereof - Google Patents

Description

This invention relates to a process for the preparation of new thieno derivatives (1.5) of benzodiazepines or their salts with valuable pharmacological properties. The purpose of the invention is to obtain new compounds expanding the arsenal of means of influencing a living organism. This is achieved by synthesizing these compounds in a manner that is based on the known l i amination reaction. A process is described for the preparation of a (1,5) benzodiazepine formula of formula I where R and R are independently of each other are hydrogen, C-alkyl, C-alkoyl, Ca, -cycloalkyl, halogen, C, -haloalkyl, nitro, amino, C, β-acylamino, hydroxyl, C, -alkoxy, C-alkylthio or a group of the formula) or, where R is C-alkyl R, is a group of the formula B of which Rg is phenyl, halophenyl yl-Sd-haloalkylphenyl C -alkyl, Cj.g-cycloalkyl, C-alkenyl, C l-alkanoyl, benzyl, C.-carboapcoch. si or (-CHg) OX, where c is an integer equal to 2 nl 3, and X means hydrogen or ether radical, group | T is a thiophene ring connected to a diazepine core, substituted or unsubstituted by one or two groups selected from C-alkyl, C-alkylene, C-haloalkyl, C-alkanoyl, nitro, halogen or phenyl, or their salts, consisting in that the amine of the formula RjH, where R has the indicated values of & PIA, is reacted with a compound of the formula {have the indicated meanings, and where Q denotes the ox-thiol radical, C-alkoxy, C alkylthio, halo or - NHjj, at a temperature of 6O -130 С in inert gas atmosphere. The target product is isolated in a CBt poor condition or as known methods. The new thien (1.5) benzodiazepines of the present invention can be ssuted into three forms, which can be represented by the following structures: In one given structural formula, the tofye ring is depicted as unspecified, but it can be substituted Preferably (i means hydroxyl or thiol, then the starting compounds exist predominantly in the form of their amide or t11OZida OS IN -NH-C-MAI-NH-C When Q is hydroxyl and the compound of the formula H is am, the reaction can be carried out in the presence of titanium tetrachloride A. The last glue reagent has the ability to interact with gamma formula to form a metal-complex. Other metal chlorides, like zirconium, hafnium or vanadium chlorides, also have this property. The reaction is preferably carried out in the presence of an acid binding agent such as a tertiary amine, for example, triethylamine. As one of the possible options, the reaction of the mucosa is carried out using an excess of the amine of the formula that combusts as an acid binding agent. Any suitable organic solvent, such as toluene or chlorobenzene, can be used in the reaction, although the use of anisole is most desirable, at least as a co-solvent due to its ability to form a soluble TiCE complex. Examples of compounds of the present invention: 2-ethyl-1O- {4-methyl-1-piperazinyl) -4H-thien 2.3-1)} (1d5) benzodiazepine; 7-chloro-2-ethyl-10- (4-methyl 1 piperazinyl) -4H-thien 2,3-t3j (1.5) benzodiazepine | J 2-ethyl-7 fluoro-10- (4-methyl-1 - piperazinyl) 4H-thien G2,3-b (1,5) benzodiazepsh; 2-ethyl-7-trifluoromethyl-10- (4-megyl-l-piperazinyl) -4H-thien 2,3-b (lj5) 6eH zodiazepine; 7-amino-2-ethyl-10- (4-methyl-1-piperazikyl) -4H-thien 2,3-b (1.5) benzodiaeepine; 2-ethyl-7-nitro 1O- (4-methyl-1-piper zinyl) -4H-tie and 2,3-b (1.5) benzodiazepine; 2-ethyl-6-fluoro-10- (4-methyl-1-piperazinyl) -4H-thien 2.3-1l (1.5) benzodiaz2-methyl-7-N, N -dimethylsulfonamido-1O- {4- methyl 1-piperazinyl) -4H-thienG2, 3-b (1.5) benzodiazepine 2-pentyl-7-fluor-1O- (4-methyl-1-piperazinyl) -4H-thien 2,3-b (1 , 5) benzodiazepine; 2-ethyl-6-methyl-1O- (4-methyl-1-piperazinyl) -4H-thien (2,3-b (1.5) benzodiazepiv; JJ 2-methyl-7-methoxy-10- ( 4-methyl-1 - -piperazinyl) -4H-thienG2, 1.5) benzodiazepine; 562 6,7-difluoro-2-ethyl-10- (4-methyl-1-piperazyl) -4H-thien | G2,3-b} (1.5) benzodiazepic; 2 Ethyl-7-methylti) 1O (1-methyl-1-piperazinyl) -4H-thien | 2.3 - | g (1.5) benzodiaepine; 6,8-difluoro-2-ethyl-10- (4-methyl-1 piperazinyl) -4H-tken G2.3-y (li5) 6eH3O, diazepine; 7-fluoro-10- (4 megyl-1-piperazinyl) -4H-thienG2,3-b (1.5) oenzodiazepine} 7-chloro-10- (4-methyl-1-piperazinyl) -4H-thien 2 , 3-bI (1., 5) benzodiazepine; 7-chloro 1-methyl-1O- (4-methyl-1-piper zinyl) -4H-yen 2.3-4z (1.5) benzodiazepine 1,2-dimethyl-7-chloro-1O- (4 - methyl 1-piperazinyl) -4H-tien G2,3-b (1.5) isodiazepine; . 7 chloro-2-methyl-10- (4-methyl-1-piperazinyl) -4H-thienG2,3-b (1.5) benzodiazepine | , 6 trifluoromethyl 2-ethyl-1O- (4-met1sh 1-piperazinyl) -4H-thienG2, (1.5) benzodiazepine 2-vinyl-7-fluoro-10- (4-methyl-1-pipa razinyl) 4H -thien 2,3-Ь (1,5) benzodiazeping 2-vinyl-7-trifluoromethyl-10- (4-methyl -1 -piperazinyl) -4H-thienG2, (1.5) benzodiazepine | 7-chloro-2 ethyl 10- (4-methyl-1-pip. Razinyl) -4I-tie 3,2- |) (1,5) benzodiaz 2-ethyl 7-fluoro 10- (4-methyl-1 piperazinyl -4H-thien 3,2-bj (1,5) benzodiazepine; 2-ethyl-1O- {4-methyl-β-piperazinyl) -4H-thien 3,2-bJ (1,5) benzodiazepine; 2-ethyl-7-trifluoromethyl-10- (4-methyl-Lrtshperazkyil) .- 4H-thien | 3,2-b | (1,5) ben "zodiazepine; 7-amYNO-2-ethyl-1O- (4-methyl-1-piperazinyl) -4H-tie11,2-bj (1.5) benzodiazepine; , 2-ethyl 7-nitro-10- (4-methyl-1-piperazinyl) -4H-thien, 2-bj (1.5) benzodiazepine | 2 "ethyl- & -fluoro-1O- (4-methyl-1-piperazinyl) -4H-thien 3,2-b (1.5) beisodiase 2-methyl-7-K, N-dimethylsulfonamido-1O- {4-methyl-1 -piperazinyl) -4H-thien {3, 2-bj (1.5) benzodiazepine; 2-ethyl-6-methyl-10- (4-methyl-1-piperazinyl), (1.5) benzodiazepine; 6 2-methyl-7 methox-10- (4-methyl-l-pipera-Eninyl) - 4H-thien 3,2-bJ (1,5) benzodiazepine; 6.7 - difluoro-2-eth cl-10- (4-methyl-1 -shterazpnil} 4H-thien | 3, 2-b1 (1.5) benzo-. Diazepine;. Jf 2 ethyl-7. methylthi1 -1O- (4-metnl-i "piperazinnl) - 4H-thien z, 2-Ь (1,5) -benzodiazepine; 6.8 dlfluoro - 2-ethyl-10 - (4.-methyl-1 -piperazinyl) -4H-thien 3,2-b} (1,5) benzodiaeepine; 7 - fluoro-10 - (4-methyl-piperazinyl) -4H ™ thien z, (1,5) benzodiazepine} 7 -Hlsr-.1O (4-methyl-1-piperazine) 4H-thien 3,2-bJ (1,5) benzodiazepine} 2,3-dimethyl 7 chloro-1- (4-methyl-1 - shterazinyl) -4H-thien z, 2-Ü1 (1,5) benzodiazepine; 7 - chloro-2 Gx1O1-l 1O- (4-methyl-1-pi-perazinyl) -4H-iHeH | j3,2-bj ( 1.5) benzodiazepine; 9-fluoro-12 (4 methyl-1-piperazinyl), 2,3,4-hegragndrobenzo (b) thienG2,3-J) J (1.5) benzodiazepine; 2-fl 1L-7-fluoro-1O-4 - (2-hydroxyethyl) -1-1 piperazyl 1 -4H thien 2,3-b (1.5) benzodnazepine} 2-ETHIL-7-FGOR-10- - ( 3-hydroxypropyl) -1-pyggerazinyl 4H-yen 2,3-b (ii5) 6eH zodiazepine; 2-octyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thien | 2,3-b (1,5) benzodiazepn 2-ethyl-7-fluoro-10- (l-liperozinyl) - -4H-thien 2,3-b (1.5) benzodiazepine; 2-ethyl-7-fluoro-1o H- (N, N -dimethyl-aminoethyl) amino2-4H-thien 2,3-1j (1.5) benzodiazepine; 2-ethyl-6-fluoro-1O- (2-M-piperadiinoethyl) amino-4H-thien G2,3-b (1.5) benzodiazepia | 2-atil-7-fluoro-1O- (4-allyl-1 -piprazine1 "1) -4H-tier1 G2,3-b (1.5) benzodiazepine; 2-ethyl-7-chloro-10 | h-4-phenyl- (1-piperazinyl) -prosh} -amino-4H-tiep 2,3- | J (1.5) benzodiazepine; 2-ethyl-7-chloro-10-z -oxyethyl- (1 t1-per-s) -propyl J-amino 4H-tien 2.3-bj ((b) benzodiazep; 3-methyl-10- (4-methyl-1 - piperazinyl) 3,4-b} (1,5) benzodiazepine; 3-methyl-7-chloro-1O (4-methyl-1-piperazinnl) -4H-thien 3,4-bJ (1,5) benzodizyeshsh 7-fluoro-1O- (4-acetyl-1-piperazinyl) - 4H-thien 3, 4- {3} (1.5) benszodiazep111; 7-three (| hydrogenmetyl-1O- {4-methyl-J. —piperazinyl-4H-thien 3, 4-b (1.5) benzodiazepine; 7-amino-1O- (4-methyl-1-piperaznyl-4H-thien 3, 4-b (1.5) benzodiazhesh; 7-acetylamino-10- (4-methyl 1 -piperazinyl) -4H-ty "n; 2, (1,5) benzodiazate 7-methipamino-1O- (4-methyl-β-piperazinyl) -4H-thienG2,3- B () beisoazePIN}, 7-dimethylamino- 1O- (4-methyl-1-piperazinyl) -4H-thien J2, 1.5) benzodioazepine {: 7-HHTpt -lO- (4-methyl 1 piperzazinyl-4H-tiev s, 4-b (1.5) 6-phor-1O- (4-methyl-1 pipera-13 Din) -4H-thien z, (1.5) benzodiazepine; 3-methyl 7 Nf N -dimethylsulfonamido-1O- (4-methyl 1 -piperazinyl) 4H 3, 4-4e (1.5) benzodiazepine ;, 2-ethyl-7-hydroxy-10- (4-methyl 1-pip & rasinil), 3-b (1.5) benzoinase pin {, 6-methyl- 10- (4-methyl 1 -type razinyl) -4H-thien 3, (155) benzodiazepin 4 i 3 methyl-7-methoxy-10- (4-methyl-1; piperazinyl) -4H-thien z, 4-b | (1,5) benzo I diazepine; ; B, 7-difluoro-10- (4 methyl-1-piperazk; nyl-4H-thien {s, 4-L1 (1.5) benzodiazepine | 7-methyl io-10 -C 4 -methyl 1 -piperazinyl) - 4H-thien 3, 4-L1 (1.5) benzodiazine N, 8-difluoro-1O- (4-methyl-1-piperazi nyl) -4H-thien 3, 4-b} (1 | 5) benzodiazepine} 7 -chloro-10- (4 m 1 -piperazinyl) -4H-thien z, 4-b (1.5) benzodiazepia} 7-fluoro-10- (4-methyl-l-piperazini) -4H-tiep h, 4 -B (1,5) benzodiazepia | 2-ethyl-7-fluoro 10- (4 - (2-.OXIETHYL) -1-pippvrazinyl) -4H-thienz, 2-b () bvn and diazvtin; New thien (1.5) benzodiazepines according to the proposed invention can be obtained in the form of free acid, but also in the form of their salts. These salts are preferably pharmaceutically acceptable, non-toxic salts of suitable acids, for example inorganic acids, such as hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or organic acids, such as organic carboxylic acids, for example glycrol, maleic, oxime of leine, fumaric, block, vinna, citric, salic 1lova, o-ecetoxybenzoic, vkot shovov or isonicotinic acids, or organic sulfonic lato62 9 oty, for example, methane sulfone, ethanophone, 2-hydroxyethane lfonova, tolol-i-sulfonic or naphthalene-2-c ulm |) O-ova acid. In addition to pharmaceutically acceptable salts, this invention also includes other salts of the compounds of this invention, for example, the salts of picric to oxalic acid, they can be used as intermediates in the purification of the proposed compounds OR for the preparation of, for example, pharmaceutically acceptable salts, or are or cleaning of the specified bases. If melting points are not given in the examples, evidence of the structure of the final product is usually obtained using thin-layer chromatography and spectral analysis data. Example 1. 2 Ethyl - 6-fluoro-10-Methyl-piperazinyl) 4H-thieno 2,3-bj (1.5) benzodiazepine, 9,1O-Dihydro-2-eth1-6-fluoro 4H-ty - eno | 2,3-b (1,5) benzodiazepin-10-one (0.5 g), phosphorus oxychloride (4 ml) and fy | , N-dimethylaniline (OD5 ml) is boiled under reflux for 3 hours. The reaction mixture is evaporated in vacuo, and the residue is evaporated twice more with xc; The crude imino chloride was dissolved in absolute dioxane (1 ml) and H-methyl piperazine (3 ml) was added. The Re-4 acid mixture is refluxed for 4 hours and then evaporated to dryness in vacuo. The residue is partitioned between aqueous ammonia and ether: the ether layer is extracted with 1N. her . The product is precipitated by adding 0.88 1. ammonia solution, extracted with ether, washed with water, dried (MgSO4) and evaporated in vacuo | m.p. 175-177 ° C (ethyl acetate / hexane). Similarly, 2-Etil-7-fluoro-1O-C1 piperazinyl) -4H-thieno 2,3-b (1.5) benzodiazepine is obtained; m.p. 138-140 ° C (carbon tetrachloride / hexane). Example 2, A 2-Etsh1 10- {4-methyl-1-piperazinyl) -4H thieno 2, (1.5) beshdiazepine, 9,10-Dihydro-2-ethyl-4H-thieno 2, 34lj (1.5) benzodiazepin-1O-one (2.4 g; O, OO1 mol) is suspended in N-methyl piperazine (10 ml). Titanium tetrachloride (1.2 ml; 0.011 mol) is added in dry anisole (5 ml) and the mixture is stirred at 120 ° C for 2 hours. The reaction mixture is poured into ice-water and, until shaken, with a grayish-white precipitate. The suspension is scrubbed with methylene chloride until a steady yellow color appears. The combined extracts were washed with water, dried with magnesium sulfate, evaporated in vacuo and the necessary compound was obtained in a solid yellow color. This substance is triturated with ether, filtered and recrystallized from hexane to give 2.1 g (64%) of the desired product; m.p. i95 197 ° C. The free base is then salified with ialeic acid; m.p. 186-188 ° C (ethanol / ether). B. 2-Ethyl - 7-fluoro-1O- (4-me-yl-1 g-piperazinyl) -44-thieno 2,3-b (1.5) benzodiazepine. The specified connection with so pl. 161 IGS C (hexane) is prepared similarly when measure 2A from 9,10-dihydro-2-ethyl-7 fluoro-4H-TIONO f2,3-bj (1,5) benzodiazepin-1O-yuna. Output 1.5 g (58%), Calculated,%; C 62.76} H 6.14 | N 16.26j F 5.51; 5 9, DA. Found,%: C 62.99; H K1 16.05; F 5.67; 5 9.32. The free base is converted to sol maleic acid; t, mp, 125-127s (ethanol / ether). Output 1.4 g. Calculated,%: C 57.37} H. 5.47} N12.16} F 4.12} S 6.36. C22H gFN404S „Found: C, 53} H 5.54}} 11.99} F 4.16} 56.93. The following benzodiazepines are prepared using the procedure of Example 2A, the NIN indicated behind the name of the main compound is the intermediate amides} also give the melting points of benzodiazepines, as well as the solvent from which the recrystallization is carried out: a) 2-ethyl-6-fluoro-1O- (4-methyl-1-piperazinyl) -4H-thieno 2, 3-Ь1 (1,5) benzodi-azazvn} 9,10-dihydro-2-ethnl-6-fluoro-4H-thieno {2, 3-Ь (1,5) benzodiazepin-1E0-one, t. Ш1 . 2O6-2O8 ° C (hexane), salt of maleic acid, m.p., 125-127 ° C (ethyl alcohol / ether); yield 2 g (61%) j b) 6,8-difluoro-2-ethnl-1O- (4-methyl-1 "Sh1perazinvl} 4H-yeno 2, 3-fa} (1.5) bevaodiazepine | 6.8 -dnftor-9,1O-DIHYDRO-2-ETHNL-4N-thienoG2 3-b} (1,5) benzodiazepin-1O-one, t, pl 243-246 C, tetrachloride yi 79 1O lerod (hexane), salt maleic acid, mp 122-124 ° C (ethyl alcohol / ether) {yield 2.5 g (78%)} c) 7-chloro-2-ethyl-10- (4-methyl-1-piperazinyl) - 4H-tneno 2, S-bJ 1.5) benzodiazepine; 7-chloro-9,1O-digiar-2-ethyl-4H-thieno 2,3-b (1,5) benzodiaepin-10-one, t, pl, 23 amp -240 ° C, maleic salt of chiols, t. , 119-12i ° C (ethyl alcohol / ether); yield 1.3 g (36%); d) 2-ethyl- & -methyl-1O- (4-methyl- "1- -piperazinyl) -4H-thieno 2,3-bJ (1,5) bezodiazepine. This compound is prepared analogously. but, using; nn 9,10-dipipro-2-ethyl-6-methyl-4H-thieno 2,3-bj (1, 5) benzo-diazepin-10-one, t, pl. 177-179 ° C (methylene chloride / hexane)} yield 1.5 g (68%): e) 7-N, N-dimethylsulfonamdo-2-ethyl-10- (4-methi; -1-piperazinyl) - 4H- “-thieno 2, Eb (1,5) -benzodiazepine; 9,1O-digndro-7-N, N-dimethylsulfonamido-2-ethyl-4H-thieno 2,3-bj (1,5) beisodiazepin-1O-one, t. Pl. 225-227 with (ethyl acetate / hexane), yield 0.75 g (68%) | oe) 7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieio 2,3-b2 (1 5) benzodiaeepin. 9,10-dihydro-7-fluor-4H-thieno 2,3-b (1.5) benzodiazepin-1O-one, t, pl. 228-23 O C (methylene chloride / hexane); yield 0.45 g (74%); g) 9-fluoro-12- (4-methyl-1-pkperazinnl) 6H-1,2,3,4-tetrahydrobenzothieno 2,3-4} j (1,5) benzodiazepine} 9-Fluoro-6H- 1,2,3,4,11,12-gvksagidrobenzothieno 2, 3-b} (1,5) benzodiazepin-12-one, so pl. 196-199 C (methylene chloride / hexane); yield 4 g (56%); h) 7-fluoro-2-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno 2,3-b (1.5) benodiazepine; 7-fluoro-2-methyl-9,10-dihydro-4H-tino 2,3-b} (1,5) benzodiazepsh1-10-one,. mp, 160-165 ° C (ethyl acetate A xan); Output 1.6 g (35%) j and) 7-h |) TOP-2-phenyl-1O- (4-methyl-1-pyrazinyl) -4H-tneno 2, (1.5) benzodisepine, dihydrochloride } this compound is obtained using 7-fluoro-2-methyl-9,1O-dihydro-4H-thieno 2,3-b (1,5) benodiazepin-10-one, with the atom getting its base, which is then converted into di hydrochloride, t, pl. 235-240 ° C decomposition; methanol / hexane); yield 1.5 g 25%);

k) 7-gri4gormmetnl. 2-ethyl .-. 10- (4-methyl 1-piperazinyl) 4H "thieno 2; -3 - LK)

b "zodiazepine

.7-trifto rmethyl-3-oti L. 9 j 1 hydro p o-4H-thieno a, 3-b (1.5) benaodiazelcn-.O-OH}

l) 10- (4-methyl 1-piperazinyl) -4H. , 2-Ь (1,5) benzod shapping: 9,1O-dihydro-4H-thieno 3, (1,5} benzodiaaie-1O-one, t. Pp. 202-20b c (th; sour carbon chloride ) | yield of the desired product 1.3 g (44%) |: m) 7-fluoro-10- (4-m ip l piperine-enanil) 4H-tieno h, (l, 5) biozondia | ; 7- "fluoro-9DO-ligidro 4H-yeno382-Ь (155) benzodiazepine-10-one 5 t. Tm, 206-.

208 ° Cj

 n) (4-methyl-.1-piperazi.

; Nile) - 4H-thieno C, (1.5) benzodiazepine |

: 7-hlrr 9DO-dihydro 4H-thieno e, 2- ..

-B} (1.5) benzodiazepine- 10 .oNa t, mp, 225i226 ° C (chloroform) I output target product 1.7 g (59%) g

i o) 7 chloro-10- {4-methyL- ™ 1-piper, zi

Nile) -4H- hyeno 3, (155) bexodiazepn

: 7-chloro 9,10 dihydro ™ 4H Thieno 35

Mlj (1,5) benzodiazepi 1-10 "on9 t„ pl, 169

 yield 640 mg (60.4%) j

; p) 7-methylthio 10- (4 me1il 1-pnpe ea t

zi il) -4H-tiepo 3, (155) beisodiasis; iTHH, t. pl. 173--174 ° С (a - ethyl ether)

yield 8OO mg (1%) |

 p) 1O- (4 megyl. 1 piperazinyl) - 7. "

Nerifluoromethyl-4H-tieno (Hgb ben: 3-diazepine |

; b-trifluoromethyl-E, L 0 dihydro 4N -ty.

| 155 (155) benzodiazepn 10- about 15

: Te p, SO2 С (uperod tetrachloride / benzyl 4О-60 С) | yield 450 mg |

c) 3 chlorine- 10. (4 Methyl "1" piper "; eNH1) h, (18.5) benzodiazepings yield 1 g (53%) |

3-chloro 951 O DIHYDRO-.4H-hyeioz, (1,5) benzodiazepine-1O-one |

t) 10 - (4-methi -1 piperazinyl) -tyeno h, 4 - Ь1 (1 (5) benzodazehgangan, t „pl. 200 201 ° С | product yield 17 g (68 4%) |

s) 7-fluoro "-10 - (4 methnl" 1 piper, zi, nil) - 4H-thieno 3,4 - bj (155) benzodkaz8P-iNg t, mp, 19O ,, 5 ° С yield 31.5% |

f) 6.7 dichloro 10- (4-methyl ™ 1 piper; and einyl) -4H-thieno 3,4-fe (i (5) benzolium and aluminum, t, pl. 20-202 ° С | output 62.5% ;;

x) 2-isopropyl-7-fluor-1O (4-label-1 "pkperazinil) 41 -} - thieno 2s3-b (1.5 J bezodiazepine, t. pl. 132--135 ° С {etyp acetate / hexane) I

c) 2 p-Hex; W ™ 7 ft R 0 (4-methyl-1-1P11-range yl) -4 {1-tnSN;) 2.3-. | 3C) bep-zedva-pi; g, pl, 101--1O5 С (“shklogeksa / hexane) 5 or 62% j

h) 1.methyl 7-vfO: -10- {4-metpl gasherasil1) "- 4H Tkeno 2, 3-4; j (1,5) ben" zodiazepn, t. pl. 209-210с {carbon tetrachloride / hexai) yield 11% |

y) 1-m-letpl -..-. 7-fluoro - 10- (. tyl 1-piperspl) )- -H-tyie 2, (i, 5) benzodiagnosis

y) 6,7 ™ dkftor 2 - ethyl-. ), 1 piperazi il) 4H-thieno 2,3-b | (1.5) ben zodiazepk; m.p. 172 C (carbon chlorine / hexethyl carbon chloride); yield 41% {.

e) 7 (} Top-10 - (1; 8Т11Л ..-- 1.Piperazi-Nil) - 1-eti.4g1-tneio Gz.4 - b1 (1, o) benzo-

diazepn;

u) 2-ethyl 7- (ptor-10 - (4-metnl.1 .-. piperaz1shil) .- 4H-two | h, 2, -b | {I.s5) benzodia, zepnk.

Example 3, 1 O- (4 "-A1etkl-1-pinperazincl) - 4H --- T 1e 10 (3..5) benzadiazepni.

4H-255-DihydroTLance 3,4-Ь (ls5) 6eH-zodiazepki-Yu-it (10 g) with dry aniso .. le (5 ml narpefsaroT with nepeMeuinBaFiHH in the best ktst.tvik chetfe;; titanium chloride C 0,04 ml) to N me1kl11perzznna to

12 ° C, After 30 iv No. n peaimHo 3 1, the mixture is blended cool with a methyl acetate and evaporated to dryness to 70 ° C under reduced pressure. The solid residue of the photographic image with the use of the FEorisfE type column, the quality of the solvent is 6epjT, the methanol solution in chloroform, the fraying is dried up with a dry j jure while the Compound “None in the form of the sound of the air flow will be removed. 2OO-2O1 C: yield of 1 g of C 9%.).

Note about p 4, 10 "14-Metkl.-1-1 type of raincl) -F-Tneno {is4-bj {1,5) benzodiazepine ...

10 D-TnO 4H-2.5-dvhydrothieno 384- «iJC 1; 5) benzodkalepsch1 (YD g) from anisole and N mecc and C10-I alternate spruce, room temperature: USheGZF in a 100m round-flow flask. The mixture is stirred and the complex is added; obtained from a four-chlorine tin tank (2.0 ml / in anisole (15 ml) ,. After that, the mixture was pumped, released, and a -1-ml mixture was stirred under a nitrogen atmosphere in a dream for a product with N A) Sherazin conducted a study of the product ghzec. With the help of thin layer; {th chromatography; which indicates the formation of an aromatized starting product. The mixture is heated overnight at 120 ° C, cooled and poured into water. The aqueous mixture is alkalinized with a dilute sodium hydroxide solution and shaken with chloroform. The organic extract is washed with water, dried and evaporated to an oil in a vacuum. The oil is chromatographed on a column of not with silicic acid, using as eluent a 5% solution of methanol in chloroform, and fractions containing thieno (1.5) benzodiazepines are obtained. Yield 100 mg (3%). Example 5.10- (4-Methyl-1-piperazinyl) -4H-thieno, 4-L5 (1.5) benzodiazepi 10-Amino-4H-thieno (3,4-bj (1.5) benzodiazepine (215 mg) in anisole (1 ml is treated with N-methyl piperazine (2.5 m at room temperature under nitrogen atmosphere. Add titanium tetrachloride (0.12 ml) to anisole. (1 ml) with stirring at room temperature) ature. C $ ic is heated to 11QC under nitrogen and stirred overnight. The resulting mixture is cooled, poured into water, alkalinized with a dilute sodium hydroxide solution and shaken with chloroform. The organic solvent is extracted, rummed with water, dried and evaporated to an oil in vacuo.The required compound was isolated by chromatography on a silica-gel deck. (5% methanol in chloroform was used as eluent) to obtain the desired product as a pale solid yellow color, mp 2OO-201 ° C; yield 12 ml (4%). The benzodiazepines given in examples 2A and 2B are prepared in the same way from the corresponding Yumino derivatives; 5% yield in many cases is low. Example 6. 1O- (4-Carboethoxy-l-piperazinyl) -2-ethyl-7-fluoro-4H-tieno 2,3-b (1 | 5) benzodiazepine, Suspension 9,10-dihydro-2-ethyl-7 - -fluoro-4H-thieno 2,3-Ü1 (1 | 5) be11 odiazepin-1O-on (2.6 g; 0.01 mol) in a mixture of anisole (5 ml), toluene (10 ml) and ethyl- - N-piperazine carboxylate (9.6 g} O, O6 mol) is treated with a solution of titanium tetrachloride (1.2 ml; 0.011 mol) in dry anisole (5 ml) and toluene (10 ml). The mixture was heated under reflux for 3 hours and poured into ice-cold water (200 ml). The aqueous solution is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated to form a sticky substance (5 g). Trituration with ether gives the desired product as a yellow solid, yield 2.2 g (55%), so pl. 168--171 With (methylene chloride / hexane), salt of maleic acid, so pl. 149-l5lC (ethane ether). Similarly, receive: 1O- (4-carbethoxy-l-piperazil) -2- -ethyl-4H-thienoG2,3-o} (1.5) benzodiazepine, so pl. 169 C (methylene chloride / carbon tetrachloride / n-hexane), yield 23.0 g (67%); 10- (4-carboethoxy-1-piperazinyl} -7-chloro-2-ethyl-4H-thieno 2,3-b (1.5) benzodiazepine, mp, 155-158 C (ethyl acetate / hexane) ; the compound is obtained analogously using 7-hlrr-9,1O-di-hydro-2-zti-4H-thieno 2,3-j J (1,5) benzodiazepin-10-one (3.8 g), mp, 155 158 C (ethyl acetate / hexane), yield 4.1 g 72%) G 10- (4-carboethoxy-1-piperidin) -2-ethyl-6-n} ztor-4H-thieno 2, 3-b1 (1.5) benzodiazepine; The title compound was prepared using 6-4J5TOP-9,10-dihydro-2-ethyl-4H-thieno 2,3-b (1.5) benzodiazepin-1On (49 g), yield 37 g (61%); 1O- (4-carboethoxy-1-piperazinyl) -4-carboethoxy 1-pperazinyl-4H-thieno 3, (1.5) benzodiazepine, t. Pl. 166 ° C (chloroform), yield 51%; 10- (4-carboethoxy-1-piperazinyl) -7fluoro-4H-thieno 3-2-1z (1.5) benzodiazine, t. Nl, 162-164C (ethyl acetate), 80%; 10- (4-carboethoxy-1-piperazinyl) 4H-thieno 3,4-b (1.5) benzodiazepine,. square 186-187 ° C, yield 74.6%; 10- (4-carboethoxy-1-piperazinyl) -7fluoro-4H-thieno, 4- and J (1,5) benzodiazine, t, pl. 197-199 ° C, yield 57.1%; 1O- (4-carboxyethyl-1-piperazinyl) - 6,7-dichlo {-4H-thieno 3, 4-b (1.5) benzoiazepine, t. mp, 213-214 ° C, yield 64.3%; 1O- (4-carboxyethyl-1-piperazinyl) -7-chloro-4H-thieno 3, 4-l1 (1.5) benzodiazine, t, pl. J 95-196 ° C, yield 51.3%. Example 7, 2-Ethyl-7-fluoro-1O3-N - (4-methyl-1-piperazinylpropylamido), 3-b (1.5) benzodiazog, and. 9,10-Dihydro-2-ethyl-7-fluoro-4H-yno 2,3-b (1.5) benzodiazepin-10-one (2 g; ОО72 mole), 1- (3-aminopropyl-4- feilpiperazine) (1.3 ml), triethylamine 8 ml) and dry dimethylformamide (10 ml) are heated under nitrogen atmosphere until the reaction is complete. This is checked by thin layer chromatography (diethyl ether, 2 h). The mixture was poured into an excess of molar solution of maleic acid, washed twice with ether, basified with 0.83N. ammonia solution and extracted with ethyl acetate. The combined extracts are washed with water, dried with MgSp, the solvent is evaporated and the necessary compound is obtained as a semi-solid yellow color, yield 1.0 g (48%), which is then recrystallized from ethyl acetate; n. Hexane, tons. square 181 ° C. The following compounds are prepared analogously; 10- (3-NI N-dimethylaminopropylamino) -2-ETHIL-7-fluoro-4H-thieno 2,3-L1 (1,5) ben-g 1zodiazepine dimaleate, t, pl. 193-195 ° C Kisopropanol / n-hexane), yield 19% j 2-ethyl-7-fluoro-10- (3-N-morpholino | propylamino) -4H-thieno 2,3-b1 (1.5) benzodiazepine dimaleate t. pl. 182-186 ° C {from O; 1 Cheopanol / n-hexane), yield 57%; 2-ethyl "7-fgol-1O- (2-hydroxyethylamino) -4H-thieno f2,3-b j (1.5) benzodise pin map, t. Pl. 196-198 ° C (ethanol / ethyladetate / n-hexane), yield 34%; 1 O-2-N, N-dimethylaminoethylamino) -2 -2-ethyl-7-fluoro-.4 H-ene of 2,3-j j (1, 5) benzodiazepine maleate, yield 74%, mp, 183 184 С (atanol / ethyl acetate / n-hexane) :, 2 ethyl-7-fluoro 1O- (3-hydroxypropylamino) - “4H-thieno J2,3-bj (1,5) benzodiaepine maleate, t. Pl. 174-175 C (ethanol / ethyl acetate / n-hexane /, yield 72%; 2-ethyl-7-or-lO- (2-N-piperidinoethylamino) -4H-thieno, 3-bj (1.5) benzodiazepine hemi fumarate , mp 184-185 (ethanop / etipacetate / n-hexane), yield 4O%; 2-9-nos-7-fluoro-10- (2-N-morpholinoethyl 1-th) -4H-thieno 2,3-bJ 1 , 5) benzodi .. azepine fumarate, yield 71%, t, pl. 1892ОЗ С (ethanol / ethyl acetate / n-hexane); 2-ethyl-7-op-lO-C 4-methyl-1-piperazinyl) J2,3-b (1,5) benzodiazopin, t. Pl. 153-155 C (ethyl acetate / n-hexane), yield 47%; 1b "tyl-7-or-1O- (4-phenyl-1-n; iperaz nnl) -4H-thieno 2,3-b (1,5) oenzodiazepine, m.p. 154-156 C (methylene chloride. Flax / hexvb), yield 27%; l ((4-6eBaim iOL-overperazinvl) -7-fluor-4H-thieno f2,3-b (1,5) -ben zodiazepn, t. pl. (di-HC6-salt) 265-270 ° С (ethanol (diatyl ester), yield 36%; 10- (4-m-chlorophenyl) -1-piperazinyl) -2-vtil-7-fluoro-4H-thieno 2,3-b3 (1.5) benziazepine hydrochloride, mp, (HC-salt) 5 ° -260 ° C, yield 44%; 2-ethyl-7-fluoro-10- (4-m-three fluorine methylenyl) -1-piperazinyl-4H-thieno 2,3-b 1,5) benzodiazepine hydrochloride, so pl. her-salt) 184-187 ° C, yield 67% ;. 10-2-b-piperidinoethylamino) -4H-tino 3, 4-b1 (1.5) benzodiazepi11, mp mp, 18 2-183 s, 53% yield. Formula of the invention 1. Method for producing thieno (1.5) benzo-azepines of the general formula 1 wherein R and Rg independently of one another are hydrogen, -alkyl, C-d-alkenyl, -cycloalkyl, halo, C / -haloalg " kil, nitro, amino. C ...-Acylamino, hydroxyl, C d-alkoxy, C-alkylthio radical or groups of the formula), where C. is alkyl; group of formula -N. M-KB in which R is phenyl, halo-phenyl or C d-haloalkylphenyl, C-alkyl, C, -. cycloalkyl, C „d-alkenyl, C, x-alkanoyl, benzyl, C.f-carboalkoxy or a group (OX, where h is an integer equal to 2 or 3, X is hydrogen or an ether radical; group 1 / is a thiophenic ring combined with diazepine core, substituted or unsubstituted by one or two groups selected from C-alkyl, C ". alkenyl, C .. -haloalkyl, Cf.-alkanoyl, nitro, halogen and phenyl, or their salts, different the fact that the amine of the formula RgH, where R has the abovementioned, is subjected to interaction with the compound of formula I

-17629879 18

I. i T / have the indicated value of the target product in free or in the form of salt. chei, and Q is a hydroxy thiol radical, C..al Istochinkn 1 information, accepted in

Coxp, C-alkylthio, halogen or NH, attention during examination:

at a temperature of 60-130 C in atmobfe-j1, UK Patent No. 1216523.

supply gas with the subsequent selection-cl. From 2 s, 1969.