DE2552403C2 - Thieno [1,5] -benzodiazepines, process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

(a> an amine of the formula R ⁵ H with a compound of the general formula

9

R ¹ I

N = C

T> (V)

R ²

wherein R ¹ , R ² and R ^{5 are} as defined in claim 1, the group

30th

ν
T

is as defined in claim 1, and Q represents a radical which is associated with the hydrogen atom of the amine

ei R ⁵ H can be split off, reacted in a manner known per se, and then

p, if desired, when R ^{5 is} the group

f —NN —R ⁶ (Ib)

I; \ /

\ means, wherein R ^{6 is} Ci- ₄ -carbalkoxy, hydrolyzed in a manner known per se to the amine, in

where R ^{6 is} hydrogen; or
(b) a compound of the general formula

45

NH

50 55

with an alkylating agent of the formula R ⁶ X, in which R ^{6 is defined} as in claim 1, with the exception of the meaning of hydrogen and phenyl, and X is a reactive atom, in a manner known per se.

5. Pharmaceutical agent, characterized in that it contains at least one compound of the general Formula (Γ) according to at least one of Claims 1 to 3 and / or pharmaceutically acceptable acid addition salts, optionally in combination with a pharmaceutical carrier suitable therefor.

65

The invention relates to new thieno [l, 5] -benzodiazepines, which have a beneficial therapeutic effect on the Central nervous system (abbreviated to »CNS«) and / or are responsible for the production of such active

compounds are suitable, as well as processes for the preparation of these compounds and pharmaceutical products containing them Means that can be used for the treatment of humans and animals by getting an effective Dose of at least one of the new compounds according to the invention or the pharmaceutical containing them Middle] administered.

The invention relates in particular to new compounds which form the previously unknown thieno [1,5] benzodiazepine ring system belong to the following formula.

ι Λ cl \ /! I * X VM) /

in which the symbol

there)

means a thiophene ring.

In recent years there has been a great deal of activity in the field of pharmaceutical chemistry, which concerned the study of tricyclic and benzodiazepine systems. The ones in these investigations The results found are described in a large number of patents, of which the British Patents 980853, 1291684, 13 80242, 13 80243, 13 80244 and US Patents 2,893,992, 3102 116, 3102 116, 3109843, 3136 815, 3474099, 3654286, 3749786 and 3842082 only a small section represent.

The invention relates to new thieno [1,5] benzodiazepines of the general formula

(D

"WX / X /

as well as their acid addition salts, in particular their pharmaceutically acceptable acid addition salts,
where mean:

R ¹ and R ² are each independently hydrogen, C, - ₄ alkyl, C ₂ _ ₄ alkenyl, C ₃ - ₆ cycloalkyl, halogen, Ci-4 haloalkyl, nitro, amino, C ₂ _ ₄ acylamino, hydroxyl C | _ ₄ alkoxy C | - N (R ⁴⁾ _2, or -SO ₂ R ^4, wherein R ⁴ is C, _ ₄ alkyl SO ₂ - ₄ alkylthio, or a group of formula;
R ⁵ either

(A) a group of the general formula
_5ü - N ^ NR ⁶ (Ib)

wherein R "is hydrogen, _{phenyl optionally substituted by halogen or C | _ 4} -haloalkyl, Ci -., - Alkyl, Ci-a-Cycloalkyl, C ₂ _ ₄ -alkenyl, C, _ ₄ -alkanoyl, benzyl, C, _ ₄ -Carbalkoxy or - (CH ₂ ) "OX, in which η is the number 2 or 3 and X is hydrogen or an ester radical, or
(B) a group of the general formula

- NH- (CH ₂ ) ,, - Z (Ic)

where η is the number 2 or 3 and Z is a radical of the formula

(i) —NN —R ⁶ (Ib)

where R '' has the meanings given above,

(ii) -N> (Id)

—N ' '- \
O
s / 25th 52 403 (iii) R "
/ - N /
R '" (iv)

Oe)

(IO

10

wherein R "and R '" are each independently hydrogen or C, _ ₄ alkyl, or

(v) OH; and

the group

there)

20th

a thiophene ring fused to the diazepine ring, which is unsubstituted or substituted by one or two radicals from the group Qg-alkyl, C ₂ -. ₄ alkenyl, C] - ₄ haloalkyl, C ₂ - ₄ alkanoyl, nitro, halogen and optionally substituted phenyl may be substituted and may be fused to a Cj-g-cycloalkyl.

In the compounds of the above general formula (I) and their acid addition salts R ¹ and ^R: are preferably independently of each other hydrogen ι- C ₄ alkyl, halogen, C] _ ₄ haloalkyl, nitro, amino, C ^ ₄ -alkoxy , C, _ ₄ alkylthio, or a group of the formula -SO ₂ N (R ⁴ J _2, wherein R ⁴ is Ci- ₄ alkyl; and

30th

(A) R ⁵ preferably denotes a group of the formula

- NN — R ⁶ (Ib)

35

in which R "is hydrogen, phenyl, optionally substituted by halogen, C _{1 -C 4} -alkyl, C _{1 -C 4} -carbalkoxy or - (CHj) _n OII, in which η denotes the number 2 or 3, or

(B) a group of the general formula

- NH- (CH ₂ ) ,, - Z (Ic) in which η is the number 2 or 3 and Z is a radical of the formula

(i) —NN —R ⁶ ob)

wherein R '' has the meanings given above,

(iii) -N O Oe)

55

R " /

(iv) - ν σο

R '"
wherein R "and R '" are each independently hydrogen or C - ₄ alkyl.

65

The novel thieno [l, 5] benzodiazepines according to the invention can exist in three forms, which by the the following structural formulas can be represented:

(H) (ΠΙ) (IV)

In the structural formulas given above, the thiophene ring is indicated as unsubstituted in each case, but it _{goes without saying that the thiophene ring can also be substituted by one or two radicals from the group consisting of C 1-8} -alkyl, preferably C 1-8 -alkyl, C _2-4 -alkenyl, C, _ ₄ -haloalkyl, C _2-4 alkanoyl, nitro, halogen and optionally substituted phenyl. In addition, in the above structural formulas II and IV of the thiophene ring ₃ _ ₈ cycloalkyl ring may be fused to a C.

Preferred compounds which come under one of the formulas I to IV given above are those which one or have several of the following characteristic features:

(A) R ¹ is a 6- or 7-halogen substituent, such as chlorine or fluorine,

(B) R ¹ is a 7-halogen substituent, such as chlorine or fluorine when R ^{2 is} hydrogen, (C) R ¹ is a 7-fluoro substituent when R ^{2 is} hydrogen,

(D) R ² is hydrogen,

(E) R ¹ or R ² means trifluoromethyl,

(F) R ¹ is a 6- or 7-trifluoromethyl substituent when R ^{2 is} hydrogen,

(G) R ¹ or R ² means methylthio or methoxy,

(H) R ^! and R ² both represent halo analogs, e.g. B. fluorine atoms,
(I) R ^{5 represents} a group of the formula

- N

NR ⁶

If)

wherein R ^{6 is} hydrogen, C ,. _4- alkyl, benzyl or - (CH ₂ ) "OX denotes, R ⁵ denotes a group of the formula

- N

N-CH ₃

(Ig)

(K) the compound of formula I has the structure II,

(L) of the thiophene ring by a C, _ ₄ alkyl group such. B. substituted by an ethyl group, (M) the thiophene ring is unsubstituted,

(N) the thiophene ring is represented by an electron attractive group such as e.g. As halogen, nitro, trifluoromethyl or C _2-4 alkanoyl substituted.

Most preferred is the class of compounds which have the features (A) to (E) given above, (J) and (L). A particularly active compound belonging to this class is e.g. B. 2-Ethy 1-7-fluoro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine both in the form of the free base and in the form of its pharmaceutically acceptable salts.

As used herein the term "C, - ₄ alkyl" is a straight (straight-chain) or branched chain alkyl group having 1 to 4 carbon atoms, such. B. methyl, ethyl, isopropyl, η-butyl. s-butyl and iso-

ξ) butyl, to understand. The term »C | ^ -Haloalkyl "is one as defined above

, iii nated alkyl group to understand which is substituted by one or more halogen atoms, such as. B.

'>, Trifluoromethyl. The terms "Ci-4-alkoxy" and "C | _ ₄ -alkylthio" used here include the above

•; to understand defined alkyl groups, which via an oxygen atom or a sulfur atom to the benzene

> l or thiophene ring are bound. The term "Cn ^ -alkenyl" used here includes groups such as. 5

V. B. vinyl, allyl and butenyl groups to understand. The term "amino" used here stands for one

J ;, ¹ group of the formula -NH ₂ and also includes substituted amino groups, such as e.g. B. Mono-C | _ ₄ -alky] amino and

Ϊ Di-Ci 4-alkylamino groups. The term "C ₂ -j-acylamino" used here is an amino group

M to understand that by a C _2-4 acyl group such. B. acetyl is substituted. The term used here

. ■■■; »C | - ₄ -Alkanoyl «refers to groups such as. B. formyl or acetyl. Under the expression 10 as used here

; '"C ₃ -" -Cycloalkyl "is a saturated ring with 3 to 8 ring carbon atoms to be understood, such as. B. Cyclopropyl,

Λ Cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. The term used here »possibly substituted

■: · tuierter Phenyl «stands for an unsubstituted phenyl group or for a phenyl group, which by an or

, ι several groups, such as B. halogen, trifluoromethyl, methyl, methoxy or nitro, is substituted. i, Examples of particularly preferred compounds according to the invention are as follows: 15

[; j 2-Ethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

ΐ 7-chloro-2-ethyI-10- (4'-methyl-l'-piperazinyl) -4H-thieno [2,3-b] [l, 5] benzodiazepine

S 2-Ethy I-7-fluoro-10- (4'-methyl-1 '-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

.C 2-Ethy 1-7-trifluoromethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 20

[i 7-Amino-2-ethyl-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

| i 2-Ethyl-7-nitro-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

i | 2-Ethyl-6-fluoro-10- (4'-methyl-r-piperazinyl) 4H-thieno2,3-b] [1,5] benzodiazepine

tf 2-Methyl-7- N, N -dimethylsulfonamido-10- (4'-methyl-r -piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

i | 2-Pentyl-7-fluoro-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 25

; | 2-Ethyl-6-methyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

> | j 2-Methyl-7-methoxy-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

t 6,7-Difluoro-2-ethyl-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

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

έ 6,8-Difluoro-2-ethyl-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 30

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

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

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

£ ■ i ^ -Dimethyl ^ -chlor-lO ^ '- melhyl-l'-piperazinylHH-thienoP ^ -blfUSJbenzodiazepine

I ", 7-Chloro-2-methyl-10 - ((4'-methyl-r -piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 35

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

t ^; 2-vinyl-7-fluoro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

| ί 2-vinyl-7-trifluoromethyl-10- (4'-methyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] -benzodiazepine

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

^ 2-Ethyl-7-fluoro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine 40

■ ·; 2-Ethyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine

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

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

!.; 2-Ethyl-7-nitro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine

f- 2-Athyi-6-fluor-i0- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine t

|; 2-methyl-7- N, N -dimethylsulfonamido-10- (4'-methyl-1'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

I 2-Ethyl-6-methyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine

| i 2-Methyl-7-methoxy-10- (4'-methyl-r -piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine

ψ 6,7-Difluoro-2-ethyl-10- (4'-methyl-r-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine

|, 2-Ethyl-7-methylthio-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine 50

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

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

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

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

7-Chloro-2-methyl-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine 55

9-Fluoro-12- (4'-methyl-r -piperazinyl) -6H-1,3,4-tetrahydrobenzo- [b] thieno [2,3-b] [1,5] benzodiazepine

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

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

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

2-Ethyl-7-fluoro-10- (l'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 60

2-Ethyl-7-fluoro-10- [N (N, N'-dimethylaminoethyl) amino] -4H-thieno [2,3-b] [1,5] benzodiazepine

2-Ethyl-7-fluoro-10- (2'-N-piperidinoethyl) amino ^ tH-thieno [2,3-b] [1,5] benzodiazepine 2-ethyl-7-trifluoromethyl! -10- (1-piperazinyI) -4H-thieno [2,3-b] -11,5] -benzodiazepine 2-Ethyl-7-fluoro-10- (4'-allyl-r-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

2-Ethyl-7-chloro-10- [3 '- (4-phenyl-1-piperazinyl) propyl] amino-4H-thieno [2,3-b] [1,5] benzodiazepine 65

2-Ethyl-7-chloro-10- [3 '- (4-hydroxyethyl-1-piperazinyl) propyl] amino-4H-thieno [2,3-b] [1,5] benzodiazepine 3-methyl-10- (4'-methyl -] '- piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

ii

7-Fluoro-10- (4'-acetyl-r -piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
7-Trifluoromethyl-10- (4'-methyl-r -piperazinyl) -1 H -thieno [3,4-b] [1,5] benzodiazepine
7-Amino-10- (4'-methyl-r-piperazinyI) -4H-thieno [3,4-b] [1,5] benzodiazepine
7-acetylamino-10- (4'-methyl-r -piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine

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

7-Dimethylamino-10- (4'-methyl-r -piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine
7-Nitro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
6-Fluoro-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
3-methyl-7- N, N -dimethylsulfonamido-10- (4'-methyl-r -piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

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

6-methyl-10- (4'-methyl-r -piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
3-methyl-7-methoxy-10- (4'-methyl-1'-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
6,7-Difluoro-10- (4'-methyl-r-piperazinyI) -4H-thieno [3,4-b] [1,5] benzodiazepine
2-Ethyl-7-chloro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b) - [1,5] -benzodiazepine

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

2-Ethy! -7-tr! Nuormethy! -10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] - [1,5] -benzodiazepine
7-methylthio-10- (4'-methyl-r-piperazinyl) -4H-thieno- [3,4-b] - [1,5] -benzodiazepine
6,8-Difluoro-10- (4'-methyl-r -piperazinyl) -4H-thieno [3,4-b] - [1,5] -benzodiazepine
7-Chloro-10- (4'-methyl-r -piperazinyl) -4H-thieno [3,4-b] - [1,5] -benzodiazepine

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

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

As indicated above, the novel thieno [l, 5] -benzodiazepines according to the invention can be used in both the form their free base as well as in the form of their acid addition salts can be used. With the acid addition salts it is preferably the pharmaceutically acceptable, non-toxic addition salts with suitable ones Acids such as B. inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, Sulfuric acid or phosphoric acid, or with organic acids, e.g. B. organic carboxylic acids, such as glycolic acid, Maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, salicylic acid, o-Acetqxybenzoic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, such as methanesilphone

acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acid. In addition to the pharmaceutically acceptable acid addition salts, the present invention also includes other acid addition salts, e.g. B. those with picric acid or oxalic acid; they can be used as intermediates for the purification of the compounds or for the production of other, for example pharmaceutically acceptable, Acid addition salts can be used or they are suitable for identification, characterization or purification of the bases.

The invention also relates to a process for the preparation of a compound of the abovementioned general formula I, which is characterized in that one

(A) an amine of the formula R ⁵ H is reacted with a compound of the formula

R ¹ I

N = C

■ / \

where R ¹ , R ^: and R ^{5 have} the meanings given above and in which

(la)

\ κ

denotes an optionally substituted, condensed thiophene ring as indicated above and in which Q represents a radical ^{which can be cleaved off with the oxygen atom of the amine R 3} H, which is if desired in the event that R ⁵ denotes a group of the formula

—NN —R ⁶ (Ib)

and R ⁶ is C] - ₄ carbalkoxy, is followed by a hydrolysis to the amine, wherein R ⁶ is hydrogen; or b) a compound of the general formula

NH

with an alkylating agent of the formula R ⁶ X, where R "has the meanings given above with the exception of hydrogen and phenyl and where X is a reactive atom.

It should be noted that the two methods (a) and (b) given above are so-called Analogy procedure of a reaction type acts as it is already described in the literature (cf.e.g. British Patent 1216 523 for implementation (a) and known standard treatises relating to Alkylation). Knowing the nature of the starting materials and end products is great for those skilled in the art easy to specify suitable Q and X residues as well as suitable reaction conditions.

It should be noted, however, that the radical Q is a hydroxyl or thiol group, an alkoxy or alkylthio group having 1 to 4 carbon atoms, e.g. B. the methoxy or methylthio group, an aryloxy, aralkylthio or arylthio group, which can be activated as a removable group by substituents that are conveniently located in their aryl radical, such as. B. the p-nitrobenzylthio group, an alkyl or arylsulfeno group, which can preferably be activated as a removable group by substituents on the sulfur atom and its hydrocarbon radical, such as. B. a tosyl group, a halogen atom, expediently a chlorine atom, an amino group or a mono- or dialkyl-substituted amino group, where he or each alkyl substituent can have 1 to 4 carbon atoms. Q preferably represents hydroxyl, thiol, C, _ ₄ alkoxy, C ₁ -4 alkylthio, halogen or NH _2. Q in particular denotes hydroxyl or thiol if the intermediates of the formula (V) are mainly in the form of their amide and thioamide:

OS

NH-C \ (Va) or NH-C / (Vb)

If Q is hydroxyl and thus the compound of the formula V is an amide, the reaction (a) can be carried out in the presence of titanium tetrachloride. This latter reagent has the ability ^{to react with the amine formula R 3} H to form a metal amine complex. Other metal chlorides, such as B. those of zirconium, hafnium or vanadium, also have this property. The reaction is preferably carried out in the presence of an acid binder, such as. B. a tertiary amine such as triethylamine performed. Alternatively, the reaction can also be ^{carried out using excess amine of the formula R 5} H, which acts as an acid-binding agent.

Any suitable organic solvent, such as. B. toluene or chlorobenzene, the use of anisole has been found to be particularly useful, at least as a cosolvent, because of its ability to form a soluble complex _{with TiCl 4.}

If desired, elevated temperatures (up to 140 ° C) can be used to accelerate the reaction. A preferred temperature range for carrying out the reaction is within the range from 50 to 100 ^° C.

The amidines of the formula V, ie in which Q is NH ₂ , can be condensed in a corresponding manner with the amine of the formula R ⁵ H, although the yield in this reaction can be quite low. This is because it is generally preferred to convert the amidine into the corresponding amide by alkaline hydrolysis and to use the amide thus formed for carrying out the condensation reaction.

Thioamides of the formula V, wherein Q is SH, can be prepared by treating a solution of the corresponding amide in an anhydrous basic solvent such as dry pyridine with phosphorus pentasulfide. In a corresponding manner, the amides can be converted into iminothioethers, iminoethers or iminohalides or other derivatives which contain the active Q radicals indicated above by treating them with conventional reagents, e.g. B. an imino chloride or phosphorus pentachloride. These derivatives derived from the amides are ^{more reactive towards the amine R 5} H and can generally be reacted with it without the presence of TiCl _{4 being} necessary.

The compounds of formula VI can be alkylated by dissolving the amine in a suitable one inert polar solvents such as ethanol, adding the alkylating agent to the solution thus formed, and Reflux in the presence of a base. X can be any suitable reactive one Atom, such as a chlorine, bromine or iodine atom, or a reactive group, such as. B. a tosyl or Mcsylgruppe, act.

Compounds of the formula I in which R ⁵ denotes a group of the formula

—Ν NH Gh)

are preferably prepared by hydrolysis of the corresponding Q-4 carbalkoxy derivative.
Electrophilic substitution reactions on the aromatic nucleus can, if desired, be carried out in the conventional manner in the case of compounds of the formula I or V, with the formation of derivatives which carry electron-attracting groups on the thiophene ring. For example, the acetylation of an amide of the formula V can be effected using acetyl chloride / SnCLt- This amide can also be halogenated using, for example, N-chlorosuccinimide to form the corresponding chlorinated one

Derivative. Products of the formula I in which R ¹ or R ² denotes NH ₂ can be alkylated or alkylated in the customary manner with formation of the corresponding N-acyl and N-alkylamino derivatives. N-hydroxyalkylpiperazines,

ie those in which R _{6 is} - (CH ₂ ) “OH, can be esterified using fatty acid chlorides

with formation of the corresponding esters, such as. B. the decanoate or enanthate.

The compounds of the formula I prepared by the process described above can be isolated or they can be converted into their corresponding acid addition salts using conventional procedures be convicted.

The amides of the formula V can be prepared by a new process, which is the intramolecular Includes ring closure of an amino ester of the general formula

R ¹ CO ₂ R ⁹

(Of X ^T / ^(VII)

^Rl N

wherein R ^{9 is} C1-4 alkyl, e.g. B. ethyl, and R ¹ , R ² and

(Ia)

have the meanings given above. This reaction can be carried out using dimsyl sodium in a suitable solvent, preferably dimethyl sulfoxide, can be carried out. Alternatively, the Amides of formula V are prepared by intramolecular ring closure of an amino acid of the general formula

(vni)

using dicyclohexylcarbodiimide (DCC) with a suitable solvent such as tetrahydrofuran. The amino acids can by basic hydrolysis using, for example, NaOH / EtOH are made from the esters.

As indicated above, a convenient route to preparing the amides of Formula V comprises the following Reaction:

(IX)

I hydrolysis O

Il NC

N
H

(X)

10

15th

20th

The hydrolysis can be carried out using alkaline hydrolytic conditions, ζ. B. using K ₂ C (VH ₂ CVAtOH).

A convenient method for the preparation of the amidines of formula IX can e.g. B. by the following reaction equation being represented:

NO ₂ CN

H ₂ N

DMSO
K ₂ CO ₃

(IXa)

(IXb)

H ₂ / Pd-C

R ¹

αχ c)

HCl / ethanol

NH ₂

R ¹

30th

35

40

45

50

55

σχ)

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

χ ¹ . χ ¹

R ¹ CN

NO ₂

BF ₃ -At ₂ OZ toluene _i ('/ -ν
Warmth "Lw.

iChloranil / Xylene
warmth

R ¹ cn

NO ₂

H ₂ ZPdC

(IXi)

wherein X ¹ and X ² are any substituents present on the thiophene ring. As can be seen from the above reaction equation, this reaction comprises an aromatization reaction using chloranil and xylene. Alternatively, the above condensation reaction can also be carried out using o-phenylenediamines instead of the nitroanilines.

The esters of the formula VlI are new compounds that can be prepared by Condensation of a thiophene compound of the general formula

R ⁹ CO ₂

H ₂ N

(VIIa)

wherein R ^{9 has} the meanings given above, with an o-fluoronitrobenzene of the general formula

NO ₂

^(vnb)

in the presence of a n-butyllithium derivative or in the presence of a base such as sodium hydride, sodium amide, triethylamine or K ₂ CO-, in dimethyl sulfoxide, with formation of a nitro ester of the general formula

(VUc)

which can then be reduced catalytically, for example using hydrogen over palladium on activated carbon, or chemically using ZnZNH ₄ Cl, ammonium polysulphide or FeZHCl, to the amino ester of the formula VII.

For example, the 4H-thieno [2,3-b] [l, 5] ben7odiazepin-10-ones according to the following reaction scheme getting produced:

CO ₂ At X

H ₂ N

Na * CH ₂ SOCH ₃

Other thieno [1,5jbenzodiazepin-10-ones can in a corresponding manner via the amino ester on the Ways outlined above are produced.

The thiophene starting materials used in the methods of the invention are known compounds (see, for example, "Chem. Reports", 99.94-100 (1966), "J. Am. Chem. Soc", 68.2232 (1946) and Dutch Patent Application No. 66 04 741) or they can be prepared from known compounds by conventional methods getting produced. The o-fluoronitrobenzene intermediates are either commercially available or can be easily prepared from commercially available substances.

As indicated above, the compounds according to the invention have a valuable, advantageous effect (Activity) on the central nervous system. This activity has been studied in extensive animal studies Proven use of methods known per se, for example by generating catalepsy Blocking of conditioned evasive sensitivity and reversing that caused by amphetamine induced stereotypical behavior in rats. The compounds of the formula I according to the invention and their Acid addition salts, especially their pharmaceutically acceptable acid addition salts, are strong Compounds acting on the central nervous system and having neuroleptic, sedative or relaxing or antiemetic properties. Because of these properties, combined with their high therapeutic index, they are suitable for the treatment of mild anxiety and certain types of psychotic States such as B. Schizophrenia and acute manias.

The compounds of the invention are effective over a wide range of doses, the each dose administered depends on various factors, such as B. the connection used in each case, the Condition being treated with it and the type and size of mammal treated. The required However, dosage will normally be within the range of 0.1 to 20 mg per kg per day, for the treatment of adult humans, for example, doses of 0.1 to 10 mg / kg are used can be.

The compounds of the invention and their salts are normally administered orally or injected and for this purpose the compounds and salts are usually in the form of a pharmaceutical preparation used. Such preparations are manufactured in a manner known per se in the pharmaceutical industry and they normally contain at least one active compound of the invention or a pharmaceutical one compatible salt thereof, if necessary in combination with a suitable pharmaceutical

zeutic carrier. The active ingredient is used to prepare the pharmaceutical compositions of the present invention (Active ingredient) usually mixed with a carrier, or diluted by a carrier, or in a carrier included that is the shape of a capsule, the shape of a sachet, the shape of a paper, or other Container can have. When the carrier acts as a diluent it can be a solid, semi-solid

5 or liquid material that acts as an excipient, carrier or medium for the active ingredient. Suitable carriers are e.g. B. lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium ¹ phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl and propyl hydroxybenzoate, talc, magnesium stearate or mineral oil. The pharmaceutical agents according to the invention can be formulated in a manner known per se so that the active ingredient (active ingredient) after administration to

ίο Deliver the patient quickly, slowly or with a delay.

Depending on the type of administration, the pharmaceutical agents according to the invention can be in the form of tablets, Capsules or suspensions for oral administration and in the form of injection solutions for parenteral use Administration can be formulated. The pharmaceutical agents are preferably in unit dosage form before, with each dose 1 to 200, preferably 5 to 100 mg of the active ingredient (active ingredient) contains.

The invention is illustrated in more detail by the following production example and the examples that follow. Examples 1 to 12 illustrate the preparation of starting materials at an early stage in the process. Examples 13 to 24 illustrate the preparation of the intermediates of Formula V and the remainder Examples 25 to 36 explain the preparation of the pharmaceutically active compounds according to the invention. Examples 37 to 40 show possible formulations for the pharmacologically active compounds. If no melting points are given for the compounds described therein, then the structure of these compounds usually by thin layer chromatography and / or by data from Spectra confirmed.

A) Production of starting substances

Production example 1
a'-Carboxymethyl-jS'-carboxyethyl-u-ethylethylmethyl sulfide

12.6 g (0.1 mol) of ethyl pent-3-enoate (J. Org. Chem. 12, 138 to 154) were added to a solution of 10.6 g (0.1 mol) of methyl thioglycolate and 0.1 ml of piperidine were added dropwise, which were stirred together in a 100 ml three-necked flask equipped with a dropping funnel, a thermometer and a reflux condenser. The reaction temperature was kept between 40 and 50 ^° C. and 0.6 ml of piperidine were added in 0.05 ml portions over a period of 45 minutes. After the addition of pentenoate, the reaction mixture was 10 minutes at 50 ⁰ C for. Then the reaction mixture was cooled, washed with water, _{dried over MgSO 4} , filtered and the filter cake was washed with ether. The combined filtrates were evaporated to dryness and the abovementioned title compound was obtained in the form of a yellow liquid.

example 1

(a) Ethyl 5-ethyl-2- (2-nitroaniIino) thiophene-3-carboxylate

40 g (0.2 Mo!) Ethyl ^ -amino-S-ethylthiophene-S-carboxylate (range 99.94-100) in 150 m! of dry tetrahydrofuran was stirred under nitrogen and cooled to 40 ⁰ C. While the temperature was maintained below -3O ⁰ C, were added 125 ml of a 10.2 Gew./Vol.-%igen solution of n-butyllithium in hexane (0.2 mol). The mixture was then stirred for a further 15 minutes at -30 ⁰ C. This solution was passed through an inverted U-tube into a solution of 28 g (0.2 mole) o-fluoronitrobenzene in 100 ml of dry tetrahydrofuran which was maintained at 15 to 3O ⁰ C, blown. The mixture was stirred overnight. The resulting ink-blue solution was poured into three volumes of ice water, extracted with 3 × 500 ml of ether, washed with 2 × 500 ml of water, dried and then evaporated to dryness. The remaining deep red oil was dissolved in 200 ml of ethanol and cooled overnight. The precipitated crystals of the title compound were filtered off and dried ^{at 50 ° C. in vacuo.} After recrystallization from ethanol, the pure product with a melting point (F.) of 66 to 68 ° C. was obtained.

(b) Ethyl 5-ethyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate

The title compound was prepared in a similar manner as in the above (a), but this time used instead of the above o-fluoronitrobenzene 2,5-Difluoronitrobenzene, F. 90 ⁰ C (after recrystallization from ethanol).

Analysis for Ci ₅ Hi ₅ FN ₂ O ₄ S:

calc .: C 53.24 H 4.45 N 8.28 F 5.61 S 9.47%;
Found: C 53.45 H 4.75 N 8.15 F 5.71 S 9.75%.

a

Similarly, using the procedure described in Example 1 (a) above,

rens made the compounds given below. In each case, instead of the above in p »

Section (a) used o-fluoronitrobenzene used nitrobenzene; the melting point of the respective title · L

14 i

|; ί The compound is given together with the recrystallization solvent (in brackets).

i, (c) ethyl 2- (3,5-difluoro-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate

^; (2,4,6-Trifluoro-nitrobenzene, m.p. 74-75 ° C (EtOH).

:; (d) Ethyl 5-ethyl-2- (5-fluoro-2-nitroanilino) -thiophene-3-carboxylate

'i 2,4-Difluoro-nitrobenzene, ^{m.p. 87 to 88 0} C (ÄtOH).

■; (e) Ethyl ^ - ^ - chloro ^ -nitroanilinoJ-S-ethyl-thiophene-S-carboxylate

f S-chloro ^ -fluomitrobenzene, m.p. 75 to 76.5 ° C (EtOH). 10

(0 ethyl 2- (2,4-dinitroanilino) -5-ethyl-thiophene-3-carboxylate
i, 2,4-ditiitro-nuorbenzene, mp 148 ° C (ÄtOH).

'f (g) Ethyl ^^^ - difluoro ^ -nitroanilinoJ-S-ethyl-thiophene-S-carboxylate 15

Γ, 2,4,5-trifluoronitrobenzene, ^{m.p. 105 0} C (ÄtOH).

,: (h) methyl 3- (2-nitroanilino) thiophene-2-carboxylate

^! The title compound was prepared using the procedure outlined in Example 1 (a),

ί but using 2-fluoro-nitrobenzene and methyl-3-aminothiophene-2-carboxylate (British 20th

I patent 837086) as starting materials, mp 184 ° C (toluene / MeOH 2/1).

£ ■ (i) Methyl 3- (4-fluoro-2-nitroanilino) thiophene-2-carboxylate

, [ι The title compound was prepared using the procedure of Example 1 (a), but under

* Use of 2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate as starting materials 25

I lien, m.p. 172 to 175 ⁰ C (benzene).

A- In a corresponding way were made:

\ ·, (K) ethyl 5-i-propyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate 30

/ f (I) ethyl 5-n-hexyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate

ff (m) ethyl 4-methyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylate

f, 35

f (n) EthyM-methyl-S-ethyl ^ - ^ - fluorine ^ -nitroanilinoMhiophene-S-carboxylate.

k example 2

H .. ⁴⁰

£ (a) Ethyl 5-ethyl-2- (2-nitroanilino) -thiophene-3-carboxylate

'ί 56.4 g (0.4 mol) of o-fluoronitrobenzene and 100 g (0.5 mol) of EthyW-amino-S-ethylthiophene-S-carboxylate were

h dissolved in 320 ml of dry dimethyl sulfoxide. The solution, stirred under nitrogen, was in a

heated iv oil bath. After the internal temperature had reached 60 ^° C., 55 g (0.4 mol) of potassium carbonate were added

ί; added and the mixture was ^{stirred at 100 0} C until the GLC (gas-liquid chromatography 45

; f phie) indicated that all of the o-fluoronitrobenzene had been consumed (after 6.5 hours). the

I; The mixture was then poured onto ice water, acidified with concentrated hydrochloric acid and

i extracted with methylene chloride. The combined extracts were washed with water, over MgSO ₄

V dried and the solvent evaporated to give a red semi-solid material which

iV. Recrystallized from ethanol to give the title compound as a solid, mp 66-50

I 68 ° C.

I In a similar manner, the compounds given below were prepared using the in

procedure given in Example 2 (a) above. In each case are the melting point of the title compound, the recrystallization solvent (in brackets) and the starting materials (if they are different from those in 55 different genes of Example 2 (a)).

(b) Ethyl 2- (4-chloro-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate 5-chloro-2-fluoro-nitrobenzene, mp 75 to 76 ° C (EtOH).

(c) Ethyl 2- (2,4-dinitroanilino) -5-ethyl-thiophene-3-carboxylate
2,4-Dinitro-fluorobenzene, m.p. 146 to 148 ° C (EtOH).

(d) Ethyl 5-ethyl-2- (2-nitro-4-trifluoromethylanilino) -thiophene-3-carboxylate 4-fluoro-3-nitrobenzotrifluoride, ^{m.p. 102 0} C (EtOH). 65

(e) Ethyl 5-ethyl-2- (5-methyl-2-nitroanilino) thiophene-3-carboxylate 3-fluoro-4-nitrotoluene, m.p. 55 to 57 ° C (EtOH).

(0 Ethyl 2- (4-difluoromethyl-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate
S-difluoromethyW-fluoro-nitrobenzene, ^{m.p. 88 to 90 0} C (EtOH).

(g) Methyl 2- (4-N, N-dimethylsulfonamido-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate

5-N, N-dimethylsulfonamido-2-fluoro-nitrobenzene and methyl ^ -amino-S-ethyl-thiophene-B-carboxylate,

M.p. 166 to 168 ° C (EtOH).

(h) Methyl-S-ethyl ^ - ^ - methoxy ^ -nitroanilinoHiophen ^ -carboxylate

2-fluoro-5-methoxy-nitrobenzene and methyl ^ -amino-S-ethyl-thiophene-B-carboxylate, mp 125 to 127 ° C ίο (ÄtOH).

(i) Ethyl 2- (4-fluoro-2-nitroanilino) thiophene-3-carboxylate

2,5-Difluoro-nitrobenzene and ethyl ^ -amino-thiophene-S-carboxylate, mp 125 ° C (EtOH).

(j) ethyl 5-ethyl-2- (4-methylthio-2-nitroanilino) thiophene-3-carboxylate

4-Fuor-3-nitro-thioanisole and ethyl 1 -amino-S-ethyl-thiophene-1-carboxylate.

(k) Ethyl 2- (2-chloro-6-nitroanilino) -5-ethyl-thiophene-3-carboxylate

Ethyl ^ -amino-S-ethyl-thiophene-S-carboxylate and 3-chloro-2-fluoro-nitrobenzene, mp 67 to 70 ° C (ÄtOH).

(1) Ethyl 5-ethyl-2- (2-trifluoromethyl-6-nitroanilino) -thiophene-3-carboxylate

Ethyl ^ -amino-S-ethylthiophene-O-carboxylate and 2-fluoro-3-trifluoromethylnitrobenzene, mp 72-73 ° C (EtOH).

(m) methyl 3- (4-chloro-2-nitroanilino) thiophene-2-carboxylate

5-chloro-2-nuoro-nitrobenzene and methyl ^ -amino-thiophene ^ -carboxyiate, mp 207-2O8 ° C (EtOH / hexane).

(n) Methyl 5-methyl-2- (2-nitro-4-fluoroanilino) thiophene-3-carboxylate

MethyW-amino-S-methyl-thiophene-S-carboxylate and 2,5-dinuor-nitrobenzene, mp 149 to 151 ⁰ C (AtOH) ₄

(o) Ethyl 2- (4-bromo-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate

Ethyl ^ -amino-S-ethyl-thiophene ^ -carboxylate and 5-bromo-2-fluoro-nitrobenzene, mp 76 to 78 ° C (ÄtOH).

(p) methyl 2- (4-fluoro-2-nitroanilino) -5-phenyl-thiophene-3-carboxylate
Methyl 1-5 amino-S-phenyl-thiophene-S-carboxylate and 2,5-difluoro-nitrobenzene, m.p. 150 ° C (CH ₂ Cl ₂ ).

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

6.0 g of ethyl 5-ethyl-2- (2-nitroanilino) thiophene-3-carboxylate, dissolved in 100 ml of ethanol, and 50 ml of water were heated ^{to 60 ° C. with stirring.} Then 50 ml of 5N sodium hydroxide was added and the temperature was maintained for 16 hours. The reaction mixture was cooled and washed with 500 ml of water

diluted, after which the precipitated solid title compound was filtered off, mp 189 to 191 ° C (ÄtOAc).

(r) 5-Ethyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-carboxylic acid

The title compound was prepared in a corresponding manner from ethyl 5-ethyl-2- (4-fluoro-2-nitroanilinoMhiophene-3-carboxylate, this time, however, using a reaction temperature of 25 ° C. F. 198

up to 200 ⁰ C (EtOAc).

(s) methyl 3- (4-fluoro-2-nitroanilino) thiophene-4-carboxylate

Example 3

(a) Methyl 3- (4-fluoro-2-nitroanilino) thiophene-4-carboxylate

48.5 g (0.25 mol) of S-carboxymethyM-aminothiophene hydrochloride (J.A.C. S. 68,2232 (1946)) were in a minimal amount of water and dissolved in the presence of a saturated sodium bicarbonate solution and

Ether shaken. The ether extract was _{dried over MgSO 4} , filtered and evaporated to an oil, dissolved in dimethylformamide (DMF), 2-methoxyethanol or dimethyl sulfoxide (DMSO) (anhydrous), preferably in the latter (100 ml). To this stirred solution C 40 g (0.25 mol) of 2,5-difluoronitrobenzene and 35 ml of triethylamine under nitrogen at 100 ⁰ added, the reaction mixture was maintained for 1 hour (under reflux) at these conditions and an additional 35 ml Triethylamine added. The reaction mixture was then heated with stirring and under nitrogen for an additional 40 hours.

The cooled mixture was poured into 1.5 l of a saturated sodium chloride solution with stirring and in the presence of ethyl acetate, and the 2-phase mixture obtained was filtered. The organic phase was stripped off, washed with a brine solution, _{dried over MgSO 4} , filtered and combined to a

evaporated brown resin (rubber). This resin was dissolved in a minimal amount of ethyl acetate and in a vacuum through a pad made of "Florisil" (trade name) contained in a sintered funnel filtered, the pad was washed with ethyl acetate until all product was removed,

the filtrates were combined, evaporated to an oil, dissolved in 250 ml of cold ethanol and left to stand at 0 ^° C. for 24 hours. The resulting red-orange crystalline product occasionally contained traces of brown tar, but it was found that this could be removed by adding a little ethyl acetate and triturating. The crystals thus obtained were filtered, washed with ethanol, petroleum ether (bp. 40 to 60 ⁰ C) and then uuter vacuo to give the title compound in the form of a solid product was obtained, mp 164 ° C.

(b) methyl 3- {2-nitro-4-trifluoromethylanilino) thiophene-4-carboxylate

The title compound was prepared in a similar manner using that in the example above 3 (a) described method, mp 175 ° C (ÄtOH).

(c) 2- {4-Fluoro-2-nitroanilino) -4,5,6,7-tetrahydrobenzo [b] -thiophene-3-nitrile (reference example for explaining the preparation of the following compounds (d) - (g)) 3.6 g (0.02 mol) of 2-amino-4,5,6,7-tetrahydrobenzo [b] -thiophene-3-nitrile and 3.2 g (0.02 mol) of 2,5-difluoronitrobenzene were in Stirred 20 ml of dry DMSO and heated on an oil bath. After the internal temperature had reached 60 ^° C., 2.76 g (0.02 mol) potassium carbonate were added and the mixture was then stirred ^{at 100 ° C. for 5 hours.} The reaction mixture was poured onto ice water, acidified and extracted with methylene chloride. The combined extracts were washed with water, _{dried over MgSO 4} and the solvent was removed in vacuo, mp 137-139 ° C. (EtOAc).

In a corresponding manner, the following compounds were prepared using l-amino-5-ethyl-thiophene-3-nitrile:

(d) 5-Ethyl-2- (4-fluoro-2-nitroanilino) -thiophene-3-nitrile

(e) 5-Ethyl-2- (4-methoxy-2-nitroanilino) -thiophene-3-nitrile

(0 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 38.1 g (0.25 mol) of S-cyanotetrahydrothiophene (Dutch patent application No. 6604742) and

51.8 g (0.28 Mo!) Of 4-chloro-2-nitroaniline were dissolved in about 200 ml of refluxing toluene in a 500 ml three-necked flask fitted with a Dean-Stark device. A few drops of boron trifluoride etherate were added and the reaction was refluxed for 4 hours, collecting the water formed. The resulting reaction mixture was allowed to cool, a brown solid precipitating which was filtered off. The solid was recrystallized from absolute ethanol using activated charcoal as a decolorizing agent and the orange-colored solid obtained was filtered off, washed with ethanol and then ^{dried at 50 °} C. under vacuum. The dried solid obtained was the title compound, mp 154-155 ° C.

(b) 3- (4-Methylthio-2-nitroanilino) -2,5-dihydrothiophene-4-nitrile

The title compound was prepared using a similar procedure as in the above Example 4 (a), F. 141-142 ⁰ C (EtOH).

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

Example 5

(a) 3- (4-Chloro-2-nitroanilino) -thiophene-4-nitrile

14.09 g (0.05 mol) of 3- (4-chloro-2-nitroanilino) -2,5-dihydrothiophene-4-nitrile, dissolved in 150 ml of xylene, were added to a solution of 12.3 g (0.05 mol) of chloranil in 100 ml of hot xylene. The mix was Heated to reflux for 2 hours. After cooling, the xylene was evaporated under vacuum, leaving a red-brown solid which was triturated with methanol to form a brick-red color Solid. The solid was recrystallized from hot methanol and red crystals were obtained. which were filtered off, washed with methanol and dried at 50 ° C under vacuum. With the one thus obtained dried product, it was the title compound, mp 214 ° C.

(b) 3- (4-methylthio-2-nitroanilino) -thiophene-4-nitrile was prepared in a corresponding manner, F. 167-169 ⁰ C (MeOH).

(c) 4- (4-Fluoro-2-nitroanilino) -2-ethyl-thiophene-3-nitrile.

Example 6

(a) Ethyl 2- (2-aminoanilino) -5-ethyl-thiophene-3-carboxylate

20 7 g of ethyl 5-ethyl-2- (2-nitroaniliuo) -thiophene-3-carboxylate in 150 ml of ethanol were poured over 2.0 g of 10% ^{strength under a pressure of 4.22 kg / cm 2 (60 psi)} Palladium catalyzed on activated carbon reduced. Of the

Catalyst was removed by filtration and the solvent was removed by distillation in vacuo removed. The title compound thus obtained had a melting point of 50 to 52 ° C (Hexane).

ίο The following connections have been made in a corresponding manner:

(b) Ethyl 2- (2-amino-4-fluoroanilino) -5-ethyl-thiophene-3-carboxylate M.p. 82 to 84 ° C (hexane).

(c) Ethyl 2- (2-amino-3,5-difluoroanilino) -5-ethyl-thiophene-3-carboxylate F. 106 ⁰ C (EtOH).

(d) Ethyl 2- (2-amino-5-fluoroanilino) -5-ethyl-thiophene-3-carboxylate F. 100 to 101 ⁰ C (EtOH).

(e) Ätbyl-2- (2-amino-4-chloroanilino) -5-ethyl-thiophene-3-carboxylate F. 119 to 121 ⁰ C (ATOH).

(0 ethyl 2- (2,4-diaminoanilino) -5-ethyl-thiophene-3-carboxylate
152-155 ° C (hexane).

(g) Ethyl 2- (2-amino-4-trifluoromethylanilino) -5-ethyl-thiophene-3-carboxylate (h) Ethyl 2- (2-amino-5-methylanilino) -5-ethyl-thiophene-3-carboxylate

(i) Ethyl ^ - ^ - difluoromethyl ^ -nitroanilinoJ-S-ethyl-thiophene-S-carboxylate (j) methyl 2- (2-amino-4-N, N-dimethylsulfonamidoanilino) -5-ethyl-thiophene-3 carboxylate (k) methyl 2- (2-amino-4-methoxyanilino) -5-ethyl-thiophene-3-carboxylate (1) ethyl 2- (2-amino-4-fluoroanilino) thiophene-3-carboxylate
(m) Ethyl 2- (2-amino-4-methylthioanilino) -5-ethyl-thiophene-3-carboxylate

(n) methyl 3- (2-aminoanilino) thiophene-2-carboxylate

F. 102 ⁰ C. The title compound was prepared by reduction of methyl 3- (2-nitroanilino) -thiophene-2-carboxylate.

(o) Methyl 3- (2-arnino-4-fluoroanilino) thiophene-2-carboxylate

The title compound was prepared in a similar manner by reducing methyl 3- (4-fluoro-2-nitroanilino) thiophene-2-carboxylate.

(p) methyl 3- (2-amino-4-chloroanilino) thiophene-2-carboxylate

(q) methyl 2- (2-amino-4-fluoroanilino) -5-methyl-thiophene-3-carboxylate

F. 116 to 118 ⁰ C.
(r) Ethyl 5-i-propyl 2- (4-fluoro-2-aminoanilino) thiophene-3-carboxylate

(s) Ethyl 5-n-hexyl-2- (4-fluoro-2-amtnoani! ino) -thiophene-3-carboxylate (t) ethyl 4-methyl-2- (4-fluoro-2-aminoanilino) -thiophene-3-carboxylate (u) ethyl-4-methyl-5-ethyl-2- (4-fluoro-2-aminoanilino) thiophene-3-carboxylate

(v) 2- (2-AminoaniIino) -5-ethyl-thiophene-3-carboxylic acid

8.0 g (0.027 mol) of 5-ethyl-2- (2-nitroanilino) -thiophene-3-carboxylic acid in 150 ml of ethanol were under a pressure of 4.22 kg / cm ² (60 psi) over 900 mg of 10% igen palladium catalytically reduced on activated carbon. The catalyst was removed by filtration and the solvent was removed by distillation in vacuo to give the title compound.

(w) methyl 5-ethyl-3- (2-amino-4-fluoroanilino) thiophene-2-carboxylate.

Example 7
Ethyl 2- (2-amino-4-nitroanilino) -5-ethyl-thiophene-3-carboxylate

0.5 g of ethyl 2- (2,4-dinitroanilino) -5-ethyl-thiophene-3-carboxylate in 25 ml of 6N ammonia and 10 ml of ethanol were stirred at the reflux temperature and hydrogen sulfide gas was released over a period of 2 hours initiated. The reaction mixture was cooled to room temperature and that in the form of a yellow The title compound obtained from the precipitate was filtered off, washed with water and in vacuo dried, m.p. 174 to 176 ° C (EtOAc).

Example 8
Ethyl 2- (2-amino-4-bromanilino) -5-ethyl-thiophene-3-carboxylate

0.4 g (0.001 mol) of ethyl 2- (4-bromo-2-nitroanilino) -5-ethyl-thiophene-3-carboxylate were added to 0.4 g of zinc powder and 0.4 g of ammonium chloride in 10 ml of water and Stirred at 50 ^° C. for 24 hours. The reaction mixture was filtered and the resulting solid was washed successively with water and ethyl acetate. The organic phase was separated, washed with water, _{dried over MgSO 4} and evaporated in vacuo to give the title compound.

Example 9

(a) Methyl 3- (2-aminoanilino) -2,5-dihydrothiophene-4-carboxylate

48.06 g (0.3 mol) of S-carboxymethyltetrahydrothiophen ^ -one and 32.4 g (0.3 mol) of o-phenylenediamine were dissolved in 500 ml of boiling ethanol to which a few drops of acetic acid had been added. The solution was then heated to reflux for 4 hours in a nitrogen atmosphere and allowed to cool. The crystalline material thus obtained was filtered off, washed with ethanol and dried under vacuum. The product was recrystallized from absolute ethanol using activated charcoal as a decolorizing agent to give a good yellow solution from which white needles crystallized. The white crystalline solid was filtered off, washed with ethanol and dried under vacuum to give the title compound, mp 101 ^° C.

(b) methyl 3- (2-amino-4,5-dichloroanilino) -2,5-dihydrothiophene-3-carboxylate

The title compound was obtained by a similar procedure to Example 9 (a), mp 162 ° C.

Example 10

(a) Methyl 3- (2-aminoanilino) thiophene-4-carboxylate

25.03 g (0.1 mol) of methyl 3- (2-aminoanilino) -2,5-dihydro-thiophene-4-carboxylate and 24.6 g (0.1 MoDChloranil were combined in 900 ml of xylene for 2 hours The solvent was then evaporated in vacuo leaving a dark brown solid which was triturated with ethyl acetate to give a light brown solid which was filtered off, washed with ethyl acetate and dried in vacuo to give the title compound, mp 120-122 ⁰ C.

The following was produced in a corresponding manner:

(b) methyl 3- (2-amino-4,5-dichloroanilino) thiophene-4-carboxylate
F. 162 to 163 ⁰ C.

Example 11

Methyl 3- (2-aminoanilino) thiophene-4-carboxylate

2.5 g (0.001 mol) of methyl 3- (2-aminoanilino) -2,5-dihydrothiophene-4-carboxylate were added to a 200 mg Catalyst composed of 5% palladium on activated carbon in 50 ml of cyclohexene (or norbornadiene or norbornylene) containing The flask was inserted and the reaction mixture was refluxed with stirring for 4 hours heated then it was subjected to TLC analysis. The reaction mixture was then cooled, the Solvent was evaporated in vacuo leaving a dark brown oil which using a "Florisil" column and was subjected to column chromatography using chlorine, wherein the Tilelverbindungen was obtained in the form of an orange solid, mp 120 to 122 ° C.

Example 12

(a) 3- (2-Amino-5-trinuomethylanilino) -2,5-dihydro-thiophene-4-nitrile 24 g (0.136 mol) of 4-trifluoromethyl-o-phenylenediamine and 17.3 g (0.136 mol) of 3-keto-4-nitrile-2,5-dihydrothiophene were dissolved in 200 ml of warm ethanol, 3 ml of acetic acid were added and the solution was refluxed for 24 hours then left to cool. That way in The title compound, obtained as a white solid, was filtered off and mixed with that on evaporation

of the filtrate to a small volume of solid obtained and cooled, mp 189 ° C.
The following was produced in a corresponding manner:

(b) 3- (2-Amino-5-chloroanilino) -2,5-dihydrothiophene-4-nitrile
164 to 165 ° C.

(c) 3- (2-aminoanilino) -2,5-dihydrothiophene-4-nitrile

80 g (0.629 mol) of S-keto ^ -cyanotetrahydrothiophene and 68 g (0.629 mol) of o-plienylenediamine were dissolved in 1.5 l of technical methylated alcohol with heating. 3 ml of glacial acetic acid were added to the solution, and the solution was then heated under reflux and with mechanical stirring for 24 hours. The solution was then cooled and filtered, whereby the title compound was obtained in the form of a solid, mp 163 ^° C.

B) Preparation of the intermediates of the general formula V
Example 13

(a) 10-Amino-7-chloro-4H-thieno [3, t-b] [1,5] benzodiazepine

17.18 g (0.06 mol) of 3- (4-chloro-2-nitroanilino) thiophene-4-nitrile were hydrogenated in 300 ml of ethanol and 100 ml of ethyl acetate using 3.5 g of a 10% palladium catalyst Activated charcoal in a Parr hydrogenator to give 3- (4-chloro-2-aminoanilino) thiophene-4-nitrile. After 2 hours the reaction was complete, the catalyst was filtered off and the solution was evaporated to dryness in vacuo. The resulting light brown solid was redissolved in 100 ml of absolute ethanol in a 500 ml three-necked flask. To the stirred solution, 12 ml of concentrated hydrochloric acid was carefully added dropwise. The alcoholic solution was then refluxed for about 24 hours. Then 60 ml of a 10% sodium hydroxide solution was added dropwise to the cooled solution until the solution was weakly basic. During the addition the title compound precipitated and was filtered off to give a pale yellow to brown solid which was washed with water and ^{dried at 50 °} C. under vacuum, mp 239 to 240 ^° C.

In a similar way were made:
(b) 10-Amino-7-methylthio-4H-thieno [3,4-b] [1,5] benzodiazepine, mp 195-197 ° C

(c) 12-Amino-9-fluoro-6H-1,2,3,4-tetrahy drobenzothieno [2,3-b] [1,5] benzodiazep in

(d) 10-Amino-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine

(e) 10-Amino-2-ethyl-7-methoxy-4H-thieno [2,3-b] [1,5] benzodiazepine
(0 10-Amino-2-ethyl-7-methylthio-4H-thieno [2,3-b] [1,5] benzodiazepine

(g) 10-Amino-2-ethyl-7-trifluoromethyl-4H-thieno [2,3-b] [1,5] benzodiazepine
(h) 10-Amino-1-ethyl-7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepine.

Example 14

(a) lO-Amino ^ H ^^ - dihydrothienoP ^ -bJfl.SJbenzodiazepine hydrochloride

84.5 g (0.39 mol) of 3- (2-aminoanilino) -2,5-dihydrothiophene-4-nitrile were suspended in 1.5 l of hot technical methylated spirit with mechanical stirring. 57 ml (0.66 mol) of concentrated hydrochloric acid were added dropwise, the solution was stirred for 1 hour at reflux temperature, then cooled and the solid obtained was filtered off, with a small amount of technical methylated spirit, petroleum ether (boiling point 40 to 60 ⁰ C) washed and ^{dried at 50 0} C under vacuum. The title compound thus obtained had a melting point of 292 ° C. (decomposition).

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

54.5 g of the hydrochloride indicated in the above section (a) were suspended in 1 l of chloroform with mechanical stirring and 500 ml of a 10% w / w% sodium hydroxide solution were added in one portion. The suspension was stirred for 2 hours to give the title compound as a white solid. This was filtered off, washed with water, ethanol and ether and dried under vacuum, whereby the free base was obtained, mp 240 to 250 ^° C. (decomposition).

(c) 9,10-dihydro-4H-2 _t 5-dihydro-thieno [3,4-b] [1,5] benzodiazepin-10-one

0.5 g (0.002 mol) of methyl 3- (2-aminoanilino) -2,5-dihydrothiophene-4-carboxylate in 2 ml of dry DMSO

were added to a solution of a 50 Gew./Gew.-%igen suspension of sodium hydride in oil (300 mg) in dry DMSO at 90 ⁰ C under nitrogen. After the evolution of gas had ceased, the solution was stirred for 2 hours and poured onto 300 ml of ice / brine. The solution was then extracted into ethyl acetate, the extract was dried over magnesium sulfate, filtered and evaporated to low volume. Ether was added to the suspension and this was filtered. The filtrate was evaporated to dryness and triturated with chloroform, whereby the title compound was obtained in the form of a yellow solid, mp 210 ^° C. (decomposition).

Example 15

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

80 g (0.629 mol) of S-cyanotetrahydrothiophen ^ -one and 68 g (0.629) o-phenylenediamine were dissolved in 1.5 l of technical methylated spirit by refluxing and stirring, then 3 ml of acetic acid were added and the mixture was under Stir under reflux for 5 hours. 92 ml (1.08 mol) of concentrated hydrochloric acid were carefully added to the cooled solution with stirring. The solution was then heated for 1 hour under reflux, and to the cooled, stirred solution of the hydrochloride of a 10 Gew./Gew.-%igen sodium hydroxide solution was added dropwise 500 ml while the temperature was kept below 40 ⁰ C. The solution was then stirred for 1 hour, the solid was filtered off, washed with water, ethanol, acetone and ether and dried under vacuum. The dried product, which is to be the title compound had a melting point of 230 to 24O ⁰ C (decomposition).

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

43 g (0.198 mol) of 10-amino-4H-2,5-dihydrothieno [3,4-b] [1,5] benzodiazepine were under mechanical Stirring suspended in 1 l of boiling xylene. To this, 49 g of chloranil were added, whereby the suspension 2 until stirred at reflux temperature for 6 hours, then left overnight at room temperature ditched. The suspension was then filtered and the solid was washed with xylene until until the wash waters were colorless. It was dried on a filter funnel. The one obtained in this way black solid was suspended in 200 ml of hot water and 36 ml of 5N hydrochloric acid became added to form a red solution which was boiled for 10 minutes. The solution was then filtered and the tar that remained was mixed with a further 36 ml of 5 η HCl in 200 ml of water extracted and filtered again. The collected hot filtrates became an ice-cold solution of

14.4 g (0.36 mol) of sodium hydroxide zugetropi't in 100 ml of water at such a rate that the temperature was raised from 4O ⁰ C is not exceeded. The solution was stirred for 1 hour, filtered, the solid was washed with water and gretrocknet under vacuum at 50 ⁰ C. The title compound obtained in this way had a melting point of 190 ^° C. (decomposition).

Example 16

(a) 10-Amino-6-trifluoromethyl-4H-2,5-dihydrothieno [3,4-b] [1,5] benzodiazepine

10.5 g (0.0368 mol) 3- (2-amino-5-trifluoromethylanilino) -4-cyano-2,5-dihydrothiophene were dissolved in 100 ml of technical methylated spirit with heating and a solution of 3, 2 ml (0.0368 mol) of concentrated hydrochloric acid were carefully added. The resulting red solution was refluxed for 1 hour. To the cooled, stirred solution a solution of 1.6 g of sodium hydroxide in 10 ml water was added dropwise while the temperature was kept below 40 ⁰ C. The thereby resulting yellow amidine was filtered off, washed with water, ethanol and petroleum ether (bp. 40 to 60 ⁰ C) and then under vacuum at 50 ⁰ C. The filtrate was diluted with excess water and the resulting solid was filtered off and dried and combined with the other solid. The title compound obtained in this way had a melting point of 200 to 210 ^° C. (decomposition).

The following was produced in a corresponding manner:

Example 17
The product of Examples 16 (a) and 16 (b) was "flavored" to give

(a) 10-Amino-6-trifluoromethyl-4H-thieno [3,4-b] [l, 5] benzodiazepine, mp 178 ° C (decomposition) and

(b) 10-Amino-6-chloro-4H-thieno [3,4-b] [l, 5] benzodiazepine,

using the procedure described in Example 15 (b).

Example 18

(a) 9,10-Dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

The Natriummethylsulfinylcarbanion was prepared by stirring 7.2 g (0.15 mol) Natriunmhydrid in 100 ml of dry dimethyl sulfoxide at 70 ⁰ C until gas evolution ceased. 14.5 g (0.05 mol) of ethyl 2- (2-aminoanilino) -5-ethyl-thiophene-3-carboxylate in 50 ml of dry dimethyl sulfoxide were added and the mixture was stirred for 15 minutes. The mixture was poured onto 600 ml of ice water and stirred for 15 minutes. The solid formed was filtered off, washed well with water, dried, washed with carbon tetrachloride and dried ^{at 60 ° C. in vacuo.} The dried product, which is to be the title compound had a melting point 218-220 ⁰ C (CHCI _1).

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

The title compound, m.p. 210 to 212 ⁰ C, was similarly prepared from ethyl 2- (2-amino-4-fluoroanilino) -5-ethyl-thiophene-3-carboxylate. The title compound was recrystallized from ethanol.

Similarly, using the procedure of Example 18 (a), the following became Connections made. In each case the thiophene starting material, the melting point is the Title compound and recrystallization solvent given.

(c) 6,8-Difluoro-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one ethyl-2- (2-amino-3, 5-difluoroanilino) -5-ethyl-thiophene-3-carboxylate, mp 230 to 232 ° C (CHCl ₁ ).

(d) 9,10-Dihydro-2-ethyl-6-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine-10-or. Ethyl 2- (2-amino-5-fluoroanilino) -5-ethyl-thiophene-3-carboxylate, mp. 255 to 257 ° C (EtOAc).

(e) 7-ChIOr ^, 10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one Ethyl ^ - ^ - amino ^ -chloranilinoJ-S-ethyl-thiophene-O-carboxylate, m.p. 216 to 218 ° C (EtOAc).

(0 7-Amino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

Ethyl 2- (2,4-diaminoanilino) -5-ethyl-thiophene-3-carboxylate, F. 230 ⁰ C (dec.) (CHClj / MeOH).

(g) 9,10-Dihydro-2-ethyl-6-methyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

2- (2-Amino-5-methylanilino) -5-äihyl-thiophene-3-carboxylate, F. 205-207 ⁰ C (ÄtOAc).

(h) 9,10-Dihydro-7-N, N-dimethylsulfonamido-2-ethyl-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one methyl-2- (2-amino- 4-N, N, -dimethylsulfonamidoanilino) -5-ethyl-thiophene-3-carboxylate, F. 258-260 ⁰ C (ÄtOAc).

(i) 9,10-Dihydro-2-ethyl-7-nitro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one Ethyl 2- (2-amino-4-nitroanilino) -5-ethyl-thiophene-3-carboxylate, mp 264 to 266 ° C (EtOAc).

(J) 9,10-Dihydro-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

Ethyl 2- (2-amino-4-fluoroanilino) -thiophene-3-carboxylate, m.p. 235 to 240 ⁰ C (CCl ₄ / hexane).

(k) 9-Fluoro-6H-1,3,4,11,12-hexahydrobenzothieno [2,3-b] [1,5} benzodiazepin-12-one

Ethyl-2- (2-amino-4-fluoroanilino) -4,5,6,7-tetrahydrobenzo [b] thiophene-3-carboxylate, F. 238 ⁰ C (ÄtOAc).

(1) 9,10-Dihydro-2-ethyl-7-trifluoromethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one Ethyl 2- (2-amino-4-trifluoromethylanilino) -5-ethyl-thiophene-3-carboxylate.

(m) 9,10-Dihydro-2-ethyl-7-methoxy-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one Ethyl 2- (2-amino4-methoxyanilino) -5-ethyl-thiophene-3-carboxylate.

(n) 9,10-Dihydro-2-ethyl-7-methylthio-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one Ethyl 2- (2-amino-4-methylthioanilino) -5-ethyl-thiophene-3-carboxylate.

(o) 6,7-Difluoro-9,10-dihydro-2-äthyWH-thieno [2,3-b] [l, 5] benzodiazepin-10-one ethyl-5-ethyl-2- (4,5- difluoro-2-nitroanilino) thiophene-3-carboxylate, m.p. 290 ⁰ C.

(p) 9,10-Dihydro-7-fluoro-2-phenyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one F. 250 to 252 ° C (decomp.) (EtOAc).

(q) 9,10-Dihydro-7-fluoro-2-methyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one F. 250 to 252 ° C (EtOAc).

(r) 9,10-Dihydro-4H-thieno [3,2-b] [1,5] benzodiazepin-10-one

Methyl 3- (2-aminoanilino) thiophene-2-carboxylate, m.p. 226 ° C (CCl ₄ ).

(s) 9,10-Dihydro-7-fluoro-4H-thieno [3,2-b] [1,5] benzodiazepin-10-one

Methyl 3- (2-amino-4-fluoroanilino) thiophene-2-carboxylate, m.p. 225-230 ° C (AtOAc).

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

Methyl 3- (2-amino-4-chloroanilino) thiophene-2-carboxylate, m.p. 255 to 256 ° C (AtOAc).

(u) 9,10-Dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one m.p. 233-234 ° C.

(v) 9,10-Dihydro-7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one Mp 238 ° C (dec.).

(w) oJ-Dichlor ^ lO-dihydro ^ H-thienoP ^ -bHl ^ lbenzodiazepin-lO-one M.p. 284 to 287 ° C.

(x) 2-i-Propyl-7-fluoro-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one
(y) 2-n-Hexyl-7-fluoro-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one
(z) 1-Methyl-7-fluoro-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one
(aa) 1-Methyl-2-ethyl-7-fluoro-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one
(bb) 2-Ethyl-7-fluoro-9,10-dihydro-4H-thieno [3,2-b] [1,5] benzodiazepin-10-one

ίο

20th 25th

(cc) 2-Ethyl-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

5-Ethyl-2- (2-aminoanilino) -thiophene-3-carboxylic acid was dissolved in 200 ml of tetrahydrofuran (distilled from lithium aluminum hydride) and 5.7 g (0.027 mol) of solid dicyclohexylcarbodiimide were added. The mixture was stirred for 16 hours under a nitrogen atmosphere and the resulting solution was filtered and evaporated to dryness. The residue was boiled with carbon tetrachloride and allowed to crystallize to give the title compound, mp 218 to 22O ⁰ C (CHCl _3).

Example 19

(a) 7-Chloro-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one 4 g (0.15 moles) 10-amino-7-chloro-4H -thieno [3,4-b] [1,5] benzodiazepine was dissolved in a minimal amount of water (100 ml), then 13.0 g of potassium carbonate in 20 ml of water was added. 40 ml of absolute ethanol were then added to redissolve the amidine and the reaction mixture was heated under gentle reflux for 17 hours, the ethanol being slowly distilled off over the last hour. The reaction mixture was then allowed to cool and, in the presence of ethyl acetate, concentrated hydrochloric acid was added dropwise to the solution until the solution was weakly acidic. The aqueous phase was extracted with ethyl acetate, _{dried over MgSO 4} and the combined extracts were evaporated to dryness in vacuo to give the title compound as a light brown solid. The solid was triturated with ether, filtered and dried under vacuum at 5Q ⁰ C, to give a Geiben solid, mp 212-213 ° C.

Using the hydrolytic procedure of Example 19 (a), the following additional amides were obtained manufactured:

(b) 9,10-Dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, mp 234 ° C (dec.)

(c) 9,10-Dih.vdro-7-methylthio-4H-thieno [3,4-b] [1,5] -benzodiazepin-10-one

(d) 9,10-Dihydro-6-trifluoromethyl-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one, m.p. 213 ° C

(e) 9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno- [2,3-b] [1,5] benzodiazepin-10-one, mp 211 ° C
(0 9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

(g) 9,10-Dihydro-2-ethyl-7-methylthio-4H-thieno [2,3-b] tl, 5] benzodiazepin-10-one

(h) 9,10-Dihydro-2-ethyl-7-trifluoromethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

(i) 9-Fluoro-6H-1,3,4,11,12-hexahydrobenzothieno [2,3-b] [1,5] benzodiazepin-12-one

(j) 9,10-Dihydro-2-ethyl-6-trifluoromethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

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

23

50 55 60 65

Example 20
9,10-Dihydro-4H-thieiio [3,4-b] [1,5] benzodiazepin-10-one

0.33 g of 9,10-dihydro-4H-2,5-dihydrothieno [3,4-b] [l, 5] benzodiazepin-10-one were taken at the reboots temperature in the presence of 0.1 g of a catalyst composed of 5% palladium on activated carbon in cyclohexene (norbornadiene or Norbornylene), then TLC measurements were carried out. The reaction mixture was then cooled, the solvent was evaporated in vacuo leaving a dark brown solid, using a "Florisil" column and using 5% methanol in chloroform was subjected to column chromatography to give the title compound as a pale yellow solid was obtained, mp 230-232 ° C.

Example 21
• 5 7-N-Acylamino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one

100 mg of 7-amino-9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one were suspended in 5 ml of methylene chloride and 0.1 ml of triethylamine. 10.1 ml of acetic anhydride were added and the reaction mixture was stirred for 18 hours. The precipitate formed was filtered, washed with water, dried in vacuo at 6O ⁰ C to give the title compound as a solid, mp 264 ⁰ C.

Example 22
3-Chloro-9,10-dihydro-4H-thieno [3,4-b] [1,5] benzodiazepin-10-one

4.32 g (0.02 mol) of 4H-thione [3,4-b] [l, 5] benzodiazepin-10-one in hot dichloromethane were stirred with 3.0 g (0.025 mol) of N-chlorosuccinimide in the presence a trace of benzoyl peroxide implemented. After refluxing for 1 hour, the hot solution was filtered. The blue residue formed was washed with 3 portions of hot ethyl acetate, the wash waters and dichloromethane filtrate were combined and evaporated to give a brown solid. After Soxhlet extraction with benzene and subsequent washing with a K ₂ CO _r solution, drying and evaporation, the title compound was obtained in the form of a yellow solid, mp 229 ° C.

Example 23

l-acetyl-9,10-dihydro-2-ethyl-7-fluoro-4H-thienof2,3-b] [l, 5] benzodiazepin-10-one

To a stirred solution of 0.26 g (0.001 mol) of 9,10-dihydro-2-ethyl-7-fluoro-thieno [2,3-b] [1,5] benzodiazepine in 3 ml of acetyl chloride were added 2 drops with stirring Tin dichloride added. The reaction mixture was diluted with 5 ml of benzene and stirred for 18 hours at room temperature. The reaction mixture was then diluted with water and extracted into chloroform, the chloroform extracts were washed with water, _{dried over MgSO 4} and evaporated in vacuo to give the title compound as a solid, mp 215-218 ° C (MeOH / hexane) .

Example 24

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

20 g (0.076 mol) of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one became a stirred solution of 17 g (0.076 mol) of phosphorus pentasulfide in 400 ml of dry pyridine was added. the

Solution was stirred under gentle reflux for 1.5 hours, poured onto ice water, stirred for 1 hour, filtered, washed with cold water and dried. After recrystallization from EtOH / water, the title compound was obtained in the form of bronze-colored plates, m.p. 203-206 ⁰ C.

(b) 9,10-dihydro-2-ethy! -4H-thieno [2,3-b] [1,5] benzodiazepine-10-thione

The title compound was prepared analogously using the procedure of Example 24 (a) and using 9,10-dihydro-2-ethyI4H-thieno [2.3-b] [1,5] benzodiazepin-10-one as starting material, F. 233 to 236 ° C (EtOH / H ₂ O).

In a corresponding way were produced:

(c) 9,10-Dihydro-2-ethyl-7-nitro-4H-thieno [2,3-b] [1,5] benzodiazepine-10-thione

(d) 9,10-Dihydro-4H-thieno [3,4-b] [1,5] benzodiazepine-10-thione, m.p. 221 ° C.

Other amides of Example 18 were prepared similarly using the procedure of Example 24 (a) converted to their thioamide derivatives. In each case the identification and confirmation took place of the end product using TLC and microanalytical evidence.

C) Preparation of the pharmacologically active compounds according to the invention:

Example 25

(a) 2-Ethyl-6-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] ben2odiazepine

0.5 g of 9,10-dihydro-2-ethyl-6-fluoro-4H-thieno [2,3-b] [l, 5] ben2odiazepin-10-one, 4 ml of phosphorus oxychloride « and 0.15 ml of Ν, Ν-diraethylaniline were refluxed for 3 hours. The reaction mixture

was evaporated in vacuo and the residue was evaporated a further two times with xylene.

The crude iminochloride obtained in this way was dissolved in 1 ml of absolute dioxane and 3 ml of N-methyl-Jl

piperazine added. The reaction mixture was refluxed for 4 hours and then in 10 U:

Evaporated to dryness in vacuo. The residue was partitioned between aqueous ammonia and ether

divides and the ether phase was extracted with 1 η HCl. By adding 0.88 ammonia, the Pro-S

product precipitated, extracted into ether, washed with water, _{dried over MgSO 4} and evaporated in vacuo, mp 175 to 177 ° C. (EtOAc / hexane).

The following was produced in a corresponding manner:
(b) 2-Äthy! -7-fluoro-10- {l-piperazinyl) -4H-thieno [2,3-b] [l, 5] benzodiazepine, m.p. 138 to 140 ⁰ C (CCyHexan).

Example 26

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

2.4 g (0.01 mol) of 9,10-dihydro-2-ethyl-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one were suspended in 10 ml of N-methylpiperazine. 1.2 ml (0.011 mol) of titanium tetrachloride in 5 ml of dry anisole were added and the mixture was stirred and ^{heated to 120 °} C. for 2 hours. The reaction mixture was poured onto ice water and shaken until an off-white precipitate formed. The suspension was extracted with methylene chloride until no further yellow color was removed. The combined extracts were washed with water, _{dried over MgSO 4} and evaporated in vacuo to give the title compound as a yellow solid. This solid was triturated with ether, filtered and recrystallized from hexane, mp 195-197 ⁰ C. The free base was then converted to its maleate salt, mp 186-188 ° C (ethanol / ether).

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

The title compound, m.p. 161-163 ° C (hexanes), was prepared using a similar procedure as in Example 26 (a) from 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

Analysis for C, ₈ H ₂ iFN ₄ S:

calc .: C 62.76 H 6.14 N 16.26 F 5.51 S 9.30%;
Found: C 62.99 H 5.87 N 16.06 F 5.67 S 9.32%.

40 The free base was transferred into its maleate salt, m.p. 125 to 127 ⁰ C (ethanol / ether).

Analysis for C ₂₂ H ₂₅ FN ₄ O ₄ S:

calc .: C57.37 H 5.47 N 12.16 F4.12 S 6.96%;
Found: C 57.53 H 5.54 N 11.99 F 4.16 S 6.93%.

Similarly, using the procedure of Example 26 (a), the following were made Benzodiazepines manufactured. The material given under the title is the amide intermediate, the melting point given is that of the title compound and the recrystallization solvent is given in brackets.

(c) 2-Ethy 1-6-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 9,10-dihydro-2-ethyl- 6-fluoro-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one, m.p. 206 to 208 ⁰ C (hexane); Maleate Salt, F, 125-127 ° C (EtOH / Et ₂ O).

(d) 6,8-Difluoro-2-ethyl-10- (4-methyl -'-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 6,8-dinuor-9.10 dihydro-2-ethyl-4H-thieno [2,3-b] tl, 5] benzodiazepin-10-one, m.p. 243-246 ⁰ C _(CCl4 / hexane); Maleate salt, m.p. 122 to 124 ° C (EtOH / Et ₂ O).

(e) 7-Chloro-2-ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 7-chloro-9,10-dihydro-2 -äthyl-4H-thieno [2,3-b] [l, 5] benzodiazepin-10-one, m.p. 235 to 240 ⁰ C; Maleate salt,

M.p. 119 to 121 ° C (EtOH / Et ₂ O).

(0 2-Ethyl-6-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine The title compound was prepared in a similar manner using 9 , 10-Dihydro-2-ethyl-6-methyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one, mp 177-179 ° C (CH _: C1 ₂ / hexane).

(g) 7-N, N-dimethylsulfonamido-2-ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] tl, 5] benzodiazepine 9,10-Dihydro-7-N, N-dimethyIsulfonainido-2-ethyl-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one, F. 225 bis 227 ° C (EtOAc / Hexane).

(h) 7-Fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 9,10-dihydro-7-fluo: 4H-thieno [2 , 3-b] [l, 5] benzodiazepin-10-one, m.p. 228 to 230 ^° C (CH ₂ Cl ₂ / hexane).

(i) 9-Fluoro-12- {4-methyl-1-piperazinyl) -6H-1,2,3,4-tetrahydrobenzothieno [2,3-B] [1,5] benzodiazepine 9-fluoro-6H-1 , 2,3,4,11,12-hexahydrobenzothieno [2,3-b] [1,5] benzodiazepin-12-one, mp 196-199 ° C (CH ₂ Cl ₂ / hexane).

Q) 7-Fluoro-2-methyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 7-fluoro-2-methyl-9,10- dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one, m.p. 160-165 ° C (dec.) (EtOAc / hexane).

(k) 7-Fluoro-2-phenyl-10- {4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine dihydrochloride The free base of the chloride given above was prepared using 7-fluoro-2-methyl-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one. This was then converted to the dihydrochloride, mp 235-240 ⁰ C (dec.) (MeOH / hexane).

(1) 7-Trifluoromethyl-2-ethyl-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 7-trifluoromethyl 1-2-ethy 1-9,10-dihydro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one.

(m) 10- (4-Methyl-l-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine 9,10-dihydro-4H-thieno [3,2-b] [l, 5] benzodiazepin-10-one, m.p. 202 to 206 ⁰ C (CCl ₄ ).

(n) 7-Fluoi-10- (4-methyl-1-piperazinyl) 4H-thieno [3,2-b] [1,5] benzodiazepine 7-fluoro-9,10-dihydro4H-thieno [3,2- b] [l, 5] benzodiazepin-10-one, F. 206 to 208 ⁰ 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] [1,5] benzodiazepin-10-one, m.p. 225-226 ° C (CHCl ₃ ).

(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] tl, 5] benzodiazepin-10-one, m.p. 169 to 170 ^° C. 35

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

(r) 10- (4-Methyl-1-piperazinyl) -7-trifluoromethyl-4H-thieno [3,4-b] [1,5] benzodiazepine 6-trinuomethyl-9,10-dihydro-4H-thieno [3 , 4-b] [l, 5] benzodiazepin-10-one, mp 202 ⁰ C (CCl "/ petroleum ether, bp. 40 to 60 ⁰ Cg

(s) S-chloro-lO - ^ - methyl-l-piperazinylMH-thienoss ^ -bJtl ^ benzodiazepine 3-Chloro-9,10-dihydro4H-thieno [3,4-b] [1,5] benzodiazepin-10-one.

(t) 10- (4-Methyl-l-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine F. 200 to 201 ⁰ C.

(u) 7-Fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine F. 190.5 to 191.5 ° C.

(v) oJ-dichloro-lO - ^ - methyl-l-piperazinyl ^ H-thienoP ^ -bin ^ jbenzodiazepine F. 200 to 202 ⁰ C.

(w) 2-i-Propyl-7-fluoror-10- (4-methyl-1-piperazinyI) -lH-thienot2,3-b] [1,5] benzodiazepine

(x) 2-n-Hexyl-7-fluoro-10- (4-methyl-1-piperazinyl) 4H-thieno [2,3-b] [1,5] benzodiazepine (y) 1-Methyl-7-Nuoro-10- (4-Methy 1-1 -piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine (z) 1-Methyl-2-ethyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [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 mp 172 ° C (CCl ₄ / hexane ).

(bb) 7-Fluoro-10- (4-methyl-1-piperazinyl) -l-ethyl4H-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.

26th

Example 27

The procedures of Example 26 were repeated using those following the procedure of Example 24 produced thioamides instead of the amides, the benzodiazepines given in Example 26 (a) to (cc) were obtained.

Example 28
10- (4-Methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepines

10 G4H-2,5-dihydrothieno [3,4-b] [l, 5] benzodiazepin-10-one in 5 ml of dry anisole were heated with stirring in the presence of 0.04 ml TitantetracfUorid and N-methylpiperazine to 120 ⁰ C. . After 1.5 hours the reaction mixture was quenched, shaken with ethyl acetate, the latter was drawn off and evaporated to dryness at −0 ° C. under reduced pressure. The solid was subjected to column chromatography using a "Florisil" column and using 5% methanol in chloroform. After evaporation to dryness, the collected fractions gave the title compound in the form of a yellow solid, mp 200 to 201 ^° C.

Example 29

20 10- (4-Methyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine

2.17 g of 10-amino-4H-2,5-dihydro-thieno [3,4-b] [l, 5] benzodiazepine in anisole and 10 ml of N-methylpiperazine were stirred at room temperature in a 100 ml round bottom flask. The complex formed from 2.6 ml of titanium tetrachloride in 15 ml of anisole was slowly added to the stirred mixture. After completion of the addition, the reaction mixture was stirred under nitrogen and heated to 12O ⁰ C. TLC analysis was then performed which indicated the formation of the flavored starting material prior to condensation with the N-methylpiperazine. The mixture was ^{heated to 120 °} C. overnight, cooled and poured into water. The aqueous mixture was made basic with a dilute sodium hydroxide solution and shaken with chloroform. The organic extract was washed with water, dried and evaporated in vacuo to an oil. After column chromatography of the oil on a silica column with 5% methanol in chloroform, fractions containing the title compound were obtained.

35 Example 30

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

215 mg of 10-amino-4H-thieno [3,4-b] [l, 5] benzodiazepine in 1 ml of anisole were treated with 2.5 ml of N-methylpiperazine at room temperature under nitrogen. 0.12 ml of titanium tetrachloride in 1 ml of anisole were added to the stirred mixture at room temperature. The mixture was ^{heated to 110 °} C. under nitrogen and stirred overnight. The resulting mixture was cooled, poured into water, made basic with a dilute sodium hydroxide solution, and shaken with chloroform. The organic solvent was extracted, washed with water, dried and evaporated in vacuo to an oil. The desired product was isolated by column chromatography using a silica column with 5% methanol in chloroform to give the title compound as a pale yellow solid, mp 200-201 ⁰ C.

In a corresponding manner, the benzodiazepines given in Example 26 (a) to (cc) were obtained from the corresponding 10-amino derivatives, although in many cases the yields were very low.

Example 31

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

A suspension of 2.6 g (0.01 mol) of 9,10-dihydro-2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepin-10-one in a mixture from 5 ml of anisole, 10 ml of toluene and 9.6 g (0.06 mol) of ethyl N-piperazinocarboxylate was treated with a solution of 1.2 ml (0.011 mol) of titanium tetrachloride in 5 ml of dry anisole and 10 ml of toluene. The mixture was refluxed for 3 hours and poured into 200 ml of ice water. The aqueous material was extracted with methylene chloride, washed with water, dried over MgSO ₄ and evaporated to give a resin (5 g). After trituration with ether, the title compound was obtained in the form of a yellow solid, mp 168 to 171 ° C. (CH ₂ Cl ₂ / hexane); Maleate salt, m.p. 149 to 151 ° C (EtOH / Et ₂ O).

In a corresponding way were produced:

(b) 10- (4-Carboethoxy-1-piperazinyl) -2-ethyl-4H-thienot2,3-b] [1,5] benzodiazepine F. 169 ⁰ C (CH ₂ Cl, / CCl ₄ / n-hexane ).

(c) lO - ^ - Caxboäthoxy-l-piperazinylH-chloro ^ -äthyMH-tWenoP ^ -bHl ^ lbenzodiazepine F. 155 to 158 ° C (EtOAc / Hexane).

The title compound was prepared in a similar manner using 7-chloro-9,10-dihydro-2-ethyWH-thieno [2,3-b] [1,5] benzodiazepin-10-one, mp 155-158 ° C (EtOAc / Hexane). 5

(d) 10- (4-Carboethoxy-1-piperazinyl) -2-ethyl-6-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine M.p. 176 to 178 ° C (EtOAc / Hexane).

(e) lO ^ -Carboethoxy-1-piperazinylMH-thienoP ^ -bjfl.Slbenzodiazepine mp 166 ° C (CHCl ₃ ).

(0 10- (4-Carboethoxy-1-piperazinyl) -7-fluoro-4H-thieno [3,2-b] [1,5] benzodiazepine M.p. 162 to 164 ° C (EtOAc).

(g) lO - ^ - Carboethoxy-l-piperazinylMH-thienoss ^ -bP ^ lbenzodiazepine F. 186 to 187 ⁰ C.

(h) 10- (4-Carboethoxy-1-piperazinyl) -7-fluoro-4H-thieno [3,4-b] [1,5] benzodiazepine 197 to 199 ° C.

(i) lO ^ -Carboxyäthyl-l-piperazinyD-öJ-dichloMH-thienoP ^ -bJil ^ Jbenzodiazepine F. 213 to 214 ⁰ C.

(j) lO - ^ - Carboxyethyl-l-piperazinylH-chloMH-thienoss ^ -bHl.Slbenzodiazepine M.p. 195 to 196 ° C.

example

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

1.0 g of 10 <4 ^ arboethoxy-1-piperazinyl) -2-ethyl-7-fluoro-4H- [2,3-b] [1,5-benzodiazepine and 6.0 g of potassium hydroxide pellets in 50 ml of 96% strength Ethaiiol was refluxed for 16 hours. The resulting suspension was evaporated to dryness and partitioned between water and chloroform. The chloroform layer was washed with water, dried and evaporated over MgSO ₄ to give the title compound as a yellow solid, m.p. 138 to 140 ⁰ C _(CCl4 / hexane).

In a similar manner, the following benzodiazepines were made:

(b) 2-Ethyl-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine F. 170 to 171 ° C (EtOAc / Hexane).

(c) 7-Chloro-2-ethyl-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine M.p. 167-169 ° C.

(d) 10- (l-piperazinyl) -4H-thieno [3,2-b] [l, 5] benzodiazepine F. 203-206 ⁰ C (ÄtOAc).

(e) 7-Fluoro-10- (l-piperazinyl) -4H-thieno [3,2-b] [l, 5] benzodiazepine F. 165 to 167 ⁰ C (CCl _4).

(0 10- (1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine M.p. 233 to 235 ° C.

(g) 7-Fluoro-10- (l-piperazinyl) -4H-thieno [3,4-b] [l, 5] benzodiazepine F. 192-193 ⁰ C.

(h) oJ-dichloro-lO-d-piperazinylMH-thienoP ^ -bHl ^ jbenzodiazepine F. 213 to 214 ⁰ C.

(i) 7-ChIoMO- (I-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine M.p. 178 to 179 ° C.

example

(a) 10- (4-p-Chlorobenzyl-1-piperazinyl; -2-ethyl-7-fluoro-4H * hieno [2,3-b] [1,5] benzodiazepine 1.0 g (0.003 mol) of 2-ethyl-7-fluoro-10- (1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine, 0.38 ml (0.0033 mol) of p-chlorobenzyl chloride and 1.0 ml of triethylamine were refluxed for 16 hours in 25 ml of 90% ethanol heated. The reaction mixture was evaporated to dryness and between Water and methylene chloride distributed. The organic extracts were washed over with water

28

_{MgSO 4} dried and evaporated in vacuo, whereby the title compound was ^{obtained in the form of a solid, mp 166 to 168 °} C. (after recrystallization from CH ₂ Cl ₂ / hexane).

The following connections were made in a corresponding manner:

(b) 10- (4-benzyl-l-piperazinyl) -2-ethyl-4H-thieno [2,3-b] [l, 5] benzodiazepine F. 79-80 ⁰ C.

However, benzyl bromide was used as the alkylating agent in this reaction.

(c) 10- (4'-Benzyl-1'-piperazinyl) -4H-thieno [3,2-b] [1,5] benzodiazepine
F. 198 to 200 ⁰ C (EtOAc).

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

F. 180 to 182 ⁰ C (CHCI.,). 15th

(e) 10- (4-Benzyl-1-piperazinyl) -4H-thieno [3,4-b] [1,5] benzodiazepine
M.p. 221 to 222.5 ° C.

(0 2-Ethyl-7-fluoro-10- (4-cyclopropyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine 20

Example 34

(a) 2-Ethyl-7-fluoro-10- [4- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine 25 1.65 g (0.005 Mol) 2-ethyl-7-fluor-10- (l-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine and 1.25 g (0.01 mol) ethylene bromohydrin in 150 ml of 90% ethanol and 2.02 g (0.02 mol) of triethylamine were refluxed for 16 hours in a nitrogen atmosphere. The reaction mixture was evaporated to dryness, partitioned between water and methylene chloride, the methylene chloride extract was washed with water, _{dried over MgSO 4} and evaporated to dryness to give the title compound as a solid, mp 173-175 ° C ( CH ₂ C1 ₂ / hexane).

In a corresponding way were produced:

(b) 7-Fluoro-10- [4- (2-hydroxyethyl) -1-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine 35 F. 205 to 210 ⁰ C (CHCI, ).

(c) 2-Ethyl-7-fluoro-10- [4- (3-hydroxypropyl) -1 -piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine m.p. 145-148 ° C (CH ₂ CI _: / hexane).

(d) 2-ethyl-10- [4- (2-hydroxyüthyl) -l-piperazinyl] -4H-thieno [2,3-b] [l, 5] benzodiazepine F. 175-176 ⁰ C (ÄtOAc / hexane ).

(e) 10- [4- (3-Hydroxypropyl) -1-piperazinyI] -4H-thieno [3,2-b] [1,5] benzodiazepine

F. 172 to 173 ⁰ C (EtOAc / hexane). 45

(f) 7-Fluoro-10- [4 '- (3-hydroxypropyl) -l' piperazinyl] -4H-thieno [3,2-b] [l, 5] benzodiazepine F. 138 to 140 ⁰ C (CHCl ,).

(g) 10- [4- (3-Hydroxypropyl) -1-piperazinyl] -4H-thieno [3,4-b] [1,5] benzodiazepine 50 M.p. 184 ° C.

Example 35

(a) 2-Ethyl-7-fluoro-10- [3-N (4-methyl-1-piperazinyl) propylamino] -4H-thieno [2,3-b] [1,5] benzodiazepine 55 2 g (0 , 0072 mol) 9,10-dihydro-2-ethyI-7-fluoro-4H-thieno [2,3-'n] [1,5] benzodiazepine-10-thione, 1.3 ml 1- (3-aminopropyl ) -4-phenylpiperazine, 8 ml of triethylamine and 10 ml of dry methylformamide were heated to 65 ° C under nitrogen until the reaction had ended, which was determined by TLC (At ₂ O)

(20 hours). The mixture was poured onto a molar excess of maleic acid solution, washed twice with ether and made basic with 0.88 ammonia solution and extracted with ethyl acetate. The combined extracts were washed with water, _{dried over MgSO 4} and the solvent was evaporated to give the title compound as a semi-solid yellow product which was recrystallized from ethyl acetate / n-hexane, mp 181 ° C.

In a similar manner the following compounds were made: 65

(b) IO- (3-N, N-dimethylaminopropylamino) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine dimaleate M.p. 193 to 195 ° C (isopropanol / n-hexane).

(c) 2-Ethyl-7-fluoro-10- (3-N-morpholinopropylamino) -4H-thieno [2,3-b] [1,5] benzodiazepine dimaleate M.p. 182 to 186 ° C (isopropanol / n-hexane).

(d) 2-Ethyl-7-fluor-10- (2-hydroxyethylamino) -4H-thieno [2,3-b] [l, 5] benzodiazepine maleate F. 196 to 198 ⁰ C (ethanol / ethyl acetate / n -Hexane).

(e) 10- (2-N, N-dimethylaminoethylamino) -2-ethyl-7-fluoro-4H-thieno [2,3-b] [1,5] benzodiazepine maleate M.p. 183 to 184 ° C (ethanol / ethyl acetate / n-hexane).

ίο (0 2-Ethyl-7-fluoro-10- (3-hydroxypropylarnino) -4H-thieno [2,3-b] [1,5] benzodiazepine maleate Mp 174 ° C to 175 ° C (ethanol / ethyl acetate / n-hexane).

(g) 2-Ethyl-7-fluoro-10- (2-N-piperidinoethylamino) -4H-thieno [2,3-b] [1,5] benzodiazepine sesquifumarate M.p. 184 to 185 ° C (ethanol / ethyl acetate / n-hexane).

..

(h) 2-ethyl-7-fluoro-10- (2-N-morpholinoäthylamino) -4H-thieno [2,3-b] [l, 5] benzodiazepin-rumarat F. 189-203 ⁰ C (ethanol / ethyl acetate / n-hexane).

(i) 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).

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

Example 37

Using the following components, tablets were produced, each containing! 0 mg of active ingredient (active ingredient) contained:

Active ingredient 10 mg

Potato starch 45 mg

Lactose 35 mg

Polyvinylpyrrolidone 4 mg
(in the form of a 10% solution in water)

Sodium Starch Glycolate 4.5 mg

30th

M.p. 154-156 ° C (CH _: C1 ₂ / hexane).

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

F. (Di-HCl-Salt) 265 to 270 ⁰ C (EtOH / Et ₂ O). I.

(1) 10- [4- (m-Chlorophenyl) -l-piperazinyl] -2-ethyl-7-fluoro-4H-thieno [2,3-b] [l, 5] benzodiazepine hydrochloride ^r -

F. (HCl salt) 250 to 260 ⁰ C. ί |

_ A

(m) 2-Ethyl-7-fluoro-10- [4- (m-trifluoromethylphenyl) -1-piperazinyl] -4H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride
F. (HCl salt) 184-187 ° C.

(n) 10- (2-N-piperidinoethylamino) -4H-thieno [3,4-b] [1,5] benzodiazepine
F. 182 to 183 ⁰ C.

B e i s ρ i e1 36;

(a) lO - ^ - iS-DecanoyloxypropyO-l-piperazinylJ ^ H-thienoP ^ -bJIl ^ benzodiazepine hydrochloride To a solution of 1.71 g (0.005 mol) of 10- [4- (3-hydroxypropyl) -1-piperazinyl] -4H-thieno [3,2-b] [1,5] benzodiazepine in 40 ml of dry benzene were 1.42 g (0.0075 mol) of decanoyl chloride in 10 ml of benzene Stirring was added dropwise and the solution was heated to 75 ° C until the reaction had ended, which was through TLC was detected. The reaction mixture after washing gave the title compound.

Similarly, using the procedure of Example 36 (a), other hydroxyalkyl derivatives were prepared of Example 34 esterified to give the corresponding decanoate and enanthate esters.

The following examples explain pharmaceutical preparations (formulations) which contain the active compounds according to the invention. The active ingredient used was 2-ethyl-7-fluoro-10- (4-methyl-1-piperazinyl) -4H-thieno [2,3-b] [1,5] benzodiazepine it should be noted however _tl that this compound according to the invention can of course be replaced by other active solid compounds of the invention ^.

"<R

D) formulation examples τ

'if magnesium stearate 0.5 mg

f; Talc 1 mg

; i 100 mg total

i; The active ingredient, the starch and the lactose were passed through a sieve with a mesh size of

;,: 0.353 mm (BSS No. 44) passed and mixed thoroughly. The polyvinylpyrrolidone solution was with

mixed with the powders obtained, which were then passed through a sieve with a mesh size of 1.405 mm (BSS No. 12). The granules thus formed were dried and happened to 60 ⁰ C at 50 through a sieve with a mesh width of 1.003 mm (BBS no. 16). The sodium starch glycolate, magnesium stearate and talc, previously passed through a 0.251 mm mesh sieve (BSS No. 60), were then added to the granules which, after mixing in a tablet maker, were compressed to form Tablets weighing 100 mg each.

Example 38

Using the following ingredients, capsules were produced, each containing 20 mg of active ingredient:

20th

Active ingredient 20 mg strength 89 mg Lactose 89 mg Magnesium stearate 2 mg All in all 200 mg

25th

The active ingredient, the lactose, the starch and the magnesium stearate were passed through a sieve with a clear Mesh size of 0.353 mm (BSS No. 44) and in quantities of 200 mg each in hard gelatin capsules filled.

Example 39

Using the following ingredients, suppositories were prepared, each containing 25 mg of active ingredient contained:

Active ingredient. 25 mg

Saturated fatty acid glycerides ad 2000 mg

The active ingredient was passed through a sieve with a mesh size of 0.251 mm (BSS No. 60) and put into saturated fatty acid glycerides suspended beforehand using the required minimum amount of heat had been melted. The mixture was then put into a suppository mold with a nominal Poured capacity of 2 g and allowed to cool.

Example 40

Suspensions were prepared from the following ingredients, each containing 5 mg of active ingredient per 5 ml dose contained:

Active ingredient 5 mg

Sodium carboxymethyl cellulose 50 50 mg

Syrup 1.25 ml

Benzoic acid solution 0.10 ml

Flavor Sufficient Amount (q. S.)

Sufficient amount of dye (q. S.)

Chloroform / water ad 5 ml

The active ingredient was passed through a sieve with a mesh size of 0.353 mm (BSS No. 44) and mixed with the sodium carboxymethyl cellulose 50 and syrup to form a smooth paste. The benzoic acid solution, the flavor and color were diluted with a portion of the chloroform water and added with constant stirring. Then it became the one required for the desired volume Amount of chloroform-water added.

65

Claims (4)

Patent claims: 1. Thieno [l, 5] benzodiazepines of the general formula
R ⁵ where mean: R ¹ and R ² are each independently hydrogen, CI_ ₄ alkyl, C ₂ -4 alkenyl, C ₃ - ₆ cycloalkyl, halogen, Ci-4 haloalkyl, nitro, amino, C ₂ _ ₄ acylamino, hydroxyl, C ^ ₄ -alkoxy, C, - 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 (A) is a group of the formula - NN —R ⁶ (Ib) wherein R ^{6 is} hydrogen, phenyl optionally substituted by halogen or Q _ ₄ -haloalkyl, Ci- ₄ -AlkyI, Cs-d-cycloalkyl, C ₂ _ ₄ alkenyl, Ci- ₄ alkanoyl, benzyl, C | _ ₄ carbalkoxy or - (CH ₂₎ "OX, wherein η is the number 2 or 3 and X represent hydrogen or an ester radical, or
(B) a group of the formula —NH- (ch ₂ ) "- z ac) where η is the number 2 or 3 and Z is a radical of the formula (i) —NN —R ⁶ (Ib) wherein R ^{6 has} the meanings given above, (ii) ~ ^N s_ ^ ^(Id) (iii) -NO (Ie) ^{N /} R " (iv) - N (IO \ R '" wherein R "and R '" are each independently hydrogen or C | - ₄ alkyl, or (ν) OH; and the group T> (Ia) a thiophene ring fused to the diazepine ring, is unsubstituted or substituted by one or two radicals from the group Q _ ₈ alkyl, C ₂ -4 alkenyl, C ₁ -4 haloalkyl, C ₂ -4 kanoyl Al, nitro, halogen and optionally substituted phenyl can be substituted, and can be _{fused to a C, - 8} cycloalkyl ring, as well as their acid addition salts. 2. Thieno [l, 5] benzodiazepines of the general formula (IO according to claim 1 wherein R ¹ and R ^2, independently of one another, are each hydrogen, halogen or Cj- ₄ haloalkyl and Y is a group of the formula - N NR ⁶ (Ib) is where R ^{6 is} methyl. 3. A compound according to claim 2, characterized in that the thiophene ring is replaced by a Q-4-alkyl group is substituted 4. A process for the preparation of a thieno [l, 5] benzodiazepine of the general formula (Γ) according to claim 1, and an acid addition salt thereof, characterized in that one