DD296491A5 - NEW HETRAZEPINE WITH PAF ANTAGONISTIC EFFECT, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT - Google Patents

Abstract

The invention relates to hetrazepinoids PAF antagonists with unusual substitution pattern, process for their preparation and their use as medicaments. According to the invention new * are claimed, having the following general formula, wherein the radicals R1 to R5, X and Y are as defined in the description. The new compounds differ from the prior art in particular in that the substituent R4 has a longer-chained radical instead of an ortho-chlorophenyl radical. Formula {new * PAF antagonist; Drug; Treatment of bronchial asthma; acute and chronic bronchitis}

Description

10. Analogy process for the preparation of compounds of the general formula I which have an acid amide in the side chain GR _a or lR _b , characterized in that a compound of the general formula I in which R ₈ or R _{b is} the radical COOH, with an amine of the formula HNR ₁₁ R ₁₂ or HNR ₁₃ R ₁₄ in the presence of sulfonyldiimidazole or carbonyldiimidazole.

The present invention relates to novel diazepines. Process for their preparation and their use as medicaments with PAF-antagonistic action.

In recent years-especially since 1984-numerous compounds have been synthesized called PAF antagonists. The term PAF antagonist has now been described and defined in detail in the literature.

A class of substances called thienodiazepines of general formula I

proved to be particularly effective compounds. Despite multiple subscriptional patterns and diverse functional groups, almost all known PAF antagonists of the structural type mentioned have a phenyl group or an ortho-chlorophenyl group in the 4- or 6-position (R ₄ ) of the central 1,4-diazepine ring.

Both the unsubstituted phenyl ring and the previously known differently substituted phenyls - such as methyl- or methoxy-substituted - have a lower potency.

Surprisingly, a structural element has now been found which - as substituent R ₄ in the 4- or 6-position of a PAF antagonist with a centrally arranged 1,4-diazepine decisively improves the potency of the PAF antagonist.

The new substituent R ₄ corresponds to the general formula

S is a single bond, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy, branched or unbranched alkenyl having 2 to 8 carbon atoms, preferably having 2 to 4 carbon atoms, optionally Halogen and / or hydroxy substituted, branched or unbranched alkynyl having 2 to 8 carbon atoms - preferably having 2 to 4 carbon atoms, if necessary substituted by halogen and / or hydroxy;

W is an optionally substituted aromatic ring having 6 to 10 carbon atoms, which may optionally contain one or more heteroatoms selected from the group nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring having 3 to 7 carbon atoms, which may also contain a double bond;

T is branched or unbranched alkyl optionally substituted by halogen or hydroxy with 1 to 8 preferred

1 to 4 carbon atom (s); branched or unbranched alkenyl of 2 to 8 carbon atoms-preferred

2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy; branched or unbranched alkynyl having 2 to 8 carbon atoms-preferably 2 to 4 carbon atoms-optionally substituted by halogen and / or hydroxy; a remainder of the formula

0 ti ii

E = O, S, N-R, C = O, C-O, C-N, N-C

6 I

C = O, O 0 Il Il NR ₆ , C-O, C-N I

wherein R, as defined above, preferably hydrogen, C ₁ - C-alkyl, or

O O

Il

CC ₁ - C, -alkyl or CH,

and R ₁ as defined above, preferably hydrogen or C, -C -alkyl;

0 0 0

I / it ii

S, S, S-NRg, wherein R ₀ is as defined above,

Ö 0 Fine branched or unbranched optionally substituted alkyl group having 1 to 8 preferred

1 to 4 carbon atom (s), an optionally substituted alkenyl group having 2 to 8 preferred

2 to 4 carbon atoms, an optionally substituted alkynyl group having 2 to 8, preferably 2 to 4, carbon atoms;

V is an optionally substituted aromatic ring of 6 to 10 carbon atoms which may optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring of 3 to 7 carbon atoms, which may also contain a double bond, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom such as ζ. Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s);

U is branched or unbranched alkyl optionally substituted by halogen or hydroxy having from 1 to 8 preferably to 4 carbon atom (s); branched or unbranched alkenyl having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy, branched or unbranched alkynyl having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy, a radical the formula

-i - ti - (γ) _λ , -

OO

fi ι π

E = O, S / N-R, C = O, C-O, C-N, N-C

⁵

wherein E, as defined above, is preferred

Hydrogen, C 1 -C 4 alkyl, or

O O

π κ

CC ^ - C _c -alkyl or CH, 1 b

and R ₁₁ as defined above, preferably hydrogen or C 1 -C 4 -alkyl;

O O O

Il Il Il

S, S, S-NR _n , where R _{n is} as previously defined,

0 o

F is a branched or unbranched optionally substituted alkyl group having 1 to 8 preferred

1 to 4 - carbon atom (s), an optionally substituted alkenyl group of 2 to 8 - preferred

2 to 4 carbon atoms, an optionally substituted alkynyl group having 2 to 8, preferably 2 to 4, carbon atoms;

an optionally substituted aromatic ring of 6 to 10 carbon atoms, which may optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring of 3 to 7 carbon atoms, which may also contain a double bond, wherein W, V and / or P may be mono- or polysubstituted by Z, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom, e.g. B, nitrogen, oxygen or sulfur - may be replaced and may be optionally fused by one or more aryl radical (s);

Hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, optionally substituted by halogen or hydroxy, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atom (s), optionally substituted branched alkoxy having 1 to 8 1 to 8 vorvoreugt 4 carbon atom (s), a radical of the formula

- ^{(F <} > 0l - ^E "- ^{(F <)} 0l - ^H '^(F>) 0-l - ^N0 2'

OH

U-I it

preferably C 1 -C ₄ -alkyl

wherein F 'is a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms and

O O

Il

Ε * = O, S, NR _c , C = CN-C-, CN

R ₁₁ R ₁₁

where, when α> 1, all Z may be the same, partly the same or different,

L = 0,1,2,

and α = 1,2,4,4,5 and E has the meaning given under T, where the sum K + L + M + N is 0 and

-Sk-Wl-Tm-V _n -To-P _n -Z ₀

generally not a phenyl radical, a phenyl radical which is substituted by halogen, CH ₃ , CF ₃ and NO ₂ , may denote a pyridyl or a thienyl radical.

The invention thus relates to PAF antagonists having a 1,4-diazepine skeleton which carries the previously defined substituent R ₄ in the 4- or 6-position.

The new hetrazepines correspond to the general formula I.

R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, preferably methoxy .

Halogen, preferably chlorine or bromine; R _{2 is} the remainder GR ₃

for> OR ₃ hydrogen, halogen, hydroxy,

N -

wherein Re and R ₇ , which may be the same or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms optionally substituted by halogen, hydroxy, phenyl, substituted phenyl, or by a C-linked heterocycle, wherein the carbon chain may be interrupted by nitrogen (also NH), oxygen or sulfur, a branched or unbranched alkylcarbonyl group having 1-6 carbon atom ( (optionally substituted hydroxy or halogen, preferably chlorine, or substituted by an amino group optionally substituted once or twice by a branched or unbranched alkyl group having from 1 to 6 carbon atoms, which alkyl group may be substituted by halogen or hydroxy) .

an optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulphonyl group, preferably phenylsulphonyloyl or tolylsulphonyl,

an alkylsulfonyl group having 1 to 4 carbon atoms, an optionally substituted Ca to C ₇ cycloalkyl group, an optionally substituted C ₅ -C ₇ cycloalkenyl group, or

R ₆ or R _{7 is} an optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atom (s), saturated or unsaturated bonded via a carbon atom 5-, 6- or 7-membered heterocyclic ring, or

R ₆ and R ₇ form, together with the nitrogen atom, a saturated or unsaturated 5- or 6-membered ring which may be mono- or di-unsubstituted or branched or unbranched with 1 to 4 carbon atoms and which contains nitrogen, oxygen as further heteroatoms or sulfur, wherein each additional nitrogen atom may optionally be substituted by a branched or unbranched alkyl group having from 1 to 4 carbon atoms, preferably methyl; R _{a is an} arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally mono- or polysubstituted

substituted by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atom (s), R, a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atom (s),

R _{a is} an arylcarbonyloxy group, preferably phenylcarbonyloxy, optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms, a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8 carbon atom (s ), wherein the alkyl chain may be interrupted by nitrogen, oxygen or sulfur;

^R 8 \ ξ} ^R 8

^R a NCO, NCN

Hi!

H H 0 Rg

wherein R _{8 is} a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 4 carbon atoms, optionally substituted by halogen, an aryl group optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atom (s), R'g is hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atom (s),

Rq 0

R _a NS

S ^ I)

R ^ O

wherein R ₀ and R ₁₀ , which may be the same or different, are hydrogen, a branched or unbranched alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 an optionally substituted C ₃ -C ₇ -CyClOalkyl residue, an optionally substituted Cs -C ₇ -cycloalkenyl radical, or R ₉ and R ₁₀ together with the nitrogen atom, a 5- or 6-membered ring optionally substituted one or more times by branched or unbranched alkyl groups having 1 to 4 carbon atom (s), which as further heteroatoms nitrogen May contain oxygen or sulfur, each additional nitrogen atom being substituted by an alkyl group having from 1 to 4 carbon atoms, preferably methyl;

Ra is a branched or unbranched alkoxy group having 1 to 4 carbon atoms; an aryloxy group, preferably phenyloxy or su-substituted phenyloxy;

R _{a is} a C-linked 5- to 7-membered non-aromatic heterocycle;

R _{3 is} an imido radical, a benzimidazoyl radical, a cyclic amide or imide which may have 5,6 or 7 ring members and in which, optionally, a carbon atom is substituted by another heteroatom such as, for example; Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s);

R _a for π is greater than or equal to O; Hydrogen, halogen, -CH = O, -CN, COOH;

R _a Alkyloxycarbonyl group having 1-10, preferably 1-4 carbon atom (s) optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by an amino group optionally substituted once or twice by a branched or unbranched alkyl group having 1 to 6 carbon atom (s) ), wherein the alkyl group may in turn be substituted by halogen or hydroxy;

R _a optionally substituted phenyloxycarbonyl,

R _{3 is} a radical of the general formula

R ₁₁ 0

N-C-

wherein R ₁₁ and R ₁₂ , which may be the same or different. Is hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, optionally substituted (by halogen, hydroxy, nitro, amino, an optionally - or in two times by a branched or unbranched alkyl group having 1 to 6 carbon atoms substituted amino group, wherein the alkyl group may be substituted by halogen or hydroxy, morpholine.Piperazin.N-alkylpiperazine, or in the case of R ₁₁ »hydrogen or alkyl and Y = CR ₁ or γ nitrogen and XC-alkyl, R ₁₂ through an ester group or an acid amide of the general formula

R ,, O

N-C-

^R 'l2

wherein R'n and RS _{2 may have the} same meaning as Rn and Ru but with the exception of an acid amide may be substituted),

R ₁₂ or R _{12 is} a saturated or unsaturated, 5- or 6-membered or heterocyclic ring bonded via a carbon atom, optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atoms.

Ri, or R _{12 is} an optionally substituted C ₃ to C ₇ cycloalkyl, an optionally substituted C ₅ to C? -Cycloalkenylrest, or

R 5 and R ₁₂ together with the nitrogen atom denote a saturated or unsaturated 5- or 6-membered ring which is optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having ibis 4 carbon atom (s), preferably methyl; R _{3 is} a radical of the general formula

e '

B is oxygen, sulfur, NH or N- (C, -C ₆ -alkyl),

D is the radical (CR.R ₍ ) _n , where η can be 0 to 3,

R _'a is hydrogen, optionally substituted by a hydroxy or amino substituted alkyl having 1 to 6 carbon atoms,

C ₁ to C ₄ alkoxycarbonyl, dialkylaminocarbonyl,

Rb. Rg, Rd. R ». Rf hydrogen,

optionally substituted by a hydroxy or amino substituted alkyl having 1 to 6 carbon atoms, or phenyl; R _{a is} phenyl or substituted phenyl; G is a branched or unbranched alkyl, alkenyl or alkynyl group with η carbon atoms, where G is optionally

may additionally be substituted by an aryl radical or additionally by R; η is one of the numbers 0, 1, 2, 3, 4, 5, 6, T.e, or where C is an alkenyl or alkynyl radical> 1 and

preferably has the meaning of 2,3 and 4; R _{3 is} hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group with

1 to 4 carbon atom (s), preferably methyl;

R ₂ and R ₃ together form a radical of the general formula

I - / A

a fused monounsaturated 5-, 6- or 7-membered ring, wherein in the case of m = 0 and Ri, = hydrogen

a carbon atom can be replaced by C = O, or A is a fused ring of the formula

R, S

means

where R _{0 is} a branched or unsubstituted alkyl group having 1 to 18, preferably 1 to 4, carbon atom (s), a branched or unbranched alkenyl or alkynyl group having 2 to 18, preferably 2 to 4 carbon atoms, an alkylcarbonyl or alkylthiocarbonyl group having 1 to 18 preferably 1 to 4, carbon atoms in the alkyl chain or an arylcarbonyl or arylthiocarbonyl group, an optionally substituted C ₃ to C ₆ cycloalkyl or cycloalkylcarbonyl group, an alkenyl or alkynylcarbonyl group having 2 to 18, preferably 2 to 4 carbon atoms, an alkoxycarbonyl group having 1 to 18, preferably 1 to 4 carbon atoms, an optionally substituted phenalkyl-phenylalkenyl group or phenalkinyl group having 1 to 6, preferably 2 to 4 carbon atoms in the carbon chain, an alkoxycarbonylalkyl group having up to 18, preferably up to 8 carbon atoms, more preferably up to 4, an alkylcarbonylalkyl group with up to 18, preferably up to 8 carbon atoms om (s), particularly preferably up to 4, a Alkylcarbonylaminoalkylcarbonylgruppe with up to 18, preferably up to 10 carbon atoms or eineAminocarbonylalkylgruppemitbiszu 18, preferably up to 4 carbon atoms in the alkyl chain or hydrogen, a radical Ri3Ri4NCO- _(CH2) o-3 'a (CH ₂ ) _o-3 linked 5 or 6 membered heterocyclic radical, via - (CH ₂ ) -O-3, -CO- (CH ₂ ) (K), -CO-CH = CH ₂ - linked CHVcycloalkyl radical, preferably cyclopropyl; a branched or unbranched alkyl, alkenyl or alkynyl group with m carbon atoms; 0,1,2,3,4,5 or 6;

Hydrogen, hydroxy, amino, formyl, carboxy, cyano, branched or unbranched alkyloxycarbonyl of 1 to 18, preferred carbon atom (s) wherein the alkyl chain may optionally be substituted by hydroxy, amino, nitro or halogen, an optionally substituted aryloxycarbonyl group; a radical of the general formula

13

Il

N-C-

"14

wherein Ri 3 and R ₁₄ , which may be identical or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms, preferably 1 to 6, particularly preferably 1 to 4 carbon atom ( optionally substituted by halogen, hydroxy, nitro, amino, substituted amino, C ₃ -C ₆ -cycloalkyl, preferably cyclopropyl, alkoxy, preferably methoxy or in the case of R ₁₃ = hydrogen or alkyl, by an ester function or by an acid amide the general formula

R ¹

13

N-C

14

wherein R'i ₃ and R'14 may have the same meaning as R ₁₃ and R ₁₄ but with the exception of an acid amide,

may be substituted

Ri3 or Ru is optionally mono- or polysubstituted by branched or unbranched alkyl

1 to 4 carbon atoms substituted, saturated or unsaturated via a carbon linked 5-, 6-, or Tgliedrigerheterocyclischer ring, an optionally substituted C 3 to C ₇ cycloalkyl, an optionally

substituted cycloalkenyl radical;

R ₁₃ and R ₁₄ together with the nitrogen atom, a saturated or unsaturated optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms substituted 5-, 6-or 7-ring, which may contain nitrogen, oxygen or sulfur as further heteroatoms wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atom (s), preferably methyl; R _{b is} a radical of the general formula

N-R 'a

N-R '\ H

where B is oxygen, sulfur, NH or N- (C ₁ -C ₆ -alkyl), D is the radical (CR _e R f) _n 1 where η can be 0 to 3,

R _'a is hydrogen, optionally substituted by a hydroxy or amino substituted alkyl having 1 to 6 carbon atom (s), C | to C ₄ alkoxycarbonyl, dialkylaminocarbonyl, Rb. Rc. Rd, Re, Rf hydrogen, optionally substituted by a hydroxy or amino group substituted alkyl with 1 to β

Carbon atom (s), or phenyl;

^R 15 ^

Rb ν

^R 16 ^

R ₁₅ = hydrogen, R ₁₆ = hydrogen, alkylcarbonyl or alkoxycarbonyl having 1 to 18, preferably 1 to 6 carbon atom (s), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl having 1 to 18, preferably 1 to 6, carbon atom (s) in the alkyl chain;

R _{b is} hydrogen, phenyl, substituted phenyl; _Rb halogen,

where R ₁₅ and R 11, which may be identical or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-18 carbon atoms, preferably 1 to 6 carbon atoms, which may optionally be substituted by halogen, hydroxy, C ₃ -C ₆ -CyClOa Ikyl or a C-linked heterocycle, wherein the carbon chain interrupted by nitrogen, oxygen or sulfur

can be,

a branched or unbranched alkylcarbonyl group having 1-6 carbon atoms, optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by an amino group optionally substituted once or twice by a branched or unbranched alkyl group having from 1 to 6 carbon atom (s), wherein the alkyl group may be substituted by halogen or hydroxy, an optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulfonyl group, preferably phenylsulfonyl or tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atom (s),

or

Ri5 or R _{16 is} a mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atom (s) substituted, saturated or unsaturated bonded via a carbon atom 5-, 6- or

7-membered heterocyclic ring,

R ₁ S or Ri _{6 is} an optionally substituted C ₃ to C ₇ cycloalkyl radical, an optionally substituted C ₅ to

C ₇ cycloalkenyl radical or

R ₁₅ and R ₁₆ together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which is optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which contains nitrogen, oxygen as further heteroatoms or sulfur, wherein each additional nitrogen atom is optionally substituted by a branched or unbranched alkyl group having 1 to 4 carbon atom (s),

preferably methyl, may be substituted;

an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having from 1 to 4 carbon atoms;

a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atom (s); an arylcarbonyloxy group, preferably tolylcarbonyloxy or phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having from 1 to 4 carbon atom (s); a branched or unbranched alkylcarbonyloxy group having 1 to 18, preferably 1 to 8, carbon atom (s), wherein the alkyl chain may be interrupted by nitrogen, oxygen or sulfur;

N - C - O, Ii - C - K

0 R ₁₈ OR _lg

wherein Ri7 is hydrogen and R ₁ S is an alkyl, alkenyl or alkynyl group having 2 to 4 carbon atoms, optionally substituted by halogen, an optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups mr to 4 carbon atoms) substituted aryl group, R ₁₉ Hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atom (s);

an imido rest,

a cyclic amide or imide which may have 5.6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom such as e.g. B. nitrogen, oxygen or sulfur can be replaced and may optionally be fused by one or more aryl radical (s), a Benzimidazolylrest; a branched or unbranched alkyloxy or. Alkylthio radical having 1 to 18, preferably 1 to 4 carbon atoms, an optionally substituted phenyloxy or phenylthio radical, an oxygen or sulfur linked, saturated or unsaturated 5 or 6-membered heterocyclic ring; a radical of the general formula

S is a single bond, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy, branched or unbranched alkenyl having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, optionally halogen and / or hydroxy, branched or unbranched alkynyl of 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy;

W is an optionally substituted aromatic ring of 5 to 10 carbon atoms which may optionally contain one or more heteroatom (s) selected from nitrogen, oxygen or sulfur; an optionally substituted carbocyclic ring of 3 to 7 carbon atoms which may also contain a double bond;

T is a single bond, branched or unbranched alkyl optionally substituted by halogen or hydroxy having from 1 to 8, preferably 1 to 4, carbon atoms; branched or unbranched alkenyl having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy; branched or unbranched alkynyl having 2 to 8 carbon atoms-preferably 2 to 4 carbon atoms-optionally substituted by halogen and / or hydroxy-a radical of the formula

- (F) ₀ -, - E- (F) ₀ -ι-

(ι

E = O, S, N-R, C = O, C-O, C-N, N-C

6 I ι

wherein R ₆ as defined above, preferably hydrogen, C ₁ -C ₄ alkyl or 0 O.

Il U

CC ₁ - C ₆ alkyl or CH,

and R ₁ ) as defined above, preferably hydrogen or C ₁ -Ca-AlCl yI; or E means 0 0 0

Il U «

S, S, S-NR, _{RQ is} as previously defined

0 0

F is a branched or unbranched optionally substituted alkyl group having 1 to 8 preferably 1 to 4 carbon atoms, an optionally substituted alkenyl group having 2 to 8 preferably 2 to 4 carbon atoms, an optionally substituted alkynyl group having 2 to 8 preferably 2 to 4 carbon atoms ; V is an optionally substituted aromatic ring of 5 to 10 carbon atoms which may optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring of 3 to 7 carbon atoms, which may also contain a double bond,

a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is another heteroatom such as e.g. Nitrogen, oxygen or sulfur - may be substituted and which may optionally be fused by one or more aryl radicals;

U is branched or unbranched alkyl optionally substituted by halogen or hydroxy with 1 to 8 preferably 1 to 4 carbon atoms, branched or unbranched alkenyl having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy; branched or unbranched alkynyl having 2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy; a remainder of the formula

₁ - E -

C = O, 0 0 , N 0 It ii ii N- C-O, C-N t - C -ν

O, S,

wherein Re as defined above, preferably hydrogen, C, -C ₄ alkyl, or OO

C-C, -C, -alkyl or C-H, 1 o

and R ₁₁ as defined above, preferably hydrogen or C ₁ -C ₄ -alkyl or E means OO 0

Il Il

S, S, S-NR _n , wherein R ₀ as previously defined, /, « ^{y J} 0 0

F is a branched or unbranched optionally substituted alkyl group having 1 to 8 preferably 4 to 4 carbon atoms, an optionally substituted alkenyl group having 2 to 8 preferably 2 to 4 carbon atoms, an optionally substituted aikinyl group having 2 to 8 preferably 2 to 4 carbon atoms; P is an optionally substituted aromatic ring having 6 to 10 carbon atoms, which may optionally contain one or more heteroatoms selected from the group of nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring having 3 to 7 carbon atoms, which may also contain a double bond, wherein W, V and / or P may be monosubstituted or polysubstituted by Z, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom, e.g. Nitrogen, oxygen or sulfur - may be replaced and which may optionally be fused by one or more aryl radical (s);

Z is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, optionally substituted by halogen or hydroxy, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atom (s), optionally substituted, branched alkoxy with 1 to 8 preferably 1 to 4 carbon atom (s), a radical of the formula

- < ^F '> 0-l - ^{E <} - ^(Ft) 0-l - ^H ' ^{(F <)} 0-l - ^N0 2 '- SO ₂ -C ₁ -C ₄ -alkyl ₇

- < ^F *> oi - ^N

R "0

OH ι

- ( FM - Γ

^K * Ό-1 V

prefers

wherein F 'is a branched or unbranched alkyl group having 1 to 4 carbon atom (s), preferably 1 to 2 carbon atom (s) or F' = Find E '= E or

O

| 1 Il

E ¹ = O, S, NR ,, C = O, NC, CN

D ι / ·

where, when α> 1, all Z can be the same, partly the same or different, K = 0.1,

L = 0,1,2,

M = 0.1,

N = 0.1

and α = 1,2,3,4,5 and E has the meaning given under T, where the sum K + L + M + N is not equal to 0 and

not represent a phenyl radical, a phenyl radical which is substituted by halogen, CH ₃ , CF ₃ and NO ₂ , a pyridyl or a thienyl radical;

R _{5 is} hydrogen, CF ₃ , hydroxy, branched or unbranched alkyl having 1 to 6, preferably 1 to 4 carbon atom (s), more preferably methyl, optionally the alkyl group is preferred by hydroxy, halogen, C ₁ - to C ₄ alkylsulfonyloxy methylsulfonyloxy,

^R 15

-N

^R 16 wherein R ₁ B and R ^ may have the abovementioned meaning, or

^R 13

-C-N I)

^R 14

wherein R ₁₃ and R _{14 may have} the abovementioned meaning, substituted; Alkylcarbonyloxy having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, alkoxycarbonyl having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, carboxyalkyl having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, alkoxycarbonylalkyl having 1 to

4 carbon atom (s) in the branched or unbranched alkyl radicals

X / Y are independently of each other C-R- ₁ or N, but not both CR ₁ where R ₁ is preferably hydrogen or methyl, or Y is the group C-COOR ', where R' is alkyl or hydrogen and X is nitrogen; optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their physiologically acceptable acid addition salts.

Preferred compounds of general formula I are those in which R ₂ and R _{3 are} a radical as for the general

Formally defined above and wherein R _{1 is} ethyl, trifluoromethyl, methoxy, ethoxy or halogen, more preferably chlorine or bromine; particularly preferred

Methyl; '

R _{8 is} hydrogen, chlorine, bromine, iodine, hydroxy, C 1 -C ₄ alkoxycarbonyl, phenyl, substituted phenyl; C ₃ -C ₆ cycloalkyl; wherein in R ₄ preferred

5 is a single bond (K = O), branched or unbranched C ₁ -C ₄ -alkyl, branched or unbranched C ₂ -C ₄ -alkenyl, branched or unbranched C ₂ -C ₄ -alkynyl,

W is a phenyl ring, a Pyridinring.einen thiophene ring-optionally with halogen, a hydroxy group, a cyclopropyl radical, a C | -C ₄ alkyl radical, a C ₁ -C ₄ -AIkOXyrest the same or different or one

substituted several times; T is an alkyl chain having up to 6 members, preferably ethyl, an alkenyl chain having 2 to 4 members preferably vinyl, an al kinylkettemit2bis4 members preferably C ^ C, which may be interrupted by a heteroatom such as oxygen, sulfur or nitrogen, or

or CH - N -, - N - CH.,

2 ι ^

CH_-N-CH ₀ -

or

the rest -C

Il

V is a phenyl group, a thienyl group or a Cs-Ce-cycloalkyl group, a substituted phenyl group, U is preferably a single bond (M = O), or -CHj-CH ₂ - when P is phenyl;

P is a phenyl group, preferably P _n = zero;

Z is hydrogen, branched or unbranched C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy, trifluoromethyl, halogen, preferably chlorine or bromine, CN, NO ₂ , cyano, COH, COOH, COO, C ₄ -alkyl, CONH _2, CON (C ₁ -C ₄ -alkyl) _2, cyclopropyl, amino, C, -C ₄ alkylamino, C ₁ -C ₄ -DIaIkYUm ino.Hydroxymethyl, SO ₂ -C ₁ -C ₄ -alkyl, SOJ -C, -C ₄ -hydroxyalkyl, hydroxy, SH,

SC, -C ₄ -alkyl,

where, when α> 1, all Z may be the same, partly the same or different,

K = 0.1, preferably 0

L = 0.1.2, preferably 1 M = 0.1, preferably 1 N = 0.1, preferably 1, but Pn preferably 0

and α = 1,2,3, where the sum K + L + M + N is not equal to 0 and -Sk-Wl-Tm-Vn-Um-Pn-Zq does not represent a phenyl radical, a phenyl radical containing halogen , CHa, CF ₃ and NO 2 is substituted, a pyridyl

or a thienyl radical

Rs is hydrogen, hydroxy, methyl or trifluoromethyl; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ , preferably both N or X = CR ₁ (R, = H, methyl)

Y = N,

G is as defined above

η can be one of the numbers 1,2,3,4,5,6,7,8,9 or 10, preferably 0,1 or 2, and optionally their

physiologically acceptable acid addition salts

Particular preference is given to compounds of the general formula 1 in which R ₂ and R _{3 are} a radical of the general formula

I -

in which A is a fused monounsaturated 5- or 6-membered ring, or a radical of the general formula

wherein Ro = hydrogen, C ₁ -C ₄ -A ^ yI, C ₃ to Cj-cycloalkyl, C ₃ to C ₆ cycloalkylcarbonyl

I is an unbranched alkyl group with m carbon atoms m 0,1,2,3 or 4;

X / Y independently of one another CR, or N, but not both CR ₁ , preferably both N or X CR, and YN (R ₁ = H, methyl);

or

Y is C-COOR ', where R' is hydrogen or lower alkyl and X is nitrogen; R, hydrogen, hydroxymethyl, chloromethyl, trifluoromethyl, cyclopropyl, ethyl, methoxy, ethoxy, chlorine or bromine,

preferably methyl; Rt, hydrogen, hydroxy, amino, aminocarbonyl, carboxy, cyano, alkyloxycarbonyl having 1 to 6 carbon atoms, an acid amide of the formula R ₁₃ R ₁₄ NCO, wherein R ₁₃ and R _{14 is} a C ₁ - to C ₄ -alkyl radical or R ₁₃ and R ₁₄ together with the nitrogen atom represent an optionally substituted 6-membered heterocycle which, as further heteroatom, oxygen,

May contain sulfur or nitrogen, in which R _{4 is} particularly preferred

S is a single bond (K = O), a methylene group or an ethylene group;

W is a phenyl ring, a thiophene ring which may optionally be monosubstituted or polysubstituted by halogen, a hydroxy group, a C ₁ -C ₄ , a C ₁ -C ₄ -alkoxy radical, a cyclopropyl radical, which may be identical or different;

T is an alkyl chain of up to 4 members, an alkenyl chain of 2 to 4 members, an alkynyl chain of 2 to 4 members, optionally interrupted by a heteroatom such as oxygen or sulfur;

or CH ₀ -N-, -N-CH ₀

Z J I Z

CH ₀ -N-CH ₂ -

C ₁ -C ₄ -alkyl or the radical -C - N-

Il I

0 C ₁ -

V is a phenyl group; a substituted phenyl ^ s-Ce cycloalkyl group, a thienyl group U is preferably a single bond (M = O), or-CH ₂ -CH ₂ -when PeinePhenylgruppe; P is a phenyl group, preferably P _n = zero; Z is branched hydrogen or branched it is C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy, trifluoromethyl, halogen- preferably chlorine or bromine, CN, NO ₂ , cyano, COH, COOH, COOC ₁ -C ₄ - AIkVl, CONH ₂ , CON (C ₁ -C ₄ -AlkVl) ₂ , cyclopropyl, amino, Ci-C ₄ alkylamino, Ct-C ^ dialkylamino, hydroxymethyl, SO ₂ -C ₁ -C ₄ -AlkYl, Ci-C ^ Dialkylamino, hydroxymethyl, SO ₂ -C ₁ -C ₄ -alkyl, SO ₂ -CC, hydroxyalkyl, hydroxy, SH, SC ₁ -C ₄ -alkyl, and K = 0.1, preferably O, L = 0, 1, preferably 1, M = 0.1, preferably 1, N = 0.1, preferably 1, but Pn is preferred

and α = 1,2,3, where the sum K + L + M + N is not equal to 0 and R _{s may be} hydrogen, hydroxy, methyl or trifluoromethyl.

Particular preference is given to compounds of the general formula I in which R _{4 has} one of the following radicals: cis-4 [(4-trifluoromethylphenyl) vinyl] phenyl, trans-4 [(4-trifluoromethylphenyl) vinyl] phenyl, trans-4 [(4 Chlorophenyl) aminocarbonyl] phenyl, 4 [2- (4-trifluoromethylphenyl) ethynyl) phenyl, 4 [(4-chlorophenyl) N-methylaminocarbonyl] phenyl, 4 [(4-chlorophenyl) thiomethylene] phenyl, 4 [(4-chlorophenyl) aminomethylenephenyl, 4 - [(4-chlorophenyl) methylenoxy] phenyl, 4 - [(4-chlorophenyl) oxymethylene) phenyl, 4 [2- (4-methylphenyl) ethyl] phenyl, 4 [2- (4-iso-butylphenyl) ethyl] phenyl, 4 [2- (phenyl) ethyl] phenyl, 4-benzylphenyl, 3-benzylphenyl,

4 [2 (3,4,5-trimethoxyphenyl) ethyl] phenyl 4-iso-butylphenyl,

4- [2- (4-phenethylphenyl) ethyl] phenyl, 4- (2- (4-methoxyphenyl) ethyl] phenyl, 4-methoxycarbonylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl,

4l (4-chlorophenyl) aminocarbonylphenyl, 4-morpholinocarbonylphenyl, biphenyl,

4- (4-phenylbutyl) phenyl, 4 - ((N-phenyl-N-acetylamino) methyl) phenyl, 4 - ((N-4-chlorophenyl-N-methylamino) methyl) phenyl, 4 [2- (4- Chlorophenyl) ethyl] phenyl, 4I2- (4-trifluoromethylphenyl) ethyl-1-phenyl, 4 [2- (4-methoxyphenyl) ethyl] -phenyl, 4 (2- (3,4,5-trimethoxyphenyl) -ethyl] -phenyl, 4l2- (4- isobutylphenyl) ethyllphenyl, 4-methoxycarbonylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl,

4 [(4-chlorophenyl) N-methylaminocarbonyl] phenyl, 4 [(4-cyclopropylphenyl) -N-propylaminocarbonyl] phenyl, 4 [(3-trifluoromethylphenyl) -N-ethylaminomethylene] phenyl, 4 [(3 Trifluoromethylphenyl) -N-butylaminomethylene] phenyl, 4 (N-ethyl-N-benzylamino) phenyl,

4l (4-cyclopropylphenyl) -N-butylaminomethylene] phenyl,

4 [2 {thien-2-yl) ethyllphenyl _/

4 [2 (4-cyclopropylphenyl) ethyl] phenyl.

The hetrazepines according to the invention can have a carbon atom with an asymmetric center and, depending on the substitution pattern, can also have a plurality of asymmetric centers and therefore exist in various stereochemical forms.

The optionally obtained in the synthesis mixtures of optically isomeric compounds can be prepared by formation of diastereomers and subsequent methods known per se, such. B. by crystallization, be separated by chromatographic or enzymatic separation methods in the individual optical isomers.

The invention relates to the individual isomers, their mixtures and the corresponding physiologically suitable acid addition salts with inorganic or organic acids. For example, preferred are salts with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric or benzoic acids.

Unless otherwise stated, the general definitions are used in the following sense:

Alkyl is in general an unbranched or branched hydrocarbon radical having 1 to 18 carbon atoms, which may be optionally fluorine-substituted with one or more halo-halogen atoms, which may be identical or different, lower-alkyl radicals being branched or unbranched Hydrocarbon radical having 1 to about 4 carbon atom (s) are preferred.

As alkyl groups (including those which are constituents of other groups), preference is given, unless stated otherwise, to methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl and tert-butyl. Of the long-chain alkyl radicals, preference is given to n-hexadecanyl and n-octadecanyl.

Alkenyl is generally a straight-chain or branched hydrocarbon radical having 2 to 18 carbon atoms and having one or more, preferably one or two, double bond (s), which may optionally be substituted by one or more halogen atoms, preferably fluorine, equal to one another or may be different. Preferred is a lower alkenyl radical having 2 to about 4 carbon atoms and one or two double bonds. Examples which may be mentioned are vinyl, allyl, propenyl, isopropenyl, pentenyl and isopentenyl.

Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 18 carbon atoms and having one or more, preferably one or two, triple bonds, which may optionally be substituted.

Preferred is a lower alkynyl group having 2 to 4 carbon atoms and one or two triple bond (s) which may be optionally substituted with one or more halogen atoms which may be the same or different from each other. Examples include ethynyl, propargyl and 2-butynyl.

Cycloalkyl is generally a saturated or unsaturated cyclic hydrocarbon radical having 3 to 9 carbon atoms, which may be optionally substituted with one or more halogen atoms of a hydroxy group, a methyl group, which may be the same or different. Preference is given to cyclic hydrocarbons having 3 to 6 carbon atoms. Examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl and cyclooctyl, cyclooctenyl, cyclooctadienyl, cyclononinyl.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms-also in compositions wherein the aromatic compound having one or more lower alkyl group (s), alkoxy group (s), nitro group (s), amino group (s) and / or one or more Halogen atom (s) - may be the same or different - substituted with each other. Preferred aryl radicals are phenyl, naphthyl and biphenyl. Particularly preferred is a phenyl radical which may optionally be substituted.

A substituted phenyl group may carry, for example, one or more of the following substituents:

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, amino, alkylamino, dialkylamino, CF ₃ , C ₁ -C 8 -cycloalkyl, cyano, NO ₂ , COH, COOH, COOC, C ₄ -alkyl, Cyclopropyl, hydroxy, SH, SC, -Ci-alkyl, hydroxymethyl.

Examples of substituted phenyl are mentioned:

3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluoromethyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 2-methylpheny, 1,4-methylphenyl, 3-ethylphenyl , 4-propylphenyl, 4-isopropylphenyl, 4-butylpheny, 1,4-tert-butylphenyl, 4-iso-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- Methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl.

Aralkyl is in general an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain, the aromatic having one or more lower alkyl group (s), alkoxy group (s), alkoxycarbonyl group (s), hydroxy group (s), cyano group (s), nitro group (n), amino group (s) and / or one or more halogen atom (s) - may be the same or different-substituted with each other. Preference is given to aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part. As preferred aralkyl radicals may be mentioned: benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 18 carbon atoms bonded via an oxygen atom. Lower alkoxy radical having 1 to about 6 carbon atoms is preferred.

Particularly preferred is an alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

The number of carbon atoms, unless stated otherwise, refers to the length of the alkyl, alkenyl or alkynyl chain without the carbonyl function.

Particularly preferred are annealed 6-membered rings A wherein the side chain -IR _{b is} in the 8 or 9 position of the hetrazepine or annealed 5-membered rings A wherein the side chain -IR _b is substituted in the 8-position of the hetrazepine.

As a heterocycle in the context of the above definition is generally a 5- to 6-membered ring, which may contain as heteroatoms oxygen, sulfur and / or nitrogen and to which a further aromatic ring preferably a phenyl ring may be fused. Preferred are 5- and 6-membered aromatic rings containing an oxygen, a sulfur

and / or up to two nitrogen atoms and optionally benzo-fused. Examples of particular heteroaryl radicals which may be mentioned are thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl.

The heterocycle may be substituted by halogen, hydroxy and / or branched or unbranched alkyl of 1 to 4 carbon atoms.

Examples of optionally substituted saturated or unsaturated heterocyclic 5, 6 or 7-membered rings or heteroaryl radicals are:

Pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine - optionally substituted by Ci-C «alkyl mono- or polysubstituted piperazine, N-methylpiperazine, N-ethylpiperazine, Nn-propylpiperazine, N-benzylpiperazine, morpholine, Thiomorpholine, imidazole, imidazoline, imidazolidine, triazole, pyrazole, pyrazoline, pyrazolidine, triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine-wherein the heterocycles mentioned can be substituted by alkyl having 1 to 4 carbon atoms - preferably methyl -;

Examples of heterocyclic radicals which may be linked via a carbon atom are thiophene, 2-methylthiophene, furan, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-hydroxymethylfuran, a-pyran, γ-pyran, 1,3-dioxolane, 1, 2-oxathiolane, 1,2-oxathiepan, tetrahydropyran, thiolane, 1,3-dithiane, 1,3-dithiolane, 1,3-dithiolene, where the heterocycle is represented by C ₁ -C 4 -alkyl, C ₁ - C ₄ -Akoxy, halogen may be substituted.

As a heterocycle in the definition given above is generally a 5- to 6-membered ring which may contain oxygen, sulfur and / or nitrogen as heteroatoms, such as thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, quinazolyl , Quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl.

The heterocycle may be substituted by halogen, hydroxy and / or branched or unbranched alkyl of 1 to 4 carbon atoms branched or unbranched alkoxy having 1 to 4 carbon atoms.

It is known that PAF (Platelet Activating Factor) is the phospholipid acetyl-glyceryl-ether-phosphorylcholine (AGEPC), which is known to be a potent lipid mediator released from animal and human proinflammatory cells. Basophilic and neutrophilic granulocytes, macrophages (from blood and tissue) and thrombocytes involved in inflammatory reactions are mainly found among such cells.

In the pharmacological experiment, PAF shows bronchoconstriction, lowering of blood pressure, triggering of platelet aggregation and a proinflammatory effect.

These experimentally demonstrable effects of PAF directly or indirectly indicate possible functions of this mediator in anaphylaxis, in the pathophysiology of bronchial asthma, and generally in inflammation.

PAF antagonists are needed, on the one hand, to elucidate further pathophysiological functions of this mediator on animals and humans and, on the other hand, to treat pathological conditions and diseases in which PAF is involved.

Examples of the indications of a PAF antagonist are inflammatory processes of the tracheobronchial tree (acute and chronic bronchitis, bronchial asthma) or kidney (glomemone epithe), joints (rheumatic diseases), anaphylactic conditions, allergies and inflammation in the mucous membranes and the skin (eg B. psoriasis) and by

Sepsis, endotoxins or burns related shock states. Other important indications for a PAF antagonist

are lesions and inflammations in the area of the stomach and intestinal mucosa, wiez. As gastritis, in general peptic ulcer, but in particular gastric ulcer and duodenal ulcer.

Furthermore, the compounds of the invention are suitable for treatment in the following indications:

Obstructive lung diseases such. B. bronchial hyperreactivity, inflammatory lung disease, such. B.

Chronic bronchitis;

Cardiovascular diseases such. As polytrauma, anaphylaxis, arteriosclerosis, inflammatory Darmerkankungen, EPH gestosis (ederma-proteinuria hypertension), disorders of the extracorporeal circulation, ischemic diseases, inflammatory and immunological diseases, immune modulation in transplantation of foreign tissues, immunomodulation in leukemia, metastatic spread z. As in bronchial neoplasia, diseases of the CNS, such as. As migraine, agoraphobia (panic disorder), further compounds of the invention prove to be cytotoxic and organoprotective, e.g. for neuroprotection, e.g. In liver cirrhosis, DIC (disfavored intravascular coagulation); Side effects of drug therapy, e.g. anaphylactoid circulatory reactions, contrast agent incidents, side effects in tumor therapy; haemolytic uremic syndrome; Incompatibilities with blood transfusions; fulminant liver failure (CCU intoxication) Amanitaphalloides intoxication (tuber toadstool poisoning); Symptoms of parasitic diseases (e.g.

Worm diseases); Autoimmune diseases.

Other indications of interest include immune function in AIDS, diabetes, juvenile diabetes, diabetic retinopathy, polytraumatic shock, hemorrhagic shock, CNS: ischaemia, multiple sclerosis, migraine, ulcerative colitis, Crohn's disease, psoriasis, pulmonary hypertension and chronic ischemic heart failure, PAF Antagonists of the general formula I are suitable for the treatment of pathological blood gas changes, such as, for example, respiratory acidosis, metabolic alkalosis. In combination with anticholinergica PAF antagonists can be used to improve blood gas levels in phosphoric ester poisoning. It is known that PAF antagonists alone or in combination with immunosuppressive compounds (e.g., cyclosporins) can be used to treat autoimmune diseases and transplantation.

Furthermore, it is proposed to use PAF antagonists in combination with antihystaminica. With regard to the definition of antihistamines, reference is made to European patent application 345731. It is also known that PAF antagonists can be used in combination with p ₂ -mimetics for the treatment of bronchial asthma.

The combination of PAF antagonists with TNF are also advantageous.

PAF associated interaction with tissue hormone (autocoid hormones), lymphokines, and other mediators.

The new hetrazepines are superior to very potent PAF antagonists and other known diazepinoid PAF antagonists in the following criteria:

there is a total dissociation between the PAF antagonism and the benzodiazpin receptor mediated effects;

superior binding affinity to the PAF receptor on washed human platelets and show greater inhibition of PAF-induced platelet aggregation;

- In addition, they inhibit in a superior way the PAF (30ng / kg χ min) induced bronchoconstriction after oral and parenteral administration to the guinea pig in combination with a very long duration of action (greater than 15 hours after oral administration to the guinea pig).

The following table shows some selected compounds with the corresponding values for inhibition of PAF

induced platelet aggregation.

Example PAF-induced thrombosis

zythogen aggregation (μΓηοΙ]

1 0,017 2 0.07 3 0.3 4 0.8 5 0.1

methodology

Healthy male and female donors aged 18 to 35 years, who do not take any blood for several days Ingesting drugs (aspirin or other non-steroidal anti-inflammatory drugs) were each 200 ml of blood

of an unstained vein using a plastic syringe containing 3.8% sodium citrate solution. The

Ratio of sodium citrate solution: blood was 1: 9. The citrated blood was placed in plastic tubes at 150 χ g (-1200 rpm) and Room temperature centrifuged for 20 min (Heraeus Christ bench centrifuge 124). The measurement of platelet aggregation in vitro was carried out according to the method of Born and Cross (1963), wherein the TRP under

agitation was added an aggregate trigger (PAF). For measurement, 0.8 ml of TRP and 0.2 ml of modified Tyrode's solution (see below) were added to 1 ml of plastic cuvettes, each containing a small metal pin (stirrer, 1000 rpm).

The test substance was added 2 to 3 minutes before the initiation of the aggregation in a volume of 10μΙ. As a solvent

served either DMSO and water or a dilute HCl solution. The control approaches contained the corresponding

Volume of these solvents. After registration of the initial absorbance (2-3 min), aggregation was induced. In

A volume of 10μΙ was added to the cuvette by PAF (5x10 " ⁸ M; Bachern fine chemicals).

The modified Tyrode solution had the following composition: 136.9 mM NaCl; 2.68 mM KCl; 0.5mM MgCl ₂ ; 1.8mM CaCl ₂ ;

0.42 mM NaH ₂ PO ₄ ; 5.55 mM glucose and 11.9 mM NaHCO ₃ .

To assess substance effects, the maximum of the first aggregation wave was used. The by the Aggregation trigger induced maximum absorption! = Maximum aggregation - 100%) was simultaneously in one Parallel batch (in the second channel of the aggregometer) for each test batch carried and used as 100% value. The under the The effect of the test substance reached aggregation value was given as% of the control value (batch). With the help of this Concentration action curves were generated with a sample size of π = 4 and IK ₅₀ -WeHe

(Concentration at 50% inhibition of aggregation).

The preparation of the compounds according to the invention can be carried out in analogy processes according to the prior art. Following European Patent 194416 and European Patent Applications 230942 and 254245 takes place

the synthesis according to subsequent reactions.

Starting from the appropriately substituted Diazepinthionen the general formula

wherein R ₂ , Rs, R4 and R _{5 are} as defined above, the compounds of the general formula Ida invention by the fact that

A) for the case that X and Y mean nitrogen

a) reacting with an acid hydrazide of the general formula R ₁ -CONHNH ₂ (III),

b) or with hydrazine in a compound of general formula

and then reacted with an acid halide of the general formula R ₁ -CO-Hal or with an orthoester of the general formula R ₁ -C (OR '> 3 in which R' denotes a lower alkyl group, or B) in the event that X. CH, C-alkyl and Y nitrogen

a) with an aminoalkyne of the general formula RVC = C-CH ₂ -NH ₂ where R ' _{t is} hydrogen or a lower alkyl group or else

b) with an a-Aminoatdehyd-alkyl acetal or a-aminoketone alkyl ketal of the general formula

H ₂ NCH ₂ -CR ₁ (OR-J ₂

wherein R, is hydrogen or an alkyl group having 1 to 4 carbon atoms and R 'is a lower alkyl group, then reacting, if desired, the compounds obtained with Ri = hydrogen in the presence of a base with a halogenating agent, such as. As with chlorine or bromine, to a compound of general formula I a with R, halogen, such as. B. Reacting chlorine or bromine;

then, if desired, the halogen compound is converted into a compound of general formula Ia with R ₁ = alkoxy having 1 to 4 carbon atoms by reaction with the corresponding alkoxide; and subsequently optionally cleaving the compounds thus obtained into their optically active compounds by means of separation processes which are known per se, and if appropriate converting the compounds thus obtained into their harmless acid addition salts.

The reaction of the thione II with an acid hydrazide III according to the process a) is carried out in an inert organic solvent, such as. As dioxane, dimethylformamide, tetrahydrofuran or a suitable hydrocarbon, such as. B. benzene or toluene at temperatures between room temperature and the boiling point of the reaction mixture. The isolation of the end products is done by known methods, e.g. by crystallization.

The reaction of thione II with hyrazine according to process b) is carried out in inert organic solvents such as, for example, tetrahydrofuran, dioxane, halogenated hydrocarbon, e.g. Methylene chloride, suitable hydrocarbons, at temperatures between room temperatures and the boiling point of the reaction mixture.

The resulting hydra2in-1,4-diazepines can be isolated by conventional methods or else further processed directly.

Further reaction with an acid halide or orthoester is carried out in an inert organic solvent, e.g.

Halogenate hydrocarbons, cyclic or aliphatic esters, but can also be made directly in substance. The isolation of the end product la is carried out by known methods, for example by crystallization. Further details of the preparation process can be found in the detailed reaction scheme and the examples.

According to the claimed method, preference is given to preparing those compounds which, in the side chain R ₂ = -GR, or R ₂ / Ra = AJ _m -Rt, as the radical R _a or R _{b are} hydrogen, an alkyl radical, a carboxylic acid or a Carboxylic acid esters, carboxylic acid amides, a hydroxy group, an ether or thioether radical, an amine, an alkyl or arylsulfonyloxy group. Other claimed residues can be advantageously prepared by subsequent reactions analogous to those disclosed in European Patent Applications 230,942 and 254,245, the contents of which are hereby incorporated by reference.

The substituent R * claimed according to the invention is introduced into the molecule as a cyanomethyl ketone derivative at the stage of the Gewald synthesis (7-8).

These are obtainable by cyanomethylation of the corresponding carboxylic ester, in particular carboxylic acid methyl ester, in the presence of sodium hydride.

Compounds of the general formula

wherein R ₂ , R ₃ and R _{4 are} as defined above, are valuable starting materials for the preparation of hetrazepines with PAF-antagonistic activity and are claimed as such

 Cyanomethyl ketones of the general formula

R _{4 is} -CH ₂ -CN

are also valuable starting materials for the synthesis of pharmacologically active compounds and are claimed as such.

The structure of the backbone of the compounds of the invention is carried out in a manner known per se (EP-OS 254245 and EP-PS 194416) and is outlined in the following reaction scheme retrosynthetic; but without limiting the process to the radicals shown.

The following examples are intended to illustrate the invention without limiting it:

PBr ₃ Vi

, OH - H ₃ COC

P (C ₆ H ₅ K

br

II

H ₃ COC-

H ₃ COC ^ '

Γ '

NaH / H ₃ C-CN

ο + s

Il

X = O

BrCH ₂ C-Br

/ -NC-CH ₂ -Br

NH-

F ₃ C ^ f V (CH ₂ I ₂

-C-CH ₂ -NH ₂

X = O

10

11

12

H ₂ N-NH ₂ -H ₂ O

^H H ₃ CC (QCH ₂ CH ₃ I ₃

(CH ₂ J ₂

14

V (CH ₂ J ₂

13

example 1

6- (4- (4-trifluoromethyl-phenethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-fH1,2,4] - triazolo [4 _/ 3-a] [1,4] · diazepine (14)

20 g (42.7 mmol) of the Hydra2moverbindung (13) are suspended in 20OmI ethanol. After addition of 2OmI triethyl orthoacetate, the solution is stirred for 1 hour under reflux. Subsequently, the alcohol is distilled off in vacuo and the remaining residue on a SiO ₂ column chromatographies. For elution, use a methylene chloride / methanol mixture (96: 4). The main fraction is evaporated and the residue recrystallized from isopropanol. This gives 6 g (28% of theory) of the title compound of mp: 245-246 ^c C.

(CH ₂ I ₂ ^

¹ H-NMR (CDCl ₃ ); 250MHz): δ = 7.49,7.18 (4Η, m, aryl-H); 7, 39, 7, 9 (4H, 2d, J = 9Hz, aryl-H); 5, 51, 4, 14 (2H, AB system, J _AB = 13Hz, CH ₂ -7 ring); 2.98 (6H, m, CH ₂ -4, CH ₂ CH ₂ ); 2.69 (3H, s, _CH3 -triazole); 2.40-2.02 (4H, m, CH ₂ CH ₂ -3).

The starting compound 13 is obtained as follows:

In 300 ml of tetrahydrofuran 20 g (43mmol) of Diazepinthions 12 are submitted. After adding 2.4 ml of hydrazine hydrate, the resulting solution is stirred for 1 hour at room temperature. After distilling off the solvent to obtain 18 g (90% of theory) of the hydrazino compound 13, which can be further processed as a crude product.

The Diazepinthion 12 is gained by the following conversion:

20 g (44 mmol) of diazepinone 11 are stirred with 7.5 g of sodium bicarbonate and 10.8 g of phosphorus pentasulfide in 370 ml of diethylene glycol dimethyl ether at 65-70 ° C. for 3 hours. The reaction solution is added with stirring to ice and the resulting precipitate is filtered off with suction after one hour. This precipitate is dissolved in methylene chloride, dried with sodium sulfate and the solvent is carefully distilled off in vacuo after removing the desiccant. The remaining residue is slurried with isopropyl ether and the crystals are filtered off with suction. This gives 20 g of the compound 12 (97% of theory) of mp 155-165 ° C.

Compound 11 is synthesized in the following way:

42g (89mmol) of the aminobenzyl compound 10 are charged with 250g SiO ₂ in 1.51 toluene and refluxed with vigorous stirring for 3 hours, collecting the resulting water in a special template. After tapping off the toluene, the remaining residue is boiled 3 times with methanol. The individual methanol fractions are combined and evaporated in vacuo. The remaining residue crystallizes after addition of isopropyl ether. This gives 26 g (64% of theory) of the diazepinone 11 of mp .: 223 ° C.

The compound 10 used above is obtained as follows:

43 g (91 mmol) of the bromoacetyl compound 9 are dissolved in 800 ml of ethyl acetate. A vigorous stream of ammonia is passed into the reaction mixture for 2 hours and stirred at room temperature for 12 hours. Subsequently, the suspension is washed 3 times with water, the organic phase separated, dried with sodium sulfate and then evaporated after removal of the drying agent in vacuo. There remain behind 35 g of aminobenzoyl compound 10 (92% of theory)

The compound 9 is obtained in the following way:

60 g (141 mmol) of aminoketone 8 are suspended in 450 ml of dioxane. 12 ml of pyridine are added and 13 ml of bromoacetyl bromide are slowly added dropwise at room temperature. The mixture is subsequently stirred at room temperature for one hour. The suspension is filtered through Krieselgur and the filtrate evaporated in vacuo. There remains an oily residue, which is chromatographed over a SiO ₂ column (methylene chloride). After evaporation of the main fraction to give 43 g of compound 9 in the form of yellow crystals (55% of theory) of mp.: 145-147 ° C.

The compound 8 used above is prepared as follows:

155 g (488 mmol) of the compound 7.46 g of cyclopentanone and 17.4 g of sulfur are suspended or dissolved in 270 ml of dimethylformamide. 38 ml of triethylamine are then added and the mixture is stirred for 3 hours at 60 ° C. After cooling, the reaction mixture is diluted with ethyl acetate and the organic phase is washed twice with water, then the solvents are evaporated off in vacuo and the residue is poured onto an SiO ₂ column The residue can be crystallized by addition of isopropyl ether / petroleum ether to give 64 g of the desired aminoketone 8 (32% of theory) of mp 140-150 ° C.

The cyanoketone 7 is synthesized as follows:

33 g (0.1 mol) of the ester 6 are dissolved in 100 ml of toluene. Are added 4.8 g of a 55% sodium hydride dispersion and then 6.9 ml of acetonitrile and the reaction mixture is refluxed for 6 hours. After cooling, it is acidified to pH 5 to 6 with dilute hydrochloric acid. The suspension is extracted 3 times with methylene chloride, the organic extracts dried and evaporated in vacuo. The residue is chromatographed on a SiO ₂ -SaeUIe with methylene chloride is used as the eluent. The main fraction is evaporated, the residue crystallized. Yield: 15.5 g (46% of theory), mp .: 105 ⁰ C.

The ester 6 used above can be prepared as follows:

37 g (0.12 mol) of the olefin 5 is hydrogenated in 600 ml of tetrahydrofuran with Raney nickel as catalyst at 20 ° C and 5bar. After suction filtration of the catalyst, the tetrahydrofuran is evaporated and obtains 33.5 g of Compound 6 as white crystals (90% of theory) of mp .: 88-90 ⁰ C.

The olefin 5 used above can be obtained by Wittig olefination:

In a nitrogen atmosphere, 8.7 g of 55% sodium hydride dispersion in 100 ml of absolute dimethyl sulfoxide are added and stirred at 80 ° C for 45 minutes. After cooling to room temperature, a suspension of 98 g (0.2 mol) of the phosphonium salt 4ein is added dropwise and the reaction mixture is stirred for 10 minutes. Then 34.8 g of trifluoromethylbenzaldehyde are added dropwise and stirred for 2 hours at room temperature. The mixture is then diluted with 400 ml of ethyl acetate and washed twice with water. The organic phase is dried and the residue is chromatographed (SiO 2 column, eluent: methylene chloride). The main fraction is evaporated in vacuo and the residue recrystallized from isopropyl ether. This gives 37.5 g (61% d.Th.) Of the stilbene derivative 5 as crystals, m.p .: 157-158 ⁰ C The phosphonium salt 4 is available as follows:

13.3 g (58 mmol) of compound 3 are refluxed with 15.1 g of triphenylphosphine in 130 ml of benzene for 6 hours. The precipitated crystals in the reaction are filtered off with suction and dried. This gives 27.4 g (96% of theory) of the Phosphoniumbromids 4 as crystals of mp. 258-260 ° C. The alkyl bromide 3 used as starting material for the preparation of the phosphonium salt 4 used in the Wittig olefination can be prepared as follows:

11.5 g (70 mmol) of methyl 4-hydroxymethylbenzoate are added to 12 mmol of methylene chloride and 47.3 ml of phosphorus tribromide are added. The mixture is stirred for one hour at room temperature and are added under ice-cooling cautious semi-concentrated solution of ammonia in water until a pH of 8 to 9 is reached. The organic phase is separated off, dried and the solvent is distilled off. 13.4 g (84% of theory) of the desired bromide 3 are obtained.

Example 2 6- (4- (4-chlorophenethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4 ] triazolo [4,3-a) - [1,4] diazepine The compound is synthesized analogously to Example 1. In Wittig olefination, p-chlorobenzaldehyde is used instead of 4-trifluoromethylbenzaldehyde.

The corresponding amino ketone is obtained in the form of a yellow oil.

The title compound melts at 198-199X.

¹ H-NMR (CDCl _3; 250MHz): δ = 7,37,7,08 (4H, 2d, J = 8Hz, aryl-H, ring A), 7,18,7,00 (4H, 2d, J = 9Hz, aryl-H, ring B); 5, 51, 4, 13 <2H, 2d, broad, AB system, CH ₂ -7 ring); 2.98 (2H, m, CH ₂ -4); 2.69 (3H, s, CH _3); 2.40-2.05 (4H, m, CH ₂ -CH ₂ -S).

Example 3 6- (4- (4-Methoxyphenethyl) -phenyl) -8,9-dihydro-1-methyl-4H, 7H.cyclopentate4,5] thieno [3,2-f] [1,2,4] triazolot4,3 -a] -t1.4] diazepine This compound prepared analogously to Example 1 is in the form of colorless crystals of mp: 185-188 ° C.

OCH ₃

¹ H-NMR (CDCl _3; 250MHz): δ = 7,37,7,12,7,00,6,77 (8H, 4d, J = 9Hz, aryl-H); 5, 51, 4, 13 (2H, AB system, J _AB = 12Hz); 3.76 (3H, s, OCH ₃ ); 2.96 (2H, m, CH ₂ -H); 2.88 (4H, m, CH ₂ CH ₂ ); 2.69 (3H, s, _CH3 -triazole); 2.45-2.07 (4H, m, CH ₂ CH ₂ -3).

Example 4

6- (4- (3,4,5-trimethoxyphenethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopentat4,5] thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] · (1,4) diazepine

Prepared in an analogous manner about the melting at 180-182 ⁰ C aminoketone.

¹ H-NMR (CDCl ₃ , 250 MHz): δ = 7.39, 7, 19 (4H, 2d, J = 8Hz, aryl-H); 6.93 (2 H, s, broad, ΝΗ ₂ ); 6.38 (2Η.8, ΑΓνΙ-Η); 3, 82.3.81 (9H, 2s.

3-OCH ₃ ); 2.92 I 4H, m, CH ₂ CH ₂ ); 2.67 (2H, m, CH ₂ -4); 2.11 (4H, m, CH _z CH _r 3).

The compound is obtained in the form of crystals of mp: 175-177 ° C.

(CH ₇ )

2'2

¹ H-NIvIR _(CDCl3, 25OMHz): δ = 7,40,7,16 (4H, 2d, J = 9 Hz, aryl-H); 6.36 (2H, s, aryl-H); 5, 52, 4, 14 (2H, AB system), J _AB = 13Hz, CH ₂ -7 ring); 3,82,3,81 (9H, 2s, 3-OCH _3); 2.98 (2H, m, CH ₂ -4); 2.90 (4H, m, CH ₂ CH ₂ ); 2.70 (3H, s, CH ₃ -Tria2Ol); 2.43-2.09 (4H, m, CH ₂ CH ₂ -3).

Example 5 6- (4- (isopropylphenethyl) -phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno (3,2-f] [1,2,4] triazolo [4,3-a] - [1,4] diazepine This compound is also synthesized analogously to Example 1. The aminoketone melts at 141-142 ° C.

-NH ₂ C = O

(CH ₂ I ₂ ^ j) -CH (CH ₃ I ₂

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.43-7.00 (8H, m, aryl-H); 6.88 (2H, S, broad, NH ₂ ); 2.93 (4H, m, CH ₂ CH ₂ ); 2.88 (1H, sep, J = 6Hz, CH); 2.67 (2H, m, CH ₂ -4); 2.14 (4H, m, CH ₂ CH ₂ -3); 1.24 (6H, d, J = 6Hz, (CH ₃ ) ₂ -C)

The final product melts at 198-200 ⁰ C.

(CH

2'2 \ _

CH (CH ₃ J ₂

¹ H-NMR (DMSO-d6; 250MHz): δ = 7,37,7,24 (4H, 2d, J = 8Hz, aryl-H, ring-A); 7.09 (4H, s, aryl-H, ring-B); 5,25,4,14 (2H, 2d, AB system, J _AB = 13Hz, CH ₂ -7 ring); 2.90 (4H, m, CH ₂ CH ₂ ); 2.82 (1H, p, J = 6Hz, CH); 2.61 (3H, s, CHj-triazole); 2.33-1.90 (4H, m, CH ₂ CH ₂ -3); 1.17 (6H, d, J = 6Hz, (CHa) ₂ -C)

 (Assignment of ring B see figure in example 2)

Example 6 6- (4-Carbomethoxyphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-l] [1,2,4] triazolo [4,3 -a] - [1,4] diazepinDieser ester starting from dimethyl terephthalate from the melting at 178-180 ⁰ C aminoketone has the following NMR spectrum:

COOCH-

¹ H-NMR (CDCl ₃ , 250 MHz); δ = 8.07.75 (4H, 2d, J = 8Hz, aryl-H); 6.72 (2H, s, broad, NH ₂ ); 3.94 (3H, s, OCH ₃ ); 2.64, (2H, m,

CH ₂ -H); 2.20-1.90 (4H, m, CH ₂ CH _r 3).

accessible.

The title compound melts at 225 ° C.

COOCH.,

'H-NMR (CDCl _3; 250MHz): δ = 8,03,7,57 (4H, 2d, J = 9Hz aryl-H); 5, 57, 4, 18 (2H, AB system, J _AB = 12Hz, CH ₂ -7 ring); 3.93 (3H, s, OCH ₃ ); 2.98 (2H, m, CH ₂ H); 2.71 (3H, s, _CH3 -triazole); 2.42-2.01 (4H, m, CH ₂ CH ₂ -3).

Example 7 6- (4-Hydroxymethylphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4-thiazolo [4,3-a ] [1,4] dia2epin 1.9 g (Smmol) of the above carboxylic acid ester are suspended in 30 ml of tetrahydrofuran, 0.19 g of lithium aluminum hydride is added and stirred for 1 hour at room temperature. 10 ml of saturated ammonium tartrate solution are added with cooling, the organic phase is separated off, the solvent is distilled off and the residue is boiled up with a little ethyl acetate. The crystals which form are filtered off with suction, washed with ethyl acetate and dried. Obtained 0.8 g of the title compound of mp.: 183-185 ° C.

CH ₂ OH

¹ H NMR (DMSO-d6; 250MHz): δ = 7.44,7.35 (4H, 2d, J = 9Hz, aryl-H); 5.30 (1H, t, J = 6H2, OH); 5,25,4,17 (2H, AB system, Jab = 13Hz, CH _r 7-ring); 4.55 (2H, d, J = 6Hz, OCH ₂ ); 2.95 (2H, m, CH ₂ -4), 2.62 (3H, s, CH ₃ -triazole), 2.34-1.96 (4H, rn, CH ₂ CH ₂ -3).

Example 8 6- (4-Carboxyphenvl) -8 _< S-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1.2 _> 4] tria20lo [4 _< 3-a ] [1 _> 4] diazepine 3.0 g (7.9 mmol) of the ester prepared according to Example 6 are stirred with 30 ml of a 2N alcoholic potassium hydroxide solution for one hour at room temperature. The reaction solution is evaporated in vacuo, the residue is taken up in 5 to 10 ml of water and acidified with 2 N hydrochloric acid (pH 6.5-7). The crystals that separate out are filtered off with suction and dried at 60 ° C. in vacuo. Vak. dried. This gives 2.5 g of the title compound, which decomposes from 205 ° C.

COOH

¹ H-NMR (DMSO-d6; 250MHz): δ = 7.99, 7.59 (4H, 2d, J = 9Hz, aryl-H); 5,34,4,25 (2H, AB system, J _AB - 12Hz, CH ₂ -7 ring); 2.95 (2H, m, CH ₂ -4); 2.63 (3H, s, CH ₃ -triazole); 2.37-1.86 (4H, m, CH ₂ CH ₂ -3); COOH strongly broadened and not visible.

Example 9

6- (4-Chloranilinylcarbonyl) phenyl-8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine 1.82 g (5 mmol) of the acid prepared in Example 8 are suspended in 20-25 ml of absolute dimethylformamide and treated with 0.64 g of p-chloroanaline and 0.7 g of hydroxybenzotriazole. With stirring and ice-cooling, 1 g of dicyclohexylcarbodiimide is added and the mixture is allowed to stir for 48 hours at 0-5 ° C. The urea formed is filtered off with suction and the filtrate is evaporated i.vac .. The residue is dissolved in methylene chloride and the solution is shaken with sodium bicarbonate solution The organic phase is separated off, dried and concentrated by evaporation From ethyl acetate, crystals of mp 312 ° C. are obtained in a yield of 1.8 g.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.91, 7, 7.74, 7.51, 7.30 (8H, 4d, J = 8Hz, aryl-H); 5,40,4,13 (2H, 2d, AB system, J _Ae = 13Hz, CH ₂ -7 ring); 2.98 (2H, m, CHj-4); 2.63 (3H, s, _CH3 -triazole); 2.38-2.03 (4H, m, CH ₂ CH ₂ -3); 9.30 (1H, s, NH).

Example 10 6- (4-Morpholinylcarbonylphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3 -a] [1,4] diazepine 1.2 g (3.3 mmol) of the carboxylic acid from Example 8 are suspended in 15 ml of methylene chloride and then admixed with 0.55 g of carbonyldiimidazole and stirred at room temperature for 30 minutes. Then add 0.3 g of morpholine, stirred for one hour at room temperature and shakes to remove unreacted carboxylic acid with sodium bicarbonate solution. The organic phase is separated off, evaporated and the remaining residue is chromatographed on a SiO ₂ column (eluent: methylene chloride / methanol 93: 7). 0.6 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.57, 7.43 (4Η, 2d, J = 9Hz, aryl-H); 5,55,4,18 (2H, AB system, J _AB = 12Hz, CH ₂ -7 ring>; 3,92-3,20 (8H, m, morpholine-H); 2,99 (2H, m, CH ₂ -4); 2.71 (3H, s, CH ₃ -triazole); 2.44-2.12 (4H, m, CH ₂ CH ₂ -3).

Example 11 2-Ethyl 4 · (4- (3,4,5-trimethoxyphenethyl) phenyl) -2-methyl-6H-thiβno [3,2-f] [1,2,4] triazolo [4,3 Starting from trimethoxybenzaldehyde and the phosphonium salt used in Example 1, 4- (3,4,5-trimethoxyphenethyl) cyanoacetophenone is obtained, which is reacted with butyraldehyde and sulfur by the method of Gewald to give the corresponding aminothiophene (M .: 128-138'C). The subsequent reaction with bromoacetyl bromide and subsequent amination with ammonia and ring closure analogously to Example 1 gives the corresponding diazepinone (mp: 150-152 ° C). The corresponding treatment of the diazepinone with P ₂ S ₅ and subsequently with hydrazine and triethyl orthoacetate gives the title compound of mp: 145-147 ° C.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.52, 7.20 (4H, 2d, J = 8 Hz, aryl-H); 6.66 (1H, s, thiophene-H); 6.36 (2H, s, aryl-H); 4.80 (2H, s, broad, CHj-7 ring); 3.82, 3.81 (9H, 2s, 3-OCH _3); 2.92 (4H, m, CH ₂ CH _2); 2.88 (2H, qu, J = 6Hz, CH ₂ -CH ₃ ); 2.70 (3H, s, _CH3 -triazole); 1.36 (3H, t, J = 6Hz, CH ₂ -CH ₃ ).

Example 12

4- (4- (3,4,5-trimethoxyphenethyl) phenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepin

From the 4- (3,4,5-trimethoxyphenethyl) cyanoacetophenone and mercaptoacetaldehyde to obtain the corresponding Aminoketone of mp: 110-112 ° C. Analogously to Example 11, the title compound is built therefrom, which is in the form of Crystals of mp: 260-261 ° C is obtained.

H ₃ C

OCH

¹ H NMR (CDCl ₃ ; 250 MHz): 5 = 7.51, 7.19 (4H, 2d, J = 8Hz, aryl H); 7.26.7.00 (2H, 2d, J = 6Hz, thiophene-H); 6.36 (2H, s, aryl-H); 4.88 (2H, s, broad, CH ₂ -7 ring); 3,82,3,81 (9H, 2s, 3-OCH _3); 2.90 (4H, m, CH ₂ CH ₂ ); 2.73 (3H, s, _CH3 -triazole).

Example 13

6- (4- (3,4,5-trimethoxyphenethyl) phenyl) -8,9-dihydro-1-methyl-8 (4-morpholinylcarbonyl) -4H, 7H-cyclopenta [4,5] thieno [3, 2-f] [1,2,4] triazolo [4,3-a] diazepin

From 4- (3,4,5-trimethoxyphenethyl) cyanoacetophenone and cyclopentanone-S-carboxylic acid methyl ester, the aminoketone is obtained in the presence of sulfur and triethylamine, mp: 165-166 ° C.

This aminothiophene derivative is further reacted analogously to the described synthesis routes and finally yields the thienotriazolodiazepine carboxylic acid ester.

N.

HXOC

OCH,

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.41, 7.18 (4H, 2d, J = 8Hz, aryl-H); 6.36 (2H, s, aryl-H); 5,52,4,15 (2H, AB system, J _AB == 13Hz, CH _r 7-ring); 3,81,3,80 (9H, 2s, 3-OCH _3); 3.69 (3H, s, OCH ₃ ); 3.58 (1H, m, H-3); 3.31 (2H, m, CH ₂ -4); 2.90 (4H, m, CH ₂ CH ₂ ); 2.69 (3H, s, _CH3 -triazole); 2.57 (2H, m, CH ₂ -2).

The ester is saponified, resulting in the corresponding carboxylic acid. Further reaction of this carboxylic acid with morpholine gives the title compound.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.41, 7.20 (4H, 2d, J = 8Hz, aryl-H); 6.37 (2H, s, aryl-H); 5, 51, 4, 13 (2H, AB system, J _AB - 13Hz, CHi-7 ring); 3,82,3,81 (9H, 2s, 3OCH ₃ ); 3.78-3.31 (8H, m, morpholine-CH ₂ ); 3.24 (2H, m, CH ₂ -4); 3.75 (1H, m, H-3); 2.90 (4H, m, CH ₂ CH ₂ ); 2.69 (3H, s, _CH3 -triazole); 2.56 (2H, m, CH ₂ -2).

Example 14

6- (4- (4-chlorophenoxymethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno (3,2-f) [1,2,4] triazolo [ 4,3-a] [1,4] diazepin

58 g (0.253 mol) of methyl p-bromomethylbenzoate are dissolved in 300 ml of absolute tetrahydrofuran. To this solution is added dropwise the phenolate prepared from 32.5 g of p-chlorophenol and 11 g of 55% sodium hydride dispersion in 300 ml of tetrahydrofuran and refluxed for 5 hours. The solid reaction components are filtered off (suction filter), the filtrate is evaporated, the residue is partitioned between water and methylene chloride and 60 g of crystals of the organic phase are isolated from the organic phase.

82-85X. From this intermediate compound can be prepared in analogy to the previously described method with acetonitrile and sodium hydride, the corresponding cyanoketone of mp.: 150-152 "C, which can be converted into the corresponding aminobenzoylthiophene derivative (pale yellow crystals of mp.: 157-158Ό.

NH-

C = O

¹ H-NMR (CDCl ₃ ; 25OMHz): δ = 7.46 (4H, m, aryl-H [ring A]); 7.27.6.90 (4H, 2d, J = 9Hz, aryl-H [ Ring B]); 6.95 (2H, s, NH ₂ ); 5.09 (2H, s, OCH ₂ ); 2.67 (2H, m CH ₂ -4); 2.09 (4H, m, CH ₂ CH ₂ -3).

From this aminoketone, the corresponding diazepinone of mp. 21O ⁰ C can be represented, which can be identified by the following NMR spectrum:

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.53, 7.40, 7.22, 6.88 (8H, 4d, J-9Hz, aryl-H); 5.06 (2H, s, OCH ₂ ); 4.40 (2H, s, CH ₂ -7 ring); 2.84 (2H, m, CH ₂ -4); 2.17 (4H, m, CH ₂ CH ₂ -3).

From this diazepinone finally the title compound is accessible.

CH, -

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.51, 7.41, 7.20, 6.88 (8H, 4d, J = 9Hz, aryl-H); 5, 53, 4, 15 (2H, AB system, J _AB = 13Hz, CH ₂ -7 ring); 5.07 (2H, s, OCH ₂ ); 2.98 (2H, m, CH ₂ -4); 2.69 (2H, s, _CH3 -triazole); 2.24 (4H, m, CH ₂ CH ₂ -3).

Example 15 6- (4- (4-phenyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine Starting from ethyl diphenylcarboxylate, the corresponding aminoketone is obtained, mp: 188-189 ° C.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.17-7.24 (9H, m, aryl-H); 6.97 (2H, s, NH ₂ ); 2.67 (2H, m, CH ₂ -4); 2.15 (4H, m, CH _a CH ₂ -3).

The synthesized therefrom in the usual way diazepinone melts at 285 ⁰ C. From the diazepinone the title compound can be prepared that 253-255 ° C is isolated in the form of crystals of mp .:.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.69-7.28 (9H, m, aryl-H); 5,55,4,18 (2H, AB system, J _A6 = 13Hz, CH ₂ -7 ring); 2.99 (2H, m, CH _r 4); 2.71 (3H, s, _CH3 -triazole); 2.29 (4H, m, CH ₂ CH ₂ -3).

Example 16 6- (4-phenbutyl) phenyl-8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3 ^ -f] [1,2,4] triazolo [4] - a] [1,4] diazepine From the phosphonium salt described in Example 1 and 3-phenylpropionaldehyde, the corresponding olefin is obtained and from this by hydrogenation the corresponding dihydro derivative, which is converted by conventional means into the cyanoketone, from which the corresponding amino ketone of the m.p .: 135-138 ° C.

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.44-7.06 (9 H, m, aryl-H); 6.84 (2H, s, NH ₂ ); 2.67 (6H, m, CH ₂ -4,2C ₆ H ₅ -CH ₂ ); 2,12,1,67 (8H, m, C ₆ H ₅ -CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ -3).

This amino ketone can be converted analogously to the abovementioned description into the title compound:

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.46-7.02 (9H, m, aryl-H); 5, 50, 4, 12 (2H, AB system, J _A8 = 13Hz, CH ₂ -7 ring); 2.72 (6H, m, CH ₂ -4, CH ₆ H ₅ -CH ₂ ); 2.70 (3H, s, _CH3 -triazole); 2.32 (8H, m, C ₆ H ₅ -CH ₂ -CH ₂ CH ₂ and CH ₂ CH ₂ -3).

Example 17

6- (4 (3,4,5-trimethoxyphenethyl) phenyl) -8,9-dihydro-1-hydroxymethyl-4H, 7H-cyclopenta [4,5] thienoI3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine

From the characterized in Example 4 aminoketone of mp.: 180-182 ° C, the corresponding diazepinone is prepared (crystals from isopropanol of mp. 198-199 ° C).

5 g (lOmmol) of this compound are reacted with P ₂ S ₅ in diglyme and provide 5.1 g of the corresponding thione of mp .: 178-180 ⁰ C.

5.3 g (10 mmol) of the resulting thione are suspended in 60 ml of dioxane and treated with 1 g of glycolic hydrazide. The mixture is stirred for 3 hours at room temperature, the solvent is removed i. Vac., The residue is taken up in methylene chloride, the organic phase is washed with water, dried and, after removal of the solvent, crystals of mp: 168-171 ° C.

HO-CH ₂

OCH ₃

7,39,7,15 (4H, 2d, J = 9Hz, aryl-H); 6.36 (2H, s, aryl-H); 5,43,4,13 <2H, AB system, J _Ae = 13Hz, CH _r 7-ring); 5.37 (1H, s, broad, OH); 4.84 (2H, AB system, J _AB = 15Hz, CH ₂ -O); 3,80,3,81 (9H, 2s, 3OCH ₃ ); 2.95 (2H, m, CH ₂ -4); 2.88 (4H, m, CH ₂ CH ₂ ); 2.20 (4 H, m, CH ₂ CH _r 3).

Example 18

6- (4- (3,4,5-trimethoxyphenethyl) phenyl) -8,9-dihydro-1-trifluoromethyl-4H, 7H-cyc1openta [4,5lthlenot3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

The thione of mp 178-18O ° C described in Example 17 gives, after the reaction with hydrazine hydrate in Tetrahydrofuran the corresponding hydrazino compound, which has a mp. Of 180-182 ⁰ C.

4.9 g of the hydrazino compound are stirred with 2.3 g of trifluoroacetic anhydride and 1.5 ml of triethylamine in 80 ml of methylene chloride for 2 hours at room temperature. The red solution is washed with water and evaporated. The residue is treated with 150 ml of toluene and 35 g of SiO ₂ and boiled under reflux for 3 hours, the resulting water in a special

Template is caught. The toluene is then decanted and the crude title compound is extracted with methanol. After chromatographic purification, the desired trifluoromethyl compound is obtained, which is determined by the following

^ NMR spectrum can be identified:

, OCH;

(CH ₂ ) ₂ X ⁷ VOCH ₃

¹ H-NMR (CDCl ₃ ; 250 MHz): δ = 7.40, 7.16 (4H, 2d, J = 9Hz, aryl-H); 6.36 (2H, s, aryl-H); 5.52, 4.14 (2H, AB system, J _Ae = 13Hz, CH ₂ -7 ring); 3,82,3,81 (9H, 2s, 3OCH ₃ ); 2.98 (2H, m, CH ₂ -4); 2.90 (4H, m, CH ₂ CH ₂ ); 2.43-2.09 (4H, m, CH ₂ CH ₂ -3).

Example 19 Example 19

cis-G- [4- (2- (4.Trifluormethylphenyl) vinyl) phenyl] -8,9-dihydro-1-methyl-4H, 7H-cvclopentat4,5] thieno (3,2-f] [1,2 , 4] triazolo [4,3-a] [1,4] diazepin

The stilbene derivative 5 obtained in the reaction route described in Example 1 (see reaction scheme) is separated by crystallization from diisopropyl ether into the two cis / trans isomers. The corresponding trans-stilbene derivative of type 5 is obtained in the form of colorless crystals of melting point 155-157 ° C (fraction A). The corresponding cis-olefin is obtained by evaporation of the mother liquor (fraction B) and reacted analogously to the route described in Example 1. In the following, therefore, only the batch sizes and the associated yields are reproduced:

a) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

30.5 g (0.1 mol) of cis-Oleflns (fraction B) are dissolved in 100 ml of toluene and treated with 4.5 g of sodium hydride dispersion (55%) and 12.8 ml of acetonitrile. After carrying out the reaction analogously to Example 1, 17.0 g (55% of theory) of the corresponding cyanoketone of mp: 95-100 ° C. are obtained.

b) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

17.0 g (50 mmol) of the unsaturated cyanoketone type 7 prepared according to process step a) are mixed with 4.2 g of cyclopentanone and 2.0 g of sulfur in dimethylformamide and mixed with 4.2 ml of triethylamine in 54 ml of ethanol and stirred at 60 ° C. for 7 hours. The reaction mixture is then diluted in a modification of Example 1 with 1,2-dichloroethane and twice washed with water. The organic phase is i. Vak. concentrated and chromatographed on a column filled with SiO ₂ column with dichloromethane as eluent. This gives 13.9 g (62% of theory) of unsaturated aminoketone (type 8) as yellow crystals of mp: 130-132 ⁰ C.

c) Preparation of bromoacetylamide (corresponding to step 8 to 9)

13.0 g (30 mmol) of the aminoketone prepared according to process step b) are dissolved in 150 ml of dichloromethane and admixed with 2.6 ml of pyridine. Thereafter, 2.9 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure analogous to Example 1 - obtained 15.0 g (89% of theory) of the corresponding stilbene derivative (type 9) in the form of yellow crystals (from petroleum ether) of mp.: 95-100 ° C.

d) Preparation of the amino derivative (corresponding to step 9 to 10)

15.0 g (28 mmol) of the bromoacetyl compound prepared according to process step c) are dissolved in 300 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 13.5 g of the corresponding amino compound of type 10 are obtained as crude product, which is immediately cyclized in the subsequent reaction step.

e) Preparation of the diazepinone (corresponding to step 10 to 11 in the reaction scheme)

13.5 g of the amino compound prepared according to process step d) are cyclized in 200 ml of toluene in the presence of 75 g of silica gel. The reaction procedure according to Example 1 leads to 12.0 g (94% of theory) of the corresponding diazepinone of the type

f) Preparation of the unsaturated diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme)

6.0 g (13.2 mmol) of the diazepinone derivative prepared according to process step e) are dissolved in 52 ml of pyridine and admixed with 4.4 g of phosphorus pentasulfide. The reaction mixture is heated to 6O ⁰ C over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i.Vak. is obtained 3.5 g (56% of theory) of the corresponding diazepinethione derivative of mp.: 178-180 ° C.

g) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme)

3.5 g (7.4 mmol) of the diazepinethione prepared according to process step f) are introduced into 30 ml of tetrahydrofuran and admixed with 0.4 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, 2.5 g (72% of theory) of the corresponding type 13 hydrazine are obtained as crystals of mp: 170 ° C. (decomposition), h) Preparation of the title compound (corresponding to step 13 of FIG in the reaction scheme) 2.5 g (5.3 mmol) of the hydrazone prepared according to process step g) are suspended in 30 ml of ethanol and reacted with 2 ml of triethyl orthoacetate to the title compound. After working up according to Example 1, 1.5 g (57% of theory) of Title compound in the form of crystals of mp. 192-195 ° C.

Example 20

trans-6- [4- (2- (4-trifluoromethylphenyl) -vinyl) phenyl] -8,9-dlhydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [ 1,2,4] triazolo [4,3-a] [1,4] diazepin

The fraction A of the 1-methoxycarbonyl-4- (2- (4-trifluoromethylphenyl) -vinyl] benzene (5) from Example 19, obtained from the isomeric separation, has the trans configuration with respect to the substitution of the olefin The following reactions with the stilbene -Derivat 5 are carried out in analogy 2U the method described in Example 19.

a) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

22.5 g (73 mmol) of the trans-olefin (fraction A) are dissolved in 75 ml of toluene and mixed with 3.3 g of sodium hydride dispersion (55%) and 9.5 ml of acetonitrile. After carrying out the reaction analogously to Example 19, 19.0 g (83% of theory) of the corresponding cyanoketone of mp: 146 ° C.

b) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

12.4 g (39 mmol) of the cyanoketone type 7 prepared according to process step a) are mixed with 3.0 g of cyclopentanone and 1.4 g of sulfur in dimethylformamide and treated with 3 ml of triethylamine in 39 ml of ethanol and stirred at 60 ° C for 7 hours. The reaction mixture is then - in a modification of Example 1 - diluted with 1,2-dichloroethane and washed twice with water. The organic phase is i.Vak. concentrated and chromatographed on a column filled with SiO ₂ column with dichloromethane as eluent. This gives 9.5 g (58% of theory) of unsaturated aminoketone (type 8) as yellow crystals of mp. 197-199 ° C.

c) Preparation of bromoacetylamide (corresponding to step 8 to 9)

9.0 g (22 mmol) of the aminoketone prepared according to process step b) are dissolved in 100 ml of dichloromethane and admixed with 1.8 ml of pyridine. Thereafter, 2.0 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure -analog Example 19, 11.0 g (95% of theory) of the corresponding stilbene derivative (of type 9) are obtained in the form of yellow crystals of the thickness: 200 ° C.

d) Preparation of the amino derivative (corresponding to step 9 to 10)

11.0 g (20 mmol) of the bromoacetyl compound prepared according to process step c) are dissolved in 200 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 9.0 g (93% of theory) of the corresponding unsaturated amino compound of type 10 are obtained as crystals of mp: 187-190X.

e) Preparation of the diazepinone (corresponding to step 10 to 11 in the reaction scheme)

9.0 g of the amino compound prepared according to process step d) are cyclized in 300 ml of toluene in the presence of 50 g of silica gel. The reaction procedure according to Example 1 leads to 8.0 g (92% of theory) of the corresponding diazepinone type II.

f) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme)

6.0 g (13.2 mmol) of the diazepinone derivative prepared according to process step e) are dissolved in 52 ml of pyridine and admixed with 4.4 g of phosphorus pentasulfide. The reaction mixture is heated to 60 ^° C. over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i.Vak. is obtained 1.6 g (26% of theory) of the corresponding Diazepinthion derivative of mp. 265 "C.

g) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme)

1.6 g (3.4 mmol) of the diazepinethione prepared according to process step 0 are initially charged in 15 ml of tetrahydrofuran and admixed with 0.2 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, 1.3 g (82% of theory) of the corresponding type 13 hydrazone are obtained as crystals of mp: 255 ° C.

 h) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 1.3 g (2.8 mmol) of the hydrazone prepared according to process step g) are suspended in 10 ml of ethanol and converted into the title compound with 1 ml of triethyl orthoacetate. After working up according to Example 1, 1.1 g (80% of theory) are obtained in the form of crystals of mp: 299-301 ° C.

Example 21

The synthesis of the stilbene derivative 5 is carried out analogously to Example 1 and the separation into cis / trans isomers analogously to Example For the further synthesis in the present example - as in Example 20 - the corresponding trans-stilbene derivative 5 is used.

a) Preparation of Type 6 Dibromoethane Derivative

22.0 g (72 mmol) of the trans-stilbene derivative 5 are initially charged in 200 ml of chloroform. Thereafter, 2.55 ml of bromine are added dropwise. The reaction mixture is stirred for 2 hours at room temperature and then treated with diisopropyl ether. The crystalline bromination product obtained is filtered off with suction and dried. 20.2 g (87% of theory) of the corresponding dibromo compound of type 6 of mp: 205 ° C. are isolated.

b) Preparation of 1-methoxycarbonyl-4- {2- (4-trifluoromethylphenyl) ethynyl] benzene

20.2 g (43 mmol) of the dibromo compound prepared according to process step a) are dissolved in 170 ml of n-butanol and washed with

52 g of potassium hydroxide and 5 ml of water and heated to reflux for a period of 3 hours with stirring.

Then the reaction mixture is diluted with 300 ml of water. Thereafter, the organic phase is separated and i.Vak. concentrated. The remaining residue is taken up in water, the solution is acidified with hydrochloric acid, wherein the reaction product is deposited in crystalline form. Is isolated 12g (96% of theory) of the corresponding alkyne in the form of colorless crystals of m.p .: 278-285 ⁰ C.

c) Preparation of 1-ethoxycarbonyl-4- (2- (4-trifluoroethylphenyl) ethynyl] benzene by transesterification

31.0 g (106 mmol) of the prepared according to step b) methoxycarbonylbenzene derivative are heated for 8 hours in a mixture of 150 ml of ethanol and 1.2 ml of concentrated sulfuric acid with stirring to reflux temperature. The resulting in this reaction - insoluble in the reaction mixture - carboxylic acid is isolated and reacted again. Subsequently, the solvent i.Vak. distilled off, the residue remaining in dichloromethane

taken up, washed twice with water and dried with sodium sulfate. Thereafter, the solvent is i. Vak. away. 26.0 g (76% of theory) of the title compound are isolated as crystals of mp: 65-68 ° C.

d) Preparation of the Cyanoketone (corresponding to step 6 to 7 in the Reaction Scheme)

Dissolved 26.0 g (81 mmol) of the ester prepared according to process step c) in 90 ml of toluene and treated with 3.8 g of sodium hydride dispersion (55%) and 11 ml of acetonitrile. After the reaction is carried out analogously to Example 1 of the corresponding cyanoketone of melting is obtained 14.0 g (55% of theory) .: 110-120 ⁰ C.

e) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

14.0 g (45 mmol) of the cyanoketone prepared according to process step d), 4.0 g of cyclopentanone and 1.85 g of sulfur in dimethylformamide are mixed and treated with 4 ml of triethylamine in 51 ml of ethanol and stirred at 60 ⁰ C over a period of 7 hours. The reaction mixture is reacted in analogy to Example 1. This gives 7.3 (40% of theory) of aminoketone (Type 8) as yellow crystals of mp. 195-200 ° C.

f) Preparation of bromoacetylamide (corresponding to step 8 to 9)

7.0 g (17 mmol) of the aminoketone prepared according to process step e) are dissolved in 80 ml of dichloromethane and admixed with 1.4 ml of pyridine. Thereafter, 1.6 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure - analogously to Example 1 - to obtain 8.0 g (88% of theory) of the corresponding bromoacetylamide in the form of yellow crystals of mp. 205-207 ° C.

g) Preparation of the amino derivative (corresponding to step 9 to 10)

8.0 g (15 mmol) of bromoacetylamide prepared according to process step f) are dissolved in 150 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After further reaction is carried out according to Example 1, 6.5 g (92% of theory) of the corresponding unsaturated amino compound as crystals, m.p .: 215-220 ⁰ C.

h) Preparation of the Diazepinone (Corresponding to Step 10 to 11 in the Reaction Scheme) 6.5 g (13.8 mmol) of the amino compound prepared according to process step g) are cyclized in 20 μl of titanium dioxide in the presence of 35 g of silica gel. The reaction procedure according to Example 1 leads to 3.0 g (48% of theory) of the corresponding diazepinone as crystals of mp: 275 "C.

i) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme) 3.0 g (6.6 mmol) of the diazepinone derivative prepared according to h) are dissolved in 30 ml of pyridine and treated with 2.2 g of phosphorus pentasulfide. The reaction mixture is heated to 60 ^° C. over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i. Vak. obtained 1.0 g (32% of theory) of the corresponding diazepinethione derivative of mp.: 255 ° C (decomposition).

j) Preparation of the Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 1.0 g (2.0 mmol) of the diazepinethione prepared according to process step i) are initially charged in 10 ml of tetrahydrofuran and admixed with 0.1 g of hydrazine hydrate. After carrying out the reaction according to Example 1, 1.0 g (100% of theory) of the corresponding type 13 hydrazone are obtained as crystals of mp: 255 ° C.

k) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 1.0 g (2.0 mmol) of the hydrazone prepared according to process step j) are suspended in 10 ml of ethanol and reacted with 1 ml of triethyl orthoacetate to give the title compound. Obtained after working up according to Example 1, 0.8 g (76% of theory) of 6- [4- (2- (4-trifluoromethylphenyl) ethynyl) phenyl] -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thienotriazolo- [3,2-f] - [1,2,4) diazepine in the form of crystals of melting point 308-310 C. ^8.

Example 22

6- (4- (4-chloro-N-methylanilino) carbonylphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2, 4] triazolo [4,3-a] [1,4] diazepin

f-UC

0.9 g (2.5 mmol) of the carboxylic acid prepared according to Example 8 are mixed with 3SO 4 mg of 4-chloro-N-methylaniline, 350 mg of 1-hydroxy-1H-benzotriazole hydrate and 500 mg of N, N'-dicyclohexylcarbodiimide for 2 days stirred at room temperature in 10 ml of dimethylformamide. Thereafter, the resulting suspension is adsorptively filtered on silica gel and the filtrate i. Vak. concentrated. The remaining residue is chromatographed on a silica-filled column with a mixture of dichloromethane and 4% methanol as eluent. 0.4 g (33% of theory) of the title compound are obtained as crystals of mp: 288-C.

Example 23

6- (4- (4-chlorophenylthiomethyl) phenyl) -B.9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3.2-f] [1, 4) triazolo [4,3-a] [1,4] diazepin

a) 1.75 g (5 mmol) of the alcohol prepared according to Example 7 are dissolved in the first reaction stage in 350 ml of dichloromethane and treated with 1.5 ml of thionyl chloride and stirred for 1 hour at room temperature. Subsequently, the reaction mixture is neutralized with aqueous ammonia solution. After separating and drying the organic phase, the solvent is removed in vacuo. 1.80 g (98% of theory) of the corresponding chlorine compound are obtained in the form of crystals having a melting point of> 300 ° C.

b) 100 mg of a 50% sodium hydride dispersion and 310 mg of p-chlorothiophenol are introduced into 20 ml of tetrahydrofuran and stirred for 10 minutes at room temperature. After addition of 800 mg (2.2 mmol) of the chloride prepared according to reaction step a), the reaction mixture is heated to reflux temperature with stirring for a period of 5 hours. Thereafter, the solvent is i.Vak. distilled off. The remaining residue is chromatographed on silica gel with a mixture of dichloromethane and 4% methanol as eluent. 450 mg (43% of theory) of the title compound are obtained as crystals of mp: 153-155 ° C.

Example 24 6- (4- (4-Chloroanilino) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] tria2-ol [4,3.a] _[1/4] dia2epin

a) The alcohol prepared according to Example 7 is converted according to Example 23, process step a) in the corresponding chloride.

b) 960 mg (2.6 mmol) of the chloride is dissolved in 20 ml of dioxane (1,4-dioxacyclohexane), treated with 650 mg of p-chloroaniline and heated with stirring for one hour at reflux temperature.

After adding 10 ml of dimethylformamide, the reaction mixture is heated at reflux temperature for a further 4 hours. Subsequently, the solvent i.Vak. The residue is partitioned between ethyl acetate and water. The organic phase is extracted and after drying with magnesium sulfate and filtering off the drying agent i.Vak. concentrated. The remaining residue is adsorptively filtered on a silica-filled column with a mixture of dichloromethane and 4% methanol. One erhält300 mg (25% of theory) of the title compound in the form of crystals of mp .: 195-200 ⁰ C.

Example 25

6- (4- (4-chlorophenylmethyleneoxy) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2 _< 4] tria20IO ' [4,3-a] [1,4] diazepin

a) Preparation of p-chlorobenzoic acid ethyl ester

83 g (0.6 mol) of 4-hydroxybenzoic acid are heated in 400 ml of ethanol at reflux temperature. At boiling temperature, hydrogen chloride is introduced into the reaction solution over a period of 2.5 hours.

After cooling the reaction mixture, the alcohol is i.Vak. removed and the residue then dissolved in diethyl ether. The solution is washed twice with water and dried with magnesium sulfate. After removal of the drying agent and removal of the solvent i.Vak. 100 g (100% of theory) of ethyl p-chlorobenzoate are obtained in the form of crystals of MP: 103-105T.

b) Preparation of 4 - [(p-chlorophenyl) methylenoxy] benzoic acid ethyl ester

52.1 g (0.3 mol) of the ester prepared according to reaction step a) are introduced into 300 ml of dimethylformamide and treated with ice cooling with 13.8 g of a 55% sodium hydride dispersion. The mixture is stirred for 10 minutes and then adds a solution of 50.2g p-chlorobenzyl chloride in 120ml dimethylformamide to the reaction mixture and the reaction mixture is heated with stirring over a period of 4 hours to 150 ⁰ C. Then allowed to cool the reaction mixture to room temperature, diluted with 600ml ethyl acetate. The organic phase is separated and washed twice with water, dried and after filtering off the drying agent i.Vak. concentrated. The remaining residue is chromatographed on silica gel with dichloromethane. This gives 62 g (68% of theory) of 4 - [(p-chlorophenyl) methylenoxy] benzoic acid ethyl ester in the form of colorless crystals of mp: 65-68 ⁰ C.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

62 g (213 mmol) of the ester prepared according to process step b) are dissolved in 200 ml of toluene and admixed with 9.7 g of sodium hydride dispersion (55%) and 13.9 ml of acetonitrile. After carrying out the reaction analogously to Example 1, 30.0 g (49% of theory) of the corresponding cyanoketone of mp.: 129-136T are obtained.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

30.0 g (105 mmol) of the cyanoketone prepared according to process step c) are mixed with 8.0 g of cyclopentanone and 3.8 g of sulfur in dimethylformamide and treated with 8.0 ml of triethylamine in 105 ml of ethanol and then - according to Example 1-7 hours at 60 stirred at ⁰ C, after which the reaction mixture is diluted with 500ml dichloromethane. Obtained after recrystallization from a mixture of diethyl ether and diisoproyl ether 16.0 g (40% of theory) of the aminoketone as yellow crystals, mp. 147-149 ° C.

e) Preparation of bromoacetylamide (corresponding to step 8 to 9)

12.3 g (32 mmol) of the aminoketone prepared according to process step d) are dissolved in 100 ml of dichloromethane and admixed with 2.5 ml of pyridine. Thereafter, 2.7 ml of bromoacetyl bromide are added dropwise. After further reaction and work-up analogously to Example 1, 13.0 g of the corresponding bromoacetyl compound are obtained in the form of yellow crystals of mp: 183-185 ° C.

f) Preparation of the diazepinone derivative

9.0 g (18 mmol) of the bromoacetyl compound prepared according to process steps) are dissolved in a mixture of 100 ml of dichloromethane and 100 ml of methanol and -analog example treated for 1-1 hour with gaseous ammonia. The reaction mixture is allowed to react for 5 days at room temperature with stirring. Thereafter, the reaction mixture i.Vak. concentrated. After repeated chromatography of the remaining residue with a mixture of dichloromethane and 2% methanol on silica gel, 300 mg (4% of theory) of the corresponding diazepinone are obtained.

g) Preparation of Diazepinethione (corresponding to step 11 to 12 in the reaction scheme)

300 mg (0.7 mmol) of the diazepinone prepared according to process step f) are dissolved in 7 ml of diethylene glycol dimethyl ether and reacted with 130 mg of sodium bicarbonate and 180 mg of phosphorus pentasulfide analogously to Example 1 to give the corresponding diazepinethione derivative. This gives 0.3 g (98% of theory) of the reaction product in crystalline form.

h) Preparation of the Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 300 mg (0.7 mmol) of the diazepinethione prepared according to process step g) are mixed with 10 ml of hydrazine hydrate in 10 ml of tetrahydrofuran. After carrying out the reaction in analogy to Example 1, 250 mg (84% of theory) of the corresponding hydrazone are obtained in the form of crystals of mp: 172 ° C.

i) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 250 mg (0.57 mmol) of the hydrazones prepared according to process step h) are suspended in 10 ml of ethanol and reacted with 0.5 ml triethyl orthoacetate to give the title compound. After working up according to Example 1, 100 mg (40% of theory) of the title compound are obtained as crystals of mp: 184-186'C.

Example 26 6- (4- (4-Methylphenethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

The synthesis procedure for the preparation of the title compound is carried out in analogy to the procedures described in Example 1 or Example 19 with the exception that in the Wittig olefination (in the reaction scheme step 4 to 5) instead of p-trifluoromethylbenzaldehyde p-tolualdehyde is used.

a) Wittig olefination (corresponding to step 4 to 5 in the reaction scheme)

12.5 g of a sodium hydride dispersion (55%) are placed under inert gas in 16OmI absolute dimethyl sulfoxide and according to Example 1 with 140.8 g (0.29 mol) of the corresponding phosphonium salt - suspended in 290ml dimethyl sulfoxide - and then with 34.8g (0.29 mol) of p-tolyaldehyde. The work-up according to Example 1 gives 62 g (85% of theory) of the corresponding olefin.

b) Reduction of the olefin (corresponding to step 5 to 6 in the reaction scheme)

Analogously to Example 1, 62 g (0.24 mol) of the olefin prepared according to process step a) are hydrogenated in 11 tetrahydrofuran in the presence of Raney nickel as catalyst at 20 ° C and Sbar hydrogen pressure over a period of 4 hours. This gives 48.5 g (78% of theory) of 1,2-Diphenylethanderivats as crystals of mp.: 75 ° C.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

48.5 g (0.19 mmol) of the diphenylethane derivative prepared according to process step b) are dissolved in 180 ml of toluene and washed with

8.7 g of sodium hydride dispersion (55%) and 25 ml of acetonitrile were added. After carrying out the reaction analogously to Example 1, 48.0 g (96% of theory) of the corresponding cyanoketone are obtained as crystals of mp; 85-90'C.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

48.0 g (182 mmol) of cyanoketone type 7 prepared according to process step c) are mixed with 14.0 g of cyclopentanone and 6.6 g of sulfur in dimethylformamide and mixed with 14 ml of triethylamine in 175 ml of ethanol and stirred over a period of 7 hours at 6OX. The reaction mixture is then - in analogy to Example 19-diluted with 1,2-dichloroethane and washed twice with water. The organic phase is i. Vak. concentrated and on a column filled with silica with dichloromethane as eluent chromatography «. After recrystallization from Oiisopropylether one obtains 17,0g (26% of theory) of the amino ketone of type (8) as yellow crystals, m.p .: 135-140 ⁰ C.

e) Preparation of bromoacetylamide (corresponding to step 8 to 9)

18.0 g (50 mmol) of the aminoketone prepared according to d) are dissolved in 200 ml of dichloromethane and admixed with 4.0 ml of pyridine. Thereafter, 4.4 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure-analogously to Example 1 and recrystallization from diisopropyl ether, 17.9 g (75% of theory) of the corresponding bromoacetylamide are obtained in the form of yellow crystals of mp: 142-145 ° C.

f) Preparation of the amino derivative (corresponding to step 9 to 10)

17.9 g (37 mmol) of the bromoacetyl compound prepared according to process step e) are dissolved in 300 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 12.0 g (77% of theory) of the corresponding amino compound of type 10 are obtained in the form of crystals of mp: 160-162 ° C.

g) Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme)

12.0 g (28.6 mmol) of the amino compound prepared according to process step f) are cyclized in 250 ml of toluene in the presence of 60 g of silica gel. The further reaction procedure and work-up according to Example 1 leads to 6.5 g (57% of theory) of the corresponding diazepinone type II in the form of crystals of mp. 232 "C.

h) Preparation of the Diazepinethione Derivative (corresponding to Step 11 of Figure 21 in the Reaction Scheme) 6.5 g (16 mmol) of the diazepinone derivative prepared according to process step g) are dissolved in 65 ml of pyridine and admixed with 5.5 g of phosphorus pentasulfide. The reaction mixture is heated to 6O ⁰ C over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i.Vak. this gives 4.0 g (59% of theory) of the corresponding diazepinethione derivative of mp: 212-215X.

i) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 4.0 g (9.6 mmol) of the diazepinethione prepared according to process step h) are initially charged in 40 ml of tetrahydrofuran and admixed with 0.5 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, 2.6 g (65% of theory) of the corresponding type 13 hydrazones are obtained as crystals of mp: 218 ° C.

j) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 2.6 g (6.3 mmol) of the hydrazones prepared according to process step i) are suspended in 30 ml of ethanol and reacted with 2 ml of triethyl orthoacetate to give the title compound. This gives 2.2 g (80% of theory) in the form of crystals of mp .: 203 ⁰ C.

Example 27 6- [4- (4-Isobutylphenethyl) phenyl] -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

The synthesis procedure for the production of the title connection takes place substantially in analogy to those in example 1 or Example 19 described method.

a) Preparation of p-isobutylbenzaldehyde

A mixture of 117.4 g (0.87 mol) of isobutylbenzene and 180 ml of benzene is introduced into the autoclave. Subsequently, the solution is saturated with hydrogen chloride under a hydrogen chloride pressure of about 2 to 3 bar. Carbon monoxide is then pressed up to a pressure of 35 bar. After an initial pressure drop, a carbon monoxide pressure in the range of 35 to 39 bar is again set in the autoclave for a period of 4 hours. After relaxing, the reaction solution is added dropwise to a mixture of 1.1 kg of ice and 10 ml of concentrated hydrochloric acid. Subsequently, the organic phase is separated and washed with water and then with a saturated sodium bicarbonate solution.

After drying and concentrating the solution, the remaining residue is distilled in a water jet vacuum to give 55g (39% of theory) of p-lsobutylbenzaldehyds Sdp.4o _{mt> af:} 132-140 ⁰ C.

b) Wittig olefination (corresponding to step 4 to 5 in the reaction scheme)

12.5 g of a sodium hydride dispersion (55%) are placed under inert gas in 150 ml of absolute dimethyl sulfoxide and according to Example 1 with 140.8 g (0.29 mol) of the corresponding phosphonium salt - suspended in 290ml dimethyl sulfoxide - and then with 47.0g (0, 29mol) of 4-isobutylbenzaldehyde. The work-up according to Example 1 provides 68 g (80% of theory) of the corresponding olefin.

c) reduction of the olefin (corresponding to step 5 to 6 in the reaction scheme)

As in Example 1, 68 g (0.23 mol) of the olefin prepared in process step b) are hydrogenated in 11 tetrahydrofuran in the presence of Raney nickel as catalyst for 5 hours at 20 ° C and a hydrogen pressure of 5 bar. This gives 58.0 g (85% of theory) of the corresponding 1,2-Diphenylethanderivats as an oil.

d) Preparation of the Cyanoketone (corresponding to step 6 to 7 in the Reaction Scheme)

58.0 g (196 mmol) of the 1,2-diphenylethane derivative prepared according to process step c) are dissolved in 185 ml of toluene and treated with 8.9 g of a 55% sodium hydride dispersion and 25.4 ml of acetonitrile. After carrying out the reaction analogously to Example 1, 83.0 g (83% of theory) of the corresponding cyanoketone are obtained as an oil.

e) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

48.0 mg (162 mmol) of cyanoketone type 7 prepared according to process step d) are mixed with 12.4 g of cyclopentanone and 5.8 g of sulfur in dimethylformamide and treated with 12.4 ml of triethylamine in 160 ml of ethanol and stirred at 60 ^{C for} 7 hours. The reaction mixture is then - in analogy to Example 19 - diluted with 1,2-dichloroethane and washed twice with water. The organic phase is i. Vak. and chromatographed on a silica-filled column with dichloromethane as eluent. After recrystallization from diisopropyl ether, 17.5 g (27% d.Th.) Of the amino ketone of type (8) as yellow crystals, m.p .: 108-110 ⁰ C.

f) Preparation of bromoacetylamide (corresponding to steps 8 and 9)

17.0 g (42 mmol) of the aminoketone prepared according to process step e) are dissolved in 150 ml of dichloromethane and admixed with 3.4 ml of pyridine. Thereafter, 3.3 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure -analog Example 19-, 18.5 g (84% of theory) of the corresponding bromoacetylamide are obtained as an oil.

g) Preparation of the amino derivative (corresponding to step 9 to 10)

18.5 g (35 mmol) of the bromoacetyl compound prepared according to process step f) are dissolved in 150 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After further reaction is carried out according to Example 1, 16.0 g (98% of theory) of the corresponding amino compound of the type 10 in the form of crystals of mp .: 133-135 ⁰ C.

h) Preparation of the Diazepinone Derivative (Corresponding to Step 10 of FIG. 11 in the Reaction Scheme) 16.0 g (35 mmol) of the amino compound prepared according to process step g) are cyclized in 200 ml of toluene in the presence of 80 g of silica gel. The further reaction procedure and working up according to Example 1 leads to 10.0 g (65% of theory) of the corresponding diazepinone of type 11 in the form of crystals, mp. 218 ° C.

i) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme) 9.0 g (20 mmol) of the diazepinone derivative prepared according to process step h) are dissolved in 165 ml of diethylene glycol dimethyl ether and treated with 3.5 g of sodium hydrogencarbonate and 5.5 g of phosphorus pentasulfide. The reaction mixture is treated as described in Example 1. After working up and recrystallization from diethyl ether to obtain 5.2 g (56% of theory) of the corresponding Diazepinthion derivative as crystals, mp. 218 ° C.

j) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 5.2 g (11.0 mmol) of the diazepinethione prepared according to process step i) are initially charged in 40 ml of tetrahydrofuran and with 0.7 ml of hydrazine hydrate added. After carrying out the reaction according to Example 1 and recrystallizing from diethyl ether to obtain 4.8 g (93% of theory) of the corresponding hydrazone of type 13 as crystals of mp.: 198-200 ° C (decomposition)

k) Preparation of the title compound (corresponding to step 13 of Figure 14 in the reaction scheme) 4.8 g (10.0 mmol) of the hydrazone prepared according to process step ()) are suspended in 30 ml of ethanol and reacted with 3 ml of triethyl orthoacetate to give the title compound. Obtained after recrystallization from ethyl acetate 4.4 g (87% of theory) of the title compound in the form of crystals of mp.: 210 ° C.

Example 28 6- (4-Phenethylphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3 -a] [1,4] diazepin

The synthesis is carried out for the preparation of the title compound in analogy to those in Example 1 or Example 19

with the exception that in the Wittig olefination (in Scheme 4 of FIG. 5) benzaldehyde is used instead of p-trifluoromethylbenzaldehyde.

a) Wittig olefination (corresponding to step 4 to 5 in the reaction scheme)

8.7 g of a sodium hydride dispersion (55%) are placed under inert gas in 100 ml of absolute dimethyl sulfoxide and according to Example 1 with 98g (0.2 mol) of the corresponding phosphonium salt suspended in 200ml Dimethylsulfoxid- and then treated with 21.5 g of benzaldehyde. The work-up according to Example 1 gives 30.2 g (48% of theory) of the corresponding olefin as an oil.

b) Reduction of the olefin (corresponding to step 5 to 6 in the reaction scheme)

Analogously to Example 1, 30.2 g (0.13 mol) of the olefin prepared according to process step a) are hydrogenated in 700 ml of tetrahydrofuran in the presence of Raney nickel as catalyst over a period of 3.5 hours at 20 ⁰ C and 5 bar hydrogen pressure. This gives 30.6 g (100% of theory) of the 1,2-diphenylethane derivative as an oil.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

30.5 g (125 mmol) of the diphenylethane derivative prepared according to process step b) are dissolved in 120 ml of toluene and admixed with 5.7 g of sodium hydride dispersion (55% strength) and 16.4 ml of acetonitrile. After the reaction is carried out analogously to Example 1--erhält 19.0 g (61% of theory) of the corresponding cyanoketone as crystals, m.p .: 80-83 ⁰ C.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

19.0 g (76 mmol) of cyanoketone type 7 prepared according to process step c) are mixed with 5.8 g of cyclopentanone and 2.8 g of sulfur in dimethylformamide and treated with 5.8 ml of triethylamine in 76 ml of ethanol and stirred at 60 ° C. for 7 hours The reaction mixture is then diluted with 1,2-dichloroethane in analogy to Example 19 and washed twice with water, the organic phase is concentrated by evaporation in a vacuum and chromatographed on a silica-filled column with dichloromethane as eluent 9.2 g (35% of theory) of the aminoketone (Type 8) are recrystallized from oiisopropyl ether as yellow crystals of mp: 118-121 ° C.

e) Preparation of bromoacetylamide (corresponding to step 8 to 9)

9.5 g (27 mmol) of the aminoketone prepared according to process step d) are dissolved in 85 ml of dichloromethane and admixed with 2.2 ml of pyridine. Thereafter, 2.3 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure - analogously to Example 19 and recrystallization from diethyl ether to obtain 12.0 g (94% of theory) of the corresponding bromoacetylamide in the form of yellow crystals of mp.: 108 ° C.

f) Preparation of the amino derivative (corresponding to step 9 to 10)

12.0 g (26 mmol) of the bromoacetyl compound prepared according to e) are dissolved in 150 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 9.5 g (92% of theory) of the corresponding amino compound of type 10, which is cyclized without further purification measures in the subsequent reaction step.

g) Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme)

9.5 g (24 mmol) of the amino compound prepared according to process step f) are cyclized in 200 ml of toluene in the presence of 50 g of silica gel. The further reaction procedure and working up according to Example 1, after recrystallization from diethyl ether to 5.2 g (57% of theory) of the corresponding diazepinone type 11 in the form of crystals, mp. 192-195 ° C.

h) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme) 3.9g dOmmol) of the diazepinone derivative prepared according to process step g) are dissolved in 80mlDiethylenglycoldimethytether and treated with 1.7 g of sodium and 2.5 g of phosphorus pentasulfide. The reaction mixture is treated as described in Example 1. After working up, 3.7 g (91% of theory..) Is the corresponding Diazepinthion derivative as crystals, m.p .: 225 ° C

i) Preparation of the Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 3.7 g (92 mmol) of the diazepinethione prepared according to process step h) are initially charged in 60 ml of tetrahydrofuran and admixed with 0.5 ml of hydrazine hydrate , After carrying out the reaction according to Example 1, after addition of the reaction solution with 800 ml of diethyl ether, 2.4 g (65% of theory) of the corresponding hydrazone of type 13 are obtained as crystals of mp: 175 ° C.

j) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 2.4 g (6.0 mmol) of the hydrazones prepared according to process step i) are suspended in 30 ml of ethanol and reacted with 2 ml of triethyl orthoacetate to give the title compound. After recrystallization from diethyl ether, 1.2 g (47% of theory) are obtained in the form of crystals. Mp 198 ° C.

Example 29 6- (4-Benzylphenyl) -8,9dihydro-1-methyl-4H, 7H-cyclopenta- [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepin

a) Preparation of 4-benzoylbenzoic acid

50.0 g (260 mmol) of 4-methylbenzophenone are initially charged in 260 ml of glacial acetic acid and heated to 100 ° C. Thereafter, a solution of 70 g of chromium VI oxide in a mixture of 160 ml of water, 260 ml of glacial acetic acid and 50 ml of concentrated sulfuric acid is slowly added dropwise ,

Subsequently, the reaction mixture is heated with stirring over a period of one hour at reflux temperature. Thereafter, the reaction mixture is poured slowly into 4 L of ice water, wherein the acid precipitates in the form of crystals. 40g (69% of theory) of 4-benzoylbenzoic acid are obtained as colorless crystals of mp 188X.

b) Preparation of 4-benzylbenzoic acid

34.0 g (IBOmnol) of 4-benzoylbenzoic acid are dissolved in 400 ml of tetrahydrofuran and hydrogenated in the presence of 7.0 g of palladium on carbon (10% Pd content) at 20 ° C. and under a hydrogen pressure of 5 bar over a period of 3 hours. After venting, the catalyst is filtered off and the solvent i.Vak. away. 30.0 g (94% of theory) of 4-benzylbenzoic acid are obtained as colorless crystals.

c) Preparation of ethyl 4-benzylbenzoate

35.0 g (165 mmol) of 4-benzylbenzoic acid are dissolved in 100 ml of ethanol and treated with 2 ml of concentrated sulfuric acid and heated with stirring over a period of 5 hours at reflux temperature. After distilling off the ethanolsi. Vak. the remaining residue is taken up in dichloromethane and washed successively with water and saturated sodium bicarbonate solution. The organic phase is separated, dried and concentrated. The remaining residue is chromatographed on a silica-filled column with dichloromethane as eluent. Those eluates which have a uniform main spot in the thin-layer chromatogram are combined and freed from the eluent. This gives 35.7 g (90% of theory) of the ester as an oil.

The following process steps are carried out analogously to the processes described in Example 1 or Example 19.

d) Preparation of the Cyanoketone (corresponding to step 6 to 7 in the Reaction Scheme)

35.7 g (148 mmol) of the benzoic acid ester prepared according to process step c) are dissolved in toluene and treated with 6.7 g of sodium hydride dispersion (55%) and 19.2 ml of acetonitrile. After the reaction is carried out-as in Example 1 to obtain 25.0 g (72% of theory) of the corresponding cyanoketone as crystals, m.p .: 102-104 ⁰ C.

e) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

23.5 g dOOmmol) of the cyanoketone prepared according to process step d) are mixed with 7.7 g of cyclopentanone and 3.6 g of sulfur in dimethylformamide and treated with 7.7 ml of triethylamine in 100 ml of ethanol and stirred at 6O ⁰ C for 7 hours. The reaction mixture is then diluted analogously to Example 19 with 1,2-dichloroethane and washed twice with water. The organic phase is i. Vak. concentrated and chromatographed on a column filled with silica with dichloromethane as eluent. This gives 12.6 g (38% of theory) of the aminoketone as crystals of mp: 115-120 ⁰ C.

f) Preparation of bromoacetylamide (corresponding to steps according to 9)

10.0 g ßOmmol) of the aminoketone prepared by process steps) are dissolved in 100 ml of dichloromethane and treated with 2.4 ml of pyridine. Thereafter, 2.6 ml of bromoacetyl bromide are added dropwise. After further carrying out the reaction and working-up analogously to Example 1, 10.5 g (75% of theory) of the corresponding bromoacetylamide are obtained in the form of crystals of melting point 113-115 ° C.

g) Preparation of the amino derivative (corresponding to step 9 to 10)

10.5 g (23 mmol) of the bromoacetyl compound prepared according to process step f) are dissolved in 200 ml of ethyl acetate and treated analogously to Example 19 with gaseous ammonia. After further reaction procedure and workup as in Example 1 to obtain 7.0 g (78% of theory) of the corresponding amino compound in the form of crystals of mp .: 118-121 ⁰ C.

h) Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme) 7.0 g (18 mmol) of the amino compound prepared according to process step g) are cyclized in 150 ml of toluene in the presence of 35 g of silica gel. The further reaction procedure on working up according to Example 1 leads to 5.5 g (82% of theory) of the corresponding diazepinone of type 11 in the form of crystals of mp: 246 ° C.

i) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme). 5.5 g (4.7 mmol) of the diazepinone derivative prepared according to step h) are dissolved in 120 ml of diethylene glycol dimethyl ether and with 3.6 g of phosphorus pentasulfide and 2.5 g of sodium bicarbonate added. The reaction mixture is treated as described in Example 1. After working up, 5.5 g (96% of theory) of the corresponding diazepinethione derivative are obtained as crystals.

j) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 5.5 g (14.0 mmol) of the diazepinethione prepared according to i) are initially charged in 90 ml of tetrahydrofuran and admixed with 0.8 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, 4.5 g (82% of theory) of the corresponding type 13 hydrazones are obtained as crystals of mp: 205 ° C.

k) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 4.5 g (12.0 mmol) of the hydrazones prepared according to process step j) are suspended in 50 ml of ethanol and reacted with 3 ml of triethyl orthoacetate to give the title compound. This gives 3.3 g (69% of theory) of the title compound in crystalline form. M.p .: 204-206 ⁰ C

Example 30

The preparation process of the title compound was carried out in analogy to Example 29. However, instead of 4-benzoylbenzoic acid, 3-benzoylbenzoic acid is used.

a) Preparation of 3-benzylbenzoic acid

40.0 g (176 mmol) of the 3-carboxybenzophenone are hydrogenated in 400 ml of tetrahydrofuran gel and in the presence of 8.0 g of palladium on carbon (10% Pd content) at 20 ° C over a period of 3 hours at 20 ⁰ C under a hydrogen pressure of 5bar. After venting, the catalyst is filtered off and the solvent i.Vak. away. This gives 37.0 g (98% of theory) of 3-benzylbenzoic acid as colorless crystals of mp, 107-108 ⁰ C.

b) Preparation of 3-Benzylbenzoic acid ethyl ester

37.0 g (174 mmol) of 3-benzylbenzoic acid are dissolved in 100 ml of ethanol and treated with 2 ml of concentrated sulfuric acid and heated with stirring over a period of 5 hours at reflux temperature. After distilling off the ethanol i.Vak. the remaining residue is taken up in dichloromethane and washed successively with water and saturated sodium bicarbonate solution. The organic phase is separated, dried and concentrated. The residual residue is chromatographed on a silica-filled column with dichloromethane as eluent. Those eluates which have a uniform main spot in the thin-layer chromatogram are combined and freed from the eluent. This gives 23.7 g (57% of theory) of the ester as a yellow oil. The following process steps are in turn carried out in analogy to Example 1 or Example 19.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

23.5 g (0.1 mol) of the benzoic acid ester prepared according to process step b) are dissolved in 90 ml of toluene and admixed with 4.5 g of sodium hydride dispersion (55% strength) and 13 ml of acetonitrile. After carrying out the reaction analogously to Example 1, i4.0 g (61% of theory) of the corresponding cyanoketone are obtained as crystals of mp: 102-104 ° C.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

14.0 g (60 mmol) of the cyanoketone prepared according to process step c) are mixed with 4.6 g of cyclopentanone and 2.2 g of sulfur in dimethylformamide and admixed with 4.6 ml of triethylamine in 60 ml of ethanol and stirred at 60 ° C. for 7 hours. The reaction mixture is then diluted analogously to Example 19 with 1,2-dichloroethane and washed twice with water. The organic phase is i.Vak. concentrated and chromatographed on a column filled with silica with dichloromethane as eluent. This gives 9.3 g (47% of theory) of the aminoketone as crystals of mp: 140-142 ⁰ C.

e) Preparation of bromoacetylamide (corresponding to steps of 9)

9.0 g (27 mmol) of the aminoketone prepared according to process step d) are dissolved in 100 ml of dichloromethane and washed with

2.2 ml of pyridine added. Thereafter, 2.1 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure analogous to Example 1 - and recrystallization from diisopropyl ether to obtain 10.0 g (82% of theory) of the corresponding bromoacetylamide as an oil.

f) Preparation of the amino derivative (corresponding to step 9 to 10)

10.0 g (22 mmol) of the Bromacelylverbindung prepared according to process step e) are dissolved in 150 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 7.0 g (81% of theory) of the corresponding amino compound of type 10 are obtained as oil, which is cyclized in the subsequent reaction step.

g) Preparation of the Dia2epinone Derivative (Corresponding to Step 10 to 11 in the Reaction Scheme)

7.0 g (18 mmol) of the amino compound prepared according to process step f) are cyclized in 150 ml of toluene in the presence of 40 g of silica gel. The further reaction procedure and workup according to Example 1, after recrystallization from ether to 6.3 g (94% of theory) of the corresponding diazepinone type 11 in the form of crystals, mp. 210-212 ⁰ C.

h) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme) 6.3 g (17 mmol) of the diazepinone derivative prepared according to process step g) are dissolved in 138 ml of diethylene glycol dimethyl ether and with 4.1 g of phosphorus pentasulfide and 2.9 g of sodium bicarbonate added. The reaction mixture is - as described in Example 1 - treated and worked up. 6.3 g (96% of theory) of the corresponding diazepinethione derivative are obtained as crystals.

i) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme)

6.3 g (16.2 mmol) of the diazepinethione prepared according to h) are initially charged in 60 ml of tetrahydrofuran and mixed with 0.9 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, 4.6 g (73% of theory) of the corresponding hydrazono compound of type 13 are obtained in the form of crystals of the mp:

190-192 ⁰ C

 j) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 4.6 g (12.0 mmol) of the hydrazones prepared according to process step i) are suspended in 30 ml of ethanol and reacted with 3 ml of triethyl orthoacetate to give the title compound. This gives 4.4 g (90% of theory) as crystals of mp. 213-215 ° C.

Example 31 6- (4-Isobutylphenyl) .8,9-dihydro-1-methyl-4H, 7H-eyclopenta [4,5-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepin

The preparation of 4-isobutylbenzaldehyde is carried out in analogy to Example 27:

a) Preparation of 4-isobutylbenzoic acid

70.0 g (430 mmol) of 4-isobutylbenzaldehyde are introduced into 11 2N sodium hydroxide solution and stirred for 2 days at room temperature after the addition of 45.3 g of potassium permanganate. The resulting dark suspension is filtered off with suction through silica gel / carbon. Acidification of the filtrate with hydrochloric acid gives 34 g (44% of theory) of 4-isobutylbenzoic acid as colorless crystals of mp: 133-140 ⁰ C. <

b) Preparation of ethyl 4-isobutylbenzoate

34.0 g (190 mmol) of 4-isobutylbenzoic acid are dissolved in 100 ml of ethanol and treated with 2 ml of concentrated sulfuric acid and heated with stirring over a period of 5 hours at reflux temperature. After distilling off the ethanol i, Vak. the remaining residue is taken up in dichloromethane and washed successively with water and saturated sodium bicarbonate solution. The organic phase is separated, dried and concentrated. The remaining residue is chromatographed on a silica-filled column with dichloromethane as eluent. Those eluates which have a uniform main spot in the thin-layer chromatogram are combined and freed from the eluent. This gives 27.0 g (69% of theory) of the ester as an oil. The following process steps are carried out in analogy to Example 1 or Example 19.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

27.0 g (131 mmol) of the benzoic acid ester prepared according to process step b) are dissolved in 125 ml of toluene and admixed with 6.0 g of sodium hydride dispersion (5% strength by weight) and 17 ml of acetonitrile. After carrying out the reaction analogously to Example 1, 21.0 g (80% of theory) of the corresponding cyanoketone are obtained.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

21.0 g (104 mmol) of cyanoketone prepared according to process step c) are mixed with 8.0 g of cyclopentanone and 3.7 g of sulfur in dimethylformamide and treated with 8 ml of triethylamine in 100 ml of ethanol and stirred at 60 ⁰ C for 7 hours. The reaction mixture is then diluted analogously to Example 19 with 1.2 dichloroethane and washed twice with water. The organic phase is i. Vak. concentrated and chromatographed on a column filled with SiOj with dichloromethane as eluent. After recrystallization from diisopropyl ether, 6.3 g (20% of theory) of the aminoketone (of type 8) are obtained as crystals of mp: 126 ° C.

e) Preparation of bromoacetylamide (corresponding to step 8 to 9)

6.0 g (20 mmol) of the aminoketone prepared according to d) are dissolved in 70 ml of dichloromethane and admixed with 1.6 ml of pyridine. Thereafter, 1.6 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure-analogously to Example 1 and recrystallization from diisopropyl ether to obtain 7.8 g (93% of theory) of the corresponding bromoacetylamide as crystals.

f) Preparation of the amino derivative (corresponding to step 9 to 10)

7.8 g (37 mmol) of the bromoacetyl compound prepared by process steps) are dissolved in 100 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 6.5 g (98% of theory) of the corresponding amino compound are obtained as foamy oil (foam).

g) Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme)

6.5 g (18 mmol) of the amino compound prepared according to process step f) are cyclized in 200 ml of toluene in the presence of 40 g of silica gel. The further reaction procedure and workup according to Example 1 leads to 5.5 g (92% of theory) of the corresponding diazepinone type 11 in the form of a foamy oil.

h) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme) 5.5 g (16 mmol) of the diazepinone derivative prepared according to process step g) are dissolved in 65 ml of pyridine and admixed with 5.5 g of phosphorus pentasulfide. The reaction mixture is heated to 60 ° C. over a period of two hours, then the mixture is diluted with water and extracted with dichloromethane, and after removal of the extractant in vacuo, 2.1 g (36% of theory) are obtained. of the corresponding diazepinethione derivative as crystals of mp: 195-200 ⁰ C.

i) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme)

2.1 g (6.0 mmol) of the diazepinethione prepared according to process step h) are initially charged in 20 ml of tetrahydrofuran and admixed with 0.4 ml of hydrazine hydrate. After carrying out the reaction according to Example 1, after recrystallization from diethyl ether, 1.3 g of the corresponding type 13 hydrazone are obtained as crystals.

j) Preparation of title compound (corresponding to step 13 to 14 in the reaction scheme)

1.3 g (3.8 mmol) of the hydrazone prepared according to process step i) are suspended in 20 ml of anhydrous ethanol and reacted with 1 ml of triethyl orthoacetate to give the title compound. This gives 1.0 g (70% of theory) in the form of colorless crystals of mp: 190-192 ° C.

Example 32 6- [4 - ((4-phenethyl) phenethyl) phenethyl] -8,9-dihydro-1-methyl-4H, 7H.cyclopenta [4,5] thieno [3,2-f] [1.2,4 ] triazolo [4 ^ -a] [1,4] diazepin

a) Preparation of 4- [2- (4-diethoxyphenyl) ethenyl] benzoic acid methyl ester (1st Wittig olefination) and conversion into the free aldehyde.

12.5 g of a 55% sodium hydride dispersion are initially charged under inert gas in 150 ml of absolute dimethyl sulfoxide and admixed with 140.8 g (287 mmol) of the phosphonium salt described in Example 1, suspended in 300 ml of dimethylsulfoxide and then with 57.7 (290 mmol of diethoxymethanebenzaldehyde. The reaction is carried out analogously to Example 1. The resulting diethyl acetal is then dissolved in methanol and converted into the free aldehyde by means of dilute hydrochloric acid For work-up, the reaction medium is removed in vacuo and the residue is taken up in dichloromethane After drying the organic phase, filtering off the drying agent and distilling off the solvent in vacuo, the mixture of the two stilbene isomers is separated by crystallization from diisopropyl ether into the isomers. Isomers in the form of colorless kris After concentrating the mother liquor, 24 g of the trans-isomer are obtained as crystals of mp: 145-148 ° C.

b) Preparation of 1- (2- (4-methoxycarbonylphenyl) ethyl) -4-phenylethenylbenzene (2nd Wittig olefination)

The aldehyde (trans-isomer) obtained after process step a) is analogous to Example 1 of a further Wittig olefination

subjected to:

5.7 g of a 55% sodium hydride dispersion are initially introduced under protective gas atmosphere in 75 ml of dimethylsulfoxide, with 61.9 g (143 mmol) of the phosphonium salt described in Example 1 - suspended in 150 ml of dimethyl sulfoxide - and with 38.0 g (143 mmol) of the after process step a ) Aldehyde added. After reaction and

Working up according to Example 1 gives 19 g (39% of theory) of the benzene derivative designated in the title as yellow crystals of Mp: 110 ° C, which is further implemented in analogy to Example 19.

c) reduction of the diolefin

19 g (55 mmol) of the diolefin prepared according to process step b) are hydrogenated in 250 ml of tetrahydrofuran in the presence of Raney nickel as catalyst at 20 ° C. and 5 bar hydrogen pressure for 2 hours. This gives 18.7 g (78% of theory) of the 1,4-diphenethylbenzene derivative as colorless crystals of mp: 97-100 ° C.

d) Preparation of the Cyanoketone (corresponding to step 6 to 7 in the Reaction Scheme)

18.7 g (54 mmol) of the diphenylethane derivative prepared according to process step c) are dissolved in 100 ml of toluene and admixed with 2.4 g of sodium hydride dispersion (55%) and 7 ml of acetonitrile. After carrying out the reaction analogously to Example 1, 9.0 g (47% of theory) of the corresponding cyanoketone are obtained as crystals of mp: 128-130 ° C.

e) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

9.0 g (25 mmol) of cyanoketone type 7 prepared according to process step d) are mixed with 2.0 g of cyclopentanone and 0.9 g of sulfur in dimethylformamide and treated with 2 ml of triethylamine in 50 ml of ethanol and stirred at 60 ⁰ C for 7 hours. The reaction mixture is then - in analogy to Example 19 - diluted with 1,2-dichloroethane and washed twice with water. The organic phase is i. Vak. concentrated and chromatographed on a column filled with silica with dichloromethane as eluent. After recrystallization from diisopropyl ether, 3.5 g (30% of theory) of the aminoketone (of type 8) are obtained as crystals of mp: 115-12O ⁰ C.

f) Preparation of bromoacetylamide (corresponding to step 8 to 9)

4.6 g dOmmol) of the aminoketone prepared by process steps) are dissolved in 50 ml of dichloromethane and admixed with 0.80 ml of pyridine. Thereafter, 0.87 ml of ßromacetylbromid 2ugetropft. After the further reaction procedure analogous to Example 19 and recrystallization from diisopropyl ether is obtained 5.0 g (86% of theory) of the corresponding bromoacetylamide in the form of yellow crystals of mp: 112-116 ⁰ C,

g) Preparation of the amino derivative (corresponding to step 9 to 10)

5.0 g (96 mmol) of the bromoacetyl compound prepared according to process step f) are dissolved in 100 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 4.4 g (99% of theory) of the corresponding amino compound of type 10, which is cyclized in the subsequent reaction step, h) Preparation of the diazepinone derivative (corresponding to step 10 after 11 in the reaction scheme) 4.4 g (8 mmol) of the amino compound prepared according to process step g) are cyclized in 150 ml of toluene in the presence of 25 g of silica gel. The further reaction procedure and workup as in Example 1 resulting in 3.4 g (80% d. Th.) Of the corresponding diazepinone of type 11 in the form of crystals of mp .: 210-215 ⁰ C.

i) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the Reaction Scheme) 3.4 g (7 mmol) of the diazepinone derivative prepared according to process step h) are dissolved in 27 ml of pyridine and treated with 2.3 g of phosphorus pentasulfide. The reaction mixture is heated to 60 ^° C. over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i. Vak. are obtained 2.6 g (74% of theory) of the corresponding diazepinethione derivative as crystals of mp: 190 "C.

j) Preparation of the Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme) 2.6 g (5 mmol) of the diazepinethione prepared according to process step i) are initially charged in 30 ml of tetrahydrofuran and 0.3 ml of hydrazine hydrate are added. After carrying out the reaction according to Example 1, 2.5 g (97% of theory) of the corresponding type 13 hydrazone are obtained.

k) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 2.5 g (5 mmol) of the hydrazones prepared according to process step j) are suspended in 20 ml of ethanol and reacted with 2 ml of ethyl orthoacetate to give the title compound. 0.4 g (15% of theory) are obtained in the form of crystals of melting point 228 ° C.

Example 33

4-methyl-6- (3 _> 4 _> 5-trimethoxyphenethyl) -phenyl-8 _> 9-dihydro-1-methyl-4H, 7H-cyclopenta [4 _> 5] thieno [3,2-f] [1,2 , 4] triazolo [4.3 · a] [1,4] diazepine

N-N

Starting material for the preparation of the title compound is the aminoketone synthesized in Example 4 as an intermediate.

a) Acylation of the Aminoketone (Analogous to Step 8 to 9 in the Reaction Scheme)

16.1 g (37 mmol) of the aminoketone prepared according to Example 4 are initially charged with 3.3 g of pyridine in 200 ml of dioxane (1,4-dioxacyclohexane) and treated dropwise with 3.9 ml of 2-Chlorpropionsäurechlorid. It is stirred for 2 hours

Room temperature and filtered the reaction solution then on kieselguhr. After concentration of the filtrate Chromatograph the residue on a silica gel column (flash chromatography) with a mixture

from dichloromethane and 2% methanol as eluent. After concentration of the eluate and recrystallization from

Diisopropyl ether is obtained 18.4 (95% d.Th.) Of the corresponding Priopionsäureamids as yellow crystals of the melting point

138-140 ° C.

b) Halogen Exchange (Finkelstein Reaction)

18.4 g (35 mmol) of the acid amide prepared according to process step a) are dissolved in 290 ml of acetone and admixed with 10.5 g of sodium iodide and heated to reflux temperature over a period of 2 hours. After distilling off the solvent, the residue is partitioned between dichloromethane and water, the organic phase is separated and dried, and after filtering off the desiccant i. Vak. concentrated. After trituration of the residue with diethyl ether to obtain 14.2 g (66% of theory) of the corresponding iodine derivative as crystals of melting point 165-167 ° C.

c) Preparation of the amino compound (corresponding to step 9 to 10)

3.9 g (37 mmol) of the iodine compound prepared according to process step b) are dissolved in 50 ml of ethyl acetate and treated with gaseous ammonia over a period of 2 hours and then stirred for 8 days at room temperature. After distilling off the solvent i. Vak. is obtained 4.0 g of the corresponding amino compound as a crude product which is cyclized without further purification steps in the subsequent reaction step.

d) Preparation of the methyldiazepinone derivative (cyclization according to step 10 to 11 in the reaction scheme)

4.0 g (about 6 mmol) of the crude product resulting from process step c) are heated in 100 ml of toluene in the presence of 20 g of silica gel over a period of 2 hours on a water separator. After decanting off the toluene, the reaction product is extracted by boiling the silica gel three times with methanol. After distilling off the extractant i. Vak. the solid residue is triturated with ethyl acetate, after which 1.8 g (62% of theory) of the corresponding diazepinone derivative are obtained in the form of yellow-brown crystals of mp: 265 ° C. The further reactions for preparing the title compound are carried out in Carried out analogously to Example 19.

e) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme)

1.0 g (2 mmol) of the methyldiazepinone derivative prepared according to process step d) are dissolved in 15 ml of pyridine and admixed with 0.5 g of phosphorus pentasulfide. The reaction mixture is heated to 60 ^° C. over a period of two hours. The mixture is then diluted with water and extracted with dichloromethane. After removal of the extractant i. Vak. 0, Sg (48% of theory) of the corresponding diazepinethione derivative is obtained as a red-brown oil.

f) Preparation of the title compound (corresponding to step 12 to 13 in the reaction scheme)

0.5 g (1 mmol) of the diazepinethione prepared according to process step e) are initially charged in 5 ml of tetrahydrofuran and admixed with 0.1 ml of hydrazine hydrate and stirred at room temperature over a period of 1 hour. After narrowing the

Reaction solution i. Vak. The residue is taken up in 10 ml of ethanol and treated with 0.4 g of triethyl orthoacetate and heated for a period of »3 hours at reflux temperature. After removal of the solvent i.Vak. 0.1 g (19% of theory) of the title compound is obtained as a foam.

Example 34

6- (4-Trifluormethylphenethyl) -phenvl-1,11-dimethvl-2,3,4,5-tetrahydro-8 H-pyrido [4 ', 3': 4,5Jthieno [3,2 - (] triazolo- [4,3-a] [1,4] diazepin

M.p .: 160-162 ⁰ C

a) Preparation of the Aminoketone (Type 8) 5.0g (44mmol) N-methylpiperin-4-one, 13.9g / 44mmol) 1- (p-Cyanomethylcarbonylphenyl W-lp-trifluoromethylphenyl) ethane, 1.4g (44mmol) sulfur and 8 , 9g (88 mmol) of triethylamine are introduced into 200 ml of ethanol and stirred for a period of 5 hours at a temperature of 60 ⁰ C. Subsequently, the reaction solution i.Vak. Concentrated and the residue taken up with dichloromethane, washed twice with water, with The filtrate is concentrated by evaporation and the remaining residue is adsorbed on silica gel with a mixture of dichloromethane and about 2 to 4% methanol, the eluate is concentrated by evaporation and the residue is triturated with diethyl ether. 4g (43% of theory) of the aminoketone in the form of yellow-beige crystals.

b) Preparation of the bromoacetyl compound (corresponding to step 8 to 9 in the reaction scheme)

2.0 g (4 mmol) of the aminoketone obtained according to process step a) are dissolved with 45 ml of toluene and admixed with 4.0 g (20 mmol) of bromoacetyl bromide and heated to reflux temperature over a period of 2 hours. Subsequently, the reaction solution is cooled. The precipitated crystals are washed with toluene and sucked dry (mp: 175-177 ⁰ C). The reaction product used without further purification steps in the next reaction stage.

c) Preparation of the amino compound (corresponding to step 9 to 10 in the reaction scheme)

The entire amount of bromoacetylamide obtained in process step b) is initially charged in 200 ml of ethyl acetate. In this solution, gaseous ammonia is introduced over a period of 4 hours. The reaction mixture is stirred for a further three hours at room temperature. Subsequently, the reaction solution is washed twice with water, the organic phase dried and after removal of the drying agent i.Vak. concentrated. 1.6 g of the amino compound are obtained as a brown foamy residue.

Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme)

1.6 g of the amino compound prepared according to process step c) are heated in 100 ml of toluene in the presence of 18 g of silica gel over a period of 6 hours in a water at the reflux temperature. The toluene is then decanted off, the silica gel is extracted three times with methanol. The combined extracts are filtered off with suction through silica gel / activated charcoal and dried i.Vak. concentrated.

The remaining residue is adsorptively filtered on silica gel with a mixture of dichloromethane and about 2-6% methanol. This gives 0.9 g of the diazepinone derivative in the form of a brown foam. Preparation of the diazepin-thione (corresponding to step 11 of Figure 12 in the reaction scheme) 2.4 g (5 mmol) of the diazepinone prepared according to process step d) are dissolved in 20 ml of pyridine and treated with 1.7 g of phosphorus pentasulfide Analogous reaction procedure and work-up as described in Example 19 gives 0 , 8 (32% of theory) of the diazepinethione derivative as a foamy oil.

Preparation of the title compound via hydrazone (corresponding to step 12 via 13 to 14 in the reaction scheme) 0.8 g (1.6 mmol) of the diazepinethione prepared by process steps) are dissolved in 10 ml of tetrahydrofuran and treated with 0.1 ml of hydrazine hydrate. Reaction and working up according to Example 1 leads to 0.8 g of the corresponding hydrazones, which is then dissolved in 10 ml of ethanol and reacted with 1.0 g of triethyl orthoacetate to the title compound. For working up the reaction mixture, the solution is evaporated and the remaining residue taken up in a mixture of 20 ml of water and 3 ml of 2 N hydrochloric acid

 The mixture is washed with dichloromethane.

Subsequently, the aqueous phase is made slightly alkaline. The precipitated at a pH of about 7 to 8 title compound is extracted with dichloromethane. The combined organic extracts are dried, filtered off with suction through silica gel / activated charcoal and concentrated by evaporation in vacuo. concentrated. This gives 0.5 g (60% of theory) of the title compound as a foam.

Example 35

6- (4-thlenylethylphenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-fJ [1,2,4] -tahozoio [OS] [ 1,4] diazepin

The synthesis procedure for the preparation of the title compound is carried out in analogy to the method described in Example 1 or Example 19 with the exception that in the Wittig olefination (in the reaction scheme step 4 to 5) instead of p-trifluoromethylbenzaldehyde thiophene-2-aldehyde is used ,

a) Wittig olefination (corresponding to step 4 to 5 in the reaction scheme)

12.5 g of a sodium hydride dispersion (55%) are placed under inert gas in 150 ml of absolute dimethyl sulfoxide and according to Example 1 with 140.8 g (287 mmol) of the corresponding phosphonium salt suspended in 300 ml of dimethyl sulfoxide - and then with 27,3ml (300mmol ) Thiophene-2-aldehyde added. The work-up according to Example 1 yields 16.7 g (23% of theory) of the corresponding olefin in the trans configuration (isomer separation S.Example 19)

b) Reduction of the olefin (corresponding to step 5 to 6 in the reaction scheme)

13g (53mmol) of the prepared according to step a) trans olefin in 20OmI tetrahydrofuran in the presence of 2.6 g of palladium on carbon (10% Pd content) as catalyst at 20 ° C and 5bar hydrogen pressure over a period of 2 Hydrogenated for 5 hours. This gives 12.0 g (92% of theory) of the hydrogenated product as an oil.

c) Preparation of the Cyanoketone (Corresponding to Step 6 to 7 in the Reaction Scheme)

13.9 g (56.4 mmol) of the diphenylethane derivative prepared according to process step b) are dissolved in 56 ml of toluene and admixed with 2.5 g of sodium hydride dispersion (55%) and 7.3 ml of acetonitrile. After the reaction is carried out analogously to Example 1 of the corresponding cyanoketone of melting is obtained 8.3 g (58% of theory) .: 97-105 ⁰ C.

d) Preparation of the aminoketone (corresponding to step 7 to 8 in the reaction scheme)

18.4 g (72 mmol) of cyanoketone prepared according to process step c) are mixed with 5.7 g of cyclopentanone and 2.6 g of sulfur in dimethylformamide and treated with 5.7 ml of triethylamine in 140 ml of ethanol and stirred at 60 ⁰ C for 7 hours. The reaction mixture is then diluted in analogy to Example 19 with 1,2-dichloroethane and washed twice with water. The organic phase is i. Vak. concentrated and chromatographed on a column filled with silica with dichloromethane as Elutionsmrttel. After recrystallization from diisopropyl ether, 6.5 g (26% of theory) of the aminoketone (of type 8) are obtained as crystals of mp: 110-113 ° C.

e) Preparation of bromoacetylamide (corresponding to step 8 to 9 in the reaction scheme)

6.5 g (18 mmol) of the aminoketone prepared according to process step d) are dissolved in 90 ml of dichloromethane and admixed with 1.5 ml of pyridine. Thereafter, 1.6 ml of bromoacetyl bromide are added dropwise. After the further reaction procedure-analogously to Example 19-and recrystallization from diisopropyl ether, 7.0 g (80% of theory) of the corresponding bromoacetylamide are obtained as an oil.

f) Preparation of the amino derivative (corresponding to step 9 to 10 in the reaction scheme)

7.0 g (15 mmol) of the bromoacetyl compound prepared by process steps) are dissolved in 140 ml of ethyl acetate and treated analogously to Example 1 with gaseous ammonia. After the further reaction procedure according to Example 1, 6.0 g (99% of theory) of the corresponding amino compound of type 10 are obtained, which is cyclized without further purification steps in the subsequent reaction step.

g) Preparation of the diazepinone derivative (corresponding to step 10 to 11 in the reaction scheme)

6.0 g (15 mmol) of the amino compound prepared according to process step f) are cyclized in 100 ml of toluene in the presence of 30 g of silica gel. The further reaction procedure and working up according to Example 1 leads to 3.7 g (63% of theory) of the corresponding diazepinone of type 11 in the form of crystals of melting point: 2OO-202 ° C. h) Preparation of the diazepinethione derivative (corresponding to step 11 of Figure 12 in the reaction scheme)

3.7 g (9.4 mmol) of the diazepinone derivative prepared according to process step g) are dissolved in 80 ml

Diethylene glycol dimethyl ether and treated with 5.5 g of phosphorus pentasulfide and 1.7 g of sodium bicarbonate. The reaction mixture is - as described in Example 1 - treated and worked up. After removal of the extractant i. Vak. Obtained 3.8 g (99% of theory) of the corresponding Diazpinthion derivative as crystals of mp: 217 ° C (decomposition).

i) Preparation of Type 13 Hydrazono Compound (Corresponding to Steps 12 to 13 in the Reaction Scheme)

3.8 g (9 mmol) of Diazeptinthions prepared according to process step h) are placed in 60 ml of tetrahydrofuran and treated with 0.6 ml of hydrazine hydrate. After carrying out the reaction according to Example 1 and recrystallizing from diethyl ether, 2.6 g (69% of theory) of the corresponding type 13 hydrazone are obtained as crystals of mp: 200 ° C. (decomposition).

j) Preparation of the title compound (corresponding to step 13 to 14 in the reaction scheme) 2.6 g (6.3 mmol) of the hydrazone prepared according to process step i) are suspended in 30 ml of ethanol and reacted with 2 ml of triethyl orthoacetate to give the title compound. After recrystallization from ethyl acetate, 1.5 g (54% of theory) of the title compound are obtained in the form of crystals of mp: 200 ° C.

Example 36

6- (4- (4-chloro-N-methylamino) methylphetiyl) -8,9-dihydro-1-Methyl-4H, 7H-cvclopenta [4,5] thieno [3,2-f] [1,2, 4y-triazolo [4,3-a] [1,4] diazepin

• ^ C n ^ N,

'N

CH ₇ N (CH,) ^ v

a) The alcohol prepared according to Example 7 is converted into the corresponding chloride as described in Example 23-.

b) 0.96 g (2.6 mmol) of the obtained after process step a) chloride are dissolved in 30 ml of dioxane (1,4-dioxacyclohexane) and treated with 0.8 g of 4-chloro-N-methylaniline and over a period of Heated to reflux for 5 hours. After distilling off the reaction medium i. Vak. the residue is taken up in a mixture of water and ethyl acetate, the organic phase is separated, dried and after filtering off the desiccant i. Vak. concentrated. The remaining residue is purified by flash chromatography on a silica gel column using as eluent a mixture of dichloromethane and 4% methanol to give 280 mg (23% of theory) of the title compound as a foam ,

Example 37 6- (4 (2-Cyclohexylethyl) phenyl) -8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5-thieno [3,2-fKi, 2,4] triazolo [4.3 -aK1,4ldiazepin

(CH

2 ^J 2

The title compound is prepared analogously to Example 1, with the difference that instead of p-trifluoromethylbenzaldehyde, cyclohexane aldehyde is used in so-called "Wittig olefination." The title compound is obtained in the form of crystals of mp: 198-200 ° C.

 In analogy to the methods described, the following compounds can be prepared:

CH ₂ M

[1,4] diazepine mp; 175-178 ° C

6- (4- (3 x TrifluoΓmethylphenyl) -N-methyl ^ aminomethylene) -phenyl) -8 ^ -dihydΓO-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-f] - [1,2,4] triazolo [4,3-al [1,4] dia2epin.

CH-N

CH ₇ -CH ₃

CF,

6- (4- (3-trifluoromethylphenyl-N-ethyl-aminomethylene) -phenyl-8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5] thieno [3,2-fl [1 , 2,4] triazolo [4,3-a] [1,4] diazepine mp: 114-116 ° C

CH ₂ N ^

CH ₂ -CH ₂ -CH ₂ -CH ₃

CF ₁

6- (4 - [(3-trifluoromethylphenyl) -N-butyl-aminomethylene] phenyl-8,9-dihydro-1-methyl-4H, 7H-cyclopentaI4,5] thieno [3,2-FJ [1 , 2,4] triazolo [4,3-a] [1,4] diazepine.

M .: 147-148 ° C

6- (4- [3,4-D-chlorophenyl-N-ethyl-aminomethylene-phenyl-8,9-dihydro-1-n-ethyl-4H _/ 7H-cyclopenta) 4,5] thieno [3.2 · f) (1,2,4] triazolo [4,3-a] [1,4] diazepin

Schmp.:1O7-nO'C

6- (4- (N -Benzyl-N-ethylamino) -phenyl) 8 -dihydro-1-methyl-4H _< 7H-cvclopenta (4,5-thieno [3.2-fl [1 _/ 2,4] triazolo (4, 3-a] - [1,4] diazepine,

6- (4- [4-cyclopropylphenyl) -N-butyl-aminomethylene) phenyl-8,9-dihydro-1-methyl-4H, 7H-cyclopenta [4,5lthieno [3,2-f) - _[1/2 , 4ltriazolol4,3-a) [4,3-a] H, 4) diazepin

The novel compounds of general formula Ia can be administered to warm-blooded animals topically, orally, parenterally transdermally or by inhalation. The compounds are present as active ingredients in conventional dosage forms, z. In compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, e.g. Tablets, dragées, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, ointments, emulsions, syrups, suppositories, etc. An effective dose of the compounds of the invention is between 1 and 50, preferably between 3 and 20 mg / dose when administered orally intravenous or intramuscular administration between 0.01 and 50, preferably between 0.1 and 10 mg / dose. For inhalation, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% of active ingredient should be used.

The following examples serve to explain the invention in more detail:

example 1

Tablets containing 10 mg of the substance of the formula I.

Composition: 10.0 mg Substance of the formula I. 57.0 mg corn starch 48.0 mg lactose 4.0 mg polyvinylpyrrolidone 1.0 mg magnesium stearate 120.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The moist mixture is forced through a sieve of 1.5 mm mesh size and dried at about 45 ° C. Dastrockne granules are passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The finished mixture is compressed on a tablet press with punches of 7 mm diameter, which are provided with a partial notch, into tablets. Tablet weight: 120 mg

Example 2

Dragees, containing 5 mg of the substance of formula I.

Composition: 5.0 mg Substance B of the formula I 41.5 mg corn starch 30.0 mg lactose 3.0 mg polyvinylpyrrolidone 0.5 mg magnesium stearate 80.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ⁰ C and then strikes the granules through the same sieve. After admixing Magnesiumsterat are on a tabletting machine curved dragoe cores with a diameter of 6mm pressed. The Dragoekerne thus prepared are coated in a known manner with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax. Dragoe weight: 130 mg

Example 3

Tablets containing 50 mg of substance of formula I.

Composition: 50.0 mg Substance B of the formula I 70.0 mg calcium phosphate 40.0 mg lactose 35.0 mg corn starch 3.5 mg polyvinylpyrrolidone 1.5 mg magnesium stearate

200.0 mg

production:

The substance, calcium phosphate, lactose and corn starch are evenly moistened with an aqueous solution of polyvinylpyrrolidone. The mass is passed through a sieve with 2 mm mesh size, dried in a convection oven at 50 ⁰ C and sieved again. After admixing the lubricant, the granules are pressed on a tableting machine.

Example 4 Capsules containing 50 mg of the substance of formula I. Composition: Substance of formula I 50.0 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg

320.0 mg

production: Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The

dry granules are sieved and mixed with magnesium stearate. The final mix is filled into hard gelatin capsules size.

Example 5 Suppositories containing 50 mg of substance of the formula I. Composition: Substance of the formula I 50 mg Adepssolidus 1650 mg

1 700 mg

production: The hard fat is melted. At 40 ^° C., the ground active substance is dispersed homogeneously. It is cooled to 38 ⁰ C and

poured into weakly pre-cooled suppository molds.

Example 6 Oral suspension containing 50 mg of the substance of formula I per 5 ml

To be added: 50 mg Substance of the formula I. 50 mg hydroxyethyl 5 mg sorbic acid 600 mg Sorbitol 70% 200 mg glycerin 15mg Aroma 5 ml Water ad

production:

Distilled water is heated to 70 ° C. Herein, hydroxyethyl cellulose is dissolved with stirring. After addition of sorbitol solution and glycerol is cooled to room temperature. At room temperature, sorbic acid, flavor and substance are added. To vent the suspension is evacuated with stirring.

Example 7 Ampoules containing 1 mg of the substance of formula I per 5 ml Composition:

Substance of the formula I 1 mg sodium chloride 45 mg water for injections ad 5 ml

production:

The substance is dissolved in water at intrinsic pH and sodium chloride added as isotope. The resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.

Example 8 Ampoules containing 5 mg of the substance of formula I per 5 ml

Composition: 5 mg Substance of the formula I. 45 mg sodium chloride Water for injection 5ml purposes ad

Preparation analogous to Example Example 9 Ampoules containing 10 mg of substance of formula I per 5 ml

Composition: 10mg Substance of the formula I. 35 mg methylglucamine 1000 mg Glucofurol polyethylene glycol polypropylene glycol 250 mg block polymer Water for injection 5ml purposes ad

production: In one part of the water, methylglucamine is dissolved and the substance is dissolved with stirring. After adding the Solvent is made up to the nominal volume with water. Example 10 Ampoules containing 20 mg of substance of formula I per 10 ml

Composition: 20,000 mg Substance of the formula I. 85,000 mg sodium chloride sodium 0.925 mg x 2 H ₂ O disodium 1.320 mg κ 2 H ₂ O ad pH 6 0.1NNaOH Water for injection ad 10ml purposes

production: The above ingredients are dissolved in water and, after filtration, the solution is filled into sterilized brown vials. Example 11 Inhalation solution containing 5 mg of the substance of formula I per 1 ml

Composition: 500 mg Substance of the formula I. 50 mg Na-EDTA 25mg benzalkonium chloride 880 mg sodium chloride 100 mg Distilled water ad

production:

60% of the amount of water are introduced, successively Na-EDTA, benzalkonium chloride, sodium chloride and substance

clearly dissolved and filled up with the remaining water. The solution is filled into 20 ml dropping bottles.

Claims (7)

1. New thienodiazepines of the general formula R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, preferably methoxy, halogen, preferably chlorine or bromine; R _{2 is} the radical-GR _a worinfürn> 0 R _{a is} hydrogen, halogen, hydroxy, R ₆ N - ^R 7 ^ wherein R ₆ and R ₇ , which may be identical or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-10 carbon atoms, preferably 1-4 carbon atoms, which may optionally be substituted by halogen, hydroxy, phenyl, substituted phenyl, or by a C-linked heterocycle, wherein the carbon chain may be interrupted by nitrogen (also NH), oxygen or sulfur, a branched or unbranched alkylcarbonyl group having 1-6 carbon atom ( en), [optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by an optionally mono- or di-substituted by a branched or unbranched alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may be substituted by halogen or hydroxy], optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted te arylsulfonyl group, preferably phenylsulfonyl or Tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atoms, an optionally substituted C ₃ - to C ₇ -cycloalkyl, an optionally substituted C5-C ₇ cycloalkenyl, or R ₆ or R ₇ optionally one or more times branched or unbranched alkyl having 1 to 4 carbon atom (s) of substituted, saturated or unsaturated bonded via a carbon atom 5-, 6- or _7- membered heterocyclic ring, or R ₆ and R ₇ form together with the nitrogen atom, a saturated or unsaturated optionally one or more times branched or unbranched alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-ring, which may contain as further heteroatoms nitrogen, oxygen or sulfur, each further nitrogen atom optionally substituted by a branched or unbranched alkyl group having 1 to 4 carbon atom (s ), preferably methyl can be; R _{a is} an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups with up to 4 carbon atoms (s), a branched or unbranched alkylsulphonyloxy group having 1 to 4 carbon atoms, an arylcarbonyloxy group, preferably phenylcarbonyloxy, optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms, a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8 carbon atoms, the alkyl chain may be interrupted by nitrogen, oxygen or sulfur; wherein R _{8 is} a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 4 carbon atoms, optionally substituted by halogen, an aryl group optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atom (s), R is hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms, Rq 0 R _a N S- ^R 10 ° wherein Rg and R ₁₀ , which may be the same or different. Hydrogen, a branched or unbranched alkyl group having 1 to 10Kohlenstoffatom (s), bevorzugtl bis4einen optionally substituted C ₃ -C ₇ -cycloalkyl radical, an optionally _C5-C7 cycloalkenyl, or R ₉ and R ₁ O together with the nitrogen atom represent an optionally mono- or 5-, 6- or 7-membered ring which is polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, each further nitrogen atom being represented by an alkyl group having 1 to 4 carbon atoms (s), preferably methyl, is substituted; R _{a is} a branched or unbranched alkoxy graft of 1 to 4 carbon atoms; an aryloxy group, preferably phenyloxy or substituted phenyloxy; R _{a is} a C-linked 5- to 7-membered non-aromatic heterocycle; R _{a is} an imido radical, a benzimidazoyl radical, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom such. Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s); R _a is greater than or equal to 0: hydrogen, halogen, -CH = 0, -CN, C00h; R _a Alkyloxycarbonylgruppe having 1-10, preferably 1-4 carbon atom (s), optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by an amino group, optionally one or two times by a branched or n-branched alkyl group having 1 to 6 Koh'lenstoffatom (s) may be substituted, wherein the alkyl group may in turn be substituted by halogen or hydroxy; R _a optionally substituted phenyloxycarbonyl, R _{a is} a radical of the general formula Ri, O Il N C - wherein Rn and Ri ₂ , which may be the same or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or Alkynyl group having 1 to 10 carbon atom (s), preferably 1 to 4 carbon atom (s), optionally [by halogen, hydroxy, nitro, amino, an optionally mono- or di-substituted by a branched or unbranched alkyl group having 1 to 6 carbon atoms amino group wherein the alkyl group may be substituted by halogen or hydroxy, morpholine, piperazine, N-alkylpiperazine, or in the case VOnR ₁₁ = hydrogen or alkyl and Y = CR ₁ or Y nitrogen and X C-alkyl, R ₁₂ by an ester group or an acid amide of the general formula R ' _{1 ±} O \ N- C - wherein R'ti and R _{'12 may have the} same meaning as R ₁₁ and R ₁₂ -but may, but have an acid amide-substituted may be], R ₁₁ or R _{12 is} an optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 Carbon atom (s) of substituted, saturated or unsaturated 5, 6 or lower heterocyclic ring bonded via a carbon atom, R ₁ -I or R _{12 represents} an optionally substituted C ₃ to C ₇ cycloalkyl radical, an optionally substituted C 5 to C ₇ cycloalkenyl radical, or R ₁₁ and R ₁₂ together with the nitrogen atom represent a saturated or unsaturated 5-, 6- or 7-membered ring which is optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, wherein each additional nitrogen atom is represented by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, subs can be substituted;
a radical of the general formula NO'
a NO' \ a K B- wherein B is oxygen, sulfur, NH or N- (Ci-C ₆ -AIkyI), D is the radical (CR _e R _f ) _n , where η can be 0 to 3, R ' _a hydrogen, optionally substituted by a hydroxy or amino group Alkyl having 1 to 6 carbon atoms, C 1 to C ₄ alkoxycarbonyl, dialkylaminocarbonyl, R _b , R _c , R d <R e »R f is hydrogen, optionally substituted by a hydroxy or amino group-substituted alkyl having 1 to 6 carbon atoms, or phenyl; R _{3 is} phenyl or substituted phenyl; G is a branched or branched alkyl, alkenyl or alkynyl group having η carbon atoms, where G may optionally be additionally substituted by an aryl radical or additionally by R ₃ ; η one of the numbers 0,1,2,3,4,5,6,7,8,9 or 10, wherein in case G is an alkenyl or Alkynyl radical is η> 1 and preferably has the meaning of 2,3 and 4; R _{3 is} hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; or R ₂ and R ₃ together form a radical of the general formula I - wherein a fused monounsaturated 5-, 6- or 7-membered ring, wherein in the case of m = 0 and R _b = hydrogen, a carbon atom can be replaced by C = 0, or A is a fused ring of the formula means wherein R _{0 is} a branched or unbranched alkyl group having 1 to 18, preferably 1 to 4, carbon atom (s), a branched or unbranched alkenyl or alkynyl group having 2 to 18, preferably 2 to 4 carbon atoms, an alkylcarbonyl or alkylthiocarbonyl group with 1 to 18, preferably 1 to 4. Carbon atoms in the alkyl chain or an arylcarbonyl or arylthiocarbonyl group, an optionally substituted C ₃ to C ₆ cycloalkyl or cycloalkylcarbonyl group, an alkenyl or alkynylcarbonyl group having 2 to 18, preferably 2 to 4 carbon atoms, an alkoxycarbonyl group up to 18, preferably 1 to 4 carbon atoms, a optionally substituted phenylalkyl-phenylalkenyl group or phenalkinyl group having 1 to 6, preferably 2 to 4 carbon atoms in the carbon chain, an alkoxycarbonylalkyl group having up to 18, preferably up to 8 carbon atoms, more preferably up to 4, an alkylcarbonylalkyl group having up to 18, preferably up to 8 carbon atom ( en), particularly preferably up to 4, an alkylcarbonylaminoalkylcarbonyl group having up to 18, preferably up to 10 carbon atoms or an aminocarbonylalkyl group having up to 18, preferably up to 4 carbon atoms in the alkyl chain or hydrogen, a radical R ₁₃ R ₁₄ NCO- (CH ₂ ) o-3, an over- (CH ₂ ) -o-3-linked 5- or 6-membered heterocyclic radical, an over- (CH ₂ ) -O-3, -CO- (CH ₂ ) o-3, -CO-CH = CH ₂ -, linked Cs-Ce-cycloalkyl radical, preferably cyclopropyl; a branched or unbranched alkyl, alkenyl or alkynyl group with m carbon atoms; 0,1,2,3,4,5 or 6; Hydrogen, hydroxy, amino, formyl, carboxy, cyano, branched or unbranched alkyloxycarbonyl of 1 to 18, preferred, carbon atom (s) wherein the alkyl chain may be optionally substituted by hydroxy, amino, nitro or halogen, an optionally substituted aryloxycarbonyl group; a radical of the general formula Il N-C- wherein R ₁₃ and R ₁₄ , which may be the same or different. Is hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms, preferably 1 to 6, particularly preferably 1 to 4 carbon atom (s), optionally substituted by halogen, hydroxy, nitro, amino . substituted amino, C ₃ -C ₆ -cycloalkyl, alkoxy, preferably methoxy or in the case of R ₁₃ - hydrogen or alkyl, by an ester function or by an acid amide of the general formula wherein R _'13 and R' ₁₄ , may have the same meaning as R ₁₃ and R ₁₄ , but with the exception of an acid amide, Ri 3 or R _{14 is} an optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atoms substituted, saturated or unsaturated carbon-linked 5, 6 or y-membered heterocyclic ring, an optionally substituted C _{3 to} C ₇ cycloalkyl group, an optionally substituted cycloalkenyl group; or R ₁₃ and R _14, together with the nitrogen atom, have a 5-, 6- or 7-membered ring which is optionally monosubstituted or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having from 1 to 4 carbon atoms, preferably methyl;
R _{b is} a radical of the general formula NP /
a NO'
\ where π η B is oxygen, sulfur, NH or N- (C ₁ -C ₆ -alkyl), D is the radical (CR _e R,) _n , where η can be O to 3, R'a is hydrogen, optionally substituted by a hydroxy or amino group Alkyl of 1 to 6 carbon atoms), C 1 to C ₄ alkoxycarbonyl, dialkylaminocarbonyl, R _b , R _c , R d / Re. Rf is hydrogen, optionally substituted by a hydroxy or amino group-substituted alkyl having 1 to 6 carbon atoms), or phenyl, R ₁₅ = hydrogen, R ₆ = hydrogen, alkylcarbonyl or alkoxycarbonyl having 1 to 18, preferably 1 to 6 carbon atom (s), aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl having 1 to 18, preferably 1 to 6, carbon atom (s) in the alkyl chain;
Hydrogen, phenyl, substituted phenyl; _Rb halogen, ^R 15 "N ^R 16 wherein R ₁₅ and R ₁₆ , which may be identical or different, represent hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-18 carbon atoms, preferably 1 to 6 carbon atoms, which may optionally be substituted by halogen, hydroxy, C ₃ -C ₆ -cycloalkyl or a C-linked heterocycle, wherein the carbon chain may be interrupted by nitrogen, oxygen or sulfur, a branched or unbranched alkylcarbonyl group having 1-6 carbon atom (s) optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by an amino group optionally substituted once or twice by a branched or unbranched alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may be substituted by halogen or hydroxy, optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulfonyl group ppe, preferably phenylsulfonyl or tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atoms, or R ₁₅ or R _{16 is} a saturated or unsaturated, optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atom (s) Carbon atom bonded 5-, 6- or 7-membered heterocyclic ring, R ₁₅ or R _{16 is} an optionally substituted C ₃ - to Cy-cycloalkyl, an optionally substituted C ₅ - to C ₇ cycloalkenyl or R ₁₅ and R ₁₆ together with the nitrogen atom form a saturated or unsaturated, optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atom (s) substituted 5-, 6- or 7-ring, which may contain nitrogen, oxygen or sulfur as further heteroatoms, each further nitrogen atom optionally by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, s may be substituted; R _{b is} an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups with up to 4 carbon atoms; R _{b is} a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atoms; R _{b is} an arylcarbonyloxy group, preferably tolylcarbonyloxy or phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having from 1 to 4 carbon atoms; R _{b is a} branched or unbranched alkylcarbonyloxy group of from one to 18, preferably from 1 to 8, carbon atom (s) wherein the alkyl chain may be interrupted by nitrogen, oxygen or sulfur; N C O-, · N C-N where R _{17 is} hydrogen and R _{18 is} an alkyl, alkenyl or alkynyl group having 2 to 4 carbon atoms, optionally substituted by halogen, an optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atom (s) substituted Aryl group, R _{19 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atom (s); R _{b is} an imido radical, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally one carbon atom is substituted by another heteroatom such. Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s), a benzimidazolyl radical; R _{b is} a branched or unbranched alkyloxy or. Alkylthio radical having 1 to 18, preferably up to 4, carbon atom (s), an optionally substituted phenyloxy or phenylthio radical, an oxygen or sulfur linked, saturated or unsaturated 5 or 6-membered heterocyclic ring; R _{4 is} a radical of the general formula wherein S is a single bond, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atom (s), optionally substituted by halogen and / or hydroxy, branched or unbranched alkenyl having 2 to 8 carbon atoms - preferably having 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy, branched or unbranched alkynyl having 2 to 8 carbon atoms, preferably substituted by 2 to 4 carbon atom (s), optionally substituted by halogen and / or hydroxy; W is an optionally substituted aromatic ring having 6 to 10 carbon atoms which may optionally contain one or more heteroatom (s) selected from the group nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring having 3 to 7 carbon atoms, which may also contain a double bond; T is branched or unbranched alkyl optionally substituted by halogen or hydroxy with 1 to 8, preferably 1 to 4 carbon atom (s); branched or unbranched alkenyl having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy; branched or unbranched alkynyl of 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy; a radical of the formula LO, S, NR ₉ , C = O, CO, (J) -N, NC, Rn Rn
wherein R _{6 is} as previously defined, preferably hydrogen, d-Ca-alkyl, or CC ₁ -C ₆ -alkyl or CH,
R ₁₁ as defined above, preferably hydrogen or C ₁ -C ₄ -alkyl; or E means OC S, $, S-NR ₉ , R ₉ as previously defined, F is a branched or unbranched optionally substituted alkyl group 1 to 8 preferably 1 to 4 carbon atom (s), an optionally substituted alkenyl group having 2 to 8 preferably 2 to 4 carbon atoms, an optionally substituted alkynyl group having 2 to 8 preferably 2 to 4 carbon atoms; V is an optionally substituted aromatic ring of 6 to 10 carbon atoms which may optionally contain one or more heteroatoms selected from nitrogen, oxygen or sulfur; an optionally substituted carbocyclic ring of 3 to 7 carbon atoms which may also contain a double bond, a cyclic amide or imide; May have 5,6 or 7 ring members and in which optionally a carbon atom by another heteroatom such. Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s); U is branched or unbranched alkyl optionally substituted by halogen or hydroxy having 1 to 8 - preferably 1 to 4 carbon atom (s), branched or unbranched alkenyl having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, optionally substituted by halogen and / or hydroxy ; branched or unbranched alkynyl having 2 to 8 carbon atoms - preferred 2 to 4 carbon atoms optionally substituted by halogen and / or hydroxy; a remainder of the formula ₆ , C = O, CO, CN, NC, wherein Re as defined above, preferably hydrogen, C ₁ -C 4 alkyl, or L ₁ -C C ₆ alkyl or CH,
and R ₁₁ as defined above, preferably hydrogen or C ₁ -C ₄ alkyl; orE means , R ₉ as defined above, F is a branched or unbranched optionally substituted alkyl group having 1 to preferably 1 to 4 carbon atoms, an optionally substituted alkenyl group having 2 to 8 preferably 2 to 4 carbon atoms, an optionally substituted alkynyl group having 2 to 8 preferably 2 to 4 carbon atoms; P is an optionally substituted aromatic ring having 6 to 10 carbon atoms, which may optionally contain one or more heteroatoms selected from the group of nitrogen, oxygen or sulfur, an optionally substituted carbocyclic ring having 3 to 7 carbon atoms, which may also contain a double bond, wherein W, V and / or P may be mono- or polysubstituted by Z, a cyclic amide or imide which may have 5,6 or 7 ring members and in which optionally a carbon atom is substituted by another heteroatom such as. Nitrogen, oxygen or sulfur may be substituted and which may be optionally fused by one or more aryl radical (s); Hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, optionally substituted by halogen or hydroxy, branched or unbranched alkyl having 1 to 8 preferably 1 to 4 carbon atom (s), optionally substituted, branched alkoxy having 1 to 8 preferably 1 to 4 carbon atom (en), a remainder of the formula - (FVi-EMFV ₁ -H, (FVi-NO ₂ , ^R 7 (FV ₁ -C - (P) ₀ -IC- (C ₁ -Ca) -alkyl, preferably C ₁ -C ₄ -alkyl, wherein F 'is a branched or unbranched alkyl group having 1 to 4 carbon atom (s), preferably 1 to 2 carbon atom (s) or F' has the same meaning as Find E '= E or -. ' = O, S, NR ₆ , C = O, NC, CN where, when α> 1, all Z can be the same, partly the same or different, K = 0.1, L = 0,1,2, M = 0.1, N = 0.1 and α = 1,2,3,4,5 and E has the meaning given, where the sum K + L + M + N is not equal to 0 and generally not a phenyl radical, a phenyl radical which is substituted by halogen, CH ₃ , CF ₃ and NO ₂ , may denote a pyridyl or a thienyl radical. R _{5 is} hydrogen, CF ₃ , hydroxy, branched or unbranched alkyl having 1 to 6, preferably 1 to 4 carbon atom (s), particularly preferably methyl, optionally the alkyl group is hydroxy, halogen, C ₁ - to C ₄ -alkylsulfonyloxy, preferably methylsulfonyloxy . wherein R ₁₅ and R ₁₆ may be as defined above, or CN
H
0 14 wherein R ₁₃ and R _{14 may have} the abovementioned meaning, substituted; Alkylcarbonyloxy having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, alkoxycarbonyl having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, carboxyalkyl having 1 to 4 carbon atoms in the branched or unbranched alkyl chain, alkoxycarbonylalkyl with 1 to 4 carbon atom (s) in the branched or unbranched alkyl radicals X / Y independently CR ₁ , or N, but not both CR ₁ , with R ₁ preferred Hydrogen or methyl, or Y is the group C-COOR ', where R' is alkyl or hydrogen and X is nitrogen; optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their physiologically acceptable acid addition salts. 2. The novel thienodiazepines of the general formula I according to claim 1, wherein R ₂ and R _{3 have} a radical as defined for the general formula 1 and wherein R _{1 is} ethyl, trifluoromethyl, methoxy, ethoxy or halogen, particularly preferably chlorine or bromine; particularly preferably methyl; R _{a is} hydrogen, chlorine, bromine, iodine, hydroxy, Gp-C-alkoxycarbonyl, phenyl, substituted phenyl; C ₃ -C ₆ -cycloalkyl;
wherein in R ₄ preferred S is a single bond (K = 0), branched or unbranched C ₁ -C ₄ -alkyl, branched or unbranched C ₂ -C ₄ -alkyl, branched or unbranched C ₂ -C ₄ -alkynyl, W is a phenyl ring, a pyridine ring, a thiophene ring optionally halogen, a hydroxy group, a cyclopropyl radical, a C ₁ -C ₄ -alkyl radical, a C ₁ -C ₄ -AIkOXYrCSt identical or different mono- or polysubstituted; T is an alkyl chain having up to 6 members, preferably ethyl, an alkenyl chain having 2 to 4 members preferably vinyl, an alkynyl chain having 2 to 4 members preferably C = C, which may be interrupted by a heteroatom such as oxygen, sulfur or nitrogen, or CH ₂ -ISI-, -IjI-CH ₂ C ₁ -C ₄ -alkyl C ₁ -C ₄ -alkyl CH ₂ -N-CH ₂ -C ₁ -C ₄ -AlkYl or the rest of C-N- C ₁ -C ₄ alkyl; tCN
0 V is a phenyl group, a thienyl group or a C ₃ -C ₆ -cycloalkyl group, a substituted phenyl group,
U prefers a single bond (M = 0), OdGr-CH ₂ -CH ₂ -if P is a phenyl group means;
P is a phenyl group; preferably P _n = zero Z is hydrogen, branched or unbranched C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, trifluoromethyl, halogen- preferably chlorine or bromine, CN, NO ₂ , cyano, COH, COOH, COOC ₁ -C ₄ - AIkYl, CONH ₂ , CON (C ₁ -C ₄ -Alkyl) ₂ , cyclopropyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, hydroxymethyl, SO ₂ -Ci-C ₄ -alkyl, SO ₂ -C, - C ₄ -hydroxyalkyl, hydroxy, SH, SC ₁ -C ₄ -alkyl, where, when α> 1, all Z can be the same, in some cases identical or different, K = 0.1, preferably 0
L = 0,1,2, preferably 1
M = O, 1, preferably 1
N = 0.1, preferably 1, but P _N preferably 0 and α = 1,2,3, where the sum K + L + M + N is not equal to 0 and -SK-WL-TM-VN-UM-PN-Za in total is not a phenyl radical, a phenyl radical containing halogen , CHs, CF ₃ and NO _{2 is} substituted, a pyridyl or a thienyl radical. R _{5 is} hydrogen, hydroxy, methyl or trifluoromethyl;
X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ , preferably both N or X = CR ₁ (R ₁ = H.Methyl) Y = N,
G is as defined above
η one of the numbers can be 1,2,3,4,5,6,7,8,9 or 10, preferably 0.1 or 2, and optionally their physiologically acceptable acid addition salts. 3. New thienodiazepines of the general formula according to claim 1, wherein R ₂ and R _{3 are} a radical of the general formula _Rb - I - (A in which A is a fused monounsaturated 5- or 6-membered ring, or a radical of the general formula wherein R ₀ = hydrogen, C ₁ -C ₄ -alkyl, C ₃ - to Ce-cycloalkyl, C ₃ - to C ₆ -cycloalkylcarbonyl, an unbranched alkyl group having m carbon atoms m, ₀ , _1, 2, ₃ or 4; X / Y are independently C-R ₁ or N, but not both, CR ₁ , preferably both N or X, CR ₁ and YN (R ₁ = H, methyl); or YC-COOR ', wherein R' is hydrogen or lower alkyl and X is nitrogen;
R _{1 is} hydrogen, hydroxymethyl, chloromethyl, trifluoromethyl, cyclopropyl, ethyl, methoxy, Ethoxy, chlorine or bromine, preferably methyl; R _{b is} hydrogen, hydroxy, amino, aminocarbonyl, carboxy, cyano, alkyloxycarbonyl of 1 to 6 carbon atoms, an acid amide of the formula R ₁₃ R ₁₄ NCO, wherein R ₁₃ and Ri _{4 are} C _{1 to} C ₄ alkyl or R ₁₃ and R ₁₄ together with the nitrogen atom represent an optionally substituted 6-membered heterocycle which may contain as further heteroatom oxygen, sulfur or nitrogen, in which R ₄ particularly preferably S is a single bond (K = O), a methylene group or an ethylene group; W is a phenyl ring, a thiophene ring which may optionally be mono- or polysubstituted by halogen, a hydroxy group, a C ₁ -C ₄ -alkyl radical, a C ₁ -C ₄ -alkoxy radical, a cyclopropyl radical, which may be identical or different to one another ; T is an alkyl chain having up to 4 members, an alkenyl chain having 2 to 4 members, an alkynyl chain having 2 to 4 members optionally interrupted by a hetero atom such as oxygen or sulfur; or CH ₂ -N-, -N-CH ₂ C, -C ₄ alkyl C ₁ -C ₄ -alkyl CH ₂ -N-CH ₂ -C ₁ -C ₄ -alkyl or the rest -C-ISI- OC ₁ -C ₄ alkyl; V is a phenyl group; a substituted phenyl group, Ca-Ce-cycloalkyl group, a thienyl
U prefers a single bond (M = 0), OdCr-CH ₂ -CH ₂ - when P represents a phenyl group; P is a phenyl group,
Z is hydrogen, branched or unbranched Ci-C ₄ alkyl or C ₁ -C ₄ -alkoxy, trifluoromethyl. Halogen, preferably chlorine or bromine, CN, NO ₂ , cyano, COH, COOH, COOC ₁ -C ₄ -alkyl, CONH ₂ , CON (C ₁ -C ₄ -alkyl) ₂ , cyclopropyl, amino, C ₁ -C ₄ Alkylamino, C ₁ -C ₄ -DJa Ikylamino, hydroxymethyl, SO ₂ -C ₁ -C ₄ alkyl, dC ^ dialkylamino, hydroxymethyl, SO ₂ -C ₁ -C ₄ alkyl, SOr-Cr-Gt-hydroxyalkyl, Hydroxy, SH, SC ₁ -C ₄ -alkyl, and K - O,!, Preferably O
L = 0.1, preferably 1
M = 0.1, preferably 1
N = 0.1, preferably 1, but P _n preferably 0 and α = 1,2,3, in which the sum K + L + M + N is not equal to 0 and R ₅ may denote hydrogen, hydroxy, methyl or trifluoromethyl, as well as optionally their physiologically acceptable acid addition salts. 4. Pharmaceutical preparations, characterized by a content of a compound according to one of claims 1 to 3. 5. Use of compounds according to any one of claims 1 to 3 in the manufacture of pharmaceutical preparations for the treatment of diseases induced by endogenously formed PAF. 6. Use of compounds according to any one of claims 1 to 3 as a medicament. 7. New diazepin of the general formula wherein R ₂ , R ₃ , R ₄ and R _{5 are} as defined in claim 1, 2 or 3. 8. New intermediates of the general formula R _{4 is} -CH ₂ -CN
wherein R _{4 is} as defined in claim 1, 2 or 3. A process for the preparation of compounds of the general formula I as defined in claims 1, 2 or 3, characterized in that a compound of the general formula wherein R ₂ , R ₃ , R ₄ and R _{5 are} as previously defined,
A) in the event that X and Y is nitrogen a) with an acid hydrazide of the general formula R ₁ -CONHNH ₂ implements, b) or with hydrazine in a compound of the general formula and then reacted with an acid halide of the general formula R ₁ -CO-Hal or with an orthoester of the general formula R ₁ -C (OR 'wherein R' denotes a lower alkyl group, or
B) In the event that X is CH, C-alkyl and Y is nitrogen a) with an aminoalkyne of the general formula R 1 -C 8 -c-C-CH ₂ -NH ₂ where R'i is hydrogen or a lower alkyl group or else b) miteinema-aminoaldehyde-alkyl acetal or a-amino ketone alkyl ketal of general formula H ₂ NCH ₂ -CR ₁ (ORI ₂ wherein R _{1 is} hydrogen or an alkyl group having 1 to 4 carbon atoms and R 'is a lower alkyl group, then, if desired, reacting the resulting compounds with R i = hydrogen in the presence of a base with a halogenating agent. As with chlorine or bromine, to a compound of general formula I a with R ₁ halogen, such as. B. Reacting chlorine or bromine; then, if desired, the halogen compound is converted into a compound of the general formula IaITMtR ₁ = alkoxy having 1 to 4 carbon atoms by reaction with the corresponding alkoxide; and subsequently optionally cleaving the compounds thus obtained into their optically active compounds by means of separation processes known per se, and if appropriate converting the compounds thus obtained into their acceptable acid addition salts.