DE3701344A1 - Novel thieno-1,4-diazepines - Google Patents

Abstract

The invention relates to novel thieno-1,4-diazepines of the general formula <IMAGE> in which R1, R2, R3, R<0>, R', Z, X, Y and n have the meaning mentioned in the description. The novel compounds are intended to be used for the treatment of pathological conditions and diseases in which PAF (platelet activating factor) is involved.

Description

The invention relates to new thieno-1,4-diazepines, their preparation by known methods and their use as medicaments and as intermediates. The new thieno-1,4-diazepines correspond to the general formula wherein
R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, preferably methoxy, halogen, preferably chlorine or bromine; for n ≦ λτ 0
R ₂ halogen, hydroxy, wherein R ₄ and R ₅ , which may be the same or different, are hydrogen, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-10 carbon atoms, which may optionally be substituted by halogen, hydroxy or by a C-linked heterocycle, where the carbon chain can be interrupted by nitrogen, oxygen or sulfur,
a branched or unbranched alkylcarbonyl group with 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 with 1 to 6 carbon atoms, the alkyl group being substituted by halogen or Hydroxy may be substituted
an optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulfonyl group, preferably phenylsulfonyl or tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atoms, or
R ₄ and R ₅ together with the nitrogen atom form a saturated or unsaturated 5-, 6- or 7-ring optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms and which contain nitrogen, oxygen or sulfur as further heteroatoms may, each further nitrogen atom optionally being substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atoms; R _{2 is} an arylcarbonyloxy group, preferably phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8, carbon atoms, it being possible for the alkyl chain to be interrupted by nitrogen, oxygen or sulfur; where R _{6 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 atoms,
R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; where R ₈ and R ₉ , which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms,
or R ₈ and R ₉ together with the nitrogen atom represent a 5-, 6- or 7-ring which may be substituted one or more times by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, where each further nitrogen atom is substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} a branched or unbranched alkoxy group having 1 to 4 carbon atoms; an aryloxy group, preferably phenyloxy or substituted phenyloxy; R _{2 is} an imido residue; Dioxolane, substituted dioxolane; for n greater than or equal to 0
R ₂ -CH = O; -COOH; Cyano; R _{2 is} a branched or unbranched
Alkoxycarbonyl group having 1 to 4 carbon atoms, with the proviso that when R ′ is hydrogen, R _{3 is} o-chlorophenyl,
X and Y both nitrogen
R ₂ Z _n cannot be methoxycarbonylethyl; R _{2 is} an aryloxycarbonyl group, preferably phenyloxycarbonyl; R _{2 is} a radical of the general formula wherein R ₁₀ and R ₁₁ , 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, which are optionally substituted by halogen, hydroxy, nitro, amino Amino or in the case of R ₁₀ = hydrogen or alkyl and Y = CR ₁ or Y nitrogen and X C-alkyl, R ₁₁ by an ester function or an acid amide of the general formula in which R ′ ₁₀ and R ′ _{11 have the} same meaning as R ₁₀ and R ₁₁ , but with the exception of an acid amide, can be substituted,
R ₁₀ or R _{11 is} a saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring optionally substituted one or more times by branched or unbranched alkyl having 1 to 4 carbon atoms, bonded via a carbon atom,
R ₁₀ and R ₁₁ together with the nitrogen atom represent a saturated or unsaturated 5-, 6- or 7-ring, optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms, which can contain nitrogen, oxygen or sulfur as further heteroatoms , wherein each further nitrogen atom can be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, with the proviso that when X, Y are both nitrogen, R 'hydrogen, Z is an unbranched alkyl chain with n carbon atoms and

• a) R ₃ = o-chlorophenyl and
  R ₁ = methyl and n = 0, 1, 2, 3 or 4
  NR ₁₀ R ₁₁ not morpholino,
  or
  n = 0 or 1
  NR ₁₀ R ₁₁ not amino,
  or
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, methylamino, isopropylamino, dimethylamino, cyclopropylamino, piperidino, pyrrolidino, cyclohexylamino, N'-methylpiperazino, amino, di (hydroxyethylamino) or hydroxyethylamino,
  or
• b) R ₃ = o-chlorophenyl
  and
  R ₁ = chloromethyl, bromomethyl, propyloxy, hydrogen, methoxy, bromine or cyclopropyl,
  and
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
  or
• c) R ₃ = o-chlorophenyl
  and R ₁ = cyclopropyl
  and
  n = 2
  NR ₁₀ R ₁₁ not diethylamino,
  or
  n = 8
  NR ₁₀ R ₁₁ not morpholino
  or
• d) R ₃ = phenyl,
  R ₁ = methyl,
  n = 2
  NR ₁₀ R ₁₁ not morpholino
• e) R ₃ = 2-nitrophenyl, 2-methylphenyl, 2-trifluoromethyl,
  R ₁ = methyl
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
• f) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, piperidino,
• g) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy,
  n = 2,
  NR ₁₀ R ₁₁ not N'-methylpiperazino

means;
R _{2 is} a radical of the general formula wherein
B oxygen, sulfur, NH or NC ₁ -C ₆ alkyl,
D the rest (C Re Rf) n , where n can be 0 to 3,
Ra is hydrogen, optionally substituted by a hydroxy or amino group, alkyl having 1 to 6 carbon atoms, C ₁ to C ₄ alkoxycarbonyl, dialkylaminocarbonyl,
Rb, Rc, Rd, Re, Rf are hydrogen, optionally alkyl with 1 to 6 carbon atoms substituted by a hydroxyl or amino group, or phenyl; R _{3 is} phenyl, where the phenyl ring can be substituted one or more times, preferably in the 2-position, by methyl, preferably halogen, particularly preferably chlorine or bromine, nitro, alkoxy, preferably methoxy and / or trifluoromethyl, pyridyl; R ^{o is} hydrogen, an alkyl or an acyl group with 1 to 4 carbon atoms in the alkyl chain, preferably acetyl; R ′ is hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ ,
or Y is the group C-COOR *, with R * = alkyl or hydrogen and X = nitrogen; Z is a branched or unbranched alkyl or alkenyl group with n-carbon atoms, where Z can optionally be additionally substituted by aryl, preferably phenyl, substituted phenyl or twice by R ₂ , where R _{2 can be} identical or different; and
n can be one of the numbers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
in the form of their racemates, their enantiomers, their diasteromers and their mixtures; in each case as free bases or their physiologically acceptable acid addition salts.

Preferred compounds of the general formulas Ia and Ib are those in which
R _{1 is} methyl, ethyl, methoxy, ethoxy or halogen, preferably chlorine or bromine; R ₂ chlorine, bromine, iodine, hydroxy, wherein R ₄ and R ₅ , which may be the same or different, are hydrogen, a branched or unbranched alkyl group having 1 to 6, particularly preferably 1 to 4, carbon atoms, it being possible for the carbon chain to be interrupted by nitrogen, a branched or unbranched alkylcarbonyl group having 1 up to 4 carbon atoms, optionally substituted by a dimethylamino group, a phenylcarbonyl group,
in the case of R ₅ = hydrogen, a phenylsulfonyl group optionally substituted by acylamino, particularly preferably acetylamino, amino, alkylamino or dialkylamino, or
R ₄ and R ₅ together with the nitrogen atom form a piperidine, pyrrolidine, N'-methylpiperazine, an optionally dimethyl-substituted morpholine ring, a pyrrole, pyrazole, imidazole or triazole ring;

R ₂ -CH = O, COOH;
a Δ ² -imidazoline, -oxazoline, -thiazoline which is optionally mono- or polysubstituted by methyl; a tolylsulfonyloxy group, a methylsulfonyloxy group;
a phenylcarbonyloxy group;
a branched or unbranched alkylcarbonyloxy group having 1 to 5 carbon atoms; a methoxy or ethoxycarbonyl group; wherein R _{6 is} a branched or unbranched alkyl group having 1 to 4 carbon atoms, R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; wherein R ₈ and R ₉ , which may be the same or different, represent a methyl, ethyl, propyl or isopropyl group or R ₈ and R ₉ together with the nitrogen atom represent an N'-methylpiperazine or morpholine ring; R _{3 is} phenyl, where the phenyl ring, preferably in the 2-position, can be substituted by H halogen, preferably chlorine; R ^{o is} hydrogen, methyl, acetyl; R ′ is hydrogen; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ , (R ₁ preferably hydrogen),
or Y is the group C-COOR *, with R * = alkyl or hydrogen and X = nitrogen; Z as defined above, preferably - (CH ₂ ) _n -, optionally substituted by phenyl or twice by R ₂ , where R _{2 can} also be different or -CH ₂ -CHR ₂ -CH ₂ -R ₂ -CH ₂ - CHR ₂ R ₂ , -CH ₂ CHR ₂ -CH ₂ -C ₆ H ₅ ;
and n can be one of the numbers 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and, if appropriate, their physiologically acceptable acid addition salts.

Compounds of the general formula Ia in which R ₁ = methyl or methoxy,
R ₃ = o-chlorophenyl, R 'hydrogen, X, Y both nitrogen, or X CH and Y nitrogen, Z (CH ₂ ) _n , n = 2, 3 or 7 and R ₂ and R ^o as previously defined.

Unless otherwise stated, halogen means one the atoms fluorine, chlorine, bromine or iodine, among aryl groups are optionally substituted one or more times aromatic residues with up to 10 carbon atoms in the Understand ring system, such as. B. phenyl, pyridyl, thienyl, Furyl or naphthyl, with the phenyl ring being preferred. As alkyl, alkenyl, alkynyl and alkoxy groups, unless otherwise stated, if necessary substituted, branched or unbranched radicals with 1 understood up to 8 carbon atoms in the carbon chain. One or more atoms from the Halogen, methyl, methoxy or hydroxy group Trifluoromethyl are present.

Preferred imido residues are the following structures Unless otherwise stated, lower alkyl or lower acyl is understood to mean branched or unbranched radicals having 1 to 4 carbon atoms in the alkyl chain.

In the general formulas, " n " in "Z _n " indicates the number of carbon atoms in the alkyl or alkenyl chain. If Z _{n is} substituted twice by R _{2, the} substituents can be the same or different. If Z _{n is} a branched alkyl or alkenyl group, the branch is preferably in the α or β position to the terminal functional group.

Alkyl chains with at least one are used as alkenyl Double bond, as alkynyl alkyl chains with at least called a triple bond.

As alkyl groups are preferred, unless otherwise the following is indicated: methyl, ethyl, propyl, isopropyl; n-butyl, iso-butyl and t-butyl, with the methyl group especially important is. The preferred alkoxy group is methoxy.

The new compounds of the general formula Ia can by known methods from the corresponding thienodiazepinthions of the general formula II or by Variation of functional groups in the side chain of the Preserved hetrazepine framework will.

The new compounds of the general formula Ib are obtained by reducing compounds of the general formula Ia. The reaction takes place with known reducing agents in organic solvents, such as. B. with zinc in a mixture of glacial acetic acid and an inert organic solvent, such as. B. halogenated hydrocarbons such. B. dichloromethane, at temperatures between room temperature and the boiling point of the reaction mixture or z. B. using lithium aluminum hydride (as far as R _{2 is} not reduced).

Compounds of the general formula Ib in which R ^{o is} an alkyl or acyl group can be prepared from the aforementioned compounds by alkylation or acylation by known processes.

Compounds of the general formula Ia wherein R ₂ -COOR * is an ester group as defined above, preferably R * = lower alkyl, particularly preferably methyl and ethyl, or R ₂ = OH, preferably protected as an acetic acid ester, are pharmacologically active and at the same time important intermediates for the preparation of further R ₂ -functionalized hetrazepines of the general formula Ia or Ib.

Compounds of the general formula Ia with R ₂ -COOR * are also referred to below as formula I.

Compounds of the general formula Ia with a fused-on triazole ring can be prepared in a conventional manner from the corresponding thieno-1,4-diazepine thiones of the general formula (R ₂ = -COOR *, (preferably R * = lower alkyl) or R ₂ Z _{n is} the meaning of a methyl or ethyl alkyldicarboxylic acid having 1 to 10 carbon atoms in the alkyl chain or R ₂ = OCOCH ₃ or SO ₂ NR ₈ R ₉ ) getting produced.

For this purpose, a compound of formula II can either

• a) reacted with an acid hydrazide of the general formula R ₁ -CONHNH ₂ , 6III, or else
• b) with hydrazine in a compound of the general formula transferred

and then with an acid halide, preferably one Acid chloride, the general formula

R ₁ -COHalV

or with an orthoester of the general formula wherein R ′ is a lower alkyl group, preferably methyl or ethyl,
be implemented.

The reaction of thion II with an acid hydrazide III Method a) is carried out in an inert organic Solvents such as B. dioxane, dimethylformamide, Tetrahydrofuran or a suitable hydrocarbon, such as B. benzene or toluene at temperatures between the Room temperature and the boiling point of the reaction mixture. The end products are isolated according to known methods Methods such as B. by crystallization.

The implementation of Thions II with hydrazine after Process b) is carried out in inert organic Solvents such as tetrahydrofuran, Dioxane, halogenated hydrocarbons, such as. B. Methylene chloride, suitable hydrocarbons Temperatures between room temperature and the boiling point of the reaction mixture.

The resulting hydrazine-1,4-diazepines can after conventional processes isolated or also directly be processed further.  

The further reaction with an acid halide V or an orthoester VI is carried out in an inert organic solvent, such as. B. halogenated hydrocarbons, cyclic or aliphatic ethers,
can also be done directly in substance. The end product Ia is isolated by known methods, for example by crystallization.

The structure of the hetrazepines of the general formula Ia, in which X is a CH group and Y is nitrogen, takes place in a manner known per se from the thione of the general formula II, by reaction with an aminoalkyne of the general formula VII, in which R _{11 is} hydrogen or an alkyl group, preferably hydrogen, means that the use of hydrochlorides for the hetrazepine ring closure makes hydrolysis-sensitive R ₂ groups accessible.

Compounds of the general formula Ia can be prepared by this process, in which R ₁ denotes an alkyl, preferably the methyl group.

Another method consists in reacting the thione of the general formula II with a
α-aminoaldehyde alkyl acetal or
α-aminoketone alkyl ketal of the general formula VIII according to the following synthesis scheme, where R _{1 is} hydrogen or an alkyl group having 1 to 4 carbon atoms or cyclopropyl group and R * is a lower alkyl group.

Analogy procedure for the synthesis of an acetal or ketal of the general formula VIII and an analogy process for the ring closure are in the Swiss patent No. 5 80 099.  

Compounds of the general formula Ia in which X is nitrogen and Y is CH can be obtained by decarboxylation of compounds of the general formula be preserved. Compounds of the general formula Ic are obtained, for example, from the diazepinthions of the general formula II by reaction with isocyanacetic acid esters. Analogous processes for the preparation of suitable compounds of the general formula Ic are described, for example, in the Dutch patent application 78 03 585.

Compounds of the general formula Ia which have a [1,5-a] linked imidazole ring, for example also in analogy to those in DE-OS 25 40 522 described.

Compounds of the general formula Ia in which R _{1 is} chlorine or bromine are prepared from compounds with R ₁ = hydrogen by reaction with chlorine or bromine in pyridine.

The corresponding alkoxy compounds are obtained for example from one of the chlorine or Bromine compound by reaction with the corresponding one Alcoholate.

The radicals R ₁ for halogen and alkoxy are preferably added, but only after the fully functionalized hetrazepine of the general formula Ia has been built up by the method described.

The processes described above for the preparation of compounds of the general formula I or Ia are carried out from the thione of the general formula II, in which the functional radical R _{2 is} not attacked under the reaction conditions used or can be protected by appropriate protective groups. This applies in particular to R ₂ an ester function, an alkylcarbonyloxy group dioxolanyl, substituted dioxolanyl as well as for R ₂ = R ₈ R ₉ NSO ₂ -.

Diazepinthione of general formula II are as follows producible.

In analogy to that of Gewald et al. Chem. Ber. 98, 3571 (1965), ibid 99, 94 (1966), starting from the correspondingly functionalized aldehydes or ketones of the general formula ª, the functionalized thienes c are obtained by reaction with the corresponding acetophenone b . According to known processes, these are converted into the ring-closed 1,4-diazepinones by bromoacetylation and subsequent reaction with ammonia, which are subsequently converted into the thione of the general formula II using phosphorus pentasulfide or Lawesson reagent ^R.

Synthesis scheme I

Preferably R _{2 has} the meaning of a carboxylic acid ester, such as. B. a carboxylic acid methyl or ethyl ester, an alkylcarbonyloxy group or an aminosulfonyl group.

The ω-functionalized ones required for production Aldehydes a can, for example, by reductive Ozone cleavage of cyclic enol ethers (L. Claisen, Ber. German chem. Ges. 40, 3907 and V. Schmid u. P. Counts, Liebigs Ann. Chem. 656, 97 (1962) Fatty acid derivatives, such as. B. acetic acid Oleylester or suitable unsaturated heterocycles can be obtained. The Ozonation is preferred in methylene chloride or Ethyl acetate at -78 ° C to + 20 ° C, preferably between -40 ° C and carried out at -20 ° C.  

Another manufacturing process is given in the following reaction scheme

The implementation of the aldehydes a leads in a manner known per se Way, as given in synthesis scheme 1, according to K. Gewald et. al., Chem. Ber. 98, 3571 (1965) and Chem. Ber. 99, 94 (1966) on the aminothiophene derivatives c.

The 2-haloacetylaminothiophene derivatives formed in the further reaction of c with a haloacetyl halide can either be isolated or else be converted as a crude product via the 2-aminoacetylaminothiophene derivative into the diazepinone d, which is then used with phosphorus pentasulfide or Lawesson reagent ^R to give the thione of the general formula II responded.

If Z _{n is} a branched alkyl or alkenyl group, optionally substituted by aryl, preferably phenyl, or Z _{n is} substituted twice by R ₂ , the branching can be carried out at the stage of the ω-functionalized aldehyde or after completion of the fully built-up hetrazepine by known methods .

In the event that Z _{n is} functionalized twice, the functional groups can be bonded to the same carbon atom or to different carbon atoms.

The carboxylic acid esters (R ₂ = COOR * R * = lower alkyl) of the general formula Ia are valuable starting compounds I for the introduction of further functional groups.

Starting from the esters, the corresponding Carboxylic acids of the general formula Ia by saponification, e.g. B. in alcoholic aqueous potassium hydroxide solution, for. B. with KOH in Ethanol, at temperatures between room temperature and the boiling point of the reaction mixture can be obtained.

Carboxamides of the general formula Ia can be prepared by known processes, such as. B. from the corresponding carboxylic acids or their carboxylic acid equivalents by reaction with a primary or secondary amine or ammonia of the general formula The conversion into a carboxylic acid chloride or acid anhydride or the conversion of the acid in the presence of carbonyldiimidazole, sulfonyldiimidazole, cyclohexylcarbodiimide is preferred.

The free acid is reacted with the amine in Presence of a carbodiimide, for example of Cyclohexylcarbodiimide, carbonyldiimidazole or Sulfonyldiimidazole in an inert solvent such as  Dimethylformamide, tetrahydrofuran, dioxane or halogenated hydrocarbon at temperatures between 0 ° C and the boiling point of the reaction mixture.

In the reaction of the amine with an acid halide or Acid anhydride turns the amine into an inert Solvents, for example dimethylformamide, Tetrahydrofuran, dioxane or a suitable Hydrocarbon such as toluene at temperatures between Room temperature and the boiling point of the reaction mixture reacted with the acid halide or the acid anhydride, where appropriate an acid-binding agent such as Sodium carbonate, sodium bicarbonate or a tertiary organic base, for example pyridine or triethylamine, is added.

If the amine is a liquid, can also be implemented in an excess of the amine without additional solvent.

The acid halide or acid anhydride is obtained from the free acid in the usual way, e.g. B. by reaction of Acid with a thionyl halide or by reaction an alkali salt of the acid with acetyl chloride or Chloroformic acid chloride.

Instead of reacting with an amine, one can also use a Amino acid derivative are implemented.

Esters of the general formula Ia, in particular the methyl or ethyl ester, can be obtained by selective reduction of the Ester function converted into the corresponding alcohol will. The reaction is carried out with the inverse addition of Reducing agent, such as. B. lithium alanate or Sodium borohydride (inverse activation), under general  usual reaction conditions, such as. B. in inert organic solvents, e.g. B. ethers, Tetrahydrofuran at temperatures between room temperature and the boiling point of the reaction mixture.

Carbamates or ureas of the general formula Ia with R ₂ = R ₆ NHCOO - or R ₆ NHCONR ₇ - are obtained from the reaction of the corresponding alcohols or amines with the desired isocyanate in organic solvents, such as, for. B. tetrahydrofuran, methylene chloride, at temperatures between room temperature and the boiling point, preferably at elevated temperatures, of the reaction mixture with the addition of base, preferably DABCO (1,4-diazabicyclo (2,2,2) octane).

Compounds in which R _{2 is} alkyl- or arylcarbonyloxy are derived from the corresponding alcohols of the general formula Ia by reaction with an acid equivalent from a carboxylic acid of the general formula wherein R is an aryl radical or preferably a branched or unbranched alkyl radical having 1 to 8 carbon atoms, where the carbon chain can be interrupted by nitrogen, oxygen or sulfur. The same reaction conditions can be used here as in the preparation of the acid amides.

From the carboxylic acids of the general formula Ia with R ₂ = COOH, the carboxylazides can be prepared by known methods. These can then be prepared in an inert organic solvent, such as. B. dioxane, are converted into the isocyanates by the Curtius rearrangement. These isocyanates can be converted into the primary amines and, as described above, into the urethanes and ureas by generally known methods.

Starting from compounds of the general formula Ia in which R ₂ = OH, reaction with alkyl or arylsulfonic acid halides gives compounds of the general formula Ia in which R _{2 represents} an alkyl or arylsulfonyloxy group. The reaction takes place in inert organic solvents, such as. As methylene chloride, with sulfonic acid halides with the addition of acid binders, such as. B. triethylamine.

The mesylates thus obtained are good leaving groups and can be exchanged nucleophilically. Correspondingly functionalized compounds of general formula Ia, e.g. B. R ₂ = CH ₃ SO ₃ -, with primary or secondary amines of the formula or an imidor residue, e.g. B. phthalimide can be implemented. Compounds of the general formula Ia are obtained in which R _{2 has} the group NR ₄ R ₅ or an imido radical.

The reaction takes place in inert organic Solvents such as B. tetrahydrofuran, dioxane, between Room temperature and the boiling point of the reaction mixture, preferably at elevated temperatures.  

Starting from the above-mentioned mesylates, compounds of the general formula Ia in which R _{2 is} an aryloxyl or alkyloxy radical are obtained by reaction with the corresponding alcoholates, either in an excess of alcohol as a solvent or in inert solvents, such as, for. B. dioxane, between room temperature and the boiling point of the solvent mixture, preferably between 60 to 80 ° C.

Compounds of the general formula Ia with R ₂ = NH ₂ are obtained analogously by known processes by cleaving the corresponding phthalimide.

The primary or secondary amines obtained in this way can be obtained by known processes using carboxylic acid equivalents derived from carboxylic acids of the general formula in which R has the meaning of R ₁₀ , to give compounds of the general formula Ia, in which R ₄ or R ₅ denotes an alkyl or arylcarbonyl group. The oxidation of the alcohols results in the aldehydes being shortened by one chain link.

Compounds of the general formula Ia, in which R _{2 is} a heterocycle, such as. B. an oxazoline, thiazoline or an imidazoline, is obtained for example from the corresponding carboxylic acids of the general formula Ia by reaction with a bisfunctionalized amine, such as. B. an amino alcohol, an aminomercaptan or a diamine, in the presence of triphenylphosphine, carbon tetrachloride and a tertiary organic base in acetonitrile. The corresponding 6- and 7-membered heterocycles can also be prepared analogously to this. The reaction takes place in a temperature range between 0 ° C. and the boiling point of the reaction mixture, preferably between 0 ° C. and room temperature. Compounds of the general formula Ia, in which R _{2 is} an oxazoline radical, are obtained from the correspondingly hydroxy-functionalized carboxamides by ring closure reaction with thionyl chloride in an inert organic solvent, such as, for. B. methylene chloride.

If desired, these can be obtained by sulfurization, e.g. B. with phosphorus pentasulfide or Lawesson reagent ^R in the corresponding thiazoline.

Compounds of the general formula Ia, in which R _{2 is} a cyano group, are obtained from the corresponding primary carboxamides by reaction with phosphorus oxychloride in an inert organic solvent, for. B. dichloroethane, under reflux conditions.

Compounds of the general formula Ia, in which R _{2 is} an imidazoline which is optionally substituted by branched or unbranched alkyl groups, can be obtained starting from compounds Ia with R ₂ = CN via the imidoethyl ester hydrochloride by reaction with a diamine (Pinner reaction). The imidoethyl ester hydrochloride is formed by treating the nitrile with an excess of ethanolic hydrochloric acid. The resulting crystalline crude product is reacted in ethanol with the diamine (e.g. ethylenediamine) first with ice cooling, then under reflux conditions. This gives compounds of the formula Ia in which R _{2 is} an imidazoline-2 radical. In the case of NH, its amino function can be alkylated by known methods.

Compounds of general formula Ia, wherein R _{2 is} a halogen atom, e.g. B. iodine, is obtained from a compound of general formula Ia, wherein R _{2 is} toluenesulfonic acid by reaction with an appropriate halogenating agent, for. B. NaJ, in anhydrous solvents, such as. B. acetone.

As far as the compounds of the invention are asymmetrical have substituted carbon atom, they can according to known methods in their optically active antipodes be separated.

The following compounds can be prepared, for example, in analogy to known processes or by the processes described above:
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] ethane-1- sulfonic acid-N-methylpiperazide
Acetic acid {3- [4- (2-chlorophenyl) -9-methyl-6H-thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl) - propyl ester}
2- [7- (N'-Methylpiperazinylcarbonyloxy) heptyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3- a] [1,4] diazepine
2- [3- (N'-Methylpiperazinylcarbonyloxy) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] [triazolo- [4,3 -a] [1,4] diazepine
2- [3- (N-Morpholinylcarbonyloxy) propyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- [7- (N-Morpholinylcarbonyloxy) heptyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (2-hydroxyethyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] -diazepine
2- (4-hydroxybutyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (5-hydroxypentyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (10-hydroxydecyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
Acetic acid- {7- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] - heptyl ester}
2- (3-acetoxypropyl) -4- (2-chlorophenyl) -9-bromo-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- [2-methylcarbonyloxy) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine
2- [4- (Isopropylcarbonyloxy) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1 , 4] diazepine
2- [5- (Methylcarbonyloxy) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1 , 4] diazepine
Methanesulfonic acid- {3- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] - propyl ester}
2- [2-methylsulfonyloxy) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine
2- [4-methylsulfonyloxy) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine
2- [5-methylsulfonyloxy) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [diazepine
2- [10-methylsulfonyloxy) decyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine
2- [3- (N-Morpholinyl) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepine
2- [2- (N-morpholinyl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepine
2- [4- (N-Morpholinyl) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepine
2- [5- (N-Morpholinyl) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepine
2- [10- (2,6-Dimethylmorpholin-4-yl) decyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1.4] diazepine
2- [3- (N-morpholinyl) propyl] -4- (4-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- [3- (N-Morpholinyl) propyl] -4- (2,6-dichlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- [3- (N-Morpholinyl) propyl] -4- (pyridin-2-yl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- (7-acetylaminoheptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (7-N-phthalimidoheptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine
2- (3-iodopropyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (7-aminoheptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- (6-formylhexyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
2- [2- (imidazol-1-yl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- [3- (Imidazol-1-yl) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- [4- (Imidazol-1-yl) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3 -a] [1,4] diazepine
2- [5- (Imidazol-1-yl) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- [7- (Imidazol-1-yl) heptyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3- a] [1,4] diazepine
2- [2 - ([1,2,4] triazol-1-yl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine
2- [3 - ([1,2,4] triazol-1-yl) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine
2- [4 - ([1,2,4] triazol-1-yl) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine
2- [5 - ([1,2,4] triazol-1-yl) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine
2- [2- (4,4-Dimethyloxazolin-2-yl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [ 4,3-a] [1,4] diazepine
2- [3- (N-Morpholinyl) propyl] -4- (3,4,5-trimethoxyphenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4, 3-a] [1,4] diazepine

The compounds according to the invention have PAF-antagonistic activity.
As is known, PAF (platelet activating factor) is the phospholipid acetyl-glyceryl-ether-phosphoryl-choline (AGEPC), which is known as a potent lipid mediator, which is released by animal and human pro-inflammatory cells. Basophilic and neutrophilic granulocytes, macrophages (from blood and tissue) and platelets, which are involved in inflammatory reactions, are mainly found among such cells.

PAF shows in pharmacological experiment Bronchoconstriction, lowering blood pressure, triggering one Platelet aggregation as well as pro-inflammatory Effect.

These experimentally demonstrable effects of PAF demonstrate directly or indirectly on possible functions of this Mediators in anaphylaxis, in the pathophysiology of the Bronchial asthma and general inflammation.

PAF antagonists are needed for more on the one hand pathophysiological functions of this mediator in animals and educate people and on the other hand pathological Conditions and diseases in which PAF is involved to treat. Examples of the indications of a PAF antagonists are inflammatory processes of the Tracheobronchial tree (acute and chronic bronchitis, Bronchial asthma) or the kidney (glomerulonephritis), anaphylactic conditions, allergies and inflammation in the Area of the mucous membranes and skin (e.g. psoriasis) as well as those caused by sepsis, endotoxins or burns Shock conditions. Other important indications for one PAF antagonists are lesions and inflammation in the area  the gastric and intestinal mucosa, such as B. gastritis, in general peptic ulcer, but especially ulcer ventriculi and duodenal ulcer.

Furthermore, the compounds according to the invention are suitable for treatment in the following indications: Obstructive pulmonary diseases, such as, for. B. bronchial hyperreactivity, inflammatory lung diseases, such as. B. chronic bronchitis;
Cardiovascular diseases, such as B. polytrauma, anaphylaxis, arteriosclerosis, inflammatory bowel diseases, EPH gestosis (edima-protein uria hypertension), diseases of the extracorporeal circulation, ischemic diseases, inflammatory and immunological diseases, immunomodulation in transplantation of foreign tissues, immunomodulation in leukemia. Metastatic spread z. B. in bronchial neoplasia, diseases of the CNS, such as. As migraines, agarosephobia (panic disorder), furthermore, the compounds according to the invention prove to be cytoprotective and organoprotective, e.g. B. for neuroprotection, e.g. B. in cirrhosis of the liver, DIC (disintegrated intravascular coagulation);

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

The PAF-antagonistic effect of individual benzodiazepines is known, cf. E. Kornecki et al, Science 226, 1454-1456 (1984). An IK ₅₀ (concentration with a 50% inhibition of aggregation) of 14 µM was measured for alprazolam and an IK ₅₀ of 9 µM for triazolam. However, these compounds, which are identified as tranquilizers or hypnotics and are commercially available, are unsuitable for use as PAF antagonists in therapy in many cases because of their pronounced sedative effect despite their good PAF-antagonistic action.

In contrast, in many of the compounds according to the invention lacks the sedative effect, while the PAF antagonistic effect compared to that of the known benzodiazepines is much better.

The following are the pharmacological Test methods communicated:

Pharmacological test methods

The PAF-antagonistic activity of some compounds Formula I was based on the inhibition of Platelet aggregation in vitro and antagonization the bronchoconstriction caused by PAF on anesthetized guinea pigs, lowering blood pressure at the anesthetized rat and cuticle on the rat examined. In addition, these connections with regard to possible side effects on the central Nervous system checked.

1. In vitro investigations: inhibition of Platelet aggregation

To determine the PAF antagonistic effect of Substances became the aggregation induced by PAF of human platelets used in vitro. For extraction of platelet-rich plasma (TRP) Withdraw blood from an undamaged vein with the help a plastic syringe containing 3.8% Sodium citrate solution. The relation between Sodium citrate solution and blood is 1: 9 the citrate blood is carefully mixed Centrifuge 150 x g (1200 rpm) for 20 minutes. The Platelet aggregation is measured after methods developed by Born and Cross (G.V.R. Born and M. J. Cross, J. Physiol. 168, 178 (1963)), with the TRP with constant stirring PAF as a trigger is added to the aggregation.  

The test substance is added in a volume of 10 µl 2-3 minutes before the aggregation is triggered. Either aqua is used as solvent. dist., ethanol and / or dimethyl sulfoxide. Control batches are given corresponding volumes of these solvents. After registration of the initial absorption (2-3 minutes) the aggregation is induced with PAF (5 × 10 ^-8 M).

The maximum is used to assess substance effects the first wave of aggregation. The through PAF induced maximum absorption rate (= maximum Aggregation × 100%) is done simultaneously in one Parallel approach (= control approach in one of the channels of the 2-channel aggregometer) for each test batch (second Channel) also checked and used as 100% value.

The reached under the influence of the test substance The aggregation value is given as 100%.

Each test substance is examined at a concentration of 10 ^-3 to 10 ^-8 M with a sample size of n = 4 in each case with regard to an inhibitory effect on the platelet aggregation induced by PAF. Then a concentration-effect curve is created based on 3 concentrations and the IK ₅₀ (concentration with a 50% inhibition of aggregation) is determined. The IK values of compounds of the general formula I are generally around values which are less than 9 μM.

2. In vivo studies 2.1. Antagonization of the bronchoconstriction caused by PAF on anesthetized guinea pigs

Spontaneously breathing male, 300-450 g heavy Guinea pigs are 1 hour before an i. v. Infusion of PAF (30 ng / (kg × min) with the Test substance or a control vehicle orally pretreated. The experimental animals are then with 2 mg / kg urethane anesthetized intraperitoneally, whereupon the jugular vein, the carotid artery and the trachea can be cannulated. The PAF infusion induced in the control animals a strong, persistent bronchoconstriction that based on tidal volume, compliance and the resistance is measured and also one Lowering blood pressure. After about 7-10 minutes death occurs. With the described PAF antagonists can have these effects on breathing and blood pressure as well as the onset of death be prevented.

2.2. Antagonizing those caused by PAF Lowering blood pressure in the anesthetized rat

Normotone, male, 200-250 g Wistar rats are treated with 2 mg / kg urethane Anesthetized intraperitoneally. The artery The carotid and jugular veins are cannulated. An intravenous infusion of PAF (30 ng / (kg × min)) induces a strong, persistent drop in blood pressure. This can dose-dependent through intravenous injections (cumulative administration) of the described Connections are canceled. Oral too  or intravenous administration of the compound before starting the PAF infusion hypotensive effect of the above Prevent PAF infusion in a dose-dependent manner.

2.3. Antagonizing those induced by PAF Quaternium on the rat (Modified from P. P. Koelzer and K. H. Wehr, drug research. 8th, 181 (1958)

An intracutaneous injection of PAF induced a cuticle that expresses one through PAF conditional increase in vascular permeability.

Male Wistar rats with a body weight the abdominal wall (short) of 250 ± 20 g sheared. Then 1 ml / kg of a 1% Trypan blue solution through a tail vein Animals injected. Symmetrical to the center line (linea alba) are in three places at intervals of about 1.5 cm intracutaneous injections of physiological saline or PAF solution (12.5 to 15.0 ng / site in 0.1 ml). While at the injection site Saline no reaction occurred PAF is a skin reaction (wheal) caused by a Blue color of different intensity - depending on the PAF dose - became visible. By simultaneous intracutaneous administration of the compounds described or by a intravenous pretreatment could be done by PAF induced skin reaction can be prevented.  

3. Effects on the central nervous system

It is generally known that substances of this type of structure cause central nervous effects, which, however, are not desirable for a compound with PAF-antagonistic activity. Therefore, the described compounds were tested with regard to their hypnogenic and anticonvulsive effects and their influence on the locomotion. A possible hypnotic effect was investigated in guinea pigs weighing 400 to 450 g. Doses up to 200 mg / kg po of these substances were unable to produce a hypnotic or sedative effect on these animals.
To test an anticonvulsant effect, the pentetrazole antagonism can be used in mice (20 to 25 g body weight) (MI Gluckmann, Current Therapeutic Research, 7: 721, 1965). Doses up to 100 mg / kg po of these compounds (1 hour before pentetrazole) showed no influence on the mortality caused by pentetrazole (125 mg / kg ip, LD 100) in this test.
The effect on night motility (locomotion) of mice (20-25 g body weight) can be examined in a light barrier cage. The number of light beam interruptions is measured. Doses up to 300 mg / kg. po of the above compounds showed no activity.

Table A shows the in vitro tests regarding platelet inhibition listed as they are described below.  

Table A:

The new compounds of the general formula Ia and Ib can warm-blooded animals topically, orally, parenterally administered transdermally or by inhalation. The Compounds are active ingredients in usual dosage forms, e.g. B. in Compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of Active ingredient exist, such as. B. tablets, coated tablets, Capsules, wafers, powders, solutions, suspensions, Inhalation aerosols, ointments, emulsions, syrups, Suppositories, etc. An effective dose of Compounds according to the invention is for oral use between 1 and 50, preferably between 3 and 20 mg / dose, for intravenous or intramuscular Use between 0.01 and 50, preferably between 0.1 and 10 mg / dose. For inhalation solutions that 0.01 to 1.0, preferably 0.1 to 0.5% active ingredient included, used.

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

Example 1: 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-sulfonic acid - N'-methylpiperazide 1.1. 3- (1,3-dioxolan-2-yl) propane-1-sulfonic acid-N'-methyl piperazide

To 23 g (0.13 mol) of methanesulfonic acid N'- methylpiperazide, dissolved in 200 ml of anhydrous Tetrahydrofuran, 87.5 ml of a 1.6 molar BuLi solution in hexane (0.14 mol) was added dropwise, the resulting suspension at room temperature Stirred for 90 minutes and then 23.4 g 2- (2-bromoethyl) -1,3-dioxolane (0.13 mol) in 200 ml anhydrous tetrahydrofuran was added dropwise, one clear solution arises. After stirring for 5 hours the solvent removed, the residue with Water / methylene chloride added and the aqueous The phase was shaken out several times with methylene chloride. The methylene chloride solution is dried and that Stripped solvent. The oily residue filtered through a silica gel column with the Eluent methylene chloride / methanol (9: 1). To pull off the solvent again 20.7 g of the desired compound as a light oil. Yield 57% of theory).

1.2. 3-formyl-propane-1-sulfonic acid-N'-methylpiperazide

20.7 g (0.074 mol) of 3- (1,3-dioxolan-2-yl) propane-1-sulfonic acid-N'-methylpiperazide and 800 ml of 2N sulfuric acid are stirred at 80 ° C. for 30 minutes, cooled and concentrated with . Bring ammonia to pH 6.5-7. The solution, which is then saturated with sodium chloride, is extracted thoroughly with methylene chloride. After drying and stripping off the solvent, 13.2 g of the aldehyde are obtained as a light oil.
(Yield 76% of theory)

1.3. 2-amino-3- (2-chlorobenzoyl) -5- [2- (N′-methylpiperazinylsulfonyl) ethyl] thiophene

10.1 g (0.056 mol) of o-chlorocanoacetophenone and 18 g (0.056 mol) of sulfur are placed in 10 ml of dimethylformamide and 7.8 ml (0.056 mol) of triethylamine are added dropwise. Then 13.2 g of 3-formyl-n-propane-1-sulfonic acid-N'-methylpiperazide in 50 ml of dimethylformamide are added dropwise and the resulting solution is stirred at 70 ° C. for 30 minutes. After 12 hours, the reaction mixture is poured into 100 ml of ice water and extracted with ethyl acetate. After washing, drying and stripping off the solvent, 18 g of oily residue remain, which is purified on a silica gel column using methylene chloride / methanol (9: 1) as the mobile phase. 15.0 g of the thiophene compound are obtained as a light oil.
(Yield 63% of theory).

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.55 (4H, m, aryl-H); 7.14 (2H, s, broad, NH ₂ ); 6.18 (1H, s, thiophene-H); 3.18-3.43 (4H, m, piperazine (CH ₂ ) ₂ -N; 3.07 (4H, s, SO ₂ CH ₂ CH ₂ ); 2.33-2.61 (4H, m, piperazine (CH ₂ ) ₂ -N-SO ₂ ); 2.33 (3H, s, N-CH ₃ ).

1.4. 2-bromoacetylamino-3- (2-chlorobenzoyl) -5- [2- (N′methylpiperazinylsulfonyl) ethyl] thiophene

14 g of the compound of Example 1.3 and 4.6 ml Triethylamine are anhydrous in 200 ml Submitted methylene chloride and 2.85 ml Bromoacetyl bromide was added dropwise at room temperature. After 4 hours, the reaction mixture with water offset, slightly alkaline and with Extracted methylene chloride. After washing and One dries the solvent at one Water bath temperature from 30 ° C. The received Residues (17.9 g) must be reacted immediately will.

1.5. 2-aminoacetylamino-3- (2-chlorobenzoyl) -5- [2- (N′- methylpiperazinylsulfonyl) ethyl] thiophene.

17.9 g (0.032 mol) of the compound of Example 1.4. are dissolved in 200 ml of ethyl acetate and ammonia is passed in for 4 hours. The reaction mixture is stirred for 12 hours at room temperature, washed several times with water, the organic phase is dried and the solvent is stripped off. 6.1 g of an oily residue are obtained.
(Yield 39% of theory).

1.6. 2- [4- (2-chlorophenyl) thieno [3,2-f] [1,4] diazepin-7-one- 2-yl] -ethane-1-sulfonic acid-N'-methylpiperazide

6.1 g (0.013 mol) of the compound of Example 1.5. and 20 g of silica gel are heated to reflux with 150 ml of toluene for 3 hours on a water separator. The silica gel is filtered off and extracted with hot methanol. The 5.3 g of crude product obtained after working up are chromatographed on silica gel (eluent:
Methylene chloride / methanol 9: 1). 2.6 g of the diazepinone (yield 44% of theory) of mp 135-138 ° C. (acetonitrile) are obtained.

1.7. 2- [4- (2-chlorophenyl) thieno [3,2-f] [1,4] diazepine-7- thion-2-yl] -ethane-1-sulfonic acid-N'-methylpiperazide

2.6 g (0.0056 mol) of the diazepinone, 1.25 g Phosphorus pentasulfide (0.0028 mol) and 1 g Sodium bicarbonate is 2 hours in 30 ml Diglyme stirred at 80 ° C. The reaction mixture is placed in 100 ml of water and the precipitated Aspirated solid. The diazepinthion obtained (Yield: 2.7 g, 100% of theory) without purification implemented further.

1.8. 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] ethane 1-sulfonic acid-N'-methylpiperazide

2.7 g (0.0056 mol) of the compound of the example 1.7. and 0.3 ml (0.0062 mol) of hydrazine hydrate at room temperature for one hour in 30 ml Tetrahydrofuran stirred. After removing the The residue with 10 ml Orthoacetic acid triethyl ester at one hour 70-80 ° C stirred. The excess orthoester then pull off and take the backlog 2N hydrochloric acid and extracted with ether and Methylene chloride. The aqueous phase becomes alkaline posed and the fancy Thienotriazole diazepine with methylene chloride extracted. after concentration and drying 1.2 g of crude product containing aluminum oxide,  neutral, activity level III with Methylene chloride / methanol 95: 5 as eluent is chromatographed. 1.0 g is obtained (Yield 35%) of thienotriazolodiazepine, mp. 148-150 ° C.

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.61 (4H, m, aryl-H); 6.48 (1H, s, thiophene-H); 4.95 (2H, s, 7-ring CH ₂ ); 3.00-3.47 (8H, m, piperazine- (CH ₂ ) ₂ -N-SO ₂ , SO ₂ -CH ₂ -CH ₂ ); 2.72 (3H, s, triazole-CH ₃ ); 2.30-2.61 (4H, m, piperazine- (CH ₂ ) ₂ -N); 2.32 (3H, s, piperazine-CH ₃ ).

Example 2: Acetic acid- {3- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - propylester} 2.1. 2-amino-3- (2-chlorobenzoyl) -5- (3-acetoxypropyl) - thiophene

Analogously to example 1, starting from 5-hydroxypentanal the 2-amino-3- (2-chlorobenzoyl) - 5- (3-hydroxypropyl) thiophene built up. 1 g (0.0034 mol) of this compound is easily Warming dissolved in 40 ml of ethyl acetate, after 20-minute introduction of hydrogen chloride is still Stirred for 2 hours at room temperature Stripped solvent, the residue in Methylene chloride added and with water washed. After drying and peeling off the The oily residue becomes solvent Silica gel with methylene chloride / methanol 9: 1 as  Chromatographed eluent. 0.75 g is obtained (Yield 65% of theory) of the above compound.

¹ H NMR (CDCl ₃ ) δ ppm 7.24-7.54 (4H, m, aryl-H); 7.09 (2H, s, broad, NH ₂ ); 6.13 (1H, s, thiophene-H); 4.07 (2H, t, J = 6 Hz, OCH ₂ ); 2.61 (2H, t, J = 6 Hz, T 65375 00070 552 001000280000000200012000285916526400040 0002003701344 00004 65256hiophen-CH ₂ ); 2.02 (3H, s, CH ₃ C = O); 1.85 (2H, m, OCH ₂ -CH ₂ -):

2.2. Acetic acid- {3- [4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2- yl] -propylester}

Based on the connection of example 2.1. is obtained analogously to Example 1 in 92% yield 2-bromoacetylamino compound, in 86% yield 2-amino-acetylamino compound, in 76% yield the ring-closed diazepinone, in 70% yield the corresponding diazepinthion and in 76% Yield the title compound of mp 153-155 ° C.

Example 3: 2- (3-hydroxypropyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine a) Synthesis from the compound of Example 2:

• 3.0 g (0.0072 mol) of the compound of Example 2 are mixed with one equivalent of potassium hydroxide in 40 ml Ethanol stirred for 12 hours at room temperature; the Stripped solvent in vacuo and the residue in Methylene chloride added. After washing, drying and stripping off the solvent gives 2 g of Title compound of mp 155-160 ° C (yield 74% of theory).

b) Synthesis from 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno- [3,2-f] [1,2,4] triazolo] 4,3-a] [1,4] diazepin-2-yl] ethane 1-carboxylic acid methyl ester

• 2.5 g (0.0062 mol) of the corresponding methyl ester are dissolved in 25 ml of anhydrous tetrahydrofuran and at room temperature in small portions with a total 0.13 g (0.0034 mol) of lithium alanate powder was added. To Stirring for 12 hours while cooling 0.2 ml of water, then 0.2 ml of 6N sodium hydroxide solution and then 0.4 ml Water added and stirred well. The solid is suctioned off and the filtrate after removing the Solvent on silica gel with methylene chloride / Chromatographed methanol (4: 1) as eluent. Traces of Output connection can over HPLC column chromatography with the eluent Methylene chloride / methanol (4: 1) are separated. Man receives 1.6 g of compound 3 (yield 69% of theory).
• ¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.52 (4H, m, aryl-H); 6.42 (1H, s, thiophene H); 4.91 (2H, s, 7-ring CH ₂ ); 3.69 (2H, t, J = 6 Hz, OCH ₂ ); 2.88 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.69 (3H, s, triazole-CH ₃ ); 1.91 (2H, m, OCH ₂ CH ₂ -); 1.78 (1H, s, broad, OH).

The starting compound, the 2- [4- (2-chlorophenyl) -9-methyl- 6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethane-1-carboxylic acid methyl ester is as follows receive:

2-amino-3-o-chlorobenzoyl-5- (2-dicarbethoxyethyl) thiophene

53.9 g (0.3 mol) of o-chlorocyanoacetophenone, 9.6 g of sulfur, 30.4 g (0.3 mol) of triethylamine and 120 ml of dimethylformamide are with stirring, starting at room temperature with 64.8  g (0.3 mol) dicarbethoxybutyraldehyde (D. T. Warner, J. Am. Chem. Soc. 70, 3470 (1948); Kp. 97 ° C / 0.1 mBar), the temperature rises to 45-50 ° C. Stir 2-3 Hours at 60-70 ° C, cools to room temperature and adds Add 400 ml of water. The thiophene derivative formed three times with 200 ml each of methyl tert-butyl ketone shaken out. After washing with water and drying the organic phase is evaporated and the crystalline Crystallized residue from isopropanol / water 7: 3. Yield: 90 g (74% of theory), mp. 96-98 ° C.

2-amino-o-chlorobenzoyl-5- (2-carbomethoxyethyl) thiophene

63 g (0.15 mol) of the above compound are refluxed with 120 ml of ethanol and 32.5 g of caustic potash in 50 ml of water for 2 hours. It is evaporated in vacuo, diluted with 50 ml of water and acidified with HCl. The greasy acid is shaken out several times with ethyl acetate. The extracts are dried and evaporated, the residue is boiled under reflux with 300 ml of toluene and 30 ml of dimethylformamide for 2 hours. After evaporation to about 50 ml, crystals of monocarboxylic acid are obtained.
Yield: 20.5 g. The purified acid melts at 171-173 ° C.
The crude acid is stirred together with 400 ml of absolute methanol and 0.4 ml of concentrated sulfuric acid at room temperature for 18 hours. After the methanol has been evaporated off, it is poured onto ice, shaken out with methylene chloride and, after renewed evaporation from isopropyl ether, 15 g of ester of mp. 89-90 ° C. are obtained.

2-bromoacetylamino-3-o-chlorobenzoyl-5- (2-carbomethoxyethyl) - thiophene

27.8 g (0.09 mol) of the above ester are suspended in 700 ml of toluene and 10 g of sodium bicarbonate in 57 ml of water are added. While stirring, 7.9 ml of bromoacetyl bromide are gradually added at 40-50 ° C. and stirring is continued for 30 minutes. It is washed with water, the toluene phase is dried, evaporated in vacuo and brought to crystallization with isopropyl ether.
Yield: 35-37 g, mp 104-106 ° C.

2-aminoacetylamino-3-o-chlorobenzoyl-5- (2-carbomethoxyethyl) - thiophene

35.8 g (0.08 mol) of the above bromoacetyl compound are dissolved in 700 ml of ethyl acetate dissolved and stirring for 2-3 hours initiated ammonia dry at room temperature. Man leaves overnight, washes with ice water, dries, evaporates and receives 22-25 g of oily amino compound.

7- (2-carbomethoxyethyl) -5-o-chlorophenylthieno-1,4- diazepinon

21.3 g (0.056 mol) of the above compound are dissolved in 500 ml of toluene and boiled under reflux with 75 g of silica gel on a water separator for 2 hours. The SiO _{2 is} suctioned off and the diazepine is extracted with hot methanol. After evaporating the methanol, 12-15 g of diazepine, mp. 160-162 ° C are obtained.

7- (2-carbomethoxyethyl) -5-o-chlorophenylthieno-1,4-diazepine 2-thion

10 g (0.03 mol) of the above diazepinons are in 100 ml Diglyme with 6.8 g of phosphorus pentasulfide and 5 g Sodium bicarbonate stirred at 70-80 ° C for 3 hours. The suspension is poured onto ice and stirred for 30-45 minutes and sucks off the crystals. After drying you get 10 g of thion, mp. 185-186 ° C.

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] - triazolo [4,3-a] [1,4] diazepin-2-yl] ethane-1-carboxylic acid methyl ester

6.1 g (0.016 mol) of the above sulfur compound are in 100 ml of tetrahydrofuran dissolved and after adding 1 g Hydrazine hydrate stirred at 45-50 ° C for 30 minutes. It is then evaporated in vacuo. Leave it behind 5-5.2 g of oil, which crystallize with isopropyl ether (Mp 175-177 ° C).

The hydrazino compound gives 35 ml when heated Ortho-acetic acid ester at 80 ° C, evaporate off Methylene chloride ester 3 g of triazolodiazepine from Mp 114-115 ° C.

The same connection is from the Thion with Acetic acid hydrazide accessible.  

Example 4: Acetic acid- {7- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - heptylester}

According to H. J. Bestmann et al., Chem. Ber. 104, 65 (1971) is subjected to Oleylacetat in methylene chloride at -40 ° C. ozonolysis and reductively cleaves the resulting ozonide with the equivalent amount of triphenylphosphine, the triphenylphosphine oxide formed thoroughly triturated with Ether is deposited. Traces not implemented Triphenylphosphins can in ethereal solution with Methyl iodide can be precipitated as a phosphonium salt. The Separation of the nonanal from the desired 9-acetoxynonanal conveniently takes place by separation by distillation in a silver mirror column. Starting from 9-acetoxynonanal is obtained analogously to Example 1 in quantitative Yields the aminothiophene compound, the 2-bromoacetylamino compound and the 2-aminoacetylamino compound, in 76% yield the diazepinone ring closure, in 65% yield the diazepinthion and in 33% yield Acetic acid- {7- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] heptyl- ester} as an oil.

¹ H NMR (CDCl ₃ ) δ ppm 7.26-7.58 (4H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.92 (2H, s, 7-ring CH ₂ ); 4.06 (2H, t, J = 6 Hz, OCH ₂ ); 2.76 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.72 (3H, s, triazole-CH ₃ ); 2.05 (3H, s, CH ₃ -C = O); 1.15-1.86 (10H, m, OCH ₂ - (CH ₂ ) ₅ -).

Example 5: 2-methylpropionic acid- {3- [4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - propylester}

0.5 g (0.0013 mol) 2- (3-hydroxypropyl) -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (Example 3), 0.12 g (0.0015 mol) pyridine and 0.2 g (0.0013 mol) of isobutyric anhydride are 4 hours stirred at 60 ° C. After stirring for a further 12 hours 20 ml are added to the reaction mixture at room temperature Water and extracted with ether. After drying and Removal of the solvent becomes the oily residue Silica gel with methylene chloride / methanol (9: 1) as the eluent chromatographed and gives the in quantitative yield Desired title compound of mp 124-125 ° C.

Example 6: Methanesulfonic acid- {3- [4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - propylester}

To 3.9 g (0.0105 mol) of 2- (3-hydroxypropyl) -4- (2- chlorphenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (Example 3) in 60 ml of anhydrous Methylene chloride are 1.7 g (0.015 mol) Given methanesulfonyl chloride and at 10 ° C 1.5 g (0.015 mol) triethylamine was added dropwise. After 12 hours Stirring at room temperature becomes the reaction mixture extracted thoroughly with water, the organic phase dried, the solvent removed and the residue on silica gel with methylene chloride / methanol (9: 1) as the eluent chromatographed. 3.8 g (yield 81% of theory) are obtained. the title compound with the mp. 130-135 ° C.  

Example 7: 2- (3-iodopropyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

0.6 g (0.0011 mol) of p-toluenesulfonic acid- {3- [4- (2- chlorphenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] propyl ester}, produced analogous to Example 6, and a solution of 0.2 g (0.0014 mol) anhydrous sodium iodide in 15 ml anhydrous acetone are stirred for 2 hours at room temperature. After this Removal of the solvent takes in the residue Methylene chloride / water, the organic phase washes several times with water, dries, removes the solvent and thus receives 0.2 g (yield 36% of theory) of the amorphous Title link.

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.67 (4H, m, aryl-H); 6.44 (1H, s, thiophene-H); 4.94 (2H, s, 7-ring CH ₂ ), 3.20 (2H, t, J = 7 Hz), CH ₂ -J); 2.92 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.12 (2H, m, JCH ₂ CH ₂ -).

Example 8: 2- (7-N-phthalimidoheptyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

3.0 g (0.006 mol) methanesulfonic acid- {7- [4- (2- chlorphenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] - triazolo [4,3-a] [1,4] diazepin-2-yl] heptyl ester} and 1.1 g (0.006 mol) of phthalimide potassium are made in anhydrous Dimethylformamide stirred at 60-70 ° C for 5 hours. After this Cooling, the reaction mixture is poured into 150 ml Ice water, extracted with methylene chloride and filtered  after drying and concentration over a small, wide Silica gel column using methylene chloride / Methanol (9: 1) as eluent. The phthalimide compound falls in quantitative yield as an oil.

¹ H NMR (CDCl ₃ ) δ ppm 7.62-7.94 (4H, m, phthal-aryl-H); 7.26-7.55 (4H, m aryl-H); 6.36 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 3.52 (2H, t, J = -6 Hz, N-CH ₂ -); 2.75 (2H, t, J = -6 Hz), thiophene-CH ₂ ); 2.69 (3H, s, triazole-CH ₃ ); 1.14 to 1.93 (10H, m, N-CH ₂ - (CH _{2) 5} -).

Example 9: 2- (7-amino-heptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno- [3,2-f] [1,2,4] -triazolo [4,3-a] [1,4] diazepine

31.7 g (0.057 mol) of the phthalimido compound of Example 8 are dissolved in 300 ml of ethanol and with 13.8 ml hydrazine hydrate (0.29 mol) for 20 hours Room temperature stirred. The precipitated solid is suction filtered and the filtrate concentrated and with 2N hydrochloric acid added. By extraction with methylene chloride leaves remove the unreacted output connection. The aqueous phase is made alkaline and again with Extracted methylene chloride. After drying and peeling off the solvent gives 14.2 g (Yield 58% of theory) of the amino compound as an oil.

¹ H NMR CDCl ₃ ) δ ppm 7.28-7.63 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H); 4.95 (2H, s, 7-ring CH ₂ ); 2,55- 3.10 (6H, m NCH _2, thiophene-CH _2, NH _2); 2.72 (3H, s, triazole-CH ₃ ); 1.07-1.90 (10H, m, N-CH ₂ - (CH ₂ ) ₅ -).

Example 10: 2- (7-acetylaminoheptyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

To 1.3 g (0.003 mol) of the amino compound of Example 9 and 0.4 ml triethylamine (0.003 mol) in 35 ml anhydrous Methylene chloride is 0.2 ml (0.003 mol) of acetyl chloride in 5 ml of anhydrous methylene chloride were added dropwise and 12 Stirred for hours at room temperature. After washing with Water, drying and solvent removal the residue is chromatographed on silica gel Methylene chloride / methanol (95: 5) as eluent and obtained 1.1 g of the acetylamino compound (yield 77% of theory) as Oil.

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.58 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 5.67 (1H, s, broad, NH); 4.94 (2H, s, 7-ring CH ₂ ); 3.24 (2H, m, _N-CH2); 2.76 (2H, t, J = 6 Hz, thiophene CH ₂ ); 2.72 (3H, s, triazole-CH ₃ ); 1.98 (3H, s, CH ₃ C = O); 1.21 to 1.83 (10H, m, N-CH ₂ (CH _{2) 5} -).

Example 11: 2- (3- (N-morpholinyl) propyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

2.7 g (0.006 mol) of the compound of Example 6 and 2.6 g (0.030 mol) morpholine in 50 ml of dioxane for 6 hours Heated to reflux, then stripped off the solvent and the residue taken up in methylene chloride / water. The organic phase is thoroughly rinsed with water shaken out, dried and the solvent removed. The residue is on silica gel with methylene chloride / Chromatographed methanol (9: 1) as eluent. You get 1.3 g of the morpholine compound (yield 50% of theory) of Mp 162-164 ° C.  

By dissolving the substance in methanolic hydrochloric acid and Precipitation with ether gives the hydrochloride Title compound of mp 95 ° C (decomposition).

Example 12: 2- (6-formylhexyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

To 1.5 g (0.0075 mol) of pyridine chlorochromate in 20 ml Methylene chloride is added dropwise to 2.1 g (0.005 mol) 2- (7-hydroxyheptyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine (Made, for example, from the compound of Example 4 by alkaline saponification) dissolved in 5 ml methylene chloride, stirred for 90 minutes at room temperature and added Solution with 50 ml ether. The fancy black, resinous Oil is thoroughly stirred several times with ether that Ether solutions are combined, suction filtered through diatomaceous earth, the filtrate was concentrated and the residue on silica gel Methylene chloride / methanol (9: 1) as eluent chromatographed. 0.6 g is obtained (yield 29% of theory) of the aldehyde as a colorless oil.

¹ H NMR (CDCl ₃ ) δ ppm 9.77 (1H, t, J = ≦ ωτ2 Hz, CHO); 7.25-7.59 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H); 4.94 (2H, s, 7-ring CH ₂ ); 2.76 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.41 (2H, m, -CH ₂ C = O); 1.17-1.90 (8H, O = CCH ₂ (CH ₂ ) ₄ -)

Example 13: 2- (3-acetoxypropyl) -4- (2-chlorophenyl) -9-bromo-6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

4 g (0.010 mol) of 2- (3-acetoxypropyl) -4- (2-chlorophenyl) -6H- thieno [3,2-f] [1,2,4] triazolo [4,3-1] [1,4] diazepine in 60 ml anhydrous chloroform, 1.9 g (0.012 mol) bromine and 1.2 g (0.015 mol) pyridine are 20 hours at room temperature touched. Then the reaction mixture becomes thorough shaken out with water, the organic phase dried, concentrated and the residue on silica gel with Methylene chloride / methanol (9: 1) as eluent cleaned chromatographically. 2.3 g are obtained (Yield 48% of theory) of the 9-bromo compound as an oil.

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.62 (4H, m, aryl-H); 6.43 (1H, s, thiophene-H); 4.90 (2H, s, 7-ring CH ₂ ); 4.11 (2H, t, J = 7 Hz, -O-CH ₂ ); 2.89 (2H, t, J = 7 Hz, thiophene CH ₂ ); 2.03 (3H, s, CH ₃ C = O); 2.00 (2H, m, OCH ₂ CH ₂ -).

Example 14 2- (3-hydroxypropyl) -4- (2-chlorophenyl) -9-methyl-6H- thieno [3,2-f] imidazo [1,2-a] [1,4] diazepine

To 15 g (0.038 mol) of 2- (3-acetoxypropyl) -4- (2-chlorophenyl) - 6H-7,8-dihydrothieno [3,2-f] [1,4] diazepin-7-thione dropwise in 200 ml of anhydrous dioxane Room temperature 6.3 g (0.114 mol) propargylamine, stirred 20 hours and removes the solvent. The residue is taken up in methylene chloride / water, the organic Phase washed thoroughly with water, dried and constricted. The crude product obtained is with Triturated isopropyl ether, where it crystallizes. Man receives 13.5 g of 2- (3-acetoxypropyl) -4- (2-chlorophenyl- 6H-7-propargylamino-thieno [3,2-f] [1,4] -diazepine (yield 86% of Th.) Mp 122-124 ° C.  

11 g (0.027 mol) of the intermediate compound thus obtained and 55 ml of concentrated sulfuric acid are in 10 minutes a preheated oil bath heated to 100 ° C, on ice poured and with concentrated ammonia to pH 10 set. Extraction with methylene chloride gives 1.2 g of residue, which was taken up in 100 ml of methanol and stirred with 0.2 g of potassium hydroxide at 60 ° C for one hour becomes. After removing the methanol, take the Residue in methylene chloride / water, washes the organic phase thoroughly with water, dries, pulls that Solvent and chromatographed on the residue Silica gel with methylene chloride / methanol (9: 1) as the eluent and thus receives 0.7 g of the imidazo compound (yield 7% d. Th.) Mp 131-134 ° C.

¹ H NMR (CDCl ₃ ) δ ppm 7.22-7.58 (4H, m, aryl-H); 6.89 (1H, q, J ≦ ωτ1 Hz, imidazole-H); 6.38 (1H, s, thiophene-H); 4.77 (2H, s, 7-ring CH ₂ ); 3.68 (2H, t, J = 7 Hz, OCH ₂ ); 2.86 (2H, t, J = 8 Hz, thiophene-CH ₂ ); 2.42 (3H, d, J = ≦ ωτ1 Hz, imidazole, CH ₃ ); 1.88 (2H, m, -OCH ₂ -CH ₂ -); 2.00 (1H, s, broad, OH).

Example 14a 2- (2-methoxycarbonylethyl) -7-ethoxycarbonyl-6- (2-chlorophenyl) - 6H-thieno [3,2-f] imidazo [1,5-a] [1,4] diazepine

9.0 (0.025 mol) 7- (2-methoxycarbonylethyl) -5-chlorophenyl) - 1,2-dihydro-3H-thieno [2,3-e] [1,4] diazepin-2-one (W.D. Bechtel and K.H. Weber, J. Pharmac. Sci 74, 1265 (1985) dated Mp 152-154 ° C in 25 ml of dimethylformamide suspended and under nitrogen with 3.5 g of potassium tert-butoxide added. The mixture is stirred for 10-15 minutes and cooled -30 ° and gives 4.7 g of diethyl chlorophosphate within 10-15 min added.  

To this solution is added the mixture prepared from 3.3 g of potassium tert-butoxide and 3.3 g of ethyl isocyanate at -40 ° in 22 ml of dimethylformamide and the temperature is kept at -10 ° C. for 2 hours and then the reaction mixture is left at room temperature heat. 2.5 ml of glacial acetic acid and then 350 ml of water are added with cooling, and the reaction mixture is then extracted with ethyl acetate. After washing, drying and evaporating the ethyl acetate phases, the residue is chromatographed on SiO ₂ . After the addition of ether, 4.0 g of crystals of mp: 139-140 ° C. are obtained from the eluate.

Example 14b 2- [2- (morpholin-4-ylcarbonyl) ethyl] -4- (2-chlorophenyl) -6H- thieno- [3,2-f] imidazo [1,5-a] [1,4] diazepine.

3.5 g (0.0076 mol) of the diester prepared according to Example 14a are refluxed in 75 ml of tetrahydrofuran with 0.75 g of NaOH in 75 ml of methanol and 40 ml of water for 1 hour. It is acidified with 2.6 ml of glacial acetic acid and the solution is concentrated. The crystals of dicarboxylic acid which precipitate after the addition of 50 ml of water melt at 275 ° C. with decomposition.
Educ. 3.0 g.

This compound was heated together with 100 ml of 1,2,4-trichlorobenzene under nitrogen for 1 hour. It is filtered and petroleum ether is added to the filtrate, the 2- (2-carboxyethyl) compound failing. The morpholide of mp 158 ° C. is obtained from this carboxylic acid analogously to Example 3.

Example 14c 2- (2-diethylaminocarbonylethyl) -6- (2-chlorophenyl) -9- methyl-6H-thieno [3,2-f] imidazo [1,2-a] [1,4] diazepine

Starting from 7- (2-methoxycarbonylethyl) -5- (2- chlorophenyl) -1,2-dihydro-3H-thieno [2,3-e] [1,4] diazepin-2-thione (W. D. Bechtel and K. H. Weber, J. Pharm. Sci 74, 1265 (1985) of mp 190 ° C contains analog the corresponding synthetic route described in Example 14 Diethylamide, mp 201-203 ° C.

Example 14d 2- [2- (morpholin-4-ylcarbonyl) ethyl] -6- (2-chlorophenyl) -9- methyl-6H-thieno [3,2-f] imidazo [1,5-a] [1,4] diazepine

The carboxylic acid described above gives the Title compound when using morpholine instead of Diethylamine. Mp: 248-250 ° C.  

Example 14e 2- [1- (morpholin-4-yl-carbonyl) prop-1-en-2-yl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

• a) 48.8 g (0.2 mol) of 2-acetylamino-3- (2-chlorobenzoyl) thiophene are heated under reflux for 1 1/2 hours with 500 ml of acetic anhydride and 6 ml of 85% phosphoric acid. You steam i. Vac. , the residue is mixed with 200 ml of water and neutralized with 40% sodium hydroxide solution. The crystals are filtered off and washed with water, methanol and ether.
  Yield: 49-51 g, mp: 228-230 ° C
• 50.3 g of this compound are dissolved in nitrogen a solution of 10 g KOH dissolved in 300 ml methanol given and 1 to 2 hours at room temperature touched. It is neutralized with 2N hydrochloric acid and extracts the amino derivative with methylene chloride. To Chromatography of the residue gives 43 g 5-Acetyl-2-amino-3- (2-chlorobenzoyl) thiophene from Mp: 190-191 ° C.
• b) 5.5 g (0.02 mol) of this compound are taken up in 50 ml of chloroform to protect the acetyl group and, after addition of 2 ml of 1,3-propanedithiol, stirred at room temperature for 5 minutes while introducing dry HCl gas. The mixture is then extracted successively with water, dilute sodium hydroxide solution and again with water, the organic phase is dried, the solvent is evaporated and the residue is chromatographed over SiO ₂ (methylene chloride / ethanol). With ether, 4.3 g of crystals of mp 162-163 ° C. are obtained from the residue of the main fraction.
• This connection can be made in a similar way as before (e.g. described in Example 3) for diazepinone (Mp. 260 ° C), diazepinthion (mp. 218 ° C) and the Triazolodiazepine (mp. 212 ° C) are implemented
• c) To remove the protective group, 9 g (0.02 mol) of the triazolodiazepine are stirred with 20 g of chloramine T in 200 ml of methanol for 2 hours at room temperature. Chromatography over SiO ₂ (methylene chloride / ethanol 98: 2) gives 3.5-4 g, 2-acetyl-4- (2-chlorophenyl) -9-methyl-6H-thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.
• 3.6 g (0.01 mol) of this compound are in 5 ml Suspended benzene and after adding 2.25 g Phosphoroacetic acid triethyl ester to one submitted solution of 0.23 g of sodium in 5 ml of ethanol dripped. The mixture is sintered at 40 ° C. for 20 hours and works on. The ester obtained is with saponified ethanolic potassium hydroxide solution. After acidification and working up, 1.4-1.6 g of crystals of Mp 296-298 ° C.
• The carboxylic acid can be analogous to that described above Examples in the morpholide from mp. 194-196 ° C. be transferred.

Example 14f 2- [2- (morpholin-4-yl-carbonyl) -pent-4-en-1-yl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

20 g (0.05 mol) of 2-amino-3- (2-chlorobenzoyl) -5- (2,2-dicarboethoxyethyl) - thiophene (W. D. Bechtel and K. H. Weber, J. Pharmac. Sci. 74, 1265 (1985) are made in 100 ml Tetrahydrofuran suspended. This suspension is dropped to 2.5 g of sodium hydride, suspended in tetrahydrofuran (100 ml) and stir at 30 ° C for 1 hour. After adding 4.5 ml of allyl bromide (0.05 mol) is added for 2 hours Stirred at room temperature, the reaction mixture was concentrated, the residue taken up with methylene chloride and with Washed water. 13 is obtained from the organic phase g crystals of mp 151-152 ° C. 13 g (0.03 mol) of this Dicarboxylic acid esters with 30 ml of ethanol, 6 ml of water saponified with 3.8 g caustic potash. 11.3 g are obtained Dicarboxylic acid, which is heated in 20 ml DMF (120-130 ° C) is decarboxylated and 6-7 g Monocarboxylic acid of mp. 202-203 ° C.

The methyl ester available from this is an oil. This is bromoacetylated, aminated and cyclized to the diazepinone in a manner analogous to that described above.
Mp 162-165 ° C.

That accessible from diazepinone with phosphorus pentasulfide Diazepinthion melts at 179 ° C and gives the Triazolo-thieno-diazepine carboxylic acid, mp. 207-208 ° C. From this, morpholide is obtained via the imidazolide according to the method described earlier as viscous oil.  

Example 14g 2- [2-benzyl-2- (morpholin-4-ylcarbonyl) ethyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

Starting from 2-amino-3- (2-chlorobenzoyl) -5- (2,2-dicarbethoxyethyl) thiophene, analogously to Example 14f, the title compound is obtained in the following stages by reaction with benzyl chloride.
Diazepinone mp 158-161 ° C
Diazepinthion mp 170-172 ° C
Triazolothienodiazepine carboxylic acid mp 158-162 ° C

Example 14h 2- [2- (N, N-Diethylaminocarbonyl) -n-propyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

2-Amino-3- (2-chlorobenzoyl) -5- (2,2-dicarboethoxyethyl) thiophene gives the corresponding C-methyl compound with methyl iodide and then the title compound according to the above-described route in the following stages:
Diethyl dicarboxylate, mp. 181-182 ° C
Monocarboxylic acid mp 161-162 ° C
Diazepinoncarbonsäuremethylester mp. 179-180 ° C.
Triazolothienodiazepine carboxylic acid methyl ester as an oil
Title compound (diethylamide) mp 102-103 ° C

Example 14i 2- [2- (morpholin-4-yl-carbonyl) -n-propyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

The title compound is obtained analogously to Example 14h using morpholine instead of diethylamine. Oil.

Example 14j 2- (2- (N, N-diethylaminocarbonylethyl) -4- (2-chlorophenyl) -9- methyl-4,5-dihydro-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

2.5 g (0.006 mol) of diethylamide (produced from the carboxylic acid, WD Bechtel and KH Weber, J. Pharm. Sci 74, 1265 (1985), with diethylamine and dicyclohexylcarbodiimide) together with 2 g of zinc dust, 50 ml of glacial acetic acid and 50 ml of methylene chloride stirred for 15 hours at room temperature. The mixture is then filtered through diatomaceous earth, washed with methylene chloride and the filtrate made alkaline with ammonia. The methylene chloride phase is separated off, washed with water, dried, evaporated and the residue is chromatographed over SiO ₂ . The main fraction obtained is 0.8 g of oil.

Example 14k 2- [2- (4,4-dimethyl-2-oxazolin-2-yl) ethyl] -4- (2-chlorophenyl) - 9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

3 g (7.7 mmol) of 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepin-2-yl] ethane 1-carboxylic acid, 0.69 g (7.7 mmol) 2-amino-2-methyl-propane 1-ol, 2.35 g (23 mmol) triethylamine and 4.8 g Carbon tetrachloride is dissolved in 15 ml pyridine / acetonitrile (1: 1) stirred at room temperature. About this mix a solution of 6.2 g is added dropwise within 2 hours (23.6 mmol) triphenylphosphine in 15 ml of the above Pyridine / acetonitrile mixture.

After 15 hours the suspension is concentrated, the residue extracted with ether / ethyl acetate mixtures (1: 1). The extracts are concentrated and the remaining residue is chromatographed on silica gel with dichloromethane / methanol (95: 5). The clean fractions are concentrated and 1.9 g (56%) of the title compound of mp 168 ° C. are obtained by recrystallization from ether.

Example 14l 2- [3- (N-Morpholinyl) -n-propyl] -4- (2-chlorophenyl) -9-methyl- 4,5-dihydro-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

1.2 g (0.0027 mol) of 2- [3- (N-morpholinyl] -n-propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepine in 20 ml of anhydrous THF are in a submitted suspension of 0.1 g (0.0027 mol) lithium aluminum hydride in 20 ml of anhydrous THF Dropped at room temperature and reflux for 1 hour heated. The reaction mixture is decomposed with 0.1 ml Water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water are stirred 30 minutes and sucks off the precipitate. The filtrate is concentrated in methylene chloride taken up, washed, dried and the solvent deducted. The residue is included as silica gel Methylene chloride / methanol 95: 5 as eluent chromatographed. 0.16 g (yield 13%) of desired connection of mp. 135-138 ° C.

Example 14m 2 - [(2-phenyl-1,3-dioxolan-4-yl) methyl] -4- (2-chlorophenyl) -9- methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

45.7 g (0.4 mol) of 3,4-dihydro-2H-pyran-2-methanol are subjected to ozonolysis in 100 ml of anhydrous methylene chloride at -40 °. 104.9 g (0.4 mol) of triphenylphosphine in 70 ml of anhydrous methylene chloride are then added dropwise, and the reaction mixture is slowly brought to room temperature over the course of 3 hours. After 12 hours, the solvent is stripped off and the residue is thoroughly digested with ether and the triphenylphosphine oxide which has precipitated is filtered off with suction. Unreacted triphenylphosphine residues are precipitated with methyl iodide as the phosphonium salt in ether and suction filtered. The solvent is drawn off from the filtrate and the residue is fractionated in vacuo. 32 g (55% yield) of 4-formyloxy-5-hydroxypentanal with a bp of _0.1 = 82-92 ° C. are obtained.

23 g (0.157 mol) of the aldehyde, 28 g (0.137 mol) of o-chlorocanoacetophenone, 5 g (0.157 mol) of sulfur and 16 g (0.157 mol) of triethylamine are used in 100 ml of DMF in a conventional manner to close the thiophene ring and the resulting
2-Amino-3- (2-chlorobenzoyl) -5- (2-formyloxy-3-hydroxy-n-propyl) thiophene as crude product with 15 g (0.16 mol) of potassium hydroxide in 500 ml of methanol heated to reflux for 2 hours . After the solvent has been stripped off, the residue is taken up in ethyl acetate, washed with water, dried and, after removal of the solvent, chromatographed on silica gel using ethyl acetate as the eluent. 19.9 g (overall yield 39%) of 2-amino-3- (2-chlorobenzoyl) -5- (2,3-dihydroxy-n-propyl) thiophene, mp 136-137 ° C., are obtained.

5 g (0.016 mol) of the dihydroxy thiophene compound, 1.7 g (0.016 mol) freshly distilled benzaldehyde and one Spatula tip p-toluenesulfonic acid on Water separator in 250 ml of toluene heated to reflux. After 2.5 hours, the toluene phase with pyrrolidine made alkaline, washed with water, dried and stripped the solvent. The residue is on silica gel Methylene chloride / methanol 9: 1 as eluent chromatographed and gives 3.8 g (59% yield) of 1,3-dioxolane compound as a reddish oil (Mixture of diastereomers).  

The 2-amino-3- (2-chlorobenzoyl) -5- thus obtained [(2-phenyl-1,3-dioxolan-4-yl) methyl] thiophene is used as described in the previous examples Title connection implemented.

Example 14n 2- (2-ethoxycarbonylethyl) -3,9-dimethyl-4- (2-chlorophenyl) -6H- thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.

Starting from 5- (2-chlorophenyl) -6-methyl-7- (2-ethoxycarbonyl-ethyl) -1,2-dihydro-3H-thieno [2,3-e] [1,4] diazepin-2-one is obtained analogously to that in Example 3 described the title compound.

The starting compound is made as follows:
11.6 g (0.073 mol) of 5-oxo-hexanoic acid ethyl ester are reacted with equimolar amounts of o-chloro-2-cyano-acetophenone and sulfur with the addition of 6.7 ml of diethylamine in 30 ml of ethanol for 5 hours at 60 ° C. according to Gewald. The residue obtained on concentrating the reaction solution is chromatographed on a silica gel column using chloroform as the eluent. The amino ketone thus obtained is converted into the title compound analogously to Example 3. The diazepinone has a melting point of 173-176 ° C (toluene / ether).

Example 14o 2- [2-morpholin-4-yl-carbonyl) -2- (ethoxycarbonyl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine

1 g (0.0021 mol) of 2- [2,2-di (ethoxycarbonyl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepine and 5 g morpholine are 10 hours stirred at 120 ° C. It is diluted with 100 ml of water, shakes several times with methylene chloride, washes the organic phase with water, dries and concentrates. The residue thus obtained is passed through a silica gel column chromatographed (methylene chloride / methanol 97: 3). To usual work-up, the title compound is obtained as amorphous powder.

The following abbreviations are sometimes used in the tables:
Et = ethyl
Me = methyl
iPr = isopropyl
t-Bu = tert-butyl
Ac = acetyl

The following intermediate compounds are prepared in analogy to the processes described in the examples:

Table 1

Table 2

Table 3

Table 4

Table 5

The compounds of the general formula I can be prepared analogously to the examples described above:

Table 6

Table 8

Compounds of formula Ib

The following are examples of some pharmaceutical Compositions using compounds of the general formula I specified as an active ingredient. Unless expressly stated otherwise, it acts parts by weight.

1. tablets

The tablet contains the following components:
Active ingredient according to formula Ia / b 0.020 parts stearic acid 0.010 parts dextrose 1.890 parts total 1.920 parts

Manufacturing:

The substances are mixed together in a known manner and compresses the mixture into tablets, each of which Weighs 1.92 g and contains 20 mg of active ingredient.

2. Ointment

The ointment consists of the following ingredients together:

Active ingredient according to formula Ia / b50 mg Neribas ointment (commercial goods Scherax), 10ad 10 g

Manufacturing:

The active ingredient is triturated with 0.5 g of ointment base and the rest of the base in 1.0 g aliquots gradually mixed intimately into an ointment. Man receives a 0.5% ointment. The distribution of the Active ingredient in the basis is optically under the Microscope checked.  

3. Cream

Composition:

Active ingredient according to formula Ia / b50 mg Neribas ointment (commercial goods Scherax), 10ad 10 g

Manufacturing

The active ingredient is triturated with 0.5 g of cream base and the rest of the base in 1.0 g increments and after incorporated with pestle. You get one 0.5% cream. The distribution of the active substance in the The basis becomes optical under the microscope controlled.

4. Ampoule solution

Composition:

Active ingredient according to formula Ia / b 1.0 mg Sodium chloride 45.0 mg Aqua per inj., 10ad 5.0 ml

Manufacturing:
The active ingredient is dissolved in water at its own pH, if necessary at pH 5-7, and sodium chloride is added as an isotonance. The solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed. The ampoules contain 1 mg, 5 mg and 1 mg of active ingredient.

5. Suppositories

Each suppository contains:
Active ingredient according to formula Ia / b 1.0 part cocoa butter (mp. 36-37 ° C) 1200.0 parts carnauba wax 5.0 parts

Manufacturing
Cocoa butter and carnauba wax are melted together. The active ingredient is added at 45 ° C. and the mixture is stirred until a complete dispersion has formed.

The mixture comes in appropriate sized shapes poured and the suppositories packed appropriately.

6. Inhalation solutions

Composition:

• a) Active ingredient according to formula Ia / b, 6500 mg Na-EDTA, 6 50 mg benzalkonium chloride, 6 25 mg sodium chloride, 6880 mg distilled water, 4ad 100 ml Preparation:
  96% of the amount of water are introduced, in which Na-EDTA, benzalkonium chloride, sodium chloride and active ingredient are dissolved in succession and made up with the remaining water. The solution is filled into 20 ml dropper bottles. One dose (20 drops, 1 ml) contains 5 mg of active ingredient.
• b) Active ingredient according to formula Ia / b, 6500 mg sodium chloride, 6820 mg distilled water, 4ad 100 ml preparation
  96% of the amount of hydrogen are introduced, the active ingredient and sodium chloride are dissolved in it in succession, made up with the remaining water and the solution is poured into a can container (4 ml). The solution contains 20 mg of active ingredient.

The NMR spectra are more selected in Table 9 Compounds of the general formula Ia / Ib listed.

Table 9 Example 15

¹ H NMR (CDCl ₃ ) δ ppm 7.23-7.62 (4H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.92 (2H, s, _CH2 -7-ring); 3.62 (2H, t, J = 6 Hz, OCH ₂ ); 2.77 (2H, t ,, J = 6 Hz, CH ₂ thiophene); 2.72 (3H, s, triazole-CH ₃ ), 2.07 (1H, s, broad, OH); 1.17-1.89 (10H, m, OCH ₂ - (CH ₂ ) ₅ -).

Example 19

¹ H NMR (CDCl ₃ ) δ ppm 7.22-7.57 (4H, m, aryl-H); 6.44 (1H, s, thiophene-H); 4.95 (2H, s, 7-ring CH ₂ ); 2.85 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.80 (2H, t, J = 6 Hz, NCH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.44 (2H, s, broad, NH ₂ ); 1.84 (2H, m, NCH ₂ -CH ₂ -).

Example 22

¹ H NMR (CDCl ₃ ) δ ppm 7.22-7.87 (8H, m, aryl-H); 6.40 (1H, s, thiophene-H); 4.92 (2H, s, 7-ring CH ₂ ); 4.06 (2H, t, J = 6 Hz, OCH ₂ ); 2.87 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.67 (3H, s, triazole-CH ₃ ); 2.44 (3H, s, aryl-CH _3); 2.01 (2H, m, -OCH ₂ CH ₂ -).

Example 23

¹ H NMR (CDCl ₃ ) δ ppm 7.23-7.58 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 4.21 (2H, t, J = 7 Hz, OCH ₂ ); 2.99 (3H, s, CH ₃ SO _2); 2.75 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.70 (3H, s, triazole-CH ₃ ); 1.14-1.98 (10H, m, OCH ₂ - (CH ₂ ) ₅ ).

Example 24

¹ H NMR (CDCl ₃ ) δ ppm 7.22-7.84 (8H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 4.01 (2H, t, J = 6 Hz, OCH ₂ ) 2.81 (2H, m, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.49 (3H, s, aryl-CH _3); 1.16-1.89 (10H, m, OCH ₂ - (CH ₂ ) ₅ ).

Example 26

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.59 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 4.95 (2H, s, 7-ring CH ₂ ); 4.06 (2H, t, J = 6 Hz, OCH ₂ -); 2.77 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.72 (3H, s, triazole-CH ₃ ); 2.53 (1H, m, CH-C = O); 1.26-1.89 (10H, m, OCH ₂ - (CH ₂ ) ₅ -); 1.28 (6H, d, J = 5 Hz, (CH ₃ ) ₂ -CH-).

Example 27

¹ H NMR (CDCl ₃ ) δ ppm 7.31-7.58 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 4.94 (2H, s, 7-ring CH ₂ ); 4.04 (2H, t, J = 6 Hz, OCH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.77 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 1.23 to 1.93 (10H, m, OCH ₂ (CH _{2) 5} -); 1.20 (9H, s, C (CH _{3) 3).}

Example 28

¹ H NMR (CDCl ₃ ) δ ppm 7.31-7.59 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 4.94 (2H, s, 7-ring CH ₂ ); 4.69 (1H, s, broad, NH); 4.04 (2H, t, J = 7 Hz, OCH ₂ ); 2.78 (3H, d, J = 6 Hz, CH ₃ N); 2.76 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 1.20-1.85 (10H, m, OCH ₂ - (CH ₂ ) ₅ -).

Example 31

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.61 (4H, m, aryl-H); 6.44 (1H, s, thiophene-H); 4.94 (2H, s, 7-ring CH ₂ ); 3.59 (2H, t, J = 7 Hz, N-CH _2); 2.81 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.71 (7H, s, succin-CH ₂ CH ₂ -, triazole-CH ₃ ); 1.93 (2H, m, N-CH ₂ CH _2).

Example 32

¹ H NMR (CDCl ₃ ) δ ppm 7.62-7.95 (4H, m, phthalide-aryl) -H); 7.28-7.56 (4H, m, aryl-H); 6.43 (1H, s, thiophene-H); 4.87 (2H, s, 7-ring CH ₂ ), 3.76 (2H, t, J = 6 Hz, N-CH ₂ ); 2.86 (2H, t, J = 6 Hz, thiophene-CH ₂ ), 2.70 (3H, s, triazole-CH ₃ ); 2.06 (2H, m, N-CH ₂ CH ₂ -).

Example 33

¹ H NMR (CDCl ₃ ) δ ppm 7.28-7.58 (4H, m, aryl-H); 6.35 (1H, s, broad, NH); 6.35 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 3.92 (2H, s, imidazolidione-CH ₂ ); 3.46 (2H, t, J = 7 Hz, N-CH ₂ ); 2.75 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 1.13 to 1.86 (10H, m, N-CH ₂ - (CH _{2) 5).}

Example 34

¹ H NMR (CDCl ₃ ) δ ppm 7.30-7.51 (4H, m, aryl-H); 6.44 (1H, s, thiophene-H); 4.98 (2H, s, 7-ring CH ₂ ); 3.51 (2H, t, J = 6 Hz, N-CH _2); 2.76 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.74 (3H, s, triazole-CH ₃ ); 2.71 (4H, s, succin-CH ₂ ); 1.23 to 1.74 (10H, m, N-CH ₂ - (CH _{2) 5} -).

Example 35

¹ H NMR (CDCl ₃ ) δ ppm 7.21-7.52 (4H, m, aryl-H); 7.27 (1H, t, J = 6 Hz, NH); 6.54 (1H, s, thiophene-H); 4.84 (2H, s, 7-ring CH ₂ ); 4.47 (2H, d, J = 6 Hz, N-CH ₂ ); 2.66 (3H, s, triazole-CH ₃ ); 2.00 (3H, s, CH ₃ -C = O).

Example 36

¹ H NMR (CDCl ₃ ) δ ppm 7.33-7.57 (4H, m, aryl-H); 6.54 (1H, t, J = 6 Hz, NH); 6.46 (1H, s, thiophene-H); 4.96 (2H, s, 7-ring CH ₂ ); 3.32 (2H, q, J = 6 Hz, _NH-CH2); 2.83 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 1.98 (3H, s, CH ₃ -CO); 1.88 (2H, m, N-CH ₂ -CH ₂ -).

Example 39

¹ H NMR (CDCl ₃ ) δ ppm 7.03-7.62 (5H, m, aryl-H and NH); 6.40 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 3.33 (2H, q, J = 6.5 Hz, CH ₂ -NH); 2.94 (2H, s, CH ₂ C = O); 2.82 (2H, m, CH ₂ thiophene); 2.70 (3H, s, triazole-CH ₃ ); 2.27 (6H, s, N- (CH _{3) 2);} 1.89 (2H, m, N-CH ₂ -CH ₂ -).

Example 41

¹ H NMR (CDCl ₃ ) δ ppm 7.25-7.60 (4H, m, aryl-H); 6.37 (1H, s, thiophene-H); 5.64 (1H, s, broad, NH); 4.94 (2H, s, 7-ring CH ₂ ); 3.23 (2H, m, _N-CH2); 2.76 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.33 (1H, m, CH-C = O); 1.21 to 1.87 (10H, m, N-CH ₂ - (CH _{2) 5);} 1.16 (6H, d, J = 8 Hz, (CH ₃ ) ₂ -C).

Example 43

¹ H NMR (CDCl ₃ ) δ ppm 7.45-7.60 (4H, m, aryl-H); 7.17 (1H, s, broad, NH); 6.34 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 3.27 (2H, q, J = 6.5 Hz, CH ₂ NH); 2.94 (2H, s, CH ₂ C = O); 2.71 (3H, s, triazole-CH ₃ ); 2.71 (2H, m, CH ₂ thiophene); 2.28 (6H, s, N (CH _{3) 2);} 1.21 to 1.88 (10H, m, (CH _{2) 5).}

Example 45

¹ H NMR (CDCl ₃ ) δ ppm 7.24-7.58 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 2.79 (2H, t, J = 8 Hz, N-CH ₂ ); 2.69 (3H, s, triazole-CH ₃ ); 1.24-2.49 (14H, m, piperidine-CH ₂ , thiophene-CH ₂ -CH ₂ ).

Example 47

¹ H NMR (CDCl ₃ ) δ ppm 7.19-7.59 (4H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 3.68 (2H, m, 2,6-morpholine-CH-); 2.71 (3H, s, triazole-CH ₃ ); 1.16, 1.23 (6H, 2d, J = 6 Hz, 2,6-morpholine-CH ₃ ); 1.01-2.91 (18H, m, morpholine-NCH ₂ / N- (CH ₂ ) ₇ )

Example 48

¹ H NMR (CDCl ₃ ) δ ppm 7.24-7.56 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H); 4.92 (2H, s, 7-ring CH ₂ ); 2.80 (2H, t, J = 7 Hz, N-CH ₂ ); 2.70 (3H, s, triazole-CH ₃ ); 2.42 (8H, s, piperazine-CH ₂ ); 2.37 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.27 (3H, s, N-CH _3), 1.86 (2H, m, N-CH ₂ -CH _2).

Example 49

¹ H NMR (CDCl ₃ ) δ ppm 7.24-7.59 (4H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 2.74 (2H, t, J = 7 Hz), N-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.44 (8H, s, piperazine-CH ₂ ); 2.28 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.27 (3H, s, N-CH _3); 1.08 to 1.88 (10H, m, N-CH ₂ - (CH _{2) 5).}

Example 54

¹ H NMR (CDCl ₃ ) δ ppm 7.20-7.73 (5H, m, aryl-H); 6.64 (1H, s, thiophene-H); 4.87 (2H, s, 7-ring CH ₂ ); 3.71 (4H, m, morpholine-OCH ₂ ); 2.89 (2H, t, J = 7 Hz, N-CH ₂ ); 2.69 (3H, s, triazole-CH ₃ ); 2.21-2.57 (6H, m, morpholine-N-CH ₂ / thiophene-CH ₂ ); 1.90 (2H, m, N-CH ₂ -CH ₂ -).

Example 56

¹ H NMR (CDCl ₃ ): δ 7.21-7.62 (m, 4H, aryl-H); 6.92 (qu, J ≦ ωτ 1 Hz, CH =); 6.41 (s, 1H, thiophene-H); 4.81 (s, 2H, _CH2 -7-ring); 4.12 (t, J = 7 Hz, 2H, OCH ₂ ); 2.86 (t, J = 7 Hz, 2H, CH ₂ thiophene); 2.45 (d, J ≦ ωτ 1 Hz, 3H, CH ₃ imidazole); 2.05 (s, 3H, CH ₃ -C = O); 2.00 (m, 2H, OCH ₂ CH ₂ ).

Example 58

¹ H NMR (CDCl ₃ ); δ 7.21-7.60 (m, 4H, aryl-H); 6.91 (qu, J ≦ ωτ 1 Hz, 1H, CH =); 6.35 (s, 1H, thiophene-H); 4.79 (s, 2H, _CH2 -7-ring); 4.06 (t, J = 7 Hz, 2H, OCH ₂ ); 2.76 (t, J = 7 Hz, 2H, CH ₂ thiophene); 2.46 (d, J = ≦ ωτ 1 Hz, 3H, CH ₃ imidazole); 2.05 (s, 3H, CH ₃ C = O); 1.15-1.91 (m, 10H, OCH ₂ - (CH ₂ ) ₅ -).

Example 65

¹ H NMR (CDCl ₃ ): δ 7.21-7.64 (m, 4H, aryl-H); 6.43 (s, 1H, thiophene-H); 4.97 (s, 2H, _CH2 -7-ring); 2.84 (t, J = 8 Hz, 2H, CH ₂ thiophene); 2.30 (t, J = 8 Hz, 2H, 2H, _N-CH2); 2.72 (s, 3H, CH ₃ -triazole; 2.22 (s, 6H, N- (CH ₃ ) ₂ ), 1.81 (m, 2H, N-CH ₂ CH ₂ ).

Example 69

¹ H NMR (CDCl ₃ ) δ ppm 7.22-7.58 (4H, m, aryl-H); 6.36 (1H, s, thiophene-H); 4.93 (2H, s, 7-ring CH ₂ ); 2.74 (2H, t, J = 7 Hz, N-CH ₂ ); 2.71 (3H, s, triazole-CH ₃ ); 2.09-2.51 (6H, m, piperidine-CH ₂ thiophene-CH ₂ ); 1.12-1.83 (16H, m, piperidine CH ₂ / N-CH ₂ - (CH ₂ ) ₅ ).

Example 71

¹ H NMR (CDCl ₃ ): δ 7.21-7.60 (m, 4H, aryl-H), 6.39 (s, 1H, thiophene H); 4.93 (s, 2H, _CH2 -7-ring); 2.79 (t, J = 8 Hz, 2H, CH ₂ thiophene); 2.69 (s, 3H, _CH3 -triazole); 2.52 (qu, J = 7 Hz, 4H, N- (CH ₂ CH ₂ ); 2.54 (t, J = 7 Hz, 2H, CH ₂ -thiophene); 1.83 (m, 2H, N -CH ₂ CH ₂ ); 0.98 (t, J = 8 Hz, 6H, N-CH ₂ CH ₃ ).

Example 72

¹ H NMR (CDCl ₃ ): δ 7.22-7.63 (m, 6H, aryl-H, pyrazole H 3/5); 6.38 (s, 1H, thiophene-H); 6.22 (t, J = 2 Hz, 1H, pyrazole H 4); 4.94 (s, 2H, _CH2 -7-ring); 4.17 (t, J = 6 Hz, 2H, _N-CH2); 2.78 (t, J = 6 Hz, 2H, CH ₂ thiophene; 2.71 (s, 3H, CH ₃ triazole); 2.26 (m, 2H, NCH ₂ CH ₂ -).

Example 73

¹ H NMR (CDCl ₃ ); δ 7.22-7.66 (m, 6H, aryl-H, pyrazole H 3/5); 6.39 (s, 1H, thiophene-H); 6.25 (t, J = 2 Hz, 1H, pyrazole-H4); 4.97 (s, 2H, _CH2 -7-ring); 4.15 (t, J = 7 Hz, 2H, _N-CH2); 2.78 (t, J = 7 Hz, 2H, CH ₂ thiophene); 2.72 (s, 3H, CH ₃ triazole); 1.08 to 2.05 (m, 10H, N-CH ₂ (CH _{2) 5} -).

Example 74 /

¹ H NMR (CDCl ₃ ): δ 7.29-7.62 (m, 4H, aryl-H); 6.67 (t, J = 2 Hz, 2H, pyrrole-H 2/5); 6.39 (s, 1H, thiopheny-H); 6.16 (t, J = 2 Hz, 2H, pyrrole-H / 3/4); 4.98 (s, 2H, _CH2 -7-ring); 3.91 (t, J = 7 Hz, 2H, _N-CH2); 2.72 (t, J = 7 Hz, 2H, CH ₂ thiophene); 2.72 (s, 3H, _CH3 -triazole); 1.07 to 2.06 (m, 10H, N-CH ₂ (CH _{2) 5;}

Example 77

¹ H NMR (CDCl ₃ ): δ 8.32 (s, 1H, NH-indole); 7.00-7.76 (m, 9H, aryl-H, indole-H); 6.35 (s, 1H, thiophene-H); 4.93 (s, 2H, _CH2 -7-ring); 3.09 (s, 4H, CH ₂ CH ₂ N); 2.68 (s, 3H, CH ₃ triazole); 2.45-2.94 (m, 4H, thiophene CH ₂ CH ₂ N-), 1.07-1.92 (m, 11H, N-CH ₂ (CH ₂ ) ₅ -, NH).

Example 81

¹ H NMR (CDCl ₃ ): δ 7.26-7.67 (4H, m, aryl-H); 6.47 (1H, s, thiophene-H); 4.96 (2H, s, _CH2 -7-ring); 4.35 (1H, m, X-part of ABX system, OCH); 4.08, 3.63 (2H, m, AB part of ABX system, OCH ₂ ); 3.02 (2H, d, J = 7 Hz, CH ₂ thiophene); 2.72 (3H, s, CH ₃ -Triazozol); 1.43, 1.37 (6H, 2 s, C (CH ₃ ) ₂ ).

Example 82

¹ H NMR (CDCl ₃ ); δ 7.11-7.71 (4H, m. aryl-H; 6.46 (1H, s, thiophene-H); 4.88 (2H, s, CH ₂ -7-ring; 4.10 (2H, s. broad, 2 OH) 3.33-4.07 (3H, m, ABX system, OCH ₂ -CH-O); 2.92 (2H, d, J = 5 Hz, CH ₂ -thiophene); 2.65 (3H, s, CH ₃ -triazole).

Example 83b

¹ H NMR (CDCl ₃ ): δ 7.03-7.62 (9H, m, aryl-H); 6.46 ( ¹ H, s, (thiophene-H), 5.00, 4.87 (2H, AB system, JAB = 15 Hz, CH ₂ ring); 4.10 (2H, m, OCH ₂ ); 2.93 (3H, s, CH ₃ SO ₂ ); 2.70 (3H, s, CH ₃ triazole); 2.81 (4H, m, CH ₂ aryl, CH ₂ thiophene); 2.35 ( ¹ H , m, -CH-).

Example 83d

¹ H NMR (CDCl ₃ ): δ 6.67-7.60 (9H, m, aryl-H); 6.42 (1H, s, thiophene-H); 4.91 (2H, s, _CH2 -7-ring); 3.98 (2H, t, J = 6 Hz, OCH ₂ ); 2.98 (2H t, J = 6 Hz, CH ₂ thiophene); 2.65 (3H, s, _CH3 -triazole); 2.11 (2H, m, = CH ₂ CH ₂ -).

Example 83e

¹ H NMR (CDCl ₃ ): δ 7.27-7.58 (4H, m, aryl-H); 6.41 (1H, s, thiophene-H); 4.95 (2H, s, _CH2 -7-ring); 3.39 (2H, t, J = 6 Hz, OCH ₂ ); 3.31 (3H, s, OCH ₃ ); 2.87 (2H, t, J = 6 Hz, CH ₂ thiophene); 2.71 (3H, s, _CH3 -triazole); 1.90 (2H, m, OCH ₂ CH ₂ ).

Example 83f

¹ H NMR (CDCl ₃ ): δ 8.31 (1H, s, broad, NH); 6.95-7.70 (9H, m, aryl-indolyl-H); 6.32 (1H, s, thiophene-H); 4.90 (2H, s, _CH2 -7-ring); 2.95 (4H, s, NHCH ₂ CH _2); 2.66 (3H, s, _CH3 -triazole); 2.52-2.92 (4H, m, NHCH ₂ , CH ₂ thiophene); 1.82 (2H, m, NH-CH ₂ CH _2).

Example 83g

¹ H NMR (CDCl ₃ ): δ 6.25 (2H, s, 2-aryl-H); 6.78 (1H, s, thiophene-H); 4.85 (2H, s, _CH2 -7-ring); 4.16 (2H, t, J = 6 Hz, OCH ₂ ); 3.86; 3.89 (9H, 2s, OCH ₃ ); 2.95 (2H, t, J = 6 Hz, CH ₂ thiophene); 2.72 (3H, s, _CH3 -triazole); 2.07 (3H, s, CH ₃ -C = O); 2.06 (2H, m, OCH ₂ CH ₂ -).
Table 10 shows the NMR spectra of selected intermediates.

Example 98

¹ H NMR (CDCl ₃ ) δ ppm 7.15-7.59 (4H, m, aryl-H); 6.14 (1H, s, thiophene-H); 5.60 (s, 1H, CH-N), 4.14 (s, 2H, CH ₂ -7 ring), 3.67 (t, J = 7 Hz, 2H, OCH ₂ ), 2.80 ( t, J = 7 Hz, 2H, CH ₂ -thiophene), 2.70 (s, 3H, CH ₃ triazole), 1.58-2.24 (m, 4H, OCH ₂ CH ₂ , NH, OH).

Example 99

¹ H NMR (CDCl ₃ ) δ ppm 7.16-7.58 (m, 4H, aryl-H), 6.14 (s, 1H, thiophene-H), 5.61 (s, 1H, CH- N), 4.14 (s, 2H, CH ₂ -7 ring), 4.08 (t, J = 7 Hz, OCH ₂ ), 2.80 (t, J = 7 Hz, 2H, CH ₂ - Thiophene), 2.71 (s, 3H, CH ₃ -triazole), 2.14 (s, broad, 1H, NH), 2.03 (s, 3H, CH ₃ CO), 1.96 (m, 2H) , OCH ₂ CH ₂ ).

Example 100

¹ H NMR (CDCl ₃ ) δ ppm 7.00-7.52 (m, 4H, aryl-H,), 7.07 (s, 1H, thiophene-H), 6.56 (s, 1H, CH -N), 4.93 / 4.70 (AB system, J _AB = 15 Hz, 2H, CH ₂ -7 ring), 4.12 (t, J = 6 Hz, 2H, OCH ₂ ), 2 , 87 (t, J = 6 Hz, 2H, thiophene-CH ₂ ), 2.61 (s, 3H, CH ₃ -triazole), 2.28 (s, 3H, CH ₃ CO N), 2.07 ( s, 3H, CH ₃ CO O), 1.98 (m, 2H, OCH ₂ CH ₂ ).

Table 10 Compound No. 1

¹ H NMR (CDCl ₃ ) δ ppm 7.29-7.54 (4H, m, aryl-H); 7.10 (2H, s, broad, NH ₂ ); 6.17 (1H, s, thiophene-H); 3.75 (4H, m, morpholine-OCH ₂ ); 3.24 (4H, m, morpholine-N-CH ₂ ); 3.06 (4H, s, SO ₂ CH ₂ CH _2).

Compound No. 3

¹ H NMR (CDCl ₃ ) δ ppm 7.33-7.78 (5H, m, aryl-H); 6.97 (2H, s, broad, NH ₂ ); 6.56 (1H, s, thiophene-H); 4.09 (2H, t, J = 6 Hz, OCH ₂ ); 2.66 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.04 (3H, s, CH ₃ C = O); 1.89 (2H, m, -O-CH ₂ CH ₂ -).

Compound No. 5

¹ H NMR (CDCl ₃ ) δ ppm 7.24-7.49 (4H, m, aryl-H); 7.07 (2H, s, broad, NH ₂ ); 6.09 (1H, s, thiophene-H); 4.05 (2H, t, J = 7 Hz, OCH ₂ ); 2.49 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.05 (3H, s, CH ₃ C = O); 1.08-1.83 (10H, m, OCH ₂ - (CH ₂ ) ₅ ).

Compound No. 5a

¹ H NMR (CDCl ₃ ): δ 6.93 (s, 2H, aryl-H); 6.64 (s, 1H, thiophene-H); 3.91; 3.92 (2 s, 9H, 3 OCH ₃ ); 3.71 (t, J = 7 Hz, 2H, OCH ₂ ); 2.72 (t, J = 7 Hz, 2H, thiophene-CH ₂ ; 1.85 (m, 2H, OCH ₂ CH ₂ ); NH ₂ and OH greatly broadened!

Connection 5b

¹ H NMR (CDCl ₃ ): δ 6.89 (s, 2H, aryl-H); 6.59 (s, 1H, thiophene-H); 4.09 (t, J = 7 Hz, 2H, OCH ₂ ); 3.90; 3.89 (2s, 9H, _3-OCH3); 2.66 (t, J = 7 Hz, 2H, thiophene-CH ₂ ); 2.03 (s, 3H, CH ₃ C = O); 1.88 (m, 2H, OCH ₂ -CH ₂ ); NH ₂ greatly broadened!

Compound 5c

¹ H NMR (CDCl ₃ ) δ ppm 7.19-7.52 (m, 4H, aryl-H), 7.07 (s, broad, 2H, NH ₂ ), 6.18 (s, 1H, thiophene -H), 3.16- 3.96 (m, 3H, OCH ₂ -CH), 2.67 (d, J = 6 Hz, CH ₂ -thiophene), 2.51 (d, J = 3 Hz, 1H, CHOH), 2.19 (t, J = 4 Hz, 1H, CH ₂ OH).

Connection 5d

¹ H NMR (CDCl ₃ ) δ ppm 7.09-7.67 (m, 9H, aryl-H), 6.97 (s, broad, 2H, NH ₂ ), 6.19 (t, J ≦ ωτ1 Hz, 1H, thiophene-H), 5.93, 5.79 (2s, 1H, O-CH-O), 3.56-4.53 (m, 3H, OCH ₂ CH), 2.88 (dd , J = 6 Hz, ≦ ωτ1 Hz, 2H, thiophene-CH ₂ ).

Compound No. 6

¹ H NMR (CDCl ₃ ) δ ppm 12.60 (1H, s, broad, NH); 7.24-7.61 (4H, m, aryl-H); 6.53 (1H, s, thiophene-H); 4.13 (2H, s, CH ₂ Br); 3.68 (4H, m, morpholine-OCH ₂ ); 3.23 (4H, m, morpholine-N-CH ₂ ); 3.17 (4H, s, SO ₂ CH ₂ CH ₂ -).

Compound No. 7

¹ H NMR (CDCl ₃ ) δ ppm 12.70 (1H, s, broad, NH); 7.34-7.62 (5H, m, aryl-H); 6.84 (1H, s, thiophene-H); 4.11 (2H, s, CH ₂ Br); 4.11 (2H, t, J = 7 Hz, OCH ₂ ); 2.82 (2H, t, J = 7 Hz, thiophene-CH ₂ -); 2.04 (3H, s, CH ₃ -C = O); 1.98 (2H, m, -OCH ₂ CH ₂ -).

Compound No. 8

¹ H NMR (CDCl ₃ ) δ ppm 12.66 (1H, s, broad, NH); 7.33-7.61 (4H, m, aryl-H); 6.46 (1H, s, thiophene-H); 4.14 (2H, s, CH ₂ Br); 4.08 (2H, t, J = 7 Hz, OCH ₂ ); 2.78 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.03 (3H, s, CH ₃ C = O); 1.93 (2H, m, OCH ₂ -CH ₂ -).

Compound No. 9

¹ H NMR (CDCl ₃ ) δ ppm 12.64 (1H, s, broad, NH); 7.31-7.44 (4H, m, aryl-H); 6.41 (1H, s, thiophene-H); 4.14 (2H, s, CH ₂ Br); 4.05 (2H, t, J = 6 Hz, OCH ₂ ); 2.68 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.04 (3H, s, CH ₃ C = O); 1.02-1.83 (10H, m, OCH ₂ (CH ₂ ) ₅ -).

Compound No. 9d

¹ H NMR (CDCl ₃ ): δ 12.56 (1H, s, NH); 7.18-7.56 (4H, m, aryl-H); 6.48 (1H, s, thiophene H); 4.11 (2H, s, CH ₂ Br); 3.45-4.47 (3H, m, OCH ₂ -CHO); 2.90 (2H, d, J = 6 Hz, CH ₂ thiophene); 1.40; 1.31 (6H, 2 s, 2 _CH3).

Compound No. 11

¹ H NMR (CDCl ₃ ) δ ppm 13.10 (1H, s, broad, NH-C = O); 7.30-7.86 (5H, m, aryl-H); 6.80 (1H, s, thiophene-H); 4.11 (2H, t, J = 7 Hz, OCH ₂ ); 3.64 (2H, s, CH ₂ C = O); 2.81 (2H, t, J = 7 Hz, thiophene-CH ₂ ); 2.04 (3H, s, CH ₃ C = O); 2.00 (2H, m, OCH ₂ CH ₂ -); 1.73 (2H, s, broad, NH ₂ ).

Compound No. 12

¹ H NMR (CDCl ₃ ) δ ppm 12.24 (1H, s, broad, NH); 7.25-7.56 (4H, m, aryl-H); 6.41 (1H, s, thiophene-H); 4.07 (2H, t, J = 6 Hz, OCH ₂ ); 3.67 (2H, s, CH ₂ C = O); 2.74 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.00 (3H, s, CH ₃ C = O); 1.92 (2H, m, OCH ₂ CH ₂ -); 1.78 (2H, s, broad, NH ₂ ).

Compound No. 13

¹ H NMR (CDCl ₃ ) δ ppm 13.60 (1H, s, broad, NH); 7.16-7.54 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H), 4.04 (2H, t, J = 6 Hz, OCH ₂ ); 3.66 (2H, s, CH ₂ -C = O); 2.65 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 1.87 (2H, s, broad, NH ₂ ); 2.04 (3H, s, CH ₃ C = O); 1.23-1.72 (10H, m, OCH ₂ - (CH ₂ ) ₅ -).

Compound No. 14

¹ H NMR (CDCl ₃ ) δ 9.29 (1H, s, broad, NH); 7.29-7.56 (4H, m, aryl-H); 6.31 (1H, s, thiophene-H); 4.48 (2H, s, 7-ring CH ₂ ); 3.75 (4H, m, morpholine-OCH ₂ ); 3.23 (4H, m, morpholine-N-CH ₂ ); 3.14 (4H, s, -SO ₂ -CH ₂ -CH ₂ ).

Compound No. 17

¹ H NMR (CDCl ₃ ) δ ppm 10.03 (1H, s, broad, NH); 7.17-7.56 (4H, m, aryl-H); 6.16 (1H, s, thiophene-H); 4.47 (2H, s, 7-ring CH ₂ ); 4.02 (2H, t, J = 6 Hz, OCH ₂ ); 2.62 (2H, t, J = 6 Hz, thiophene-CH ₂ ); 2.02 (3H, s, CH ₃ -C = O); 1.03-1.82 (10H, m, OCH ₂ - (CH ₂ ) ₅ ).

Compound No. 17c

¹ H NMR (CDCl ₃ ): δ 9.33 (1H, s, broad, NH); 7.18-7.56 (4H, m, aryl-H); 6.25 (1H, s, thiophene-H); 4.46 (2H, s, _CH2 -7-ring); 3.45 to 4.37 (3H, m, OCH ₂ -CH-O); 2.88 (2H, d, J = 6 Hz), CH ₂ thiophene); 1.40; 1.32 (6H, 2 s, 2 _CH3).

Compound No. 17d

¹ H NMR (CD ₃ OD / CDCl ₃ 1: 1): δ 7.42 (4H, s, aryl-H); 6.29 (1H, s, thiophene-H); 4.35 (2H, s, _CH2 -7-ring); 3.53-3.87 (1H, m, CH-O); 3.45 (2H, d, J = 5 Hz, OCH ₂ ); 2.52 (2H, m, CH ₂ -thiophene); NH, OH, is the solvent blind peak.

Claims (17)

1. Thieno-1,4-diazepines of the general formula wherein
R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, preferably methoxy, halogen, preferably chlorine or bromine; for n ≦ λτ 0
R ₂ halogen, hydroxy, wherein R ₄ and R ₅ , which may be the same or different, are hydrogen, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-10 carbon atoms, which may optionally be substituted by halogen, hydroxy or by a C-linked heterocycle, where the carbon chain can be interrupted by nitrogen, oxygen or sulfur,
a branched or unbranched alkylcarbonyl group with 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 with 1 to 6 carbon atoms, the alkyl group being substituted by halogen or Hydroxy may be substituted
an optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulfonyl group, preferably phenylsulfonyl or tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atoms, or
R ₄ and R ₅ together with the nitrogen atom form a saturated or unsaturated 5-, 6- or 7-ring optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms and which contain nitrogen, oxygen or sulfur as further heteroatoms may, each further nitrogen atom optionally being substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atoms; R _{2 is} an arylcarbonyloxy group, preferably phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8, carbon atoms, it being possible for the alkyl chain to be interrupted by nitrogen, oxygen or sulfur; where R _{6 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 atoms,
R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; where R ₈ and R ₉ , which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms,
or R ₈ and R ₉ together with the nitrogen atom represent a 5-, 6- or 7-ring which may be substituted one or more times by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, where each further nitrogen atom is substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} a branched or unbranched alkoxy group having 1 to 4 carbon atoms; an aryloxy group, preferably phenyloxy or substituted phenyloxy; R _{2 is} an imido residue; Dioxolane; substituted dioxolane; for n greater than or equal to 0
R ₂ -CH = O; -COOH; Cyano; R _{2 is} a branched or unbranched alkoxycarbonyl group having 1 to 4 carbon atoms, with the proviso that when R ′ is hydrogen,
R ₃ o-chlorophenyl,
X and Y both nitrogen
R ₂ Z _n cannot be methoxycarbonylethyl; R _{2 is} an aryloxycarbonyl group, preferably phenyloxycarbonyl; R _{2 is} a radical of the general formula wherein R ₁₀ and R ₁₁ , 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, which are optionally substituted by halogen, hydroxy, nitro, amino Amino or in the case of R ₁₀ = hydrogen or alkyl and Y = CR ₁ or Y nitrogen and X C-alkyl, R ₁₁ by an ester function or an acid amide of the general formula in which R ′ ₁₀ and R ′ _{11 have the} same meaning as R ₁₀ and R ₁₁ , but with the exception of an acid amide, can be substituted,
R ₁₀ or R _{11 is} a saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring optionally substituted one or more times by branched or unbranched alkyl having 1 to 4 carbon atoms, bonded via a carbon atom,
R ₁₀ and R ₁₁ together with the nitrogen atom represent a saturated or unsaturated 5-, 6- or 7-ring, optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms, which can contain nitrogen, oxygen or sulfur as further heteroatoms , wherein each further nitrogen atom can be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, with the proviso that when X, Y are both nitrogen, R 'hydrogen, Z is an unbranched alkyl chain with n carbon atoms and

• a) R ₃ = o-chlorophenyl and
  R ₁ = methyl and n = 0, 1, 2, 3 or 4
  NR ₁₀ R ₁₁ not morpholino,
  or
  n = 0 or 1
  NR ₁₀ R ₁₁ not amino,
  or
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, methylamino, isopropylamino, dimethylamino, cyclopropylamino, piperidino, pyrrolidino, cyclohexylamino, N'-methylpiperazino, amino, di (hydroxyethylamino) or hydroxyethylamino,
  or
• b) R ₃ = o-chlorophenyl
  and
  R ₁ = chloromethyl, bromomethyl, propyloxy, hydrogen, methoxy, bromine or cyclopropyl,
  and
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
  or
• c) R ₃ = o-chlorophenyl
  and R ₁ = cyclopropyl
  and
  n = 2
  NR ₁₀ R ₁₁ not diethylamino,
  or
  n = 8
  NR ₁₀ R ₁₁ not morpholino
  or
• d) R ₃ = phenyl,
  R ₁ = methyl,
  n = 2
  NR ₁₀ R ₁₁ not morpholino
• e) R ₃ = 2-nitrophenyl, 2-methylphenyl,
  2-trifluoromethyl,
  R ₁ = methyl
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
• f) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, piperidino,
• g) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy,
  n = 2,
  NR ₁₀ R ₁₁ not N'-methylpiperazino

means;
R _{2 is} a radical of the general formula wherein
B oxygen, sulfur NH or NC ₁ -C ₆ alkyl D the radical (C Re Rf) n , where n can be 0 to 3, Ra is hydrogen, alkyl with 1 to 6 carbon atoms optionally substituted by a hydroxyl or amino group, C ₁ to C ₄ alkoxycarbonyl, dialkylaminocarbonyl,
Rb, Rc, Rd, Re, Rf are hydrogen, optionally substituted by a hydroxyl or amino group, alkyl having 1 to 6 carbon atoms, or phenyl; R _{3 is} phenyl, where the phenyl ring can be substituted one or more times, preferably in the 2-position, by methyl, preferably halogen, particularly preferably chlorine or bromine, nitro, alkoxy, preferably methoxy and / or trifluoromethyl, pyridyl; R ° is hydrogen, an alkyl or an acyl group having 1 to 4 carbon atoms, preferably acetyl; R ′ is hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ ,
or Y is the group C-COOR *, with R * = alkyl or hydrogen and X = nitrogen; Z is a branched or unbranched alkyl or alkenyl group with n-carbon atoms, where Z can optionally be additionally substituted by aryl, preferably phenyl, substituted phenyl or twice by R ₂ , where R _{2 can be} identical or different; and
n can be one of the numbers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
in the form of their racemates, their enantiomers, their diasteromers and their mixtures; in each case as free bases or their physiologically acceptable acid addition salts. 2. Compounds of general formula Ia or Ib according to claim 1, wherein
R _{1 is} methyl, ethyl, methoxy, ethoxy or halogen, preferably chlorine or bromine; R ₂ chlorine, bromine, iodine, hydroxy, wherein R ₄ and R ₅ , which may be the same or different, are hydrogen, a branched or unbranched alkyl group having 1 to 6, particularly preferably 1 to 4, carbon atoms, where the carbon chain can be interrupted by nitrogen, a branched or unbranched alkylcarbonyl group having 1 up to 4 carbon atoms, optionally substituted by a dimethylamino group, a phenylcarbonyl group,
in the case of R ₅ = hydrogen, a phenylsulfonyl group optionally substituted by acylamino, particularly preferably acetylamino, amino, alkylamino or dialkylamino, or
R ₄ and R ₅ together with the nitrogen atom form a piperidine, pyrrolidine, N'-methylpiperazine, an optionally dimethyl-substituted morpholine ring, a pyrrole, pyrazole, imidazole or triazole ring;
R ₂ -CH = O, COOH;
a Δ ² -imidazoline, -oxazoline, -thiazoline which is optionally mono- or polysubstituted by methyl; a tolylsulfonyloxy group; a methylsulfonyloxy group;
a phenylcarbonyloxy group;
a branched or unbranched alkylcarbonyloxy group having 1 to 5 carbon atoms; a methoxy or ethoxycarbonyl group; wherein R _{6 is} a branched or unbranched alkyl group having 1 to 4 carbon atoms, R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; wherein R ₈ and R ₉ , which may be the same or different, represent a methyl, ethyl, propyl or isopropyl group or R ₈ and R ₉ together with the nitrogen atom represent an N'-methylpiperazine or morpholine ring; R _{3 is} phenyl, where the phenyl ring, preferably in the 2-position, can be substituted by H halogen, preferably chlorine; R ° hydrogen, methyl, acetyl; R ′ is hydrogen; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ , (R ₁ preferably hydrogen),
or Y is the group C-COOR *, with R * = alkyl or hydrogen and X = nitrogen; Z as defined above, preferably - (CH ₂ ) _n -, optionally substituted by phenyl or twice by R ₂ , where R _{2 can} also be different or -CH ₂ -CHR ₂ -CH ₂ -R ₂ , CH ₂ - CHR ₂ R ₂ -CH ₂ CHR ₂ -CH ₂ -C ₆ H ₅ ;
and n can be one of the numbers 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and, if appropriate, their physiologically acceptable acid addition salts. 3) Compounds of general formula Ia according to claim 1 or 2, wherein R ₂ as defined above and R _{1 is} methyl or methoxy, R ₃ o-chlorophenyl, R 'hydrogen, X, Y both nitrogen or X CH and Y nitrogen, Z - (CH ₂ ) _n -, n are the numbers 2, 3 or 7. 4) Process for the preparation of compounds of general formula Ia according to claim 1, 2 or 3,
wherein R ₁ , R ₃ , R ', Z, X, Y and n as previously defined, R ₂ - COOR *, with R * = alkyl, or R ₂ hydroxy, alkylcarbonyloxy, alkoxycarbonyl, aryloxycarbonyl, dioxolane, substituted dioxolane or R ₈ R ₉ NSO ₂ - can mean
characterized in that a corresponding compound of the general formula

• A) in the event that X and Y are nitrogen
  • a) reacted with an acid hydrazide of the general formula R ₁ -CONHNH ₂ .
  • b) or with hydrazine in a compound of the general formula converted and then ₁ -CO-Haloder with an acid halide of the formula R with a Orthoester of the general formula R ₁ - _'3 wherein R represents a lower alkyl group C (OR)' is reacted, or
• B) in the event that X CH and Y nitrogen
  • a) with an aminoalkyne of the general formula R ₁₁ - C≡C - CH ₂ -NH ₂ wherein R _{11 is} hydrogen or a lower alkyl group or else
  • b) with an α-aminoaldehyde alkyl acetal or α-amino ketone alkyl ketal of the general formula H ₂ NCH ₂ -CR ₁ (OR ′) ₂ in which R ₁ denotes a lower alkyl group or a cyclopropyl group;
• C) in the event that X is nitrogen and Y CH is a compound of the general formula R ^x = lower alkyl
  decarboxylated.
  and if necessary converted into their harmless acid addition salts.

5. Process for the preparation of compounds of the formula wherein
R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, preferably methoxy, halogen, preferably chlorine or bromine; for n ≦ λτ 0
R ₂ halogen, hydroxy, wherein R ₄ and R ₅ , which may be the same or different, are hydrogen, a branched or unbranched alkyl, alkenyl or alkynyl group having 1-10 carbon atoms, which may optionally be substituted by halogen, hydroxy or by a C-linked heterocycle, where the carbon chain can be interrupted by nitrogen, oxygen or sulfur,
a branched or unbranched alkylcarbonyl group with 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 with 1 to 6 carbon atoms, the alkyl group being substituted by halogen or Hydroxy may be substituted
an optionally substituted arylcarbonyl group, preferably phenylcarbonyl, an optionally substituted arylsulfonyl group, preferably phenylsulfonyl or tolylsulfonyl, an alkylsulfonyl group having 1 to 4 carbon atoms, or
R ₄ and R ₅ together with the nitrogen atom form a saturated or unsaturated 5-, 6- or 7-ring optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms and which contain nitrogen, oxygen or sulfur as further heteroatoms may, each further nitrogen atom optionally being substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atoms; R _{2 is} an arylcarbonyloxy group, preferably phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms; R _{2 is} a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8, carbon atoms, it being possible for the alkyl chain to be interrupted by nitrogen, oxygen or sulfur; where R _{6 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 atoms,
R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; where R ₈ and R ₉ , which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms,
or R ₈ and R ₉ together with the nitrogen atom represent a 5-, 6- or 7-ring which may be substituted one or more times by branched or unbranched alkyl groups having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, where each further nitrogen atom is substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{2 is} a branched or unbranched alkoxy group having 1 to 4 carbon atoms; an aryloxy group, preferably phenyloxy or substituted phenyloxy; R _{2 is} an imido residue; Dioxolane, substituted dioxolane; for n greater than or equal to 0
R ₂ -CH = 0; -COOH; Cyano; R _{2 is} a branched or unbranched alkoxycarbonyl group having 1 to 4 carbon atoms, with the proviso that when R ′ is hydrogen,
R ₃ o-chlorophenyl,
X and Y both nitrogen
R ₂ Z _n cannot be methoxycarbonylethyl; R _{2 is} an aryloxycarbonyl group, preferably phenyloxycarbonyl; R _{2 is} a radical of the general formula wherein R ₁₀ and R ₁₁ , 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, which are optionally substituted by halogen, hydroxy, nitro, amino Amino or in the case of R ₁₀ = hydrogen or alkyl and Y = CR ₁ or Y nitrogen and X C-alkyl, R ₁₁ by an ester function or an acid amide of the general formula in which R ′ ₁₀ and R ′ _{11 have the} same meaning as R ₁₀ and R ₁₁ , but with the exception of an acid amide, can be substituted,
R ₁₀ or R _{11 is} a saturated or unsaturated 5-, 6- or 7-membered heterocyclic ring optionally substituted one or more times by branched or unbranched alkyl having 1 to 4 carbon atoms, bonded via a carbon atom,
R ₁₀ and R ₁₁ together with the nitrogen atom represent a saturated or unsaturated 5-, 6- or 7-ring, optionally substituted one or more times by branched or unbranched alkyl groups with 1 to 4 carbon atoms, which can contain nitrogen, oxygen or sulfur as further heteroatoms , wherein each further nitrogen atom can be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, with the proviso that when X, Y are both nitrogen, R 'hydrogen, Z is an unbranched alkyl chain with n carbon atoms and

• a) R ₃ = o-chlorophenyl and
  R ₁ = methyl and n = 0, 1, 2, 3 or 4
  NR ₁₀ R ₁₁ not morpholino,
  or
  n = 0 or 1
  NR ₁₀ R ₁₁ not amino,
  or
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, methylamino, isopropylamino, dimethylamino, cyclopropylamino, piperidino, pyrrolidino, cyclohexylamino, N'-methylpiperazino, amino, di (hydroxyethylamino) or hydroxyethylamino,
  or
• b) R ₃ = o-chlorophenyl
  and
  R ₁ = chloromethyl, bromomethyl, propyloxy, hydrogen, methoxy, bromine or cyclopropyl,
  and
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
  or
• c) R ₃ = o-chlorophenyl
  and R ₁ = cyclopropyl
  and
  n = 2
  NR ₁₀ R ₁₁ not diethylamino,
  or
  n = 8
  NR ₁₀ R ₁₁ not morpholino
  or
• d) R ₃ = phenyl,
  R ₁ = methyl,
  n = 2
  NR ₁₀ R ₁₁ not morpholino
• e) R ₃ = 2-nitrophenyl, 2-methylphenyl, 2-trifluoromethyl,
  R ₁ = methyl
  n = 2
  NR ₁₀ R ₁₁ not morpholino,
• f) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy
  n = 2
  NR ₁₀ R ₁₁ not diethylamino, piperidino,
• g) R ₃ = 2-chlorophenyl,
  R ₁ = methoxy,
  n = 2,
  NR ₁₀ R ₁₁ not N'-methylpiperazino

means;
R _{2 is} a radical of the general formula wherein
B oxygen, sulfur, NH or NC ₁ -C ₆ -alkyl D the radical (C Re Rf) n , where n can be 0 to 3, Ra is hydrogen, alkyl with 1 to 6 carbon atoms optionally substituted by a hydroxyl or amino group, C ₁ to C ₄ alkoxycarbonyl, dialkylaminocarbonyl,
Rb, Rc, Rd, Re, Rf are hydrogen, optionally alkyl with 1 to 6 carbon atoms substituted by a hydroxyl or amino group, or phenyl; R _{3 is} phenyl, where the phenyl ring can be substituted one or more times, preferably in the 2-position, by methyl, preferably halogen, particularly preferably chlorine or bromine, nitro, alkoxy, preferably methoxy and / or trifluoromethyl, pyridyl; R ° is hydrogen, alkyl or an alkyl group, preferably acetyl; R ′ is hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; X, Y independently of one another CR ₁ or N, but not simultaneously both CR ₁ ,
or Y is the group C-COOR *, with R * = alkyl or hydrogen and X = nitrogen; Z is a branched or unbranched alkyl or alkenyl group with n-carbon atoms, where Z can optionally be additionally substituted by aryl, preferably phenyl, substituted phenyl or twice by R ₂ , where R _{2 can be} identical or different; and
n can be one of the numbers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
in the form of their racemates, their enantiomers, their diasteromers and their mixtures; in each case as free bases or their physiologically acceptable acid addition salts,
characterized in that a compound of general formula I wherein R ₁ = hydrogen, alkyl, cycloalkyl;
Z, X, Y, R ′, n and R ₃ as previously defined and R is a lower alkyl group,
implemented as follows:

• 1) Compounds of the general formula Ia with R ₂ = COOH are obtained by saponification of compounds of the formula I;
• 2) Compounds of general formula Ia wherein R ₂ = R ₁₀ R ₁₁ NCO is obtained by reacting Ia with R ₂ = COOHmit an amine of FormelHNR ₁₀ R _11, for example in the presence of Sulfonyldiimidazol or carbonyldiimidazole;
• 3) Compounds of the general formula Ia with R ₂ = OH are obtained by selective reduction of I, e.g. B. with lithium alanate or sodium borohydride; or by hydrolysis of a compound of general formula Ia, in which R _{2 represents} an alkylcarbonyloxy radical;
• 4) Compounds of the general formula Ia with R ₂ = R ₆ NH-COO-, R ₆ NHCONR ₇ - are obtained by reaction of the alcohol, e.g. B. prepared according to 3) or amine R ₂ = NHR ₇ , z. B. prepared according to 7), with an isocyanate of the general formula R ₆ -N = C = O;
• 5) Compounds of the general formula Ia with R ₂ = alkyl- or arylcarbonyloxy are obtained by reaction of the alcohol, e.g. B. prepared according to 3), with an acid equivalent of a carboxylic acid of the formula R-COOH, wherein R is an aryl radical or a branched or unbranched alkyl radical having 1 to 8 carbon atoms, where the carbon chain can be interrupted by nitrogen, oxygen or sulfur; means;
• 6) Compounds of the general formula Ia with R ₂ = alkylsulfonyloxy or arylsulfonyloxy are obtained by reaction of the alcohol, e.g. B. prepared according to 3), with an alkyl or arylsulfonyl halide with the addition of an acid-binding agent;
• 7) Compounds of the general formula Ia with R ₂ = NR ₄ R ₅ or an imido residue
  is obtained by reaction of the mesylate, e.g. B. prepared according to 6), with an amine of the formula HNR ₄ R ₅ or an imide;
• 8) Compounds of the general formula Ia with R ₂ = NH _{2 are} obtained, for example, by cleaving the phthalimide or from the corresponding isocyanates, R ₂ = N = C = O by hydrolysis;
• 9) Compounds of the general formula Ia with R ₂ = NR ₄ R ₅ with R ₄ or R ₅ alkyl or arylcarbonyl
  is obtained by reacting a primary or secondary amine, e.g. B. prepared according to 7) or 8), with a carboxylic acid equivalent derived from a carboxylic acid of the formula
• 10) Compounds of the general formula Ia with R ₂ = formyl are obtained by oxidation of the alcohol, for. B. produced according to 3), shortening the chain from n to n -1;
• 11) Compounds of the general formula Ia in which
  R _{2 is} a radical of the general formula means
  is obtained by reacting a compound of the general formula Ia with R ₂ = COOH with an amine of the general formula where R _a , R _b , R _c , R _d , D and B has the meaning given above,
  in the presence of triphenylphosphine, CCl ₄ and a base;
• 11a) Compounds of the general formula Ia, in which R _{2 is} an optionally substituted thiazoline radical, are obtained from the corresponding oxazolines, for. B. prepared according to 11) by sulfurization, for. B. with phosphorus pentasulfide or Lawesson reagent ^R.
• 12) Compounds of the general formula Ia in which R ₂ = CN are obtained by reacting compounds of the general formula Ia
  wherein R ₂ = CONH ₂ with phosphorus oxychloride;
• 13) Compounds of the general formula Ia
  where R ₂ = a 2-imidazoline which is optionally substituted by branched or unbranched alkyl groups,
  is obtained by reacting compounds of the general formula Ia with R ₂ = CN
  • a) with ethanolic HCl,
  • b) reacting the resulting imidoethyl ester with an ethylenediamine optionally substituted by branched or unbranched alkyl groups,
  • c) optionally the alkylation of the free NH function is carried out using known alkylating agents;
• 14) Compounds of the general formula Ia with R ₂ an aryloxy or alkyloxy radical are obtained, for example, by reaction of the mesylate, for. B. prepared according to 6), with the corresponding alcoholates;
• 15) compounds of the general formula Ia,
  where R ₂ = alkyl- or aryloxycarbonyl, is obtained, for example, by reacting an acid equivalent of I, R ₂ COOH with the corresponding alcohols;
• 16) Compounds of the general formula Ia
  with R ₂ = halogen,
  is obtained by reaction of the tosylate, e.g. B. prepared according to 6), with a halogenating agent;

then, if desired, the compounds Ia obtained
with R ₁ = hydrogen
in the presence of a base with a
Halogenating agents, such as. B. with chlorine or bromine, to a compound of general formula Ia with R ₁ halogen, such as. B. reacting chlorine or bromine;
if desired, the halogen compound is then converted into a compound of the general formula Ia with R ₁ = alkoxy having 1 to 4 carbon atoms by reaction with the corresponding alcoholate; then, if desired, selectively reducing a compound of the general formula Ia to a compound of the general formula Ib with R ^o = hydrogen and then, if desired, alkylating or acylating;
and optionally the compounds Ia or Ib thus obtained are converted into their harmless acid addition salts. 6) Process for the preparation of compounds of general formula Ia according to claim 4, wherein R _{1 is} halogen or alkoxy, characterized in that a compound of general formula Ia with R _{1 is} hydrogen

• a) with a halogenating agent, such as. B. halogenated chlorine or bromine
  and then if desired
• b) reacting the halogen compound with the corresponding alcoholate

and possibly in their harmless Acid addition salt transferred. 7) Process for the preparation of compounds of the general formula Ib according to Claim 1, 2 or 3, characterized in that a compound of the general formula Ia is selectively reduced and, if desired, the compound Ib obtained in which R ^{o is} hydrogen, alkylated or acylated and optionally in their transferred pharmacologically acceptable acid addition salts. 8) Pharmaceutical preparations containing as active ingredients Compounds of the general formula Ia or Ib in Combination with usual auxiliaries and / or carriers. 9) Process for the production of pharmaceutical Preparations according to claim 8, characterized in that compounds of the general formula Ia or Ib with conventional pharmaceutical auxiliaries and / or carriers to common pharmaceutical forms of use processed.   10) Compound of the general formula Ia or Ib according to Claim 1, 2 or 3 for use in the Manufacture of drugs with PAF-antagonistic Effect. 11) method of treating pathological conditions and Diseases where PAF (platelet activating Factor) is involved, characterized in that one a compound of the general formula Ia or Ib used. 12) process for the manufacture of medicinal products, containing compounds of general formula Ia or Ib according to one of claims 1, 2 or 3, for Treatment of diseases in which PAF is involved. 13) As new intermediates thienodiazepinthione of the general formula wherein
R ′ is hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; R _{3 is} phenyl, where the phenyl ring can be substituted one or more times, preferably in the 2-position, by methyl, preferably halogen, particularly preferably chlorine or bromine, nitro, alkoxy, preferably methyl and / or trifluoromethyl, pyridyl; Z is a branched or unbranched alkyl or alkenyl group with n-carbon atoms, where Z can optionally be additionally substituted by aryl, preferably phenyl, substituted phenyl or twice by R ₂ , where R _{2 can be} identical or different; n is one of the numbers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R ₂ hydroxy, alkylcarbonyloxy, dioxolane, substituted dioxolane or where R ₈ and R ₉ , which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms,
or R ₈ and R ₉ together with the nitrogen atom represent a 5-, 6- or 7-ring which may be substituted one or more times by a branched or unbranched alkyl group having 1 to 4 carbon atoms and which may contain nitrogen, oxygen or sulfur as further heteroatoms, wherein each further nitrogen atom is substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl; or
if R ′ ≠ is hydrogen
R _{2 can} also mean alkoxycarbonyl.