DD265405A5 - NEW THIENO-1,4-DIAZEPINE - Google Patents

Abstract

The invention relates to a process for the preparation of novel thieno-1,4-diazepines of the general formula in which R1, R2, R3, R, R, Z, X, Y and n have the meaning given in the description. The new compounds are said to be used to treat pathological conditions and diseases involving PAF (Plaque Activating Factor). Formula I a, I b

Description

- ι _

Ancestors for the preparation of novel thiono-1,4-diazepines Field of application of the invention

The invention relates to a process for the preparation of novel thiono-1,4-diazepines which can be used for the treatment of pathological conditions in which bionilijit is PAF (Platelet Activating Factor).

Characteristic of bokannton prior art

For the formation of the present ring-stoma of the new oridentuncjsgetiuisson compounds, some analogy ancestors have bokannt govvordon. Boispiolowoiso are described in NL-PS 7 OU3 585 compounds of vvoiter unton defined formula Ic. Compounds of the general formula Ia ₁ which contain one l, 5-a} linked imidazole ring can boispiolsweiso prepared according to DE-OS 25 40 522. Dio Synthoso oinoo Acotalc or Kotais the allgonioinon Formol VIII, as well as an analogy precoron to the Ringachluß can be found in CH-PS 580 099. IVoitoro spiked Hinwoiso to don ont3prochondon ancestors of the Standoo dor technique have been passed v / eitor unton anesprochendor Stollo.

Object of the invention

Ziol dor invention is the search for new precursors, dio bsi the treatment of pathological stateon, to which donen PAF is borated, used ivordonjkünnon.

üarlocjunn of the 'Voaonc of invention

The invention relates to an ancestor for the nostril

Thieno-l, 4 ~ diazopino. Dio neuon Tliiono-l, 4-diazopine met dor allgomoinon formula

Ια

ib

wherein

Waösorotoff, os.no vorzwoigto odor unvorzvvoigto Alkylgruppo with 1 to 4 carbon atoms, the gegobononfallo by hydroxy or halogen may be substituted, a cyclopropyl group, a vorzvvoigto or vorvorvveigto Alkoxygruppo with 1 to 4 Kchlon9toffatomen, preferably Mothoxy "halogen, preferably chlorine or bromine;

for η> O

Halogen, hydroxy,

where R

N -

^R5 and

the same odor may be different,

V / aaeorotoff, a branched or unvorzvvoigto alkyl,

Alkenediyl alkynyl group having 1 to 10 carbon atoms, which may be gegobononfoils by halogen, hydroxy or by oinon C-hi <hopped by heterocycle substituted, wherein the carbon chain may be interrupted by nitrogen, oxygen or sulfur, a branched or unbranched alkylcarbonyl group with 1 to 6 carbon atoms, optionally substituted by hydroxy or halogen, preferably chlorine, or substituted by a benzene optionally substituted once or twice by a branched or unbranched alkyl group having from 1 to 6 carbon atoms, said alkyl group being able to be oxy- substituted by halogen or hydroxy,

a gegebononfalls substituted arylcarbonyl group, preferably phonylcarbonyl, a gobobononfalls substituted arylsulfonyl, preferably phenylsulfonyl or Tolylsulfc.'iyl, oine alkylsulfonylgruppo with 1 bi3 4 carbon atom, or

R. and K_ together form a nitrogen atom, 4 5

saturated or unsaturated, optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atomson the 5-, 6- odor 7 ~ ing, which may contain as further Hotorootomo nitrogen, oxygen or sorbofol, wherein each further nitrogen atom optionally by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, substituted 3oin may;

2 ^ 5405

R is an arylsulfonyloxy group, preferred

Tolylsulfonyloxy or phenylsulfonyloxy, optionally mono- or polysubstituted by branched or unbranched alkyl and / or alkoxy groups rait I to 4 carbon atoms:

R is a branched or unbranched Alkylsulfonyloxy group having 1 to 4 carbon atoms; R is an acylcarbonyloxy group, preferred

Phenylcarbonyloxy, optionally substituted one or more times by branched or ur. Branched alkyl and / or alkoxy groups having 1 to 4 carbon atoms;

R is a branched or unbranched

Alkylcarbonyloyygruppe having 1 to 12, preferably 1 to 8, carbon atoms, wherein the alkyl chain may be interrupted by nitrogen, oxygen or sulfur;

N-C-N-i Μ ι K O R "

where R, is a branched or unbranched alkyl,

Alkenyl or alkynyl group having 1 to 4 carbon atoms, optionally substituted by halogen, an optionally mono- or polysubstituted by "branched or unbranched alkyl and / or alkoxy groups having 1 to 4 carbon atoms substituted aryl group, R _{7 is} hydrogen or a branched or unbranched alkyl group 1 to 4 carbon atoms;

R 2 R 6s N - C - - O- ι Il H O

R "RO

^ N - S-

wherein R and R, which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms, or R. and R _Q together with the nitrogen atom, a 5 optionally substituted one or more times by branched or unbranched alkyl groups having 1 to 4 carbon atoms -, 6- or 7-membered ring, which may contain as further heteroatoms nitrogen, oxygen or sulfur, each further nitrogen atom being substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl;

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

R an imido radical; Dioxolane, substituted dioxolane; for η greater than or equal to O

R "-CH = O; -COOH; C ^ Cc ^ -o \ ^v ι

R is a branched or unbranched Alkoxycarbonyl group having 1 to 4 carbon atoms,

with the proviso that when P 'is hydrogen,

R o -chlorophenyl, X and Y are both nitrogen RZ can not be methyxycarbonylethyl;

2654

R is an aryloxycarbonyl group, preferably phenyloxycarbonyl;

R is a radical of the general formula

10

wherein R and R ,, which may be the same or different, are hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group of 1 to 10 carbon atoms, optionally substituted by halogen, hydroxy, nitro, amino Amino or in the case of R = hydrogen or A] kyl and Y = CR or Y nitrogen and X C-alkyl, R by an ester function or an acid amide of the general formula

^R "10"

^ • N - C ^Rf ii

wherein R ¹ and R *. have the same meaning as Rio and R, but with the exception of an acid amide, may be substituted,

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

R and R together with the nitrogen atom a saturated or unsaturated optionally mono- or polysubstituted by branched or unbranched alkyl groups rait I to 4 carbon atoms substituted 5-, 6- or 7-ring, eggs may contain as further heteroatoms nitrogen, oxygen or sulfur, wherein each additional nitrogen atom may 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 ^{1 is} hydrogen, Z is an unbranched alkyl chain with η carbon atoms and

a) R a o-chlorophenyl and

R - methyl and η = 0, 1, 2, 3 or NR R not morpholino,

or η = O or

NR ₁ -R ₁₁ not amino,

or II ->

NR _1n R ₁ . not diethylamino, methylamino,

i.0

Isopropylamino, dimethylamino, cyclopropylamino, piperidino, pyrrolidino, cyclohexylamines, N'-methylpiperazino, amino, di (hydroxyethylaiiino) or hydroxyethylamino, or

b) R = o-chlorophenyl and

R = chloromethyl, bromomethyl, propyloxy, Hydrogen, methoxy, bromine or cyclopropyl,

and η a

NR R not morpholino,

or

2654 OS

c) R = o-chlorophenyl and R = »cyclopcopyl and

η = 2

Wd ₁ -R ₁₁ not diethylamino,

or η = · 8

NR R _{1 is} not morpholino

or

d) R = phenyl, R =. Methyl, η * 2

NR ₁ R ₁₁ not morpholino

e) R = 2-nitroph'enyl, 2-methylphenyl

2-trifluoroethyl, R = η »2

R = methyl

NR ₁ -R ₁₁ not morpholino,

f) R β 2-chlorophenyl, R = methoxy η * 2

NR ₁ -R ₁₁ not diethylamino, piperidino

g) R - 2-chlorophenyl, R = methoxy, η »2,

NR ₁ -R ₁₁ not N ¹ -methylpiperazino

means; R- is a radical of the general formula

wherein

B oxygen, sulfur, NH or NC.-O, -AlUyI,

JL O

D is the radical (C Re Rf) n, where η can be 0 to 3, Ra is hydrogen, optionally substituted by a hydroxy or amino group-substituted alkyl having 1 to 6 carbon atoms, C. to C. alkoxycarbonyl, DialkylarainocarbonyI,

Rb, Rc, Rd, Re, Rf are hydrogen, optionally substituted by hydroxy or amino substituted alkyl of 1 to 6 carbon atoms, or phenyl;

R is phenyl, where the phenyl ring may be mono- or polysubstituted, preferably in the 2-position, by methyl, preferably halogen, particularly preferably chlorine or bromine, nitro, alkoxy, preferably methoxy and / or trifluorraethyl, pyridyl;

R ° is hydrogen, an alkyl or an acyl group having 1 to 4 carbon atoms in the alkyl chain, preferably acetyl;

R ^{1 is} hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl;

X, 7 independently of one another are C-R or N, but not simultaneously both C-R,

or Y is the group C-COOR *, where R * = alkyl or hydrogen and X = nitrogen;

Z is a branched or unbranched alkyl or alkenyl group having η-carbon atoms, wherein Z may optionally additionally be substituted by aryl, preferably phenyl, substituted phenyl or 2-fold by R ₂ , wherein R may be the same or different;

η can be a dec numbers O, 1, 2, 3, 4, b, 6, 7, 8, 9 or

in the form of their racemates, their enantiomers, their diastereomers and their geroics; in each case as free bases or their physiologically harmless acid cadmium salts.

Preference is given to compounds of the. general formula Ia and Ib, in which

R, methyl, ethyl, methoxy, ethoxy or halogen,

preferably chlorine or bromine; R is chlorine, bromine, iodine, hydroxy,

N-

wherein R. and R_, the same or different 4 5

may be hydrogen, a branched or unbranched alkyl group having 1 to 6, particularly preferably 1 to 4, carbon atoms, wherein the

Carbon chain interrupted by nitrogen

can be a branched or unbranched

Alkylcarbonyl group with 1 to 4 Konlenstoffatomen, optionally substituted

by a dimethylamino group, a

phenylcarbonyl,

in the case of R = hydrogen, optionally by acylamino, more preferably acetylamino, amino, alkylamino or

Dialkylamino-substituted phenylsulfonyl group,

or

26 54 OS

R and R together with the 4 5

Nitrogen atom, a piperidine, pyrrolidine, N ¹ -methylpiperazine, an optionally dimethyl-substituted morpholine ing, a pyrrole, pyrazole, imidazole or triazole ring;

-CH = .0, COOH;

an optionally substituted by methyl mono- or polysubstituted Δ-imidazoline, -oxazoline, -Thiazolin; a tolylsulfonyloxy group, a

methylsulfonyloxy;

a phenylcarbonyloxy group;

a branched or unbranched

Alkylcarbonyloxy group with 1 to 5 Carbon atoms; a methoxy or Ethoxycarbony group!;

C - O- R 6 ν 9 N - C -N- Il ι Il I N - O H 0 ^R 7 ι H

where R is a branched or unbranched

6 alkyl group having 1 to 4 carbon atoms, R is hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms;

R ₀ N O 8 "- ·>. Il -S Il ^R 9 O

wherein R and R, which may be the same or different, represent a methyl, ethyl, propyl or isopropyl group, or R. and R _n together with the nitrogen atom represent an N'-methylpiperazine or morpholine ring;

O OO

Il ^ o. Il

HN J ¹ "·

Il^ s ^ Il

0 0.0

R is phenyl, where the phenyl ring, preferably in the 2-position, can be substituted by H halogen, preferably chlorine;

R ° is hydrogen, methyl, acetyl; R ^{1 is} hydrogen;

X, Y are independently C-Ri or N, but not

at the same time both C-Ri, (Ri preferred

Hydrogen),

or Y is the group C-COOR *, where R * = alkyl or

Hydrogen and X * nitrogen; Z as defined above, preferably - (CH ₉ ) -, optionally substituted by phenyl or 2-fold by R, wherein R may also be different

or -CH-CHR-CH-R - CH-CHR R, 2 2 2 2 2 2 2

η one of the numbers 1, 2, 3, 4, 5, 6, 7, 8, 9 or may mean and optionally their physiologically acceptable acid addition salts.

Particularly preferred are compounds of the general Formula Ia, wherein R = methyl or methoxy, R = »o-chlorophenyl, R ^{1 is} hydrogen, X, Y both Nitrogen, or X is CH and Y is nitrogen, Z (CHa),

η = 2, 3 or 7 and R and R ° as previously defined.

Unless otherwise indicated, halogen of one of the atoms is fluorine, chlorine, bromine or iodine, aryl groups are to be understood as meaning optionally mono- or polysubstituted aromatic radicals having up to 10 carbon atoms in the ring system, such as e.g. Phenyl, pyridyl, thienyl, furyl or naphthyl, with the phenyl ring being preferred. Unless otherwise stated, alkyl, alkenyl, alkynyl and alkoxy groups are understood as meaning optionally substituted, branched or unbranched radicals having 1 to 8 carbon atoms in the carbon chain. As substituents, one or more atoms from the group halogen, methyl, methoxy, hydroxy or trifluoromethyl can be present.

Preferred imido radicals are the following structures

o oo

N-

Unless stated otherwise, lower alkyl or lower acyl is understood as meaning branched or unbranched radicals having 1 to 4 carbon atoms in the alkyl chain.

In the general formulas, "n" in "Z" indicates the number of carbon atoms in the alkyl or alkenyl chain, respectively.

If Z is substituted twice by R ", then the η 2

Substituents be the same or different. When Z is a branched alkyl or alfcenyl group, the branch is preferably in the α or β position to the terminal functional group.

Alkenyl denotes alkyl chains having at least one double bond, alkynyl alkyl chains having at least one triple bond.

As alkyl groups are preferred, unless stated otherwise: methyl, ethyl, propyl, iso-propyl; n-butyl, iso-butyl and t-butyl, with the methyl group being particularly important. Preferred alkoxy group is methoxy.

The novel compounds of the general formula Ia can be obtained by known processes from the corresponding thienodiazepinions of the general formula II or else by variation of functional groups of the side chain of the already completed hetrazepinger system.

The novel compounds of general formula Ib are obtained by reduction of compounds of general formula Ia. The reaction is carried out with known reducing agents in organic solvents, e.g. with zinc in a mixture of glacial acetic acid and an inert organic solvent, e.g. halogenating hydrocarbons, e.g. Dichloromethane, at temperatures between room temperature and the boiling point of the reaction mixture or e.g. by means of lithium aluminum hydride (as far as R, is not reduced).

15 2 6 5 4 QS

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

Compounds of the general formula Ia

R '

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

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

¹⁶ 2 6 5 4 OS

Compounds of general formula Ia with a fused thiazole ring can in the usual way from the corresponding thieno-1,4-diazepine-thionen of the general formula

(R a -COOR *, (preferably R * = lower alkyl) or

R _n Z is the meaning of a Alkyldicarbonsäuremethyl-2 η

or ethyl ester having 1 to 10 carbon atoms in the alkyl chain or R ₀ =. OCOCH, or SO. NR ₀ R ₀ )

2 3 2 8 9

getting produced.

For this purpose, a compound of formula II either

a) with an acid hydrazide of the general formula

R -CONHNH III

implemented, or else

b) with hydrazine in a compound of the general formula

NNH '

IV exercises

and subsequently with an acid halide, preferably an acid chloride, of the general formula

R-COHaI V

or with an orthoester of the general formula

OR '

R ₁ -C OR ¹ VI

OR ¹

wherein R ^{1 represents} a lower alkyl group, preferably methyl or ethyl, are reacted.

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

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

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

18

2-554 OS

Further reaction with an acid halide V or an orthoester VI is carried out in an inert organic solvent, e.g. halogenated hydrocarbons, cyclic or aliphatic ethers, but can also be Jirekt in substance. The isolation of the final product Ia is carried out by known methods, for example by crystallization.

The structure of the hetrazepines of general formula Ia in which X represents a CH group and Y is nitrogen, takes place in a manner known per se from the thione of general formula II, by reaction with an araoalkyne of general formula VII, in which Rn is hydrogen or a Alkyl group, preferably hydrogen, means by the use of hydrochlorides for Hetrazepinringschluß hydrol / seerapfindliche R_ groups

it

become accessible.

R ₁₁ -CSC

_n ^ t CSC-CH ₂ NH _{2 L} y- £ jf ^N >

VII

Λ R₂ Z_n-k Χ ν

Ia

According to this process, it is possible to prepare compounds of the general formula Ia in which R denotes an alkyl, preferably the methyl group,

19

2 6 5 4

Another method consists in the reaction of the thione of the general formula II with an a-Arainoaldehyd-alkyl acetal or

α-aminoketone alkyl ketal of the general formula VIII according to the following synthesis Scheraa, R.

(FFO) ₂ C

ii

₂ NH ₂ CH ₂ CR ₁ (OrT)

LJ

VIII

* = ^R 2

wherein R represents hydrogen or an alkyl group having 1 to 4 carbon atoms or cyclopropyl group and R * represents a lower alkyl group.

Analogy processes for the synthesis of an acetal of a ketal of general formula VIII and an analogy process for ring closure are described in Swiss Patent Specification No. 580,099.

Compounds of the general formula Ia in which X is nitrogen and Y is CH, can be prepared by decarboxylation of compounds of the general formula

¹ Vz _n ^ ₁

W /

IC

R ¹

R- * = lower alkyl

to be obtained. Compounds of the general formula Ic are obtained, for example, from the diazepin of the general formula II by reaction with Isocyanessigsäureeetern. Analogy 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 contain a [1,5-a] linked imidazole ring can also be prepared, for example, in analogy processes to those described in DE-OS 25 40 522.

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

21 ^ 6 5 4 05

The corresponding alkoxy compounds are obtained, for example, from one of the abovementioned chlorine or bromine compounds by reaction with the corresponding alkoxide.

The radicals R are preferably halogen and alkoxy, but only after the construction of the fully functionalized hetrazepine of the general formula Ia according to 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 is not attacked under the reaction conditions used or can be protected by appropriate protecting groups. This is especially true for R.sup.1 an ester function, an alkylcarbonyloxy group dioxolanyl, substituted

Dioxolanyl as well as R ₀ = R ₀ R ₀ NSO ₀ - to.

/ ο y ζ

Thus, diazepin of the general formula II can be prepared as follows.

In analogy to that of Gewald et al. Chera. Ber. 98., 3571 (1965), ibid, 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. By known methods, these are converted by bromoacetylation and subsequent reaction with ammonia in the ring-closed 1,4-diazepinones, which then with

Phosphorus pentasulfide or Laweseon reagent are converted into the Thion dor general formula II.

5 54

Synthetic Scheme I

or

Y-CH ₂ -CHO HC-CN

Y CHfCR'O

S / Base

Y = R ₂ Z _n -

I. Hal-CO-CH ₉ -HaI

2 NH

3 · -H ^ O I

PoS,

Y -

Preferably, R has the meaning of a carboxylic acid ester, such as £ .B. Of a carboxylic acid ethyl or ethyl ester, an alkylcarbonyloxy group or an aminosulfonyl group.

The ω-functionalized aldehydes a required for the preparation can be synthesized, for example, by reductive ozone cleavage of cyclic enol ethers (L. Claisen, Berdsch. Chera., Ges. 4J), 3907 and V. Schraid i. Count, Liebige Ann. Chera. 656 , 97 (1962), suitable fatty acid derivatives, such as acetic acid oleyl esters or suitable unsaturated heterocycles. The ozonization is preferably carried out in methylene chloride or ethyl acetate at -78 ° C to +20 ⁰ C, preferably between -40 ⁰ C and -20 ⁰ C.

Another approach is given in the following reaction scheme

\ _8th^ "

N-SO-CH, > N-SO-CH- (CHj -CH J

/ 23 ΛΚ / 2 2 2 η ^

R ₉ 2. Br- (CH ₂ ) -CH Ί R ₉

R ₉

The reaction of the aldehydes a leads in a manner known per se, as indicated in the synthesis scheme 1, according to K. GewaId et.al., Chem. Ber. 98, 3571 (1965) and Chem. Ber. 9: 9, 94 (1966) on the aminothiophene derivatives c.

The resulting in the further reaction of c with a Halögenacetylhalogenid 2-Halogenacetylaminothiophenderivate can either be isolated, or else be converted as a crude product via the 2-Aminoacetylaminothiophenderivat in the Diazepinon d, which subsequently with

Phosphorus pentasulfide or Lawesson's reagent to the thione of general formula II.

Z is a branched alkyl or alkenyl group, η

optionally by aryl, preferably phenyl, or Z

Substituted twice by R, the structure of the branching at the stage of the ω-functionalized aldehyde or after completion of the fully assembled hetranepin can be carried out by known methods.

2 6 54 OS

In the case that Z is double-functionalized, η

the functional groups are bonded to the same carbon atom or to different carbon atoms.

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

Starting from the esters, the corresponding carboxylic acids of general formula Ia may be obtained by saponification, e.g. in alcoholic aqueous potassium hydroxide, e.g. with KOH in ethanol, at temperatures between room temperature and the boiling point of the reaction mixture.

Carboxylic acid amides of the general formula Ia can be prepared by known processes, such as ,, BB. from the corresponding carboxylic acids or their carboxylic acid by reaction with a primary or secondary amine or ammonia of the general formula

HN

Preference is given to the conversion into a carboxylic acid chloride or acid anhydride or the reaction of the acid in the presence of carbonyldiimidazole, sulfonyldiimidazole, cyclohexylcarbodiimide.

The reaction of the free acid with the amine takes place in the presence of a carbodiimide, for example of cyclohexylcarbodiimide, carbonyldiiroidazole or sulfonyldiimidazole in an inert solvent such as

Dimethylformamide, tetrahydrofuran, dioxane or halogenate hydrocarbon at temperatures between ^{0 0} C and the boiling point of the reaction mixture.

In the reaction of the amine with an acid halide or acid anhydride, the amine is reacted in an inert solvent, for example dimethylformamide, tetrahydrofuran, dioxane or a suitable Kohlenwaeserstoff such as toluene at temperatures between room temperature and the boiling point of the reaction mixture with the acid halide or acid anhydride, optionally with 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, the reaction can also be carried out in an excess of the amine without additional solvent.

The acid halide or acid anhydride is obtained from the free acid in a conventional manner, e.g. by reaction of the acid with a thionyl halide or by reaction of an alkali metal salt of the acid with acetyl chloride or chloroformic acid chloride.

Instead of the reaction with an amine can also be reacted with an amino acid derivative.

Esters of the general formula Ia, in particular the methyl or ethyl esters, can be converted into the corresponding alcohol by selective reduction of the ester function. The reaction is carried out with inverse addition of the reducing agent, e.g. Lithium alanate or sodium borohydride (inverse activation), under general

under usual reaction conditions, e.g. in inert organic solvents, e.g. Ethers, tetrahydrofuran at temperatures between room temperature and the boiling point of the reaction mixture.

Carbamates or ureas of the general formula Ia where R - = R, NHCOO - or R.NHCONR., - are obtained from the reaction of the corresponding alcohols or amines with the desired isocyanate in organic solvents, e.g. 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 wherein R is alkyl or arylcarbonyloxy are derived from the corresponding alcohols of general formula Ia by reaction with an acid equivalent of a carboxylic acid of the general formula

OH

wherein R is an aryl radical or preferably a branched or unbranched alkyl with 1 to 8 carbon atoms, wherein the carbon chain may be interrupted by nitrogen, oxygen or sulfur, prepared. Here, the same reaction conditions as in the production of acid amides can be applied.

From the carboxylic acids of general formula Ia with R a COOH can be prepared by known methods, the carboxylazides, these can then be in an inert organic solvent, such. Dioxane, by the

2 <5 4 O 5

Curtiusumlagerung be converted into the isocyanates. These isocyanates can be converted into the primary amines by well-known procedures and into the urethanes and ureas as described above.

Starting from compounds of the general formula Ia in which R = OH, compounds of the general formula Ia in which R is an alkyl- or arylsulfonyloxy group are obtained by reaction with alkyl- or arylsulfonic acid halides. The reaction is carried out in inert organic solvents, e.g. Methylene chloride, with sulfonic acid halides with addition of acid binders, such as a. B. Triethylamine.

The mesylates thus obtained are good leaving groups and can be exchanged nucleophilically. Correspondingly functionalized compounds of general formula Ia, e.g. R = »CK-SO-, can with primary or secondary amines of the formula

HN

or an imido radical, for example phthalimide. Compounds of the general formula Ia in which R, the group NR ₄ R ₅ or an imido radical are obtained.

The reaction is carried out in inert organic solvents, e.g. Tetrahydrofuran, dioxane, between room temperature and the boiling point of the reaction mixture, preferably at elevated temperatures.

2 6 54 OS

Starting from the mesylates mentioned above, one obtains

Compounds of the general formula Ia in which R _{2 is} an aryloxy or alkyloxy radical, by combination with the corresponding alcoholates, either in an excess of alcohol as solvent or in inert solvents, such as dioxane, between room temperature and the boiling point of the Löeungsmittelgeraisches ,, preferably between 60 and 80 ^° C.

Compounds of general formula Ia with R = »NH are obtained in analogy to known processes by cleavage of the entoprechenden Fhthalimids.

The primary or secondary amines thus obtained can be derived by known methods with carboxylic acid equivalents of carboxylic acids of the general formula

OH

wherein R has the meaning of R, to compounds of general formula Ia, wherein R or R is an alkyl

4 5

or arylcarbonyl group.

The oxidation of the alcohols gives the order of a chain link

truncated aldehydes.

Compounds of the general formula Ia in which R is a heterocycle, e.g. an oxazoline, thiazoline or imidazoline is obtained, for example, from the corresponding carboxylic acids of general formula Ia by reaction with a bis-functionalized amine, e.g. an aminoalcohol, an aminomercaptan or a diamine in the presence of triphenylphosphine, carbon tetrachloride and a tertiary organic base

in acetonitrile. By analogy with this, it is also possible to prepare the corresponding 6- and 7-membered heterocycles. 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 corresponding hydroxy-functionalized carboxamides by ring closure reaction with thionyl chloride in an inert organic solvent such as methylene chloride.

These may, if desired, be obtained by sulfurization, e.g.

with phosphorus pentasulfide or Lawesson reagent into the corresponding thiazoline.

Compounds of general formula Ia in which R is a

it

Cyano group, is obtained from the corresponding primary carboxylic acid amides by reaction with phosphorus oxychloride in an inert organic solvent, e.g. Dichlor) than, under reflux conditions.

Compounds of general formula Ia, wherein R is a

ct

optionally imidazoline substituted by branched or unbranched alkyl groups, can be obtained starting from compounds Ia with R. = CN on the Imidoethylesterhydrochlorid by reaction with a diamine (Pinner reaction). The formation of Imidoethylesterhydrochlorids carried out by treatment of 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 under ice-cooling, then under reflux conditions. This gives compounds of the formula Ia in which R is a

* t

Imidazoline-2-rest is. Its amino function can be alkylated in the case of N-H by known methods.

Compounds of general formula Ia wherein R is a halogen atom, e.g. Iodine, is obtained from a compound of general formula Ia wherein R is toluenesulfonic acid residue by reaction with a corresponding halogenating agent, e.g. NaJ, in anhydrous solvents, e.g. Acetone.

As far as the compounds according to the invention have an asymmetrically substituted carbon atom, they can be separated into their optically active antipodes by known methods.

By analogy with known processes or according to the processes described above, for example, the following compounds can be prepared:

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-t] [1,2,4] triazolo [4,3-a] [1,4-ethoxide] sulfonic acid-N-raethylpiperazid

Es8igsäure {3- [4 - (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 2-4Jdiazepin yl) propyl}

2- [7- (N, ^1- methylpiperazinylcarbonyloxy) heptyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-fHi ₁ 2,4] triazolo [4,3-a] [ l, 4Jdiazepin

2- [3- (N'-Methylpiperazinylcarbonyloxy) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3- a] [l, 4] diazepin

2- [3- (N-Morpholinylcarbonyloxy) propyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [I, 4] -diazepine

2- [7- (N-Morpholinylcarbonyloxy) heptyl] -4- (2-chlorphenylj-9-methyl ~ 6H-thieno [3,2-f] [l, 2,4] triazoloi4,3-a] [l, 4] diazepine

2- (2-hydroxyethyl) -4- (2-chlorophenyl) -9-methyl-6H ~ thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4 ] diazepin

2- (4-hydroxybutyl) -4- (2-chlorophenyl) -9-raethyl-6 H -.> Nieno- [3,2-f] [l, 2,4] triazolo [4,3-a] (l, 4 ] diazepin

2- (5-hydroxypentyl) -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-f | [l, 2,4] triazolo [4,3-a] [l, 4 ] diazepin

2- (10-hydroxydecyl) -4- (2-chlorophenyl) -9-methyl-6H-thi ⁱ eno [3,2-f] [l, 2,4] triazolo [4,3-a] [l , 4] diazepin

E88igeaurc- {7- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4jtriazolo [4,3-a] [l, 4] diazepin-2 yl] -heptylester}

2- (3-acetoxypropyl) -4- (2-chlorophenyl) -9-Brora-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4] diazepin

2- [2- (methylcarbonyloxy) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1 , 4] diazepin

2- [4- (isopropylcarbonyloxy) butyl] -4- (2-chloro-phenyl) -9-methyl-6H-thienot3,2-f] [1,2,4] triazolo [4,3-a] [ l, 4] diazepin

2- [5- (methylcarbonyloxy) pentyl] -4- (2-chloro-phenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazo. .O [4 , 3-a] [1, 4] diazepine

Methanesulphonic acid {3- [4- (2-chloro-p] itanyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4] diazepin-2-yljpropyloster}

2- [2- (Methylsulfonyloxy) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4 ] diazepin

2- [4-methylsulphonyloxy) butyl] -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepin

2- [5- (Methylsulfonyloxy) pentyl] -4- (2-chlorophenyl) -9-mer. Ethyl-6H-thieno [3,2-f] [1,2,4] criazolo [4,3-a] [1 , 4] diazepin

2- [10- (MechylauIfonyloxy) decyl] -4- (2-chlorophenyl) -9-raethyl-6H-thienot3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

2- [3- (N-Mocpholinyl) pcopylj-4- (2-chlocphenyl) -9-methyl-6H-thieno [3,2-f] TLR2 _f 4] tria7.olo [4 _# 3-a] [1.4 ] diazepin

2-t2- (N-Mocpholinyl) ethyl] -4- (2-chlocphenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] tciazolo [4,? - a] [ 1.4] diazepin

2- [4- (N-morpholinyl) tutyl] -4- (2-chlocphenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepin

2- [5- (N-Morpholinyl) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] t'.iazviO [4 , 3-a] [1,4] dia ^ ePIN

2- [10- (2,6-Dimethylraorpholin-4-yl) decyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepin

2- [3- (N-Mocpholinyl) pcopyl] -4- (4-chlorophenyl) -9-raethyl-6H-thieno [3, rf] [1,2,4] triazolo [4,3-a] [l , 4] diazepin

2- [3- (N-Motpholinyl) propyl] -4- (2, .S dichlocpheriyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] tria2Olo [4,3- -a] [l, 4] diazepin

2- [3- (N-MOr ¹ JHO liny Dpcopyl] -4- (pyc-iu-in-2-yl) -9-ylethyl 1-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazipin

2 (7-acetylaminoheptyl) -4 - (?, - chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

2- ( ^T -N-phthalimidoheptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [Ii4] diazepin

2- (3-iodopropyl) -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4 ] diazepln

2- (7-aminoheptyl) -4- (2-chlocptu "nyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] trlazolo [4,3-a] [l, 4 ] diazepin

2- (6-Focmylhexyl) -4- (2-chlocphenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin

2- [2- (im -dazol-1-yl) ethyl] -4- (2-chloro-phenyl) -9-methy1,6-thieno [3.2-f] [1,2,4] triazoles [4.3 -a] [1,4Jdiazepin

2- [3- (imidazol-1-yl) -popyl] -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1,2,4] tiazolo [4,3- a] [1,4] diazepin

2- [4- (imidazol-l-yl) butyl] -4- (2-chlocphenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] tr? * - olo [4,3-a] [1,4] diazepine

2- [5- (imidazol-1-yl) pentyl] -4- (2-chlorophenyl) -9-methyl-6H-thio; no [3,2-f] [1,2,4] -tziazolo [4,3- a] [l, 4] diazepin

2- [7- (imidazol-1-yl) heptyl] -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3, 2-f] [L, 2, 4] triazole »[4, 3 -a] [1, 4] diazepine

2- [2 - ([1,2,4] triazol-l-yl) ethyl] -4- (2-chlorophenyl) -9-methy1-6H-thieno [3,2-f] [l, 2,4 ] triazolo [4,3-a] [l, 4] diazepin

2- [3 - ([l, 2,4] triazol-1-yl) propyl] - 4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1, 2, 4] Triaz ". , [4, 3-a] [1, 4] diazepine

³⁴ 26S4 05

2- [4 - ([l, 2,4] triazol-1-yl) butyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f H, 2,4] triazolo [4,3-a] [l, 4] diazepin

2- [5 - ([l, 2,4] Ti: iazol-1-yl) pentyl] -, - (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2 , 4] triazolo [4,3-a] [1,4] diazepin

2- [2- (4, 4-Dimethyloxazolin-2-yl) ethyl] -4- (2-chlorophenyl) dibromo-1-6H-thieno [3, 2-f] [1,2,4] triazolo [4 , 3-a] [l, 4] diazepin

2- [3- (N-Mocpholinyl) propyl] -4- (3,4,5-triraethoxyphenyi) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4.3- a] [l »4] diazepin

35 2 6 5 4 OS

The compounds according to the invention have PAF-antagonistic activity.

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

In a pharmacological experiment, PAF shows bronchoconstriction, lowering of blood pressure, triggering of platelet aggregation and a pro-inflammatory effect.

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

PAF antagonists are needed, on the one hand, to elucidate further pathophysiological functions of this mediator on animals and humans and, on the other hand, to treat pathological conditions and diseases in which PAF is involved. Examples of the indications of a PAF antagonist are inflammatory pathogens of the tracheobronchial tree (acute and chronic bronchitis, bronchial asthma) or kidney (glomerulonephritis), anaphylactic conditions, allergies and inflammations in the mucous membranes and the skin (eg psoriasis) as well as sepsis, endotoxins or burns related shock states. Other important indications for a PAF antagonist are lesions and inflammation in the area

the stomach and Darraschleirahaut, such. Gastritis, generally peptic ulcer, but especially Ulcue ventriculi and duodenal ulcer.

Furthermore, the compounds according to the invention are suitable for treatment in the following indications: Obstructive lung diseases, such as e.g. bronchial hyperroactivity, inflammatory lung pathologies, e.g. Chronic bronchitis;

Cardiovascular diseases, such as Polytrauma, anaphylaxis, arteriosclerosis, inflammatory bowel disease, edema-protein urea hypertension, extracorporeal circulation disorders, ischemic diseases, inflammatory and immunological disorders, immune modulation in transplantation of premec tissues, immune modulation in leukemia. Metastasis spread, e.g. in bronchial neoplasia, diseases of the CNS, e.g. Migraine, agarose phobia (panic disorder), further compounds of the invention prove to be cytotoxic and organoprotective, e.g. to the Neuroprotectiorx, z.P. in liver cirrhosis, DIC (denirated intravascular coagulation);

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

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

2 * 54 05

By contrast, many of the compounds according to the invention lack the sedative action, while the PAF-antagonistic composition is considerably better in comparison with that of the known benzodiazepines.

In the following the pharmacological investigation methods are communicated:

Pharmacological Methods

The PAF antagonistic activity of some compounds of formula I was tested by inhibition of platelet aggregation in vitro and antagonization of PAF-induced bronchoconstriction in the anesthetized guinea pig, blood pressure lowering in the anesthetized rat, and skin rat in the rat. In addition, these compounds have been tested for potential side effects on the central nervous system.

1. In Vitro Examinations: Determination of Platelet Aggreqation

To determine the PAF antagonist activity of substances, PAF-induced aggregation of human thrombocytes in vitro was used. To obtain platelet-rich plasma (TRP), blood is collected from an unstained vein using a plunger syringe containing 3.8% sodium citrate solution. The ratio between sodium citrate solution and blood is 1: 9. After careful mixing, the citrated blood is centrifuged at 150 χ g (1200 rpm) for 20 minutes. The measurement of platelet aggregation is carried out according to the method developed by Born and CrosB (G.V.R. Born and M.J. Cros, J. Physiol., 168, 178 (1963)), in which 3-aggregation is added to the TRP as a trigger under constant stirring.

38 2 6 S 4 05

The test substance is added in each case 2-3 minutes before the initiation of the aggregation in a volume of 10 μΐ. The solvents used are either Aqua.dest., Ethanol and / or Diraethylsulfoxyd. Controllantsets receive appropriate volumes of these solvents. After registration of the

After adsorption (2-3 minutes), aggregation is induced with PAF (5 χ 1 (T ⁸ M).

To assess substance effects, the maximum of the first aggregation wave is used. The maximum absorption rate induced by PAF (= maximum aggregation χ 100%) is tested simultaneously in each case in a parallel batch (control batch in one of the channels of the 2-channel aggregometer) for each test batch (second channel) and used as 100% value.

The aggregation value achieved under the influence of the test substance is expressed as 100%.

Jode test substance is at concentrations of 10 ~

- 8th

to 10 M with a sample size of η = 4 in each case for an inhibitory effect on PAF-induced platelet aggregation. Thereafter, a concentration-response curve is generated from 3 concentrations and the IK ... (concentration at 50% inhibition of aggregation) is determined. Di * IK values of compounds of the general formula I generally move s * .ch by values which are smaller than 9 μΜ.

2. In vivo explorati ^K unq in

2.1. Antagonization of PAF-induced bronchoconstriction on anesthetized guinea pigs

Spontaneously breathing male guinea pigs weighing 300-450 g are weighed 1 hour before i.v. The test animals are then anesthetized intraperitoneally with 2 mg / kg urethane, followed by the jugular, carotid and tracheal cannulas, and the PAF is infused with PAF (30 ng / kg · min) with the test substance or a control vehicle Infusion induces a strong, persistent bronchoconstriction in the control animals as measured by tidal volume, compliance, and resistance, as well as a decrease in blood pressure, and death occurs after about 7-10 minutes with the described PAF antagonists These effects on breathing and blood pressure as well as the onset of death are prevented.

2.2. Antagonization of PAF-induced blood-drenching in the anesthetized rat

Normotone male 200 to 250 g Wistar rats are anesthetized with 2 mg / kg urethane intraperitoneally. The Aiceria carotid and the jugular vein are cannulated. Intravenous PAF infusion (30 ng / (kg χ min)) induces a strong, sustained lowering of blood pressure in the control animals. This can be reversed dose-dependently by intravenous injections (cumulative administration) of the compounds described. Also an oral

40

or intravenous administration of the compound "Ci beginning of the PAF infusion may dose-dependently prevent the hypotensive effect of the above-mentioned PAF infusion.

2.3- Antagonization of the PAF-Induced Skin Squareness in the Rat (Modified by PP Koelzer and KH Wehr, Arzneira.-Forsch., 181 (1958)

Intracutaneous injection of PAF induces a squaring of the skin which is indicative of a PAF-induced increase in vascular permeability.

Male Wistar rats with a body weight of 2SO t 20 g, the Bauehdücke (short) sheared. Thereafter, 1 ml / kg is added to the animals by injecting a trypan blue solution through a tail vein. Symmetrically to the midline (linea alba), intracutaneous injections of physiological saline or PAF solution (1?, 5 to 15.0 ng / site in 0.1 ml) are administered in three places at intervals of approximately 1.5 cm. While no reaction occurred at the saline injection site, PAF caused a skin reaction (wheal) that became visible through a blue staining of varying intensity depending on the PAF dose. By simultaneous intracutaneous administration of r.er beechrieben-jn compounds or by intravenous pretreatment, this could be prevented by FAF i.iduzierto skin reaction.

3. Effects on the central nervous system

It is well known that substances of this structural type cause central nervous effects, but these are not desirable for a compound having PAF antagonist activity. Therefore, the compounds described were tested for their hypnogenic and anticonvulsant activity as well as their influence on the lotion. A possible hypnotic effect was investigated on guinea pigs weighing 400 to 450 g. Doses up to 200 rag / kg p.o. These substances were unable to produce a hypnotic or sedative effect on these animals.

To test for anticonvulsant activity, pentetrazole antagonist may be used in mice (20 to 25 g body weight) (Gluckman, M., Current Therapeutic Research, 7: 721, 1965). Doses up to 100 mg / kg p.o. of these compounds (1 hour before pentetrazole) did not affect the mortality caused by pentetrazole (125 mg / kg i.p., LD 100) in this assay.

The effect on the night motility (locomotion) of mice (20-25 g body weight) can be examined in a photoelectric cage. The number of light beam interruptions is measured. Doses up to 300 mg / kg p.o. Of the above compounds showed no activity.

Table A lists the in vitro assays for inhibition of platelets as described below.

42

Table A:

-6 substance IK ₅₀ χ 10 mol

Alprazolara 14 Triazolam 9

Example friu.

1 0.3

2 <0.2 4 <C, 2 θ <0.3

9 0.2

10 1.7

11 <0.2 x 2 0.3 13 f, 3 14i 0.4 141 0.6 20 0.3 23 0.9 25 0.9 27 0.2 45 0.3

49 1.0

50 0.6 54 1.1 56 0.3 58 <0.2 60 0.9 64 <0.2 71 0.9 7! J 1.9 9β 2,3

ΙΟΊ 2,2

The novel compounds of general formulas Ia and Ib can be administered to warm-blooded animals topically, orally, parenterally transdermally or by inhalation. The compounds are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees .. capsules, wafers, powders, solutions, suspensions, inhalation aerosols , Ointments, emulsions, syrups, suppositories, etc. An effective dose of the compounds according to the invention is between 1 and 50, preferably between 3 and 20 rag / dose when administered orally, between 0.01 and 60, preferably between 0 and 30, when administered intravenously or intramuscularly , 1 and 10 mg / dose. For inhalation, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% of active ingredient should be used.

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

44

265

05

At game 1:

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [l, 4] diazepin-2- yl] -ethane-l-suifonsäure-N'-raethylpiperazid

1.1. 3- (l, 3-dioxolan-2-yl) -propan-1-suIfonsäure-N'-methyl

pip.irazid

To 23 g (0.13 mmol) of methanesulfonic acid-N ¹ -methylpiperazid, dissolved in 200 mmol of anhydrous tetrahydrofuran are added at 0-5 ⁰ C 87.5 ml of a 1.6 molar BuLi solution in hexane (0.14 raol) added dropwise, the resulting suspension was stirred at room temperature for 90 minutes and then added dropwise 23.4 g of 2- (2-bromoethyl) -1,1-dioxolane (0.13 mol) in 200 ml of anhydrous tetrahydrofuran to give a clear solution. After stirring for 5 hours, the solvent is removed, the residue taken up in water / methylene chloride and the aqueous phase extracted several times with methylene chloride. The methylene chloride solution is dried and the solvent stripped off. The oily residue is filtered through a silica gel column with the mobile phase methylene chloride / methanol (9: 1). After renewed removal of the solvent remain 20.7 g of the desired compound as a light oil. (Yield 57% of theory).

1.2. S-Forrayl-propane-l-sulfonic acid-N'-raethylpiperazid

20.7 g (0.074 mol) 3- (l, 3-dioxolan-2-yl) propane-leulfonsäure-N · -raethylpiperazid and 800 ml 2U sulfuric acid are stirred for 30 minutes at 80 ⁰ C,

cooled and with conc. Ammonia brought to pH 6.5-7. The then saturated with sodium chloride solution is extracted thoroughly with methylene chloride. After drying and removal of the solvent is obtained 13.2 g of the aldehyde as a light oil

 (Yield 76% of theory).

1.3. 2 - Amino-3- (2-chloLbenzo> ι) -5- [2- (N '-Wet u _x> .- pi per az iny lsulfony :.) ethyl] - thiophene

10.1 g (0.056 mol) of o-chlorocyanoacetophenone and 18 g (0.056 mol) of sulfur are introduced into 10 ml of dimethylformamide and 7.8 ml (0.056 mol) of triethylamine are added dropwise. Subsequently, 13.2 g of 3-forinyl-n-propane-l-sulfonic acid-N'-methylpiperazide are added dropwise in 50 ml of dimethylformamide and the resulting solution is stirred at 70 ⁰ 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 of the solvent remain 18 g of oily residue, which is purified on a silica gel column with methylene chloride / methanol (9: 1) as a flow agent. 15.0 g of the thiophene compound are obtained as pale oil. (Yield 63% of theory).

¹ H-NMR (CDClia) δ ppm 7.30-7.55 (4H, m, aryl-H); 7.14 (2H, s, broad, NH ₂ ); 6.18 (IH, s, thiophene-H); 3.18-3.43 (4H, ra, piperazine (CHa) ₂ -N); 3.07 (4H, S, SOaCH ₂ CH ₂ ); 2,33-2,61 (4H, m, piperazine (CHa) ₂ -N-SOa); 2.33 (3H, S, N-CHj).

1.4. 2-Bromoacetylamino-3- (2-chlorobenzoyl) -5- [2- (N--luoro-piperazinyl-sulfonyl) -ethyl] -thiophene

14 g of the compound of Example 1.3 and 4.6 ml of triethylamine are initially charged in 200 ml of anhydrous methylene chloride and 2.85 ml of bromoacetyl bromide are added dropwise at room temperature. After 4 hours, the reaction mixture is mixed with water, made slightly alkaline and extracted with methylene chloride. After washing and drying, the solvent is removed at a water bath temperature of 30 ^° C. The resulting residues (17.9 g) must be reacted immediately.

1.5. 2-Arainoacetylamino-3- (2-chlorobenzoyl) -5- [2- (N ^l ~ methyIpiperazinylsulfonyl) ethyl] -thicphen.

17.9 g (0.032 mol) of the compound of Example 1.4. are dissolved in 200 ml of ethyl acetate and 4 hours ammonia introduced. 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] [l, 'J] diazepin-7-one-2-yl] ^{-ethane-l-N-l} 8Uli'onsäure -methylpiperazid

6.1 g (0.013 mol) of the compound of Example 1.5. and 20 g of silica gel are heated with 150 ml of toluene for 3 hours on a water to reflux. The silica gel is filtered off with suction and extracted with hot methanol. The 5.3 g of crude product obtained after working up are chromatographed on silica gel

chromatographed (fluid: methylene chloride / methanol 9: 1). This gives 2.6 g of diazepinone (yield 44% of theory), mp 135-138 ° C (acetonitrile).

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

2.6 g (0.0056 mol) of the diazepinonec, 1.25 g of phosphorus pentasulfide (0.0028 mol) and 1 g of sodium bicarbonate are stirred for 2 hours in 30 ml of diglyracene at 80 ⁰ C. The Reaktiont gemiech ^r is given in 100 ml of water and the solid is suction filtered ausgefΛΐίβηβ. The resulting diazepinethione (yield: 2.7 g, 100% of theory) is reacted further without purification.

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

2.7 g (0.0056 mol) of the compound of Example 1.7. and 0.3 ml (0.0062 mol) of hydrazine hydrate are stirred at room temperature for one hour in 30 ml of tetrahydrofuran. After removal of the solvent, the residue with 10 ml of triethyl orthoacetate is stirred for one hour at 70-80 ⁰ C. The excess orthoester is then taken off, the residue is taken up in 2N hydrochloric acid and extracted with ether and methylene chloride. The aqueous phase is made alkaline and extracted the precipitated Thienotriazolodiazepin with methylene chloride. After concentration and drying, 1.2 g of crude product, which is alumina,

neutral, activity level III rait 2 6 R λ λ

^{0 4} OS methylene chloride / methanol 95: 5 as eluent ^{v is} chromatographed. This gives 1.0 g (yield 35 %) of Thienotriazolodiazepins, mp. 148-150 ⁰ C.

¹ H-NMR (CDClia) δ ppm 7.30-7.61 (4H, m, aryl-H); 6.43 (IH, S, thiophene-H); 4.95 (2H, s, 7-ring CHa); 3.00-3.47 (8H, m, piperazine- (CHa) aN-SOa, SOa-CHa-CHa-); 2.72 (3H, 8, triazole-CH3); 2.30-2.61 (4H, m, piperazine (Ciia) aN): 2.32 (3H, s, piperazine-CHi).

Example 2;

Eseig8äure- {3- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4] diazepin -2-yl] propyl}

2.1. 2-Amino-3- (2-chlorobenzoyl) -5- (3-acetoxypropyl) thiophene

Starting from 5-hydroxypentanal, the 2-amino-3- (2-chlorobenzoyl) -5- (3-hydroxy-propyl) -thiophene is synthesized analogously to Example 1. 1 g (0.0034 mol) of this compound is dissolved with gentle heating in 40 ml of ethyl acetate, after 20 minutes of hydrogen chloride introduction is stirred for 2 hours at room temperature, the solvent was removed, the residue taken up in methylene chloride and washed with water. After drying and removal of the solvent, the oily residue on silica gel with methylene chloride / methanol 9: 1 as

49

Γ <5405

Eluent chromatographed. This gives 0.75 g (yield 65% of theory) of the abovementioned compound

¹ H-NMR vCDCla) δ ppm 7.24-7.54 (4H, m, aryl-H); 7.09 (2H, 8, broad, NHa); 6.13 (IH, s, thiophene-H); 4.07 (2H, t J = 6 Hz, OCH ₂ ); 2.61 (2H, t, J "6Hz, thiophene CHa); 2.02 (3H, 8, CHaC = O); 1.85 (2H, Γ0, OCHa-CHa):

2.2. E8sigsäure- {3- [4- (2-chlorophenyl) -i / methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [I, 'Uüiazepin- 2-yl] propyl}

Based on the connection of Example 2.1. the 2-bromoacetylamino compound is obtained in 92% yield, the 2-aminoacetylamino compound is obtained in 86% yield, the ring-closed diazepinone is obtained in 76% yield, the corresponding diazepinethione in 70% yield and the title compound from the title compound in 76% yield Mp 153-li 5 ° C.

Example 3 :

2- (3-hydroxypropyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4 ] diazepin

a) Synthesis from the compound of Example 2:

3.0 g (0.0072 mol) of the compound of Example 2 are stirred with one equivalent of potassium hydroxide in 40 ml of ethanol for 12 hours at room temperature; the solvent removed in vacuo and the residue taken up in methylene chloride. After washing, drying and removal of the solvent, 2 g of the title compound of mp. 155-160 ⁰ C (yield 74% of theory).

b) Synthesis of 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [I _f 4] dir> zepin-2-yl] -etaane 1-carboxylic acid ethyl ester

2.5 g (0.0062 mol) of the corresponding methyl ester are dissolved in 25 ml of anhydrous tetrahydrofuran and mixed at room temperature in small portions with a total of 0.13 g (0.0034 mol) of lithium alanate powder. After stirring for 12 hours, 0.2 ml of water, then 0.2 ml of 6N sodium hydroxide solution and then 0.4 ml of Waseer are added with cooling and thoroughly stirred. The solid is filtered off with suction and the filtrate after evaporation of the solvent at Kieselodl with methylene chloride / methanol (4: 1) as Eluene chromatographed _t tracks of Auegangsverbindung can HPLC column chromatography using the mobile phase methylene chloride / methanol (4: 1) to be separated. This gives 1.6 g of compound 3 (yield 69% of theory).

¹ H-NMR (CDCl 3) δ ppm 7.30-7.52 (4H, m, aryl-K); 6.42 (IH, s, thiophenH); 4.91 (2H, s, 7-ring CHa); 3.69 (2H, t, J = 6HZ, OCHa); 2.88 (2H, t, J = 6Hz, thiophene CHa); 2.69 OH, s, triazole-CHa); 1.91 (2H, ra, OCHaCHa); 1.78 (IH, s, broad, OH).

The starting compound containing 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-fJ [I, 2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethan-1-carboxylic acid methyl ester is obtained as follows:

2-amino-3-o-chlorobenzoyl-5- (2-dicai: bethoxyethyl) 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 turn with stirring, starting at room temperature with 64.8

2654

added, whereupon the temperature rises to 45-50 ⁰ C; g (0.3 mol) Dicarbethoxybutyraldehyd (bp 97 ° C / 0, l mBar DTWarner, J. Am Soc CHDM 70- 3470 (1948)....). The mixture is stirred for 2-3 hours at 60-70 ⁰ C, cooled to room temperature and added 400 ml of water. The resulting thiophene derivative is extracted by shaking three times with 200 ml of methyl tert-butyl ketone each time. After washing with water and drying the organic phase is evaporated and the crystalline residue from isopropanol / water 7: 3 recrystallized. Yield: 90 g (74% of theory), mp 96-90 ⁰ C..

thiophene 2-Amino-o ~ chlorobenzoyl-5- (2 ~ carboraethoxyethyl)

63 g (0.15 mol) of the above compound are refluxed with 120 ml of ethanol and 32.5 g of potassium hydroxide 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 precipitated acid is shaken out several times with ethyl acetate. The extracts are dried and evaporated, the residue mi. 300 ml of toluene and 30 ml of dimethylformamide boiled under reflux for 2 hours. After evaporation to about 50 ml to obtain crystals of monocarboxylic acid.

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. It is poured, after evaporation of the methanol on ice, extracted with methylene chloride and, after renewed evaporation from isopropyl ester 15 g of mp. 89-90 ⁰ C.

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

27.8 g (0.09 mol) of the above ester are suspended in 700 ml of toluene and mixed with 10 g of sodium bicarbonate in 57 ml of water. 7.9 ml Broraacetylbromid is added gradually with stirring at 40-5O ⁰ C and stirred for 30 minutes. It is washed with water, the toluene phase is dried, evaporated in vacuo and crystallized with isopropyl ether

Yield: 35-37g, mp 104-106 ⁰ C..

2 ~ Arainoacetylamino-3-o-chlorobenzoyl-5- (2-cat: boraethoxyethyl) thiophene

35.8 g (0.08 mol) of the above bromoacetyl compound are dissolved in 700 ml of ethyl acetate and, while stirring, dry ammonia is introduced at room temperature for 2-3 hours. It is left to stand overnight, washed with ice-water, dried, evaporated and gives 22-25 g of oily amino compound.

7- (2-carbomethoxyethyl) -5-o-chlorophenyl-thieno-1,4-diazepinone

21.3 q above (0.056 mol) of Compound was dissolved in 500 ml of toluene and boiled with 75 g of silica gel in a water separator for 2 hours under reflux. The silica is then extracted and the diazepine is extracted with hot methanol. After evaporation of the methanol to be 12 - 1. 5 g diazepine of melting point 160-162 ⁰ C obtained..

7- (2-carbomethoxyethyl) -5-o ~ chlorophenyl-thieno-l, 4-diazepin-2-thione

10 g (U, 03 mol) of the above diazepinone are stirred in IQO ml Diglyrae rait 6.8 g of phosphorus pentasulfide and 5 g of sodium bicarbonate for 3 hours at 70 - 80 ⁰ C stirred. The suspension is poured onto ice, stirred for 30-45 minutes and the crystals are filtered off with suction. After drying, 10 g of thione of mp. 185-186 ° C.

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine ~ 2 yl] ethan-l-carbonsäuremethylester

6.1 g (0.016 mol) of the above sulfur compound are dissolved in 100 ml of tetrahydrofuran and stirred for 30 minutes at 45 - 50 ⁰ C after addition of 1 g of hydrazine hydrate. It is then evaporated in vacuo. There are left behind 5 - 5.2 g of oil which crystallize with tsopropyl ether (mp 175-177 ° C).

The hydrazino compound gives on heating in 35 ml of orthoacetic acid ester to 80 ⁰ C, evaporation of methylene chloride ester 3 g of triazolodiazepine, mp. 114-115 ° C.

The same compound is accessible from the thione with acetic hydrazide.

Example 4:

Acetic acid {7- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-fJ [l, 2,4] triazolo [4,3-a] [l, 4] diazepin 2-yl]} -hiiptyleeter

Gombe HJ Beetmann et al., Chem. Ber. 104 , 65 (1971), one subjects Oleylacetat in methylene chloride at -40 ⁰ C of ozonolysis and cleaves the resulting ozonide reductively with the equivalent amount of triphenylphosphine, the resulting triphenylphosphine oxide is thoroughly triturated with ether deposited. Traces of unreacted triphenylphosphine can be precipitated in ethereal solution with methyl iodide as Phosphoniumealz. The separation of the nonanal from the desired 9-acetoxynonanal is expediently carried out by distillative separation in a silver mirror column. Starting from 9-Acetoxynonanal obtained analogously to Example 1 in quantitative yields, the Aminothiophenverbindung, the 2-Bromoacetylaminoverbindung and 2-Aminoacetylaminoverbindung, in 76% yield the DiazepinonringschluB, in 65% yield the Diazepinthion and in 33% yield the Es8igsäure- {7 - [4- (2-chlorophenyl) -9-methyl-6H-thieno- (3,2-f] [l, 2,4] triazolot4,3-a] [l, 4] diazepin-2-yl] - heptyliister} as an oil.

³ H-NMR (CDCl ₁₎ δ ppm 7.26 to 7.58 (4H, aryl-H m,); 6.36 (IH, s, thiophene-H); 4.92 (2H, s, 7-ring CHa); 4.06 (2H, t :, J * 6Hz, OCHa); 2.76 (2H, t, J »6Hz, thiophene CHa); 2.72 (3H, S, triazole-CHj); 2.05 (3H, s,]., 15-1.86 (1OH, m, OCHa (CHa) S-).

54

Example 5:

2-Methylpropionic acid {3- [4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [l »2,4] triazolo [4 _f 3-a] [l, 4] diazepin-2-yl]} -pcopylester

0.5 g (0.0013 mol) of 2- (3-hydroxypropyl) -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4 , 3-a] [1,4] diazepine (example 3), 0.12 g (0.0015 Raol) of pyridine and 0.2 g (0.0013 mol) of isobutyric anhydride are stirred for 4 hours at 60 ⁰ C. After stirring at room temperature for a further 12 hours, the reaction mixture is mixed with 20 ml of water and extracted with ether. After drying and removal of the solvent, the oily residue is chromatographed on silica gel with methylene chloride / methanol (9: 1) as the eluent and gives in quantitative yield the desired title compound, mp. 124-125 ° C.

Example 6:

Methanesulfonic acid {3- [4- (2-chloro-phenyl) -9-met: hy 1-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-aJ [l, 4Jdiazopin-2-yl] propyl}

To 3.9 g (0.0105 mol) of 2- (3-hydroxy-propyl) -4- (2-chlorophenyl) -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 added 1.7 g (0.015 mol) of methanesulfonyl chloride and added dropwise at 10 ⁰ O 1.5 g (0.015 mol) of triethylamine. After 12 hours of stirring at room temperature, the reaction mixture is extracted thoroughly with water, the organic phase is dried, the solvent is stripped off and the residue is chromatographed on silica gel with methylene chloride / methanol (9: 1) as the eluent. This gives 3.8 g (yield 81% of theory) of the title compound with mp. 13O-135 ° C.

⁵⁶ 26 54QS

Example 7:

2- (3-iodopropyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4 ] diazepin

0.6 g (0.0011 IQOI) of p-toluenesulfonic acid {3- [4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-fJ [1,2,4] triazophosphone 4.3 -a] [l, 4] diazepin-2-yl] -propyl ester}, prepared analogously to Example 6, and a solution of 0.2 g (0.0014 mmol) of anhydrous sodium iodide in 15 ml of anhydrous acetone are stirred for 2 hours at room temperature , After removal of the solvent, the residue is taken up in methylene chloride / water, the organic phase is washed several times with water, dried, the solvent is removed to give 0.2 g (yield 36% of theory) of the amorphous title compound.

¹ K NMR (CDCl 3) δ ppm 7.30-7.67 (4H, m, aryl-H); 6.44 (IH, s, thiophene-H); 4.94 (2H, s, 7-ring CHa), 3.20 (2H, t, J »7Hz), CH ₂ -J); 2.92 (2H, t, J »7Hz, thiophene CHa); 2.71 (3H, s, triazole-CHj); 2,12 (2H, ra, JCHaCHa).

Example 8:

2- (7-N-phthalimidoheptyl) -4- (2-chloro-3-phenyl) -9-mer. Ethyl-6H-thieno [3, 2-f] 11, 2,4] triazolo [4, 3-a] [1 , 4] diaz - r.

3.0 g (0.006 mol) of methanesulfonic 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} and

1.1 g (0.006 mol) of phthalimide potassium are stirred in anhydrous dimethylformamide at 60-70 ⁰ C for 5 hours. After cooling, the reaction mixture is poured into 150 ml of 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 is obtained in quantitative yield as an oil.

¹ H-NMR (CDCIs) δ ppm 7.62-7.94 (4H, m, phthalaryl-H); 7.26-7.55 (4H, methyl-H); 6.36 (IH, s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 3.52 (2H, t, J = 16 Hz, N-CH-); 2.75 (2H, t, J = -6 Hz), thiophene CHa); 2.69 (3H, ü, triazole-CHa); 1.14-1.93 (1OH, m, N-CHa- (CHa) e-).

Example 9:

2- (7-amino-heptyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4] -triazolo [4,3-a] [ l, 4] di.azepin

31.7 g (0.057 mol) of the phthalimido compound of Example θ are dissolved in 300 ml of ethanol and washed with

13.8 ml of hydrazine hydrate (0.29 mol) stirred for 20 hours at room temperature. The precipitated solid is filtered off with suction and the filtrate is concentrated and taken up with 2N hydrochloric acid. By extraction with methylene chloride, the unreacted starting compound can be removed. The aqueous phase is made alkaline and extracted again with methylene chloride. After drying and removal of the solvent, 14.2 g (yield 58% of theory) of the amino compound are obtained as an oil.

¹ H-NMR CDClA) 6 ppm 7.28-7.63 (4H, m, aryl-H); 6.38 (IH, S, thiophene-H); 4.95 (2H, S, 7-ring CHa); 2.55-3.10 (6H, mNCHa, thiophene-CHa, NHa); 2.72 (3H, S, triazole-CHa); 1.07-1.90 (1OH, m, N-CHa- (CHa) * -).

Example 10:

2- (7-Acetylaminoheptyl) -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-fJ [l, 2,4] triazolo [4,3-a] [1,4Jdiazepin

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

¹ H NMR (CDClI) δ ppm 7.30 - 7.58 (4H, m, aryl-H); 6.37 (IH, 8, thiophene-H); 5.67 (IH, s, broad, NH); 4.94 (2H, 8, 7-ring CHa); 3.24 (2H, m, N-CHa); 2.76 (2H, t, J = »6Hz, thiophene CHa); 2.72 (3H, 8, triazole CHs); 1.98 (3H, 8, CHjC-O); 1.21-1.83 (1OH, m, N-CHa (CHa) 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] [1.4Jdiazepin

2.7 g (0.006 mol) of the compound of Example 6 and 2.6 g (0.030 mol) of morpholine are heated in 50 ml üioxan for 6 hours to reflux, then the solvent was removed and the residue taken up in methylene chloride / water. The organic phase is shaken thoroughly with water, dried and the solvent removed. The residue is chromatographed on silica gel with methylene chloride / methanol (9: 1) as the eluent. This gives 1.3 g of the morpholine compound (yield 50 * of theory), mp. 162-164 ° C.

By dissolving the substance in methanolic hydrochloric acid and precipitating with ether to give the hydrochloride of the title compound of mp. 95 ° C (decomposition).

Example 12

2- (6-Forraylhexyl) -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1,2,4] triazole [4,3-a] [1,4] diazepin

2.1 g (0.005 mmol) of 2- (7-hydroxyheptyl) -4- (2-chlorophenyl) -9-ethyl-6H-thieno are added dropwise to 1.5 g (0.0075 mmol) of pyridinechlorochromate in 20 ml of methylene chloride. 3,2-f] [1,2,4] triazolo [4,3-a] [l, 4] diazepine (prepared, for example, from the compound of Example 4 by alkaline saponification) dissolved in 5 ml of methylene chloride, stirring still 90 Minutes at room temperature and the solution is mixed with 50 ml of ether. The precipitated black, resinous oil is repeatedly stirred thoroughly with ether, the ether solutions are combined, filtered off with suction through kieselguhr, the filtrate is concentrated and the residue is chromatographed on silica gel with methylene chloride / methanol (9: 1) as the eluent. This gives 0.6 g (yield 29% of theory) of the aldehyde as a colorless oil.

¹ H-NMR (CDCl3) 6 ppm 9.77 (1H, t, J = <2 Hz, CHO); 7.25 - 7.59 (4H, m, aryl-H); 6.38 (1H, s, thiophene-H); 4.94 (2H, S, 7-ring CHa); 2.76 (2H, t, J * 6Hz, thiophene CHa); 2.71 (3H, s, triazole-CHa); 2.41 (2H, m, O); 1.17-1.90 (8H, O = CCHa (CHa) 4-)

60 26S4Q5

Example 13:

2- (3-acetoxypropyl) -4- (2-chlorophenyl) -9-Brora-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [l, 4] diazepin

4 g (0.010 mmol) 2- (3-acetoxypropyl) -4- (2-chlorophenyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [I, 4] diazepine in 60 ml of water-free chloroform, 1.9 g (0.012 mol) of bromine and 1.2 g (0.015 mol) of pyridine are stirred for 20 hours at room temperature. The reaction mixture is then shaken thoroughly with water, the organic phase is dried, concentrated and the residue is purified by chromatography on silica gel with methylene chloride / methanol (9: 1) as a Bluens. This gives 2.3 g (yield 48% of theory) of the 9-Brora compound as an oil.

¹ H-NMR (CDCIs) δ ppm 7.30-7.62 (4H, m, aryl-H); 6.43 (IH, s, thiophene-H); 4.90 (2H, s, 7-ring CHa); 4.11 (2H, t, J-7 HZ, -O-CHa); 2.89 (2H, t, J * 7Hz, thiophene CHa); 2.03 (3H, S, CHaC = O); 2.00 (2H, m, OCHaCHa).

Example 14

2- (3-hydroxypropyl) -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-f] imidazo [I, 2-a] [l, 4] diazepin

To 15 g (0.038 mol) of 2- (3-acetoxy-propyl) -4- (2-chloropentyl) -6H-7,8-dihydrothieno [3,2-f] [1,4] diazepine-7-thione in 200 ml Anhydrous dioxane is added dropwise at room temperature 6.3 g (0.114 mol) of propargylarain, stirred for 20 hours and the solvent is removed. The residue is taken up in methylene chloride / water, the organic phase is washed thoroughly with water, dried and concentrated. The resulting crude product is triturated with Ieopropylether, whereby it crystallizes. This gives 13.5 g of 2- (3-acetoxypropyl) -4- (2-chlorophenyl-6H-7-propargylamino-thieno [3,2-f] [l, 4] -diazepine (yield 86% of theory). ) of the melting point 122-124 ° C.

11 g (0.027 mol) of the intermediate compound thus obtained and 55 ml of concentrated sulfuric acid are heated for 10 minutes in a preheated oil bath at 100 ⁰ C, poured onto ice and adjusted to pH 10 with concentrated ammonia. Extraction with methylene chloride gives 1.2 g of the residue, which is taken up in 100 ml of methanol and stirred with 0.2 g of potassium hydroxide at 60 ⁰ C for one hour. After stripping off the methanol, the residue is taken up in methylene chloride / water, the organic phase is washed thoroughly with water, dried, the solvent is removed and the residue is chromatographed on silica gel with methylene chloride / methanol (9: 1) as eluent, thus obtaining 0 , 7 g of imidazo compound (Auebe 7% of theory), mp 131-134 ° C.

¹ H-NMR (CDCl 3) O ppm 7.22-7.58 (4H, m, aryl-H); 6.89 (IH, q, J <1 Hz, imidazole-H); 6.38 (1H, 1, thiophene-H); 4.77 (2H, s, 7-ring CH. '); 3.68 (2H, t, J = 7Hz, OCH2); 2.86 (2H, t, J = 8Hz, thiophene CHa); 2.42 (3H, d, J = <1Hz, imidazole, CH3); 1.88 (2H, m -OCHa-CHa); 2.00 (IH, s, wide, OH).

Example 14a

2- (2-Methoxycarbonylethyl) -7-ethoxycarbonyl-6- (2-chlorophenyl) -6H-tienyl [3, 2-f] iuidazo [l, 5-a] [l, 4] diazepine

9.0 (0.025 mol) of 7- (2-methoxycarbonylethyl) -5-chlorophenyl) -1,2-dihydro-3H-thieno [2,3-e] [1,4-dia2epin-2-one (WD Bechtel and KHWeber, J.Pharmac., 74, 1265 (1985), 152-154 ° C., are suspended in 25 ml of dimethylformamide, and 3.5 g of potassium tert-butylate are added under nitrogen, the mixture is stirred for 10-15 minutes and cooled -30 ° and added within 10-15 min 4.7 g Diethylchlorphosphat.

For this solution add the 3.3g Kaiiura-tert.

ο Butylate and 3.3g Isocyanessigsäureeechylestec at -40 in 22 ml of dimethylformamide prepared mixture and the temperature is kept for 2 hours at -10 C and then allowed to warm the reaction mixture to room temperature. With cooling, 2.5 ml of glacial acetic acid and then 350 ml of water are added and then the reaction mixture extracted with Es & igester. After washing, drying and evaporating the Essigesterphasen the residue is chromatographed on SiO. ₇ From the eluate, 4.0 g of crystals of mp: 139-140 ° C. are obtained after ether addition.

C 57.7, H 4.40, N 9.18 C 7.74 S 7.00 58.0 4.44 9.04 7.55 6.87

Example 14b

2- [2- (morpholin-4-y1-carbonyl) -ethyl] -4- (2-chlorophenyl) -6H-thieno [3,2-f] imidazo [1,5-a] [l, 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 precipitated after addition of 50 ml of water crystals of dicarboxylic acid melt at 275 ° C with decomposition

 Y. 3.0g.

63 2 * 5405

This compound was nourished with 100 ml of 1,2,4-trichlorobenzene under nitrogen for 1 hour. It is filtered and the filtrate is treated with petroleum ether, wherein the 2- (2-carboxyethyl) compound precipitates. From this carboxylic acid is obtained analogously to Example 3, the morpholide, mp. 158 ° C.

₉ H ClN OS (440.9) 22 21 4 2

C 59.12 H 4.80 N 12.71 S 7.27

60.12 4.91 12.54 7.06

Example 14c

2- (2-diethylaminocarbonyl) -6- (2-chloro-1-yl) -9-methyl-6H-thieno [:. -f] imidazo [l, 2-a] [l, 4] diazepin

Starting from 7- (2-methoxycarbonylethyl) -5- (2-chlorophenyl) -l, 2-dihydro-3H-thieno [2,3-e] [l, 4] -diazepine-2-thione (WD Bechtel and KH Weber, J. Pharm. Be 74., 1265 (1985) of mp 190 C is analogous to the synthesis route described in Example 14, the corresponding diethylamide, mp. 2O1-2O3 ° C.

Example 14d

2- [2- (morpholin-4-yl-carbonyl) -ethylJ-6- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] imidazo [l, 5-a] [l, 4] diazepin

From the carboxylic acid described above, the title compound is obtained using morpholine instead of diethylamine. Mp: 248-250 ⁰ C.

Example 14e

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

a) 48.8 g (0.2 mol) of 2-Acetylaraino-3- (2-chloro-tozo) -thiophene are heated with 500 ml of acetic anhydride and 6 ml of 85% phosphoric acid for 1 1/2 hours under reflux. It is steamed i. Vak. a, the residue is mixed with 200 ml of water and neutralized with 40% sodium hydroxide solution. The crystals are filtered off with suction and washed with water, mathanol and ether.

Yield: 49-51 g, mp. 228-230 ° C

Under nitrogen, 50.3 g of this compound are dissolved in a solution of 10 g of KOH in 300 ml of methanol and stirred for 1 to 2 hours at room temperature. It is neutralized with 2N hydrochloric acid and the amino derivative is extracted with methylene chloride. After chromatography of the residue, 43 g of 5-acetyl-2-amino-3- (2-chlorobenzoyl) thioihene of mp: 190-191 ⁰ C.

b) 5.5 g (0.02 mol) of this compound are added to protect the acetyl group in 50 ml of chloroform and stirred after addition of 2 ml of 1,3-propanedithiol at room temperature with the introduction of dry HCl gas for 5 min. 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 off and the residue is chromatographed on 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 compound (212 ° C mp.) May in an analogous way as before (3 ZBBeispiel described) for diazepinone (Fp.260 ⁰ C), Diazepinthion (mp. 2I8 ^e C) and the Triazolodiazepin are reacted

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. After the chromatography over SiO

(Methylene chloride / ethanol 98: 2) to give 3.5-4 g, 2-acetyl-4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 2,4 ] triazolo [4,3-a3 [l # 4] diazepine.

3.6 g (0.01 mol) of this compound are suspended in 5 ml of benzene and added dropwise after addition of 2.25 g Pho8phoroe88igsäure-triethylGster to riner solution of 0-23 g of sodium in 5 ml of ethanol. Allow to sinter for 20 hours at 40 ⁰ C and working. The resulting ester is saponified with ethanolic potassium hydroxide. After acidification and workup, 1.4-1.6 g of crystals, mp. 296-298 ° C.

This carboxylic acid can be converted analogously to previously described examples in the morpholide, mp. 194-196 ° C.

Example 14f

2- [2- (morpholin-4-yl-carbonyl) -pent-4-en-1-yl] -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1 , 2,4] triazolo [4,3-a] - [l, 4] diazepin

20 g (0.05 mol) of 2-amino-3- (2-chlorobenzoyl) -5- (2, -dicarboethoxyethyl) -dithiophene (WDBechtel and κ.H.Weber, J.Pharraac, p.74 , 1265 (1985)). are suspended in 100 ml of tetrahydrofuran.This suspension is added dropwise to 2.5 g Natriurahydrid suspended in tetrahydrofuran (100 ml) and stirred for 1 hour at 30 ⁰ C. After addition of 4.5 ml of allyl bromide (0.05 mol) is stirred for 2 hours at room temperature The reaction mixture is concentrated by evaporation, the residue is taken up in methylene chloride and washed with water, and the organic phase gives 13 g of crystals of melting point 151-152 ° C. 13 g (0.03 mol) of this dicarboxylic acid ester are mixed with 30 ml of ethanol, 6 ml of water saponified with 3.8 g of caustic potash, giving 11.3 g of dicarboxylic acid to (120-130 ° C) is decarboxylated by heating for one hour in 20 ml of DMF and b -. 7 g Mon ^-. carboxylic acid, mp 202 - 203 ° C result.

The methyl ester available therefrom is an oil. This is, as described above, bromoacetylated, aminated and cyclisieit to Diazepinon.

Mp 162-165 ° C.

The Diazepinthion accessible from the diazepinone with Phorphorpentasulfid melts at 179 ° C and gives the Triazolo-thieno-diazepincaiboneäure, mp. 207 - 208 ⁰ C. Hietraue obtained morpholide on the Imidaznlid according to the method previously described as a tough oil.

Example 14q

2- [2-Benzyl-2- (morpholine-4-yl-cyano-1-ethyl] -4- (2-chloro-phenyl) -9-methyl-6H-thieno [3,2-f] l, 2,4] triazoloi4,3-a] - [1,4] diazepin

Starting from 2-amino-3- (2-chlorobenzoyl) -5- (2,2-dicarbethoxyethyl) thiophene obtained analogously to Example 14 f by reaction with benzyl chloride, the title compound via the following steps.

Diazepinone mp. 158-161 ° C Diazepinthion mp. 170-172 ⁰ C Triazolothienodiazepincarbonsäuce mp. 158-162 ° C

Example 14h

2- [2- (N, N-Diethylaroinocarbonyl) -n-propyl] -4- (2-chlorophenyl) -9-raethyl-6H-thieno [3,2-f] [1,2,4] triazolo [4 , 3-a] [1,4] diazopin

2-Amino-3- (2-chlorobenzoyl) -5- (2,2-dicarboethoxyethyl) thiophene with methyl iodide affords the corresponding C-methyl prebound and further the title compound as described above via the following steps:

Dicarboxylic acid diethyl ester mp 181-182 ° C monocarboxylic acid mp 161-162 ° C diazepinonecarboxylic acid methyl ester mp 179-180 ⁰ C triazolothieno-diazepinecarboxylic acid methyl ester as oil title compound (dieuhylamide) mp 1O2-1O3 ° 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] - [1,4Jdiazepin

In analogy to Example 14h, the title compound is obtained using morpholine instead of diethylamine, oil.

Example 14i

2- (2- (N, N-Diethylaminocarbonylethyl) -4- (2-chlorophenyl) -9-raethyl-4,5-dihydro-6H-thieno [3,2-f] [1,2,4] triazolo [ 4,3-a] - [l, 4] diazepin

2.5 g (0.006 mol) of diethylamide (prepared from the carboxylic acid, WD Bechtel and KH Weber, J. Pharra, pages 74., 1265 (1965) with diethylamine and dicyclohexylcarbodiiride) 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. It is then filtered through diatomaceous earth, washed with methylene chloride and the filtrate makes alkaline with ammonia. The methylene chloride phase is separated off, washed with water, dried, evaporated and the residue is chromatographed on SiO 2. 0.8 g of oil is obtained as the main fraction.

2 * 5405

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] [l, 4] diazepin

3 g (7.7 mmol) of 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [l, 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-propanol, 2.35 g (23 mmol) triethylamine and 4 , 8 g of carbon tetrachloride are stirred in 15 ml of pyridine / acetonitrile (1: 1) at room temperature. To this mixture is added dropwise within 2 hours a solution of 6.2 g (23.6 mmol) Triphenylphoephin 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 on silica gel with dichloromethane / methanol (95: 5) chromatog ^p aphiert. The clean fractions are concentrated and, by recrystallization from ether, 1.9 g (56%) of the title compound of mp. 168 ° C. are obtained.

^C 22 ^H 2I C > 60 (439 97 ) 04 N 15 , 92 Cl 8th , 06 S 7, 29 About: 59, 05 H 5, 08 15 , 64 8th , 11 7, 17 Found .: 53 5,

Example 14 1

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] diazepin

1.2 g (0.0027 mol) of 2- [3- (N-morpholinyl) -n-propyl] -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1 »2 , 4] Triazolo [4,3-aj [l, 4] diazepine in 20 ml of anhydrous THF are added dropwise at room temperature in a given suspension of 0.1 g (0.0027 mol) Lithiumaluraiiiiumhydrid in 20 ml of anhydrous THF and for 1 hour at reflux heated. The reaction mixture is decomposed with 0.1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water, stirred for 30 minutes and the resulting precipitate is filtered off with suction. The filtrate is concentrated, taken up in methylene chloride, washed, dried and the solvent evaporated. The residue is chromatographed as silica gel with methylene chloride / methanol 95: 5 as the eluent. This gives 0.16 g (yield 13 %) of the desired compound, mp. 135-138 ° C.

Example 14m

2 - [(2-phenyl-l, 3-dioxolan-4-yl) -raethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [l, 4] diazepin

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 °. Subsequently, 104.9 g (0.4 mol)

Triphenylphosphine in 70 ml of anhydrous methylene chloride

added dropwise and the reaction mixture slowly brought to room temperature over 3 hours. After 12 hours, the solvent is deducted and the residue

26 5 4 OS

thoroughly digested with ether and the precipitated Triphenylphosphinoxid filtered off with suction. Unreacted triphenylphosphine radicals are precipitated with methyl iodide as the phosphonium salt in ether and filtered off with suction. From the filtrate, the solvent is removed and the residue is fractionated in vacuo. This gives 32 g (55% yield) of 4-forrayloxy-5-hydroxypentanal Kp = 82-92 ° C.

U f JL

23 g (0.157 mol) of the aldehyde, 28 g (0.137 mol) of o-chlorocyanoacetophenone, 5 g (0.157 mol) of sulfur and 16 g (0.157 mmol) of triethylamine are used in 100 ml of DMF in the usual way for ThiophenringschluB and the resulting

2-amino-3- (2-chlorobenzoyl) -5- (2-forrayloxy-3-hydroxy-propyl) -thiophene as a crude product with 15 g (0.16 mol) of potassium hydroxide in 500 ml of methanol for 2 hours to reflux. After removal of the solvent, the residue is taken up in ethyl acetate, washed with water, dried and chromatographed after removal of the solvent on silica gel with ethyl acetate as the eluent. This gives 19.9 g (overall yield 39%) of 2-amino-3- (2-chlorobenzoyl) -5- (2,3-dihydroxy-n-propyl) -thiophene, mp. 136-137 ° C.

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

The resulting 2-amino-3- (2-chlorobenzoyl) -5 - [(2-phenyl-1,3-dioxolan-4-yl) -raethyl] -thiophane is converted to the title compound as described in the preceding examples.

Example 14 η

2- (2-Ethoxycarbonylethy1) -3,9-diraethy1-4- (2-chlorophenyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [l, 4] diazepine.

Starting from 5- (2-chlorophenyl) -6-ethyl-7- (2-ethoxycarbony1-ethyl) -1,2-dihydro-3H-thieno [2,3-e] [1,4] diazepine-2 on is obtained in analogy to the method described in Example 3, the title compound.

The starting compound is prepared 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 ⁰ C by Gewald implemented. The residue obtained upon concentration of the reaction solution is chromatographed on a silica gel column with chloroform as the eluent. The aminoketone thus obtained is converted into the title compound analogously to Example 3 ». The diazepinone has a melting point of 173-176 ° C (toluene / ether).

(390.9)

Calc .: C 58.38 H 4.90 Cl 9.07 N 7.17 S 8.20 GOf: 58.08 4.83 8.94 7.11 8.11

2654 OS

For example, 14 ο

2- [2- (moc-4-yl-carbonyl) -2- (ethoxycarbonyl) ethyl] -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [l, 4] diazepin

1 g (0.0021 mmol) of 2- [2,2-di (ethoxycarbonyl) ethyl] -4- (2-chlorophenyl) -9-ethyl-6H-thieno [3,2-f] [1,2, 4] triazolo [4,3-a] [1,4] diazepine and 5 g of morpholine are stirred at 120 ⁰ C for 10 hours. It is diluted with 100 ml of water, extracted several times with methylene chloride, the organic phase is washed with water, dried and concentrated. The residue thus obtained is chromatographed on a silica gel column (methylene chloride / methanol 97: 3). After usual work-up, the title compound is obtained as an amorphous powder.

The tables sometimes use the following abbreviations:

Et = ethyl Me = methyl iPr a iso-propyl t-Bu a tert-butyl Ac = acetyl

74

Analogously to the processes described in the examples, the following intermediates are prepared:

Table 1 No. η

RrlCH ₂ ) _n -dj

CL

-SOa-N 0 oil

-OH

96-98 ° C

or '

-0-C-CH ₃

Il 0

-OH

oil

146-148 ⁰ C

5a 3

5b 3

5c I

5e 0

CMe

-O-C-CH ₃ Il 0

-OH

-OCOCH ₃

-CHOHCHaOH

-α-

oil

oil

oil

136-137 ° C

oil

228-230 ⁰ C

CH ₃

75

26S4 05

Table 2 No. η

NHCOCH ₂ Br

Mp.

-SOa-N \) oil

-0-C-CH ₃ Oil

Il 0

CC -0-C-CHa

ii

oil

-0-C CHa

II 0 oil

9a 0

 -C

CH-

9b 1

-CH (COOCaH ₅ L 83-85 ⁰ C

9c 1

-CH

oil

oil

76

R ₂ - [ CH ₂ ) _n

Tabel le 3 Ra .. * Mp. No. η -SOa-N, 0 90-92 ⁰ C 10 2 Ο "" -0-C-CHa II oil 11 3 Il 0 -0-C-CHa II 0 oil 12 3 -0-C-CHa II 0 oil 13 7

13a 0

13b 1

CH (COOCaHs) ^ oil

RfJ- (CH ₂ I _n -

Table 4 No. η Pp.

14 2

15 3

16 3

17 7

CL

17a O

SOA-N \ > 200 ° C 0-C-CHi II 122-124 ⁰ C Il 0 0-C-CHs M 153-155 ⁰ C Il 0 0-C-CH3 Il 0 oil 242-244-C

17b 1

CH (COOCsH ₅ ) 144-145 ⁰ C

i7c

200 ⁰ C

17d 1

-CH - CH

oil

OH OH

Table No. η

18 2

19 3

20 3

21 7

21a 0

21b 1

Ba

Cvt ^ o

Mp.

-SOa- / \> 215-218 ⁰ C

-O-C-CHa II 170-172 ⁰ C -O-C-CHa II 184-185 ⁰ C -O-C-CHa II 132-135 ⁰ C oo 223-225 ⁰ C -CH (COOCaHsL 158-160 ⁰ C

CH-

2654 OS

By analogy with the examples described above, for example, the compounds of general formula I can be prepared:

2- (CH ₂ I _n

Table 6

No. Ri R ₃

X η mp. ° C

15 CHs OH 16 CHa -Cl

| Γ Ν 7 oil

N 3 142-144

17 CH ₃ -qi

N 7 8 '.- 87

18 CH ₃ J

N 7

19 CH ₃ -NHa

N ') oil

No. Ri R:

Ra Xn Fp. ⁰ C

20 CHa -SO ₂ -N,, 0 N 2 126-128

21 CHa -O-SOa-l-Pr N 3

22 CHa -O-SOa-fVcHa N 3 oil

23 CHa -O-SOa-CH a N 7 oil

24 CHa -O-SOa-fV-CHi N 7 oil

25 CHa -O-CO-t-Bu N 3 163-165

26 CHa -O-CO-1-γγ N 7 oil

27 CHa -O-CO-t-Bu-N 7 oil

28 CHa -O-CO-NHCHa N 7 oil

29 CHa

N 7 70-74 (HCl)

30 CHa -N

N 1 286-287

31 CHa -N

N 3 oil

81

No. Ri Ra

Ra Xn Fp. ⁰ C

32 CHa

33 CHa

34 CHa

 v

35 CHa -NH-CO-CHa 36 CHa -NH-CO-CHa 37 CHa -NH-CO-i-Pr 38 CHa -NH-CO-

or "

39 CHa -NH-CO-CHa ι -NH-CO-i-Pc I N (CHa) a 40 CHa -NH-SOa-ZO) -NH CO I CH 41 CHa

42 CHa -NH-CO-Zo)

43 CHa -NH-CO-CHa

IN (CHa) ₂ N 3 oil

N 7 oil

N 7 oil

N 1 decomp.

N 3 oil

N 3 75-85

N 3 105-115

N 3 oil

N 3 148-155

N 7 oil

N 7 105 / Zers.

N 7 oil

No. B ₁ Ha

Ra Xn Fp. ⁰ C

44 CHs -NH-SOA (O) Il -NH I / -N I co ι I 2Ha 45 CHa -O ^ - 46 CHa / -N ν ^ CH ₃ N 0 s 47 CHa CH ₃ 48 CHa Λ N-CHs

N 7 135 / Z.

N 3 oil

N 3 86-90

N 7 oil

N 3 oil

49 CHa -NN-CHa

N 7 oil

50 H-O-CO-CHs

N 3 97-98

51 CHa -O-CO-CHj

N 3 143-145

52 CH ₃ -OH

160 Ν 3 160-163

53 CHs -0-SOa-CIia

N 3 76-79

54 CHa -NO

Ii N 3 oil

55 OCHa -O-CO-CHa

56 CHa -O-CO-CHj

CH 3 oil

2654 OS

No. Ri

* Ra

57 CHa -OH

Ra Xn Fp. ⁰ C

ct

CH 7

58 CHa -O-CO-CHa CH 7 oil

59 CHa -N (CHaJa N 7 92-95 ⁰ C (HCl)

60 CHa

NH (CHa) aN (CH 3) aN 7 55-6O ⁰ C (HCl)

61 CHa -NN 7 80-83 ⁰ C (HCl)

62 CHa -N N 7 85-87 ° C (HCl)

63 CHa

64 CHa

N 3 56- * 0 ° C

N 3 61-65 ⁰ C

65 CHa -N (CHa) ₂ N 3 oil

66 CHa-NH (CHa) ₂

N (CHa) ₂ N 3 60-65 ⁰ C

84

No. Ri Ra

Rs Xn Fp. ⁰ C

.α

67 CHa -NH-SOa- / \ -tiH2 Γ | j N 3

68 CHj -NH-SOa -f \> - NHa U N 7

69 CH

N 7 oil

70 OCHa -OH N 3

71 CHA N (CaHs) ₃ N 3 oil

72 CHi 73 CHa

N 3 oil

N 7 oil

74 CH

' -ON 7 oil

75 CHa -NH (CH ^ a

-O N 3

76 CHs -NHCHa-

N 7 70-73

77 CHa -NH (CHaYa <f

ι H N 7 amorphous

78 CHs

N o 174-176

2 * 5405

No. Ri

Ra

X η mp ⁰ C

COsC ₂ Hs

79 CHa-CH

COsCsHs

N 1 112-114

CH

80 CHa-CH

0-f-H CHs N 1

81 CHA

CHs / N.

-CH

\ O A-CHa

CHa N 1

C3I

82 CHa -CH - CHs

I i

OH OH

N 1

(Jl

83 CHa -CH - CHs I I

OAc OAc N 1

86

No. R ₁

X η mp ^e C

83a CHa CeHs-CHa-CH-

N 1 134-138 «

O N-CHa

83b CHa CeHs-CHa-CH-N 1 oil

CHa-sOA-O-CHa

83c CHa CeHs-CHa-CH-N 1 148-150 «

HO-CHa

83d CH - ° ^C A

N 3 oil

83e CH-OCH

N 3 oil

83f CH -NH- (CH)

l H

83g CH-Oe

MTO

N 3 oil

OM t

N 3 oil

OM t

No. R:

Ra

ka

X η mp ⁰ C

CH ₃

CH ₉ SOaO

\ -CH - CHa

t OSOaCH ₃

N 1

CH ₃

- CH Ν

CHa N 1

Bö CH ₃ -CH

CH. N

: η _ί

CH ₃ - CH CHa

I /

NEt a SEt:

N 1 N 1

CH ₃

CH CHa

Me IPr Me IPr

N 1

CH ₃ -CH

I H

-θ ο »

CHa

N 1

No. R ₁ Ra

X η mp ⁰ C

CHa-CH-CHa

I / NHaNHs

U 1

91 CHj -CH - J - CHa j NHAc NHAc 92 CHa -CH - CHA j OAc O 93 CH ₃ -CH - j Oil CHa 6 94 CHu -CH - 6 CHa OAc 95 CHa -CH - I CHA I O OH 96 CHa -CH - I OAc CHi J NEt ₂ 97 CHa -CH - I CHA j I NEt ₂

N 1 N 1 N 1 N 1 N 1 N 1 N 1

89

Tabo'.la 8

Compounds of the formula Ib

No. Bi Ba

Zn

B ₃

B ⁰ R ¹ X Ϊ Mp

98 CHa -OH

- (CHa) s

Cl

H H N N oil

99 CHa -OAc

- (CHa) a-

H H N N oil

10Ü CHa -OAc

- (CHa) S-

-AC H N N oil

The following are examples of some pharmaceutical compositions using compounds of general formula I as the active ingredient. Unless otherwise stated, the parts are parts by weight.

1. tablets

The tablet contains the following ingredients: Active ingredient according to formula Ia / b 0.020 part stearic acid 0.010 "Dextrose 1.890

total 1,920 parts

production:

The materials are mixed together in a known manner and the mixture is made into tablets, each of which weighs 1.92 g and contains 20 mg of active ingredient.

2nd ointment

The ointment is composed of the following components:

Active ingredient according to formula Ia / b 50 mg Neribas ointment (commodity Scherax) ad 10 g production:

The active ingredient is triturated with 0.5 g ointment base and the remaining base in portions to 1.0 g gradually mixed intimately into an ointment. This gives a 0.5% ointment. The distribution of the active ingredient in the base is optically controlled under the.

3rd cream

Composition: Active ingredient according to formula Ia / b 50 mg Neribas ointment (commodity Scherax) ad 10 g Her Se ttings

The active ingredient is shaved with 0.5 g of cream base and the rest of the base in increments of 1.0 g gradually incorporated with pestle. This gives a 0.5% cream. The distribution of the active ingredient in the base is optically controlled under the microscope.

4. Ampoule solution

Composition: Active substance according to formula Ia / b 1.0 mg Sodium chloride 45.0 mg Aqua p'.o in j. ad 5.0 ml production:

The active ingredient is dissolved in Gigen-pH, optionally at pH 5-7 in water-jr, and sodium chloride is added as iGotonanz. The resulting solution is filtered pyrogen-free and is aseptischet FJltrat under. Conditions filled in ampoules, which were then sterilized and sealed. ¹ ampoule contains 1 mg, 5 mg and 1 mg active substance.

5. Suppositories

Each suppository contains: Wicking agent according to formula Ia / b 1.0 parts Cocoa butter (mp. 36-37 ° C> 1200.0 parts Carnauba Wax 5.0 parts manufacturing

Cocoa butter and carnauba wax are melted together. At 45 ° C, the active ingredient is added and stirred until a complete dispersion formed i;

The mixture is poured into shapes of appropriate size and the suppositories packed appropriately.

6. Inhalation solutions Composition:

a) Active substance according to formula Ia / b 500 mg Na-EDTA 50 mg benzoic arachloride 25 mg sodium chloride 880 mg distilled water ad 100 ml

manufacture;

96% of the amount of water are submitted, in succession, Na-EDTA, Benzalkoniumchlrr d, sodium chloride and active ingredient clearly dissolved u.:d filled up with the remaining water. The solution is filled into 20 ml dropping bottles. One dose (20 drops, 1 ml) contains 5 mg of active substance.

b) Active substance according to formula Ia / b 500 mg sodium chloride 820 mg distilled water ad IGO ml

Manufacture

96% of the amount of hydrogen are introduced, dissolved in succession, the active ingredient and sodium chloride, then filled up with the remaining water and the solution in single-dose container (4 ml) filled. The solution contains 20 mg of active ingredient.

26S4 05

93

Table 9 lists the NMR spectra of selected compounds of general formula Ia / Ib.

Table 9 Example 15

¹ H-NMR (CDCl ₃₎ δ ppm 7.23 to 7.62 (4H, aryl-H m,); 6.36 (IH, s, thiophene-H); 4.92 (2H, s, CHa - / - ring); 3.62 (2H, t, J6HZ, OCHa); 2.77 (2H, t ,, J = 6Hz, CH2-thiophene); 2.72 (3H, s, triazole CHa), 2.07 (IH, 8, broad, OH); 1.17-1.89 (1OH, ra, OCHa (CHa) S-).

Example 19

¹ H-NMR (CDCl 3) δ ppm 7.22-7.57 (4H, m, aryl-H); 6.44 (IH, s, thiophene-H); 4.95 (2H, s, 7-ring CHa); 2.85 (2H, t, J a 6 tiz, thiophene CHa); 2.80 (2H, t, J = 6Hz, NCHa); 2.71 (3H, S, triazole-CHa); 2.44 (2H, S, broad, NHa); 1.84 (2H, m, NCHa-CHa).

Example 22

¹ H-NMR (CDCl ₃₎ δ ppm 7.22 to 7.87 (8H, aryl-H m,); 6.40 (IH, s, thiophen-H); 4.92 (2H, S, 7-ring CHa); 4.06 (2H, t, J = f ΗΔ, OCHa); 2.87 (2H, t, J = 6Hz, thiophene CHa); 2.67 (3H, s, triazole-CH ₃ ); 2.44 (311, s, aryl-CHs); 2.01 (2H, m, -OCHaCHa).

Beiupiel 23

¹ H-NMR (CDCl ₃₎ δ ppm 7.23 to 7.58 (4H, aryl-H m,); 6.37 (LH.s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 4.21 (2H, t, J7HZ, OCHa); 2.99 (3H, S, _CH3 SOa); 2.75 (2H, t, ti = 7Hz, thiophene CHa); 2.70 3H, s, triazole-CH ₃ ); 1.14-1.98 (1 OH, m, OCHa (CHa) s).

94

Example 24

¹ H-NMR (CDcIa) S ppm 7.22-7.84 (8H, m, aryl-H); 6.36, 1H, s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 4.01 (2H, '., J »6KZ, OCHa) 2.81 (2H, m, thiophene CHa); 2.71 (3H, s, triazole-CHa); 2.49 (3H, s, aryl-CHa); 1.16-1.89 (1OH, ra, OCHa (CHa) e).

Example 26

¹ H-NHR (CDClA) δ ppm 7.30-7.59 (4H, m, aryl-H) J 6.37 (IH, s, thiophene-H); 4.9.5 (2H, s, 7-ring CHa); 4.06 (2H, t, J - 6Hz, OCHa); 2.77 (2H, t, J = 6Hz, thiophene CHa); 2.72 (3H, s, Tcazol-CHa); 2.53 (IH, in, CH-C = O); 1.26-1.89 (1 OH, m, OCHa (CHa) s -); 1.28 (6H, d, J = 5HZ, (CHa) a-CH-).

Example 27

¹ H-NMR (CDClia) δ ppm 7.31-7.58 (41.m, aryl-H); 6.37 (IH, s, thiophene-H); 4.94 (2H, s, 7-ring CHa); 4.04 (2H, t J = i 6 Hz, OCHa); 2,7i (3H, S, Tcazol-CHa); 2.77 (2H, t, J = 7Hz, thiophene CHa); 1.23-1.93 (1 OH, m, OCHa (CHa) ₅ -); 1.20 (9H, S, C (CHa) a).

Example 28

¹ H-NMR (CDClia) 6 ppm 7.31-7.59 (4H, m, aryl-H); 6.37 (IH, s, thiophene-H); 4.94 (2H, s, 7-ring CHa); 4.69 (IH, S, broad, NH); 4.04 (2H, t, J = .7 Hz, OCHa); 2.78 (3H, i.e. J = 6HZ, CHaN); 2.76 (2H, t, J = 7Hz, thiophene CHa); 2.71 (3H, s, triazole-CH?); 1.20-1.85 (1 OH, m, OCHa (CHa) e-).

2454 05

Example 31

¹ H-NMR (CDCl ₃₎ δ ppm 7.30 to 7.61 (4H, aryl-H m,); 6.44 (IH, s, thiophen-H); 4.94 (2H, a, 7-ring CHa); 3.59 (2H, t, J = 7Hz, N-CHa); 2.81 (2H, t, J => 7Hz, thiophene CHa); 2.71 (7H, s, succin-CHaCHa, tcazol-CHa); 1.93 (2H, m, N-CHaCHa).

Example 32

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

Example · 33

¹ H-NMR (CDClI) δ ppm 7.28-7.58 (4H, m, aryl-H); 6.35 (IH, s, broad, NH); 6.35 (IH, s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 3.92 (2H, s, imidazolidione-CHa); 3.46 (2H, t, J = 7 HZ, N-CHa); 2.75 (2H, t, J = 7Hz, thiophene CHa); 2.71 (3H, s, triazole CHs); 1.13-1.86 (1 OH, m, N-CHa- (CHa) S).

Example 34

¹ H-NMR (CDCl ₃₎ δ ppm 7.30 to 7.51 (4H, aryl-H m,); 6.44 (IH, s, thiophene-H); 4.98 (2H, s, 7-ring CHa); 3.51 (2H, t, J = 6Hz, N-CHa); 2.76 (2H, t, J = 6Hz, thiophene CHa); 2.74 (3H, s, TridZol CHa); 2.71 (4H, s, succin-CHa); 1.23-1.74 (1OH, m, N-tria (CIiOi).

96

2 ό 54

Example 35

¹ H-NMR (CDClia) δ ppm 7.21-7.52 (4Η, ro, aryl-H); 7.27 (IH, t, J = 16Hz, NH); 6.54 (IH, 8, thicphene-H); 4.84 (2H, s, 7-ring CHa); 4.47 (2H, d, J = 6Hz, N-CHa); 2.66 (3H, s, triazole-CHa); 2.00 (3H, s, CHa-C * O) \

Example 36

¹ H-NMR (CDClia) δ ppm 7.33-7.57 (4H, m, aryl-H); 6.54 (IH, t, J = »6 HZ, NH); 6,46 (IH, 8, thiophen-H); 4.96 (2H, 8, 7-ring qHa); 3.32 (2H, q, J = 6Hz, NH-CH?); 2.83 (2H, t, J a 6 HZ, thiophene-CHa); 2.71 (3H, 8, triazole-CF ..) · 1.98 (3H, 8, CHa-CO); 1.88 (2H, m, N-CH-CHa).

Example 39

¹ H-NMR (CDClia) δ ppm 7.03-7.62 (SH, m, Aeryl-H and NH); 6.40 (IH, s, thiophene-H); 4.93 (2H, s, 7-aing-CHa); 3.33 (2H, q, J = 6.5Hz, CHa-NH); 2.94 (2H, 8, CHaC = O); 2.82 (2H, m, CHa -thiophene); 2.70 (3H, 8, triazole CHa); 2.27 (6H, 8, N- (CHa) O; 1.89 (2H, m, N-CHa-CHa).

Example 41

¹ H-NMR (JDCIa) δ ppm 7.25-7.60 (4H, m, aryl-H); 6.37 (IH, a, thiophene-H); 5.64 (IH, s, broad, NH); 4.94 (2H, s, 7-ring CHa); 3.23 (2H, m, N-CHa); 2.76 (2H, t, J * 6Hh, Tl.iophene-CHa); 2.71 (3H, 8, triazole-CHa); 2.33 (IH, m, CH-C = O); 1.21-1.07 (1 OH, m, N-CHa- (CHa) ₅ ); 1.16 (6H, d, J = 9 Hz,

Example 43

¹ H-NMR _(CDCl3) 6 ppm 7.45-7.60 (4H, m, aryl-H); 7.17 (IH, s, broad, NH); 6.34 (IH, s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 3.27 (2H, q, J = 6.5 Hz, CHaNH); 2.94 (2H, S. CH ₂ C = O): 2.71 (3H, S, triazole CHs); 2.71 (2H, m, CHa-thiophene); 2.28 (6H, S, N (CHa) a); 1.21-1.88 (1OH, m, (CHa) ₅ ) -

Beispiol 45

¹ H-NWR (CDCiO δ ppm 7.24-7.58 (4H, m, aryl-H); 6.38 '(IH, 8, thiophene-H); 4.93 (2H, S, 7-ring 2.79 (2H, t, J = 8HZ, N-CHa); 2.6: 3 (3H, S, triazole-CHs); 1.24-2.49 (14H, m, Piperidine-CHa, thiophene-CHa-CHa).

Example 47

¹ H-NMR (CDClia) δ ppm 7.19-7.59 (4H, m, aryl-H); 6.36 (IH, s, thiophene-H); 4.93 (2H, s, 7-ring CHa); 3.68 (2H, ra. 2,6-morpholine-CH-); 2.71 (3H, s, triazole CHs); 1.16, 1.23 (6H, 2d, J = 6Hz, 2.6-morpholine-CHs); 1.01-2.91 (18H, m, morpholine-NCHa / N- (CHa) 7)

Example 48

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

98

Example 49

¹ H-NMR (CDClia) S ppm 7.24-7.59 (4H, m, aryl-H); 6.36 (IH, s, thiophene-H); 4.93 (2H, β, 7-ring CHa); 2.74 (2H, t, J => 7HZ), N-CHa); 2.71 (3H, 8, triazole-CHa); 2.44 (8H, s, piperazine-CHa); 2.28 (2H, t, J = 7Hz, thiophene CHa); 2.27 (3H, s, N-CHa); 1.08-1.88 (1 OH, m, N-CHa- (CHa) ₅ ).

Example 54

¹ H-NMR (CDClia) δ ppm 7.20-7.73 (5H, m, aryl-H); 6.64 (IH, s, thiophene-H); 4.87 (2H, β, 7-ring CHa); 3.71 (4H, m, morpholine-OCHa); 2.89 (2H, t, J - 7Hz, N-CHa); 2.69 (3H, 8, triazole-CHa); 2.21-2.57 (6H, m, mcrpholine-N-CHa / thiophene-CHa); 1.90 (2H, m, N-CHa-CHa).

Example 56

¹ H-NMR (CDCIs): & 7.21-7.62 (m, 4H, aryl-H); 6.92 (qu, J <1 Hz, CH =); 6.41 (s, IH, thiophene-H); 4.81 (3, 2H, CHa-7 ring); 4.12 (t, J - 7 Hz, 2H, OCHa); 2.86 (t, J7Hz, 2H, CHa-thiophene); 2.45 (d, J <1HZ, 3H, CHa-imidazole); 2.05 (β, 3Η, CHs-C = O); 2.00 (ΠΙ. 2Η, OCHaCHa).

Example 58

¹ H-NMR (CDClA); δ 7.21-7.60 (m, 4H, aryl-H);

6.91 (qu, J <1 Hz, IH, CH = O, 6.35 (s, 1H, thiophene-H);

'4.79 (S, 2H, CHa-7 ring); 4.06 (t, J * 7 Hz, 2Η,

OCHA); 2.76 (t J = 7 Hz, 2H, CHa-thiophene); 2.46

(d, J * <1Hz, 3H, CHs-imidazole); 2.05 (s, 3H,

CHSC = O); 1.15-1.91 (m, 1OH, OCHa (CHa) ₅ -).

99

Example 65

¹ H-NMR (CDClia): δ 7.21-7.64 (m, 4H, aryl-H); 6.43 (8, IH, thiophene-H); 4.97 (s, 2H, CHa-7 ring); 2.84 (t, J8HZ, 2H, CHa-thiophene); 2.30 (t, J - 8 Hz, 2H, N-CKa); 2.72 (s, 3H, CHa-triazole; 2.22 (8, 6H, N- (CHa) a), 1.81 (m, 2H, N-CHaCHa).

Example 69

¹ H NMR (CDClia) δ ppm 7.22-7.58 (4H, m, aryl H) 5.6.36 (IH, s, thiophene H); 4.93 (2H, s, 7-ring CHa); 2.74 (2H, t, J = 7HZ, N-CHa); 2.71 (3H, S, triazole-CHa); 2.09-2.51 (6H, m, piperidine-CHa, thiophene-CHa); 1.12-1.83 (16H, m, piper id in CHa / N-CHa- (CHa) s).

Example 71

¹ H-NMR (CDClia): δ 7.21-7.60 (m, 4H, aryl-H), 6.39 (S, IH, thiophene H); 4.93 (s, 2H, CHa-7 ring); 2.79 (t, J = 8 HZ, 2H, CHa-thiophene); 2.69 (s, 3H, CHa-triazole); 2.52 (qu, J = 7Hz, 4H, N- (CHaCHa); 2.54 (t, J = 7Hz, 2H, CHa -thiophene); 1.83 (m, 2H, N-CHaCHa); 0.98 (t, J = 8 Hz, 6H, N-CHaCHa).

Example 72

¹ H-NMR (CDClia): δ 7.22 - 7.63 (m, 6H, aryl-H, pyrazole H 3/5); 6.38 (s, IH, thiophene-H); 6.22 (t, J 2 Hz, IH, pyrazole H 4); 4.94 (8, 2H, CHa-7 ring); 4.17 (t, J = 6Hz, 2H, N-CHa); 2.78 (t, J = 6Hz, 2H, CHa -thiophene; 2.71 (s, 3H, CHa-triazole); 2.26 (m, 2H _t NCHaCHa).

^100V

Example 73

¹ H-NMR (CDClA); δ7.22-7.66 (m, 6Η, aryl-H, pycazole H 3/5); 6.39 (s, IH, thiophene-H); 6.25 (t, J = 2H '., IH, pyrazole-H4); 4.97 (s, 2H, CHa-7 ring); 4.15 (t, J u 7 Hz, 2K N-CH 2); 2.78 (t, J * 7Hz ¹ , 2H, CHa-thiophene); z, 72 (s, 3H, CHs Triazoles 1.08 - 2.05 (m, 1OK, N-CHa (CHa) - ).

Example 74

¹ H NMR (CDClI): δ 7.29-7.62 (m, 4H, aryl-H); 6.67 (t, J = * 2HZ, 2H, Pyccol-H 2/5); 6.39 (β, IH, thiopheny-H); 6.16 (t, J - 2 Hz, 2H, Pyro-H / 3/4); 4.98 (8, 2H, CHa-7 ring); 3.91 (t, J = 7Hz, 2H, N-CHa); 2.72 (t, J = 7HZ, 2H, CHa-thiophene); 2.72 (s, 3H, CHs-triazole); 1.07 - 2.06 (m, 10 H, N-CHa (CHaJs;

Example 77

¹ H-NMR (CDClI): δ 8.32 (s, IH, NH-indole); 7.00 7.76 (ra, 9H, aryl-H, indole-H); 6.35 (s, IH, thiophene-H); 4.93 (8, 2H, CHa-7 ring); 3.09 (8, 4H, CHaCHaN); 2.68 (s, 3H, CHa triazole); 2.45-2.94 (m, 4H, thiophene

CHaCHaN-), 1.07-1.92 (m, HH, N-CHa (CHa) -, NH). Example 83b

¹ H-NMR (CDCIs): δ 7.0?, - 7.62 (9H, ro, aryl-H); 6.46 ⁽¹ H, s, thiophene-H, (); 5.00, 4.87 (2H, AB system, JAB = 15 HZ CHa-ring);. 4.10 (2H, m, OCHA), 2.93 ( 3H, 8, CHaSOa); 2.70 (3H, 3, CHs triazole); 2.81 (4H, m, CHa aryl, CHa thiophene); 2.35 ⁽¹ H, ra, -CH-).

101

Example 83d

¹ H-NMR _(CDCl3): δ 6.67 to 7.60 (9Η, acyl-H m,); 6.42 (IH, 8, thiophene-H); 4.91 (2H, 3, CHa-7 ring); 3.98 (2H, t, J = 6Hz, OCHa); 2.98 (2H, t, J - = 6H2, CH-thiophane); 2.65 (3H, 8, CHA-Tcazeol); 2,11 (2H, m, ^ CHaCHa).

Example 83e

¹ H-NMR _(CDCl3): δ 7.27 - 7:58 (4H, acyl-H m,); 6.41 (IH, s, thiophene ~ H); 4.95 (2H, s, CHa-7 ring); 3.3 ^f j (2H, t, J => 6HZ, OCHa); 3.31 (3H, S, OCH ₃ ); 2.87 (2H, t, J = 6Hz, CHa-thiophene); 2.71 (3H, s, _CH3 -triazole); 1.90 (2H, in, OCHaCHa).

Example 83f

¹ H-NMR _(CDCl3): 6 8.31 (1 H, s, broad, NH); 6.95-7.70 (9H, m, aryl-indolyl-H); 6.32 (IH, s, Thiopnen-H); 4.90 (2H, s, CHa-7 ring); 2.95 (4H, s, NHCHaCHa); 2.66 (3H, S, CHs-triazole); 2.52-2.92 (4H, ra, NHCHa, CHa-thiophene); 1.82 (2H, m, NH-CHaCHa).

Example 83 q

IH-NMR _(CDCl3): δ 6.25 (2H, S, 2-aryl-H); 6.78 (IH, s, thiophene-H); 4.85 (2H, * CHa 7-ring); 4.16 (2H, t, J ^ 6 Hz, OCHa); 3.86; 3.89 F9H, 2s, _OCH3); 2.95 (2H, t, J = 6 Hz, CHa-thiophene) · 2.72 (3H, s, _CH3 -triazole): 2.07 (3H, S, CH ₃ -C = O); 2.06 (2H, m, OCHaCHa). Table 10 lists the NMR spectra of selected intermediates.

102

Beiaplel 98

¹ H-NMR (CDClia) δ ppm 7.15-7.59 (4H, ra, aryl-H); 6.14 (IH, 8, thiophene-H); 5.60 (s, IH, CH-N), 4.14 (β, 2Η, CHa-7 ring), 3.67 (t, J »7Hz, 2H, OCHa), 2.80 (t, J = 7Hz, 2H, CH »thiophene). 2.70 (s, 3 H, CK a Tciazol) \, ui - 2.24 (ra, 4H, CCH iCH · », NH, OH).

Example 99

¹ H-NMR (CDClia) δ ppm 7.16 - 7.58 (m, 4H, acyl-H), 6.14 (a, IH, thiophene-H) ', 5.61 (a, IH, CH-) N), 4.14 (β, 2Η,

CHa-7 ring), 4.08 (t, J * 7Hz, OCHa), 2.80 (t, J * 7Hz.

2H, CHa-thiophene), 2.71 (s, 3H, CHa-tcazol), 2.14 (8, bceit, IH, NH), 2.03 (s, 3H, CHaCO), 1.96 (m, 2H, OCHaCHa).

Example 100

¹ H-NMR (CDClia) δ ppm 7.00 - 7.52 (m, 4H, aryl-H,), 7.07 (8, IH, thiophene-H), 6.56 (S, IH, CH-) N), 4.93 / 4.70 (AB-Sy8tem, J _β = 15ΗΖ, 2H, CHa-7-ring), 4.12 (t, J '6 Hz, 2H, OCHA), 2.87 (t, J * 6Hz, 2H, thiophene-CHa), 2.61 (s, 3H, CHa-tcazol), 2.28 (8, 3H, CHaCON), 2.07 (8, 3H, CHaCOO), 1.98 ( m, 2H, OCHaCHa).

103

Table 10 Compound No. 1

¹ H-NMR (CDCl-O δ ppm 7.29-7.54 (4H, m, aryl-H); 7.10 (2H, s, broad, NHa); 6.17 (IH, s, thiophene); H); 3.75 (4H, m, morpholine-OCHa); 3.24 (4H, m, morpholine-N-CHa); 3.06 (4H, S, SOa-CHa-CHa).

Connection No. 3

¹ H-NMR (CDCl ₁ ) δ ppm 7.33-7.78 (5H, ra, aryl-H); 6.97 (2H, 8, broad, NHa); 6.56 (IH 8, Thlophen-H); 4.09 (2H, t, J »6 Iu OCHa); 2.66 (2H, t, J = 7Hz, thiophene CHa); 2.04 (3H, S, CHjC = O); 1.89 (2H, m, -O-CHaCHa).

Connection No. 5

¹ H-NMR (CDCl ₃₎ δ ppm 7.24 to 7.49 (4H, aryl-H m,); 7.07 (2H, s, broad, NHa); 6.09 (IH, s, thiophene-H); 4.05 (2H, t, J = 7Hz, OCHa); 2.49 (2H, t, J »7Hz, thiophene CHa); 2.05 (3H, s, CHaC = O); 1.08-1.83 (lOH, ItI, OCHa (CHa) s).

Connection No. 5a

¹ H-NMR _(CDCl3): δ 6.93 (8, 2H, aryl-H); 6.64 (S, IH, thiophene-H); 3.91; 3.92 (2 s, 9H, 3 OCH ₃ ); 3.71 (t, J = 7HZ, 2H, OCHa); 2.72 (t, J = 7 Hz, 2H, thiophene-CHa, 1.85 (ra, 2H, OCHaCHa), NHa and OH are broader!

104 2 65 4 OS

Connection Sb

¹ H-NMR _(CDCl3): δ 6.89 (S, 2H, aryl-H); 6.5 *; IH thiophene-H); 4.09 (t, J = 7Hz, 2H, OCHa); 3.90; 3.3 ° (28, 9H, 3-OCHa); 2.66 (t, J = »7Hz, 2H, thiophene-CHa); 2.03 (S, 3H, CHaC-O); 1.88 cm, 2H, OCHa-CHa); NHa greatly broadened!

Connection 5c

¹ H-NMR (CDClia) δ ppm 7.19-7.52 (m, 4H, aryl-H), 7.07 (s, broad, 2H, NH ₂ ), 6.18 (s, IH, thiophene) H), 3.16-3.96 (m, 3H, OCHa-CH), 2.67 (d, J = 6Hz, CHa-thiophene), 2.51 (d "J" 3HZ, IH, CHOH), 2.19 (t, J = »4HZ, IH, CHaOH).

Compound 5d

¹ H-NMR (CDClia) δ ppm 7.09-7.67 (m, 9H, aryl-H), 6.97 (S, broad, 2H, NHa), 6.19 (t, J <1HZ, IH , Thiophene-H), 5.93, 5.79 (2S, IH, O-CH-O), 3.56 - 4.53 'm, 3H, OCHaCH), 2.88 (dd, J * 6Hz, <1HZ, 2H, thiophene-CHa).

Connection No. 6

¹ H-NMR (CDClia) δ ppm 12.60 (IH, s, broad, NH); 7.24-7.61 (4H, m, aryl-H); 6.53 (IH, 8, thiophene-H); 4.13 (2H, 8, CHaBr); 3.68 (4H, m, morpholine-OCHa); 3.23 (4H, m, morpholine-N-CHa); 3,17 (4H, S, SOaCHaCHa).

ü 4: 4 υ

105

Connection No. 7

¹ H-NMR (CDClia) δ ppm 12.70 (IH, S. bceU, NH); 7.34-7.62 (BH, m, aryl-H); 6.84 (IM, S, thiophene-H); 4,11 (2H, S, CHaBr); 4,11 (2H, t, J = * 7H, OCHa); 2.82 (2H, t, J * 7Hz, thlophen-CHa-); 2.04 (3H, 8, CHA-C = O); 1.98 (2H, m, -OCHaCHa).

Compound No. 8

¹ H NMR (CDCl 3) δ ppm 12.66 (IH, s, broad, NH); 7.33-7.61 (4H, m, aryl-H); 6.46 (IH, s, Thiopher.-H); 4.14 (2H, 8, CHaBr); 4.08 (2H, t, J »7Hz, OCHa); 2.78 (2H, t, J-7HZ, thiophene CHa); 2.03 (3H, S * _f ChAc O); 1.93 (2H, m, OCHa-CHa).

Connection No. 9

¹ H-NMR (CDCl 3) δ ppm 12.64 (IH, 8, t-rblt, NH); 7.31-7.44 (4K, m, aryl-H); 6.41 (II, ε, thiophene-H); 4.14 (2H, S, CHaBr); 4.05 (2H, t, J - 6 Hz, OCHa); 2.68 (2H, t, J = 6Hz, thiophene CHa); 2.04 (3H, s, CHaC = O);

1.02-1.83 (IUH, m, OCHa (CHa) s-). Compound No. 9 d

¹ H-NMR (CDClia): δ 12.56 (IH, S, NH); 7.18 - 7.56 (4H, m, aryl-H); 6.48 (IH, s, thiophene H); 4,11 (2H, s, CHaBr); 3.45-4.47 (3H, m, OCHa-CHO); 2.90 (2H, d, J = 6H2, CHa-thiophene); 1.40; 1.31 (6H, 2s, 2CHa).

Connection No. 11

¹ H-NMR (CDClia) δ ppm 13.10 (IH, S, broad, NH-C = O); 7.30-7.86 (5H, ra, aryl-H); 6.80 (IH, s, thiophene-H); 4.11 (2H, t, J = 7 HZ, OCHa); 3.64 (2H, 8, CHAc ^ O); 7.81 (2H, t, J = 7H2, thiophene CHa); 2.04 (3H, 8, CHaCaO); 2.00 (2H, m, OCHaCHa); 1.73 (2H, 8, broad, NHa).

Connection No. 1?

¹ H-NMR (CDClO δ ppm 12.24 (IH, s, broad, NH); 7.25-7.56 (4H, m, aryl-H); .i, 41 (IH, β, thiophene-H 4.07 (2H, t, J a 6 HZ, OCHa); 3.67 (2H, S, CHaC = O); 2.74 (2H, t, J = 6HZ, thiophene-CHa); 2.00 (3H, 8, CHaCaO); 1.92 (2H, m, OCHaCHa); 1.78 (2H, 8, broad, NHa).

Connection No. 13

¹ H-NMR (CDClia) δ ppm 13.60 (IH, s, broad, NH); 7.1Λ-7.54 (4H, m, aryl-H); 6.38 (IH, S, thiophene-H), 4.04 (2H, t, J = 6HZ, OCHa); 3.66 (2H, 8, CHA-C = O); 2.65 (2H, t, J * 6Hz, thiophene CHa); 1.87 (2H, s, broad, NHa); 2.04 (3H, 8, CHaC = O); 1.23-1.72 (1OH, m, OCHa (CHa) s-).

Connection No. 14

¹ H NMR (CDClia) δ 9.29 (IH, S, broad, NH); 7.29-7.56 (4H, m, aryl-H); 6.31 (IH, s, thiophene-H); 4.48 (2H, s, 7-ring CHa); 3.75 (4H, m, morpholine-OCHa), 3.23 (4H, m, morpholine-N-CHa); 3.14 (4H, S, -SOa-CHa-CHa).

107

Compound Nc. 17

¹ H-NMR (CDCIs) S ppm 10.03 (IH, S, broad, NH); 7,17-7,56 (4H, ra, aryl-H); 6.16 (IH, s, thiophene-H); 4.47 (2H, S, 7-fing-CHa); 4.02 (2H, t, J = 6Hz, OCHa); 2.62 (2H, t, J = 6Hz, thiophene CHa); 2.02 (3H, s, CHA-C = O); 1.03-1.82 (1 OH, m, OCHa (CHa) s).

Connection No. 1 7 c

¹ H-NMR _(CDCl3): δ 9:33 (IH, s, broad, NH); 7.18 - 7.56 (4H, Ul, aryl-H); 6.25 (IH, S, T'liophen-H); 4.46 (2H, 8, CHa-7 ring); 3.45-4.37 (3H, m, OCHa-CH-O); 2.88 (2H, d, J = 6Hz), CHa -thiophene); 1.40; 1.32 (6H, 2S, 2CHa).

Compound no. 17 d

¹ H-NMR (CDaOD / CDCla 1: 1): δ 7.42 (4H, S, aryl-H); 6.29 (IH, s, thiophene-H); 4.35 (2H, s, CHa-7 ring); 3.53 - 3.87 (IH, m, CH-O); 3.45 (2H, d, J = 5HZ, OCHa); 2.52 (2H, ITI, CHa-thiophene); NH, OH, the solvent blind peak.

Example 81

1 H-NMR (CDCl ₃ ) δ 7.26-7.67 (4H, m, aryl-H), 6.47 (1H, s, thiophene-H),

4.96 I2H, s, CH ₂ -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, a, j = 7 Hz,

CH ₂ thiopheny, 2.72 (3H, s, CH ₃ -triazole), 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 ₁ s, CH ₂ - 7Ring, 4.10 (2H, s, broad, 2, OH), 3.33-4.07 (3H, m, abx system) OCH ₂ -CH-O), 2.92 (2H, d, j -5Hz, CH ₂ -thiophene), 2.65 (3H, s, CH ₃ -triarol).

Claims (1)

- -> c8 - claims Ancestors for the preparation of compounds of the formula ib 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 η> O Rg halogen, hydroxy, ^R 4 26540S wherein R ₄ and R _5, which eein may be the same oäer different, Waeaeretoff "is a branched or unbranched alkyl, alkenyl or Alkinylgruooe having 1 to IO Kohlenbtoffatomen _# which may optionally be substituted by halogen, hydroxy or a C-linked Heterocyclic" wherein the carbon chain may be interrupted by nitrogen "oxygen or sulfur" a branched or unbranched alkylcarbonyl group having 1 to 6 carbon atoms "optionally substituted by hydroxy or halogen, preferably chlorine" or substituted by an optionally one or two times by a branched or unbranched alkyl group 1 to 6 carbon atoms substituted amino groups where the alkyl group may be substituted by halogen or hydroxy » an optionally substituted arylcarbonyl group, preferably phenylcarbonyl "an optionally substituted arylsulfonyl group" preferably phenylsulfonyl or tolylsulfonyl "an alkylsulfonyl group having 1 to 4 carbon atoms" or R ₄ and R ₅ together with the nitrogen atom form a saturated or unsaturated, optionally mono- or polysubstituted by branched or unbranched Alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-membered ring which may contain as further heteroatoms nitrogen "oxygen or sulfur" wherein each additional nitrogen atom optionally substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl substituted his kan; an arylsulfonyloxy group, preferably tolylsulfonyloxy or phenylsulfonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having from 1 to 4 carbon atoms; - ήΑΟ - a branched or unbranched alkylsulfonyloxy group having 1 to 4 carbon atoms; an aryloarbonyloxy group, preferably phenylcarbonyloxy, optionally substituted one or more times by branched or unbranched alkyl and / or alkoxy groups having Ibis carbon atoms; a branched or unbranched alkylcarbonyloxy group having 1 to 12, preferably 1 to 8, carbon atoms, wherein the alkyl chain may be interrupted by nitrogen, oxygen or sulfur; ⁶ ^ NCO-, ⁶ ^ NCN- I Ii ι ι / ι HO H 0 R ₇ wherein R _{β is} a branched or unbranched alkyl, alkenyl or alkiryl group having 1 to 4 carbon atoms, optionally substituted by halogen, optionally mono- or polysubstituted by branched or unsubstituted alkyl and / or alkoxy groups having 1 to 4 carbon atoms substituted aryl group, R _{7 is} hydrogen or a branched or unbranched alkyl group having 1 to 4 carbon atoms; R ₈ 0 \ U N-S S " S 0 ^R 9 where Rg and R _g , which may be the same or different, are a branched or unbranched alkyl group having 1 to 4 carbon atoms ». or Rg and R ₉ together with the nitrogen atom is a 5- or 6-membered ring optionally substituted one or more times by branched or unbranched alkyl groups containing 1 to 4 carbon atoms, which may contain nitrogen, oxygen or sulfur as further heteroatoms another nitrogen atom is substituted by an alkyl group having 1 to 4 carbon atoms, preferably methyl, 3 R _{2 is} a branched or unbranched alkoxy group having 1 to 4 carbon atoms; an aryloxy group, preferably ohenyloxy or substituted phenyloxy; Rp an imido radical; Dioxolane, substituted dioxolane; for η is greater than or equal to O, R _{2 is} -CHmOj-COOHi 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 are both nitrogen »
RgZ can not be methoxycarbonylethyl; R _{2 is} an aryloxycarbonyl group, preferably phenyloxycarbonyl; R ₂ oo KeoC the general formula -C- 54 05 -AT THE- wherein R ₁₀ and R ₁₁ * which may be identical or different, represent hydrogen, phenyl, substituted phenyl, a branched or unbranched alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms, which may be substituted by halogen, hydroxy, nitro, amino, substituted
Amino or in the case of R. _Q «hydrogen or alkyl and
Y = CR ₁ or Y is nitrogen and XC * alkyl, R ₁₁ by an ethers function or an acid amide of the general formula wherein R 'and R _1O ¹ - * has the same meaning wio R ₁₀ and R ₁₁ *
However, with the exception of one acid amide, it may be substituted, R ₁₀ or R _{11 is} a saturated or unsaturated, 5- or 6-membered heterocyclic ring bonded via a carbon atom, optionally mono- or polysubstituted by branched or unbranched alkyl having from 1 to 4 carbon atoms, R ₁₀ and R ₁₁ together with the nitrogen atom, a saturated or unsaturated optionally mono- or polysubstituted by branched or prerindicated alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-ring, as further heteroatoms nitrogen, oxygen and
iichwefel may contain, wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl. - A li the proviso «that if X, Y are both nitrogen, Γ hydrogen, Z is an unbranched alkyl chain with η carbon atoms a) R, β o -chiorphanyl and R ₁ a methyl and η » 0, 1, 2 _# 3 or NR ₁₀ R ₁₁ not morpholino, or η β 0 odor NR ^ ₀ R ₁₁ not amino, or η » NR ₁₀ R ₁₁ not Oiethylamino, Methylamines, Ieopropyl amino * dimethylamines, cyclopropylamino, piperidino, Pyrrolidino, cyclohexylamines, N'-methylpiperazino, Amino, Oi (hydroxyethylamino) or hydroxyethylamino, or b) R, "o-chlorophenyl, and R _{1 is} chloromethyl, bromomethyl, propyloxy, hydrogen, methoxy, bromine or cyclopropyl, and η" NR ₁₀ R _{11 is} not morpholino, or c) R, o-chlorophenyl and R ₁ β cyclopropyl and η - NR ₁₀ R ₁₁ not Oiethylamino, or η - NR ₁₀ R ₁₁ not morpholino or 2 6 54 QS d) R ₃ π phenyl, R ₁ = methyl, η μ 2 NR ₁₀ R ₁₁ not morpholino e) R ₃ o Z -titrophenyl, 2-methylphenyl, 2-trifluoromethyl, R ₁ = methyl, η = 2 NR ₁₀ R ₁₁ not morpholino, f) R ₃ = 2-chlorophonyl, R ₁ = methoxy, η = »2, NR ₁₀ R ₁₁ not dimethylamino, piperidino, g) R ₃ = 2-chlorophenyl _# R ₁ = mothoxy, η a 2, NR ₁₀ R _{11 is} not N'-methylpiperazino means; a radical of the general formula C R ^ B-D B is oxygen, sulfur, NH or NCj-Cg-alkyl, O is the radical (C Re Rf) n, where η can be 0 to 3, Ra hydrogen, optionally by a hydroxy » or amino-substituted alkyl having 1 to 6 carbon atoms Linde atoms, C ₁ to C ₄ alkoxycarbonyl, Oialkylaminocarbonyl, ^R b * ^R c * ^R d * ^R e * ^R f is hydrogen, optionally substituted by hydroxy or amino substituted alkyl of 1 to 6 carbon atoms, or phenyl; R is phenyl, where the phenyl ring may be mono- or polysubstituted, preferably in the 2-position, by methyl, preferably halogen, more preferably chlorine or bromine, nitro, alkoxy, preferably methoxy and / or trifluoromethyl. Pyridyl? R is hydrogen, alkyl or an alkyl group, preferably acetyl; R ^{1 is} hydrogen, phenyl, substituted phenyl or a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl; X, Y independently of each other C- _{1 in} time both CR ₁ , or Y the group C-COOR *, with R * material and X «nitrogen; or N, above not equal to alkyl or water a branched or unbranched alkyl or alkenyl group having η-carbon atoms, wherein Z may optionally be additionally substituted by aryl, preferably phenyl, substituted phenyl or _2- fold by R ₂ , wherein R _{2 may be the} same or different; η can be one of the numbers O, 1, 2, 3, 4 _# 5, 6, 7, 8, 9 or 10. 2 * 5405 in the form of their racemates, their enantiomers *, their Diaitereomere and mixtures thereof, each as free bases or their physiologically acceptable Säureadditionssal2-.e _f characterized in that as external compound a compound of the general formula 1 R θ / VV ml ^R 3 wherein R. = hydrogen, alkyl, cycloalkyl; Z _t X, Y, R ·, η and R_ as previously defined and R a is lower alkyl group, as follows: 1) compounds of general formula Ia with R ₂ * COOH is obtained by pre-soaking compounds of formula I; 2) compounds of general formula Ia with R ₂ -R ₁₀ R ₁₁ NCO- is obtained by reaction of Ia with 2 6 5 / η 5 R ₂ = COOH
with an amine of the formula for example, in the presence of sulfonyldiimidezole or carbonyldiimidazolej 3} compounds of general formula Ia with R ₂ - OH obtained by selective reduction of I, ζ · Θ. with lithium alanate or sodium borohydride, or by hydrolysis of a compound of general formula Ia wherein R _{2 represents} an alkylcarbonyloxy radical; 4) Compounds of the general formula Ia where R ₀ β R _{c is} NH-COO-, R-NHCONR., - is obtained by reaction of the alcohol, for. B ₀ prepared according to 3) or amines R ₀ NHR_ _# z _o B prepared according to 7), with an isocyanate of the general formula R-N = C-O; 5) Compounds of general formula Ia with R ₂ a alkyl or Arylcarbonyloxy   AU nan obtained by reaction of the alcohol, for. 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 a
unsubstituted alkyl radical of 1 to 8 carbon atoms, which carbon chain may be interrupted by nitrogen, oxygen or sulfur; 6) compounds of general formula Ia with
Rp = alkylsulfonyloxy or arylsulfonyloxy is obtained by reaction of the alcohols »z. B ₀ prepared according to 3), with an alkyl or Arylsulfonylhalogenid with the addition of an acid-binding agent; 7) compounds of general formula Ia with R ₂ "NR ₄ R ₅
or an Imido rest is obtained by reaction of the mesylate, z. B * prepared according to 6), with an amine of the formula HNR "R _r
4 5 or an irid; 2654QS 413 ~ 8) compounds of general formula Ia with R ₂ »NH ₂ obtained, for example, by cleavage of the phthalimides or from the corresponding isocyanates, R ₀ u NC a O by hydrolysis; 9) compounds of general formula Ia with R ₀ »NR, R _K
2 4 5 with R. or R_ alkyl or arylcerbonyl is obtained by reaction of a primary or secondary amine, -. B. 'produced according to 7) or 8), with a carbonic acid equivalent »derived from a carboxylic acid of the formula ^Rt io OH 10) compounds of general formula Ia with R ₂ a formyl obtained by oxidation of the alcohol, z »B * prepared according to 3), shortening the chain from η to n-1; 2654 OS - AlO - 11) Compounds of general formula Ia> wherein R _{9 is} a radical of general formula B-D means is obtained by reaction of a compound of general formula Ia with R ₂ = COOH with an amine of the general formula ^R a ^R c J 1 D-B-H ^R b ^R d where R, R, R, R, and B are the abovementioned Have meaning, in the presence of triphenylphosphine, CCl. and a base; Ha) Compounds of the general formula Ia in which R _{2 is} an optionally substituted thiazoline radical are obtained from the corresponding oxazolines, z, b. provided by 11) by sulfurization, z, B. with phosphorus pentasulfide or Laweeeon reagents 12) compounds of general formula Ia with wherein R ₂ »CN is obtained by reaction of compounds of general formula Ia wherein R ₂ * CONH ₂ means »with phosphorus oxychloride; 13) compounds of general formula Ia wherein R ₂ = »is a 2-imidazoline optionally substituted by branched or unbranched alkyl groups, is obtained by reaction of the compounds of general formula Ia R ₂ «CN a) mi: 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 N-H function takes place with known alkylating agents; - / 111 14) Compounds of the general formula Ia where R _{2 is} an aryloxy or acyloxy radical are obtained, for example, by reaction of the mesylate, z _c B ₀ prepared according to 6), with the corresponding alcoholates; 15) compounds of general formula Ia, wherein R ₂ = alkyl or aryloxycarbonyl, is obtained for example by reacting an acid equivalent of I, R ₂ COOH ₁ with the corresponding alcohols; 16) compounds of general formula Ia with R _{2 is} a halogen, obtained by reaction of the tosylate, z, prepared according to 6), with a halogenating agent; subsequently, if desired, the resulting compounds Ia with R ₁ = »hydrogen in the presence of a base with a halogenating agent, such as. B _e with chlorine or bromine, to a compound of general formula Ia with R. halogen, such as z, 3 _e chlorine or bromine, reacts j subsequently, if desired, the halogen compound is converted into a compound of general formula Ie with R ₁ χ alkoxy having 1 to 4 carbon atoms by reaction with the corresponding alkoxide) subsequently, a compound of the general formula Ia desires to be selective to a compound of the general formula 26 54 OS Ib with R ⁰ reduces hydrogen and then, if desired, alkylates or acylates; and, if appropriate, the compounds Ia or Ib thus obtained are converted into their harmless acid addition salts. "