WO2009063029A2 - Substituted amides, manufacturing and use thereof as medicaments - Google Patents

Abstract

The present invention relates to new substituted amides of general formula (I) wherein D, L, B, R4 und R5 are defined as in the specification, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

Description

Substituted amides, manufacturing and use thereof as medicaments

The present invention relates to new substituted amides of general formula

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

The compounds of the above general formula I as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and the stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.

The present application relates to new compounds of the above general formula I, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.

A first embodiment of the present invention encompasses those compounds of general formula I wherein

D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR 2a -CR^2bR^2c or a -C(O) group, and wherein

_R2a_/R2b_/R2c each independently of one another denote a fluorine atom, a hydroxy, Ci_-5-alkyloxy, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)- amino, Cs-s-cycloalkyleneimino, Ci_-5-alkylcarbonylamino group, a Ci-5-alkyl group which may be substituted by 1 -3 fluorine atoms, a hydroxy-Ci-₅-alkyl, Ci-s-alkyloxy-Ci-s-alkyl, amino-Ci_-5-alkyl, Ci-s-alkylamino-Ci-s-alkyl, di-(Ci-₅-alkyl)-amino-Ci-₅-alkyl, C_4-7- cycloalkyleneimino-Ci-₅-alkyl, carboxy-Co-₅-alkyl, Ci_-5- alkyloxycarbonyl-Co-₅-alkyl, aminocarbonyl-Co-₅-alkyl, Ci-s-alkylaminocarbonyl-Co-s-alkyl, di-(Ci_-5-alkyl)-aminocarbonyl- Co-₅-alkyl or a C_4-7-cycloalkyleneiminocarbonyl-Co-₅-alkyl group, while the two groups R^2b/R^2c cannot both simultaneously be bound to the cyclic carbon atom via a heteroatom, except where -C(R j2b_D R2c)- corresponds to a -CF₂ group, or

R ,2a denotes a phenyl or monocyclic heteroaryl group substituted by fluorine, chlorine, bromine, methyl, methoxy, amino or nitrogen, or

two groups R^2b/R^2c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetan, azetidine, thietan, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide, hexamethyleneimine, 1 ,3- dioxolane, 1 ,4-dioxane, hexahydropyridazine, piperazine, thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone, tetrahydro-2(1 H)-pyrinnidinone or [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by

1 -2 Ci-₃-alkyl or CF₃- groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1 -2 fluorine atoms, and/or wherein a -CH₂ group besides an N atom may be replaced by a -CO group, and/or the imino groups of which may each be substituted by a Ci- 3-alkyl or Ci-₃-alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to a sulphoxide or sulphone group,

K² and K³ each independently of one another denote a -CH₂, -CHR^6a, - C_R ^6b _R ^6c _{or a} __Cpj group, wherein

_R6a_/R6b_/R6c each independently of one another denote a Ci_-5-alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci_-5- alkyl, Ci_-5-alkyloxy-Ci-₅-alkyl, amino-Ci_-5-alkyl, Ci_-5-alkylamino-Ci- 5-alkyl, di-(Ci_-5-alkyl)-amino-Ci-₅-alkyl, C_4-7-cycloalkyleneimino-Ci-

₅-alkyl, carboxy-Co-₅-alkyl, Ci-s-alkyloxycarbonyl-Co-s-alkyl, aminocarbonyl-Co-₅-alkyl, Ci-s-alkylaminocarbonyl-Co-s-alkyl, di- (Ci-₅-alkyl)-aminocarbonyl-Co-₅-alkyl or a C_4-7- cycloalkyleneiminocarbonyl-Co-₅-alkyl group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2(1 H)-pyrimidinone, [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by 1 -2 Ci-3-alkyl or CF₃- groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1 -2 fluorine atoms, and/or wherein a -CH₂ group besides a nitrogen atom may be replaced by a -CO group, and/or the imino groups of which may each be substituted by a Ci- 3-alkyl or Ci-₃-alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to a sulphoxide or sulphone group, with the proviso that a heteroatom introduced by R^6b or R^6c cannot be only one carbon atom away from the cyclic nitrogen -N(R¹)- in formula (I), and

in total in formula (II) a maximum of four groups selected from R^2a, R^2b, R^2c, R^6a, R^6b and R^6c may be present, and

R¹ denotes a hydrogen atom or a hydroxy, Ci-3-alkyloxy, amino,

Ci-3-alkylamino, di-(Ci_-3-alkyl)-amino, a Ci_-5-alkyl, C_2-5-alkenyl- CH₂, C_2-5-alkynyl-CH₂, C_3-6-cycloalkyl, C_4-6-cycloalkenyl, oxetan-3- yl, tetrahydrofuran-3-yl, benzyl, Ci_-5-alkyl-carbonyl, trifluoromethylcarbonyl, Cs-β-cycloalkyl-carbonyl, Ci_-5-alkyl- sulphonyl, Cs-β-cycloalkyl-sulphonyl, aminocarbonyl,

Ci-₅-alkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, Ci_-5- alkyloxycarbonyl, C_4-7-cycloalkyleneiminocarbonyl group, while the methylene and methyl groups contained in the groups mentioned previously may additionally be substituted by a Ci-3-alkyl, carboxy, Ci_-5 - alkoxycarbonyl group, or by a hydroxy, Ci_-5-alkyloxy, amino, Ci_-5-alkylamino, Ci_-5-dialkylamino or C_4-7- cycloalkyleneimino group, provided that the methylene or methyl groups are not directly bound to a heteroatom selected from among O, N or S, and/or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or methyl groups are not directly bound to a heteroatom selected from among O, N or S,

and wherein

A¹ denotes either N or CR⁹,

A² denotes either N or CR¹⁰,

A³ denotes either N or CR¹¹,

while R⁹, R¹⁰ and R¹¹ each independently of one another denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a phenyl, Ci-5-alkyl, CF₃, C_2-5 -alkenyl, C_2-5-alkynyl, a cyano, carboxy, Ci_-5- alkyloxycarbonyl, hydroxy, Ci_-3-alkyloxy, CF₃O, CHF₂O, CH₂FO, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)-amino or C_4-7- cycloalkyleneimino group, and

R⁵ each independently of one another denote

a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a Ci_-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group,

L denotes a 5-membered monocyclic heteroarylene group optionally substituted in the carbon skeleton by a group R⁶ and the two bonds shown in formula (I) may be provided by two carbon atoms or an imino group and a carbon atom of the heterocyclic group, while any -NH group present may be replaced by an -NR⁶ group, or

a group of general formula (III)

while if the bond is provided via an imino group the group D of general formula (I) is linked to the nitrogen atom of the group L, and

R⁶ denotes a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a

Ci-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group, while the heteroatoms O or S optionally introduced as substituents are not separated by precisely one carbon atom from the nitrogen atom in the heterocyclic group substituted by R⁶,

B denotes a thiophene ring according to formula (IV),

which is bound to the carbonyl group in formula (I) via the 2 position and which is substituted in the 5 position by R⁷ and optionally additionally by R⁸, where

R⁷ denotes a fluorine, chlorine, bromine or iodine atom, or a methoxy, Ci-₂-alkyl or ethynyl group,

R⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci-₂-alkyl or amino group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant a monocyclic 5- or 6-membered heteroaryl group wherein

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and

the 5-membered heteroaryl group contains an imino group optionally substituted according to the above description, or an oxygen or sulphur atom, or

an imino group optionally substituted according to the above description or an oxygen or sulphur atom and additionally one or two nitrogen atoms, or

an imino group optionally substituted according to the above description and three nitrogen atoms, and furthermore, unless stated otherwise, a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a Ci-3-alkyl, hydroxy, Ci-3-alkyloxy group, amino, Ci-3-alkylamino, di-(Ci-3-alkyl)-amino or C-3-6- cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms,

and the bond is provided in each case via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

while, unless stated otherwise, by the term "halogen atom" mentioned hereinbefore in the definitions is meant an atom selected from among fluorine, chlorine, bromine and iodine,

while unless stated otherwise the alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned previously which have more than two carbon atoms may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

Within the scope of the present application, unless otherwise defined, the following general terms mentioned in the definitions are defined as shown below or illustrated by examples.

Examples of the monocyclic heteroaryl groups mentioned hereinbefore in the definitions are the pyridyl, /V-oxy-pyhdyl, pyrazolyl, pyhdazinyl, pyrimidinyl, pyrazinyl, [1 ,2,3]triazinyl, [1 ,3,5]triazinyl, [1 ,2,4]triazinyl, pyrrolyl, imidazolyl, [1 ,2,4]triazolyl, [1 ,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1 ,2,3]oxadiazolyl, [1 ,2,4]oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1 ,2,3]thiadiazolyl, [1 ,3,4]thiadiazolyl or [1 ,2,5]thiadiazolyl group.

Examples of the bicyclic heteroaryl groups mentioned hereinbefore in the definitions are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]isothiazolyl, benzo[c/] isothiazolyl, benzoxazolyl, benzo[c] isoxazolyl, benzo[c/]isoxazolyl, benzo[1 ,2,5]oxadiazolyl, benzo[1 ,2,5]thiadiazolyl, benzo[1 ,2,3]thiadiazolyl, benzo[c/][1 ,2,3]thazinyl, benzo[1 ,2,4]thazinyl, benzotriazolyl, cinnolinyl, quinolinyl, /V-oxy-quinolinyl, isoquinolinyl, quinazolinyl, /V-oxy-quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1 -oxa-2,3-diaza-indenyl group.

Examples of the Ci_-5-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, te/t-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl or 3-methyl-2-butyl group.

Examples of the Ci_-5-alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1 -propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, te/t-butyloxy, 1 -pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.

Examples of the C2-5-alkenyl groups mentioned hereinbefore in the definitions are the ethenyl, 1 -propen-1 -yl, 2-propen-1 -yl, 1 -buten-1 -yl, 2-buten-1 -yl, 3- buten-1-yl, 1-penten-1-yl, 2-penten-1 -yl, 3-penten-1-yl, 4-penten-1 -yl, 1 -hexen-

1 -yl, 2-hexen-1-yl, 3-hexen-1 -yl, 4-hexen-1 -yl, 5-hexen-1 -yl, but-1-en-2-yl, but-

2-en-2-yl, but-1 -en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1 -en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pent-2-en-3-yl, 2-methyl-but-1 -en- 1 -yl, 2-methyl-but-2-en-1 -yl, 2-methyl-but-3-en-1 -yl or 2-ethyl-prop-2-en-1 -yl group, Examples of the C2-5-alkynyl groups mentioned hereinbefore in the definitions are the ethynyl, 1 -propynyl, 2-propynyl, 1 -butyn-1 -yl, 1 -butyn-3-yl, 2-butyn-1-yl, 3-butyn-1 -yl, 1 -pentyn-1 -yl, 1-pentyn-3-yl, 1 -pentyn-4-yl, 2-pentyn-1 -yl, 2- pentyn-3-yl, 3-pentyn-1 -yl, 4-pentyn-1-yl, 2-methyl-1 -butyn-4-yl, 3-methyl-1 - butyn-1-yl or 3-methyl-1 -butyn-3-yl group.

A 2nd embodiment of the present invention includes those compounds of general formula (I) wherein D, R⁴, R⁵ and B are defined as described in embodiment 1 , and wherein

L denotes a group of general formula

while if the bond is provided via an imino group the group D of general formula (I) is linked to the nitrogen atom of the group L, and

R⁶ denotes a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a Ci-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group, while the heteroatoms O or S optionally introduced as substituents are not separated by precisely one carbon atom from the nitrogen atom substituted by R⁶ in the heterocyclic group.

A 3rd embodiment of the present invention includes those compounds of general formula (I), wherein L, R⁴, R⁵ and B are defined as described in embodiment 1 or 2, and wherein

D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR^2a- or a -CR^2bR^2c group, and wherein

_R2a_/R2b_/R2c each independently of one another denote a fluorine atom, a methoxy or a methyl group, or two groups R^2b/R^2c together with the cyclic carbon atom may form a cyclopropyl ring, and

K² and K³ each independently of one another denote a -CH₂, -CHR^6a or -CR^6bR^6c- group, wherein

_R6a_/R6b_/R6c each independently of one another denote a methyl group, a CF₃ or a cyano group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a cyclopropyl ring, and R¹ denotes a hydrogen atom or a Ci_-3-alkyl, or C_3-6-cycloalkyl group,

and

A¹ denotes CR⁹,

A² denotes CR¹⁰,

A³ denotes CR¹¹,

while R j9 , r R-»10 and J i R-.1 1 each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, methoxy, CF₃O, CHF₂O, CH₂FO- group.

A 4th embodiment of the present invention includes those compounds of general formula (I), wherein

D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR^2a- or a -CR^2bR^2c group, and wherein _R2a_/R2b_/R2c each independently of one another denote a methyl group, or two groups R^2b/R^2c together with the cyclic carbon atom may form a cyclopropyl ring, and

K² and K³ each independently of one another denote a -CH₂, -CHR^6a or -CR^6bR^6c- group, wherein

R^6a/R^6b/R^6c each independently of one another denote a methyl group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a cyclopropyl ring, and

R¹ denotes a hydrogen atom or a Ci_-3-alkyl, or C_3-6-cycloalkyl group,

and

A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes CR¹²,

while R¹⁰, R¹¹, R¹² and R¹³ each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, methoxy, CF₃O, CHF₂O, CH₂FO- group, and enotes a group of general formula

while the group D of general formula (I) is linked to the nitrogen atom of the group L, and

R⁴ and R⁵ in each case represent a hydrogen atom, and

B denotes a thiophene ring according to formula (IV),

which is bound to the carbonyl group in formula (I) via the 2 position and which is substituted in the 5 position by R⁷, while

R⁷ denotes a chlorine or bromine atom, or an ethynyl group,

while unless stated otherwise the alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned previously which have more than two carbon atoms may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. Within the scope of the present application, where applicable, the "isomer", "stereoisomer", "diastereomer", "enantiomer", "chiral", "racemate" or "racemic mixture" are defined as follows. Compounds of the same empirical formula which differ in the nature or arrangement of the bonding of their atoms or their connectivity or the spatial arrangement of the atoms in the molecule are known as "isomers". Isomers which differ in the spatial arrangement of the atoms in the molecule and are not congruent, while having the same type of connectivity of their atoms, are known as "stereoisomers". Stereoisomers which do not behave as image and mirror image to one another are known as "diastereomers", and stereoisomers which behave as an image and mirror image to one another are known as "enantiomers". Where an asymmetric centre or atom is present (also known as a stereocentre or chiral centre), for example in the case of a carbon atom substituted by four different substituents, the molecule has the attribute "chiral", and a pair of enantiomers (also known as optical antipodes) is possible. An enantiomer may be characterised by the absolute configuration of its stereocentre. The absolute configuration is described by means of the descriptors (R) and (S), which are determined by the application of the sequence rules according to Cahn, lngold and Prelog , or by describing the rotation of the plane of polarised light as it interacts with the molecule, which is referred to as dextrorotatory or laevorotatory (i.e. Accordingly with (+) or (-) as the descriptor). A chiral compound may occur both as an individual enantiomer or as a mixture of the corresponding enantiomers. A mixture which contains equal amounts of both enantiomers of a compound is known as a "racemate" or "racemic mixture". (a) According to the invention the compounds of general formula (I) are obtained by methods known per se, for example by the following methods:

(1 ) Scheme 1

R-N I I ₂ -^*— L R¹— N I ₂ -i— U

_KVV* _KL_KΛ_A3-^A

(II) (Hl) (IV)

(VIM)

wherein A¹ -A³, B, K¹-K⁴, R¹, R⁴ and R⁵ are defined as described in the first embodiment and Q⁷ denotes a halogen atom or a hydroxyl or alkoxy group.

The reaction steps described in Scheme 1 may be carried out in the manner described in the Examples or according to conditions known from the literature, for example as follows:

(1 a) is a reduction of the nitro group. This is expediently carried out in a solvent or mixture of solvents such as water, aqueous ammonium chloride solution, hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, acetic anhydride with base metals such as iron, zinc, tin or sulphur compounds such as ammonium sulphide, sodium sulphide or sodium dithionite or metal salts with a metal in a low oxidation state, such as for example tin(ll)chlohde, iron(ll)sulphate, chromium(ll)chloride or titanium(ll)chlohde, or by catalytic hydrogenation with hydrogen, for example at a pressure between 0.5 and 100 bar, but preferably between 1 and 50 bar, or with hydrazine as reducing agent, conveniently in the presence of a catalyst such as for example Raney nickel, palladium charcoal, platinum oxide, platinum on mineral fibres or rhodium, or with complex hydrides such as lithium aluminium hydride, sodium borohydhde, sodium cyanoborohydride, diisobutylaluminium hydride, conveniently in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, ethyl acetate, methylpropionate, glycol, glycoldimethylether, diethyleneglycol dimethylether, dioxane, tetrahydrofuran, /V-methylpyrrolidinone, or /V-ethyl- diisopropylamine, Λ/-Ci_-5-alkylnnorpholine, /V-Ci_-5-alkylpipehdine, /V-Ci-5-alkylpyrrolidine, thethylamine, pyridine, for example at temperatures between -30 and 250⁰C, but preferably between 0 and 150⁰C.

(1 b) is the introduction of an azido group after diazotisation of compounds The diazotisation is carried out for example in a solvent or mixture of solvents such as water, methanol, ethanol, propanol, dimethylformamide or tetrahydrofuran, conveniently in the presence of an acid such as formic acid, acetic acid, trichloroacetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or perchloric acid, with salts of nitric acid such as sodium nitrite or potassium nitrite, at temperatures between -30 and 100°C, but preferably between -20 and 40⁰C. The azido group is then conveniently added directly with sodium azide in aqueous solution at temperatures between -20 and 100°C, but preferably between -20 and 60°C.

(1 c) is an acylation. This is conveniently carried out with a corresponding halide or anhydride in a solvent such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200⁰C, but preferably between -10 and 160°C. The acylation may however also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, thmethyl-chlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluene-sulphonic acid, phosphorus trichloride, phosphorus pentoxide, N.N'-dicyclohexylcarbodiimide, N,N'-dicyclo- hexylcarbodiimide / N-hydroxysuccinimide or 1 -hydroxy-benzotriazole, N,N'-carbonyl-diimidazole, O-(benzotriazol-1 -yl)-N,N,N',N'-tetra-methyl-uroniunn tetrafluoroborate / N-methylmorpholine, O-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate / N-ethyldiisopropylamine, O-penta- fluorophenyl-N,N,N',N'-tetramethyluroniunn hexafluorophosphate / triethylamine, N,N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200⁰C, but preferably at temperatures between -10 and 160⁰C.

Other methods of amide coupling are described for example in P. D. Bailey, I. D. Collier, K. M. Morgan in "Comprehensive Functional Group Interconversions", Vol. 5, page 257ff., Pergamon 1995.

(1d) is a 1 ,3-dipolar cycloaddition. This is carried out in a solvent or mixture of solvents such as dimethylsulphoxide, dioxane, dimethylformamide, tetrahydrofuran, N-methyl-pyrrolidinone, sulpholane or water, expediently in the presence of a catalyst such as copper(l)chlohde, copper(l)sulphate, copper(ll)sulphate in the presence of a reducing agent such as sodium ascorbate, magnesium or zinc at temperatures between -20 and 100°C.

(2) Scheme 2

wherein A¹ -A³, B, K¹-K⁴, R¹, R⁴ and R⁵ are defined as described in the first embodiment and Q⁷ denotes a halogen atom or a hydroxyl or alkoxy group. Compounds of type (IX) are known from the literature, or their synthesis is described in the embodiments by way of example, or they may for example be prepared by methods of synthesis known from the literature or analogously to methods of synthesis known from the literature or may be prepared in the same way as compounds of type (IV).

The reaction steps illustrated in Scheme 2 may be carried out as described in the Examples or under conditions known from the literature, for example as follows:

(2a) is a nucleophilic attack on the nitrile group by hydroxylamine. This is conveniently carried out in a solvent or mixture of solvents such as water, ethanol, propanol, butanol, dimethylformamide, dimethylsulphoxide or sulpholane at temperatures between 0 and 250⁰C, preferably between 20 and 150⁰C.

(2b) is a sequence comprising acylation and cyclisation by condensation. The acylation is carried out as described under (1 c). The condensation is conveniently carried out subsequently in a solvent or mixture of solvents such as diphenylether, dimethylformamide, N-methyl-pyrrolidinone, dimethylsulphoxide, sulpholane, toluene, optionally with a catalyst such as toluenesulphonic acid, zinc(ll)chlohde, boron trifluoride or titanium(IV) chloride, at temperatures between 20 and 250°C, preferably between 50 and 180⁰C.

(3) Scheme 3

(XIV) (XV)

(XVI II) wherein A¹ -A³, B, K¹-K⁴, R¹, R⁴ and R⁵ are defined as described in the first embodiment and Q¹⁰ denotes a hydroxyl or alkoxy group and Q¹¹ denotes a Ci-5-alkyl group. Substances of general formula (XIV) are known from the literature, or their synthesis is described in the embodiments by way of example, or they may for example be prepared by methods of synthesis known from the literature or analogously to methods of synthesis known from the literature as described for example in WO2000/09480; S. Komoriya et al. Bioorg. Med. Chem. 2006, 14, 1309, US2005/0020645.

The reaction steps described in Scheme 3 may be carried out as described in the Examples or under conditions known from the literature as follows, for example:

(3a) is the synthesis of a hydrazide from a benzoic acid ester. It is carried out in a solvent or mixture of solvents such as ethanol, propanol, dimethylformamide or dimethylsulphoxide with the addition of hydrazine or hydrazine hydrate at temperatures from 0 to 250⁰C, preferably at temperatures from 20 to 150⁰C. (3b) is a sequence comprising an acylation reaction followed by synthesis of an iminoester from a nitrile group. The acylation is carried out as described under (1 c). The synthesis of the iminoester is carried out in a solvent or mixture of solvents such as methanol, ethanol, propanol or isopropanol with the effect of an acid such as hydrogen chloride or hydrogen bromide at temperatures from -30 to 100⁰C, but preferably from -20 to 50⁰C.

(3c) is an intermolecular condensation, followed by an intramolecular condensation with cyclisation. This is carried out in a solvent or mixture of solvents such as acetonitrile, chloroform, dichloroethane, chlorobenzene, toluene, dimethylformamide, dimethylsulphoxide or sulpholane, conveniently under the effect of a base such as triethylamine, N-ethyl-diisopropylamine, potassium carbonate or sodium hydroxide at temperatures from -10 to 220°C, preferably from 0 to 150⁰C.

(4) Scheme 4

(XXi)

wherein A¹ -A³, B, K¹-K⁴, R¹, R⁴ and R⁵ are defined as described in the first embodiment.

The reaction steps described in Scheme 4 may be carried out as described in the Examples or under conditions known from the literature, e.g. as follows:

(4a) is a condensation for synthesising aldoximes from aldehydes which may be obtained for example from compounds of general formula (XIV) by methods known from the literature. It is carried out by the action of hydroxylamine- hydrochloride in a solvent or mixture of solvents such as ethanol, methanol, water, tetrahydrofuran or glycol in the presence of a salt of a weak acid such as sodium acetate, disodium hydrogen phosphate or sodium citrate at temperatures from -10 to 220⁰C, preferably from 0 to 150⁰C.

(4b) is a synthesis sequence comprising chlorination of the aldoxime, intermediate formation of the nitrile oxide and 1 ,3-dipolar cycloaddition with compounds of type (VII). It may be carried out as a one-pot reaction by the action of /V-chlorosuccinimide followed by the addition of a compound of type (VII) as well as a base such as thethylamine, /V-ethyl-diisoprolylamine, pyridine or potassium carbonate in a solvent or mixture of solvents such as dichloromethane, chloroform or pyridine, at temperatures of -20 to 150°C, preferably from 0⁰C to 100⁰C.

(5) Scheme 5

<^xv) (XXIi) (XXIIi)

wherein A¹ -A³, B, K¹-K⁴ and R¹ are defined as described in the first embodiment and Q⁷ denotes a halogen atom or a hydroxyl or alkoxy group.

The reaction steps described in Scheme 5 may be carried out as described in the Examples or under conditions known from the literature, for example as follows:

(5a) is a synthesis sequence comprising a condensation with 1 -chloro-2,2,2- trimethoxy-ethane followed by conversion of the chloromethyl into an aminomethyl group.

The condensation for synthesising the [1 ,2,4]oxadiazole may be carried out by the action of 1 -chloro-2,2,2-thmethoxy-ethane on compounds of type (XV) without a solvent or in a solvent such as dimethylformamide, dimethylsulphoxide or i -butyl-3-nnethyl-innidazoliunn-tetrafluoroborate with irradiation in a microwave oven at temperatures from 20 to 300⁰C, preferably from 50 to 220⁰C, optionally in the presence of molecular sieve. The conversion of the chloromethyl into an aminomethyl group is carried out by the action of sodium azide in a solvent or mixture of solvents selected from among acetonitrile, dimethylformamide, dimethylsulphoxide, sulpholane or tetrahydrofuran at temperatures from -30 to 150°C, preferably from -20 to 100⁰C, followed by treatment of the resulting azide with triphenylphosphine in a solvent or mixture of solvents such as diethyl ether, tetrahydrofuran, dichloromethane, chloroform, benzene, pyridine, dimethylformamide or dimethylsulphoxide at temperatures from -30 to 150°C, preferably from -20 to 100°C.

(5b) is an acylation reaction. It is carried out analogously to (1 c).

(b) The components of general formula

wherein A¹, A², A³, K¹, K², K³, K⁴ and R¹ are defined as mentioned in embodiment 1 , and which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by the usual protective groups, such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", and the protective groups of which can be cleaved in a manner known from the literature in the course of the synthesis sequence to form compounds of formula (I), are known from the literature, or the synthesis thereof is described in the embodiments by way of example, or they may for example be prepared by methods of synthesis known from the literature or analogously to methods of synthesis known from the literature as described for example in EP1818330, WO07/009963, WO07/003536, DE4429079, US4490369, DE3515864, US5175157, DE1921861 , WO85/00808 or in G. Bobowski et al., J. Heterocyclic Chem. 16, 1525, 1979 or in P. D. Johnson et al.,

Bioorg. Med. Chem. Lett 2003, 4197.

For example, a compound of general formula (H-A), wherein A¹, A², A³, K¹, K², K³, K⁴ and R¹ are defined as in embodiment 1 , may be prepared by reduction of the nitro group of a compound of general formula (M-B)

wherein A¹, A², A³, K¹, K², K³, K⁴ and R¹ are defined as in embodiment 1 , as follows.

The reduction of the nitro group is for example conveniently carried out in a solvent or mixture of solvents such as water, aqueous ammonium chloride solution, hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, acetic anhydride with base metals such as iron, zinc, tin or sulphur compounds such as ammonium sulphide, sodium sulphide or sodium dithionite or by catalytic hydrogenation with hydrogen, for example at a pressure between 0.5 and 100 bar, but preferably between 1 and 50 bar, or with hydrazine as reducing agent, conveniently in the presence of a catalyst such as for example Raney nickel, palladium charcoal, platinum oxide, platinum on mineral fibres or rhodium, or with complex hydrides such as lithium aluminium hydride, sodium borohydride, sodium cyanoborohydride, diisobutylaluminium hydride, conveniently in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, ethyl acetate, methyl propionate, glycol, glycoldimethylether, diethyleneglycoldimethylether, dioxane, tetrahydrofuran, /V-methylpyrrolidinone, or /V-ethyl-diisopropylamine, /V-Ci-5-alkylmorpholine, A/-Ci-₅-alkylpiperidine, /V-Ci-s-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and

250⁰C, but preferably between 0 and 150⁰C.

In the reactions described above any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example

a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert. butyl, trityl, benzyl or tetrahydropyranyl group,

suitable protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl group, and

suitable protecting groups for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group.

Other protective groups and their cleaving are described in T.W. Greene,

P. G. M. Wuts, "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

Any protective group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodothmethylsilane, at temperatures between 0 and 100⁰C, preferably at temperatures between 10 and 50⁰C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cehum(IV)ammonium nitrate in a solvent such as methylene chloride, acetonithle or acetonitrile/water at temperatures of between 0 and 50⁰C, but preferably at ambient temperature.

A methoxy group is expediently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25°C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A te/t.butyl or te/tbutyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C. An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(thphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1 ,3-dimedone at temperatures between 0 and 100⁰C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(thphenylphosphine)-rhodium(l)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1 ,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70⁰C.

Moreover the compounds of general formula (I) obtained may be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by chromatographic column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and thethanolamine.

As already mentioned, the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and/or on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor Xl and factor XII.

The compounds listed in the experimental section were investigated for their effect on the inhibition of factor Xa as follows: Method:

Enzyme-kinetic measurement with chromogenic substrate. The quantity of p- nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC₅O is calculated, as the concentration which inhibits the factor Xa used by 50 %.

Material:

Ths(hydroxymethyl)-aminomethane buffer (100 mMol) and sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free.

Factor Xa (Calbiochem), spec. Activity: 217 IU/mg, final concentration: 7 IU/ml for each reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/l (1 KM) for each reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1 , 0.3, 0.1 , 0.03, 0.01 , 0.003, 0.001 μMol/l

Procedure:

10 μl of a 23,5-times concentrated starting solution of the test substance or solvent (control), 175 μl of TRIS/HSA buffer and 25 μl of a 65.8 U/L Factor Xa working solution are incubated for 10 minutes at 37°C. After the addition of 25 μl of S 2765 working solution (2.82 mMol/l) the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37°C. Evaluation:

1. Determining the maximum increase (deltaOD/minutes) over 21 measuring points.

2. Determining the % inhibition based on the solvent control.

3. Plotting a dosage/activity curve (% inhibition vs substance concentration).

4. Determining the IC₅O by interpolating the X-value (substance concentration) of the dosage/activity curve at Y = 50 % inhibition.

All the compounds tested had an IC₅O value of less than 100 μmol/L. The compounds prepared according to the invention are generally well tolerated.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD, for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts.

In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic events in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin-dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are also suitable for treating Alzheimer's and Parkinson^'s disease. One rationale for this can be seen for example in the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could be valuable drugs for treating Alzheimer's and Parkinson^'s disease. Clinical and experimental studies indicate that neurotoxic mechanisms, for example the inflammation that accompanies the activation of proteases of the clotting cascade, are involved in the dying off of neurones following brain damage. Various studies indicate an involvement of thrombin in neurodegenerative processes, e.g. following a stroke, repeated bypass operations or traumatic brain injury. An increased thrombin activity was able to be detected for example some days after peripheral nerve damage. It was also shown that thrombin causes neurite retraction and glia proliferation, and apoptosis in primary cultures of neurones and neuroblastoma cells (for an overview see: Neurobiol. Aging, 2004, 25(6), 783-793). In addition, various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a part in the pathogenesis of this disease (Neurosci. Lett., 1992, 146, 152-54). An accumulation of immunoreactive thrombin has been detected in neurite plaques in the brains of Alzheimer's patients. It was demonstrated in vitro that thrombin also plays a part in the regulation and stimulation of the production of Amyloid Precursor Protein (APP) as well as in the cleaving of APP into fragments which can be detected in the amyloid plaques in the brains of Alzheimer's patients. It has also been shown that thrombin-induced microglial activation in vivo leads to the degeneration of nigral dopaminergic neurones. These findings lead one to conclude that microglial activation, triggered by endogenous substance(s) such as thrombin, for example, are involved in the neuropathological process of the cell death of dopaminergic neurones, such as occurs in patients with Parkinson's disease {J. Neurosci., 2003, 23, 5877-86).

The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The following Examples are intended to illustrate the invention, without restricting its scope.

Experimental section

As a rule, melting points and/or IR, UV, ¹H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, Rf values were obtained using ready-made silica gel 60 F₂54 TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The R_f values obtained under the name Alox were determined using ready-made aluminium oxide 60 F₂₅4 TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The Rf values obtained under the name Reversed-phase-8 were determined using ready-made RP-8 F₂5_4s TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation. The ratios given for the eluants refer to units by volume of the solvents in question. Chromatographic purification was done using silica gel supplied by Messrs Millipore (MATREX™, 35-70 μm). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer.

In the descriptions of the experiments the following abbreviations are used:

Boc te/t.-butoxycarbonyl

DCC Λ/,Λ/'-dicyclohexylcarbodiimide

DIC Λ/,Λ/'-diisopropylcarbodiimide

DIPEA /V-ethyl-diisopropylamine

DMSO dimethylsulphoxide

DMF N, N-ύ imethylformam ide

DPPA diphenylphosphorylazide sat. saturated h hour(s)

HATU O-(7-azabenzotriazol-1 -yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate

HOBt /V-hydroxy-benzothazole

HPLC High Performance/Pressure Liquid Chromatography i. vac. in vacuo cone. concentrated min minute(s)

NCS /V-chloro-succinimide

NMM /V-methyl-morpholine

NMP /V-methyl-pyrrolidin-2-one

O ortho

PfTU O-pentafluorophenyl-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium- hexafluorophosphate

PPA propanephosphonic acid cycloanhydride quant. quantitative

Rf retention factor

Rt retention time rac. racemic

RP reversed phase

TBTU O-(benzotriazol-1 -yl)-/V,/V,ΛΛ/V-tetramethyluronium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran tert. tertiary dil. dilute

Σ yield over all the steps carried out analogously

The HPLC data were produced under the following conditions:

Method A

HP1100 HPLC, Waters Micromass ZQ2000 mass spectrometer with diode array detector 2996.

The mobile phase used was: A: water with 0.10% TFA B: acetonitrile with 0.10% TFA

time in min %A %B flow rate in ml/min

0.00 95 5 1.50

2.00 0 100 1.50

2.50 0 100 1.50

2.60 95 5 1.50

6.05 95 5 1.50

6.55 95 5 1.50 The stationary phase used was an XBhdge C18 column, 3.5 μm, 4.6 mm x 50 mm.

The diode array detection was carried out in the wavelength range from 210- 500 nm.

Method B

HP1100 HPLC, Waters Micromass ZQ2000 mass spectrometer with diode array detector 2996. The mobile phase used was: A: water with 0.10% TFA B: acetonitrile with 0.10% TFA

time in min %A %B flow rate in ml/min

0.00 95 5 1.50

2.00 0 100 1.50

2.50 0 100 1.50

2.60 95 5 1.50

6.05 95 5 1.50

6.55 95 5 1.50

The stationary phase used was a Sunfire C18 column, 3.5 μm, 4.6 mm x 50 mm.

The diode array detection was carried out in the wavelength range from 210- 500 nm.

Method C

Waters Alliance 2695, Waters Micromass ZQ mass spectrometer with diode array detector 2996.

The mobile phase used was: A: water with O.13% TFA B: acetonitrile with 0.10% TFA

time in min %A %B flow rate in ml/min

0.00 95 5 1 .00

0.75 95 5 1 .00

5.25 2 98 1 .00 5.75 2 98 1 .00

6.05 95 5 1 .00

6.55 95 5 1 .00

The stationary phase used was a Varian MS 100 C18 column, 3 μm, 4.6 mm x 50 mm.

The diode array detection was carried out in the wavelength range from 210- 300 nm.

Example 1

5-chloro-thiophene-2-carboxylic acid-[1 -(2-methyl-1 ,2,3,4-tetrahydro-1 H-

[1 ,2,3]triazol-4-ylmethyl]-amide

(a) 6-azido-2-methyl-1 ,2,3,4-tetrahvdro-isoquinoline

500 mg (3.1 mmol) 6-amino-2-methyl-1 ,2,3,4-tetrahydro-isoquinoline are dissolved in 15 ml of water and 4.3 ml (51.7 mmol) cone, hydrochloric acid, cooled to 3°C and combined with 272 mg (4 mmol) sodium nitrite, dissolved in 5 ml of water. The mixture is stirred for 45 minutes at 0-5⁰C, then a solution of 262 mg (4 mmol) sodium azide in 10 ml of water is added dropwise and the mixture is stirred for one hour at the same temperature. Then the reaction mixture is diluted with 150 ml of water and made alkaline with sat. Sodium hydrogen carbonate solution. It is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate and concentrated in vacuo.

Rf value: 0.58 (silica gel; dichloromethane/ethanol/conc. ammonia 9:1 :0.1 ) Ci₀Hi₂N₄ (188.23)

Mass spectrum: (M+H)⁺ = 189

(b) δ-chloro-thiophene^-carboxylic acid-prop-2-ynylamide

0.7 ml (10.5 mmol) propargylamine and 2.9 ml (21.0 mmol) TEA are dissolved in 20 ml dichloromethane and at 0-5⁰C combined with 2.0 g (10.5 mmol) 5- chloro-thiophene-2-carboxylic acid chloride, dissolved in 15 ml dichloromethane. The mixture is heated to RT and stirred for 3.5 hours. Then the reaction mixture is washed successively with sat. sodium hydrogen carbonate solution and water. The organic phase is dried on magnesium sulphate, filtered and evaporated to dryness i. vac. The residue is triturated in diisopropylether and dried.

R_f value: 0.68 (silica gel; ethyl acetate/petroleum ether 1 :1 ) C₈H₆CINOS (199.66) Mass spectrum: (M+H)⁺ = 200/202 (chlorine isotopes)

(c) 5-chloro-thiophene-2-carboxylic acid-[1 -(2-methyl-1 ,2,3,4-tetrahydro-1 H- ri ,2,31triazol-4-ylmethyl1-amide

180 mg (0.95 mmol) 6-azido-2-methyl-1 ,2,3,4-tetrahydro-isoquinoline and 190 mg (0.95 mmol) 5-chloro-thiophene-2-carboxylic acid-prop-2-ynylamide are placed in 5 ml dimethylsulphoxide and combined with 12 mg (48 μmol) copper(ll)sulphate-pentahydrate, dissolved in 0.3 ml of water, and with 85 mg (482 μmol) L-(+)-ascorbic acid, dissolved in 0.6 ml of water. The mixture is stirred for four hours at 45°C and then cooled to RT. The reaction mixture is acidified with formic acid and purified by reversed-phase chromatography. The product eluates are freed from acetonitrile i. vac. and washed with sat. sodium hydrogen carbonate solution. The precipitate formed is washed with water until neutral and dried.

Rf value: 0.48 (silica gel; dichloromethane/ethanol/conc. Ammonia 9:1 :0.1 )

Ci₈Hi₈CIN₅OS (387.89)

Mass spectrum: (M+H)⁺ = 388/390 (chlorine isotopes)

The following compounds may be prepared analogously:

Example 5 δ-chloro-thiophene^-carboxylic acid-[1 -(3-methyl-2,3,4,5-tetrahydro-1 H- benzo[d]azepin-7-yl)-2-oxo-2,3-dihydro-1 H-imidazol-4-ylnnethyl]-annide (as the trifluoracetate salt)

(a) δ-chloro-thiophene^-carboxylic acid-(2,3-dihydroxy-propyl)-annide

2.2 g (24.6 mmol) 3-amino-1 ,2-propanediol and 3.1 g (36.9 mmol) sodium hydrogen carbonate are dissolved in 12 ml of water and at 0-5⁰C slowly combined with a solution of 4.5 g (24.6 mmol) δ-chlorothiophene^-carboxylic acid chloride in 12 ml THF. The cooling bath is removed and the mixture is stirred for one hour at RT. The reaction mixture is then filtered to remove insoluble matter and evaporated down i.vaα. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol 100:5 - 90:10). Rf value: 0.17 (silica gel; dichloromethane/methanol 95:5) C₈HioCIN₃OS (235.69)

Mass spectrum: (M+H)⁺ = 236/238 (chlorine isotopes)

(b) δ-chloro-thiophene^-carboxylic acid-(2-hvdroxy-3-trimethylsilanyloxy- propyD-amide 2.8 g (11.7 mmol) δ-chloro-thiophene^-carboxylic acid-(2,3-dihydroxy-propyl)- amide and 1.2 g (17.2 mmol) imidazole are dissolved in 31 ml THF and at 0-5⁰C slowly combined with a solution of 2.0 g (12.7 mmol) thmethylsilyl chloride in 2 ml THF. The cooling bath is removed and the mixture is stirred for three hours at RT. The reaction mixture is then filtered to remove insoluble matter and evaporated down i.vaα. The residue is purified by chromatography on silica gel (petroleum ether/ethyl acetate 4:1 ). Rf value: 0.32 (silica gel; dichloromethane/methanol 4:1 ) Ci₄H₂₈ClN₃OSSi (349.95)

Mass spectrum: (M+H)⁺ = 350/352 (chlorine isotopes)

(c) δ-chloro-thiophene^-carboxylic acid-(3-hvdroxy-2-oxo-propyl)-amide

1.5 ml (17.0 mmol) oxalyl chloride are dissolved in 4 ml dichloromethane and at -70⁰C combined with 1.5 ml dimethylsulphoxide. After 15 minutes stirring 3.0 g (8.5 mmol) 5-chloro-thiophene-2-carboxylic acid-(2-hydroxy-3- trimethylsilanyloxy-propyl)-amide, dissolved in 3 ml dichloromethane, are added. The reaction mixture is stirred for one hour, then combined with 6.0 ml (43.3 mmol) TEA and stirred for another 1.5 hours at -70⁰C. Then the mixture is slowly heated to RT, diluted with dichloromethane and washed successively with 1 N hydrochloric acid, water and sat. saline solution. The organic phase is dried on sodium sulphate and evaporated down i.vaα. The residue is purified by chromatography on silica gel (dichloromethane/methanol 95:5). Rf value: 0.28 (silica gel; dichloromethane/methanol 95:5) C₈H₈CIN₃OS (233.67) Mass spectrum: (M-H)^" = 232/234 (chlorine isotopes)

(d) (3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d1azepin-7-yl)-urea (as the acetate salt)

500 mg (2 mmol) 3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-ylamine (as the bis-HCI salt) and 180 mg (2.2 mmol) potassium cyanate are dissolved in a mixture of 5 ml glacial acetic acid and 25 ml of ethanol and refluxed for four hours. Then the mixture is slowly cooled to RT and evaporated down i.vaα.

The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol 8:2 - 7:3).

Rf value: 0.20 (silica gel; dichloromethane/methanol 7:3) Ci₂Hi₇N₃O x CH₃CO₂H (219.29)

Mass spectrum: (M+H)⁺ = 220 (e) δ-chloro-thiophene^-carboxylic acid-[1 -(3-methyl-2,3,4,5-tetrahvdro-1 H- benzo[d1azepin-7-yl)-2-oxo-2,3-dihvdro-1 H-imidazol-4-ylmethvπ-amide (as the trifluoracetate salt)

70 mg (251 μmol) (3-methyl-2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-yl)-urea

(as the acetate salt) and 73 mg (312 μmol) δ-chloro-thiophene^-carboxylic acid-(3-hydroxy-2-oxo-propyl)-amide are dissolved in a mixture of 1.4 ml of toluene and 0.3 ml DMF and stirred for one hour in the pressure tube at 110⁰C.

Then the mixture is slowly cooled to RT and evaporated down i.vaα. The residue is purified by reversed-phase chromatography.

Rt value: 2.54 min (Method C)

C₂₀H₂INCIN₄O₂S x CF₃CO₂H (416.93)

Mass spectrum: (M+H)⁺ = 417/419 (chlorine isotopes)

The following compounds may be synthesised from derivatives that are known from the literature or that may be prepared analogously to methods of synthesis known from the literature, analogously to the above synthesis steps or analogously to methods of synthesis known from the literature:

The Examples that follow describe the preparation of some pharmaceutical formulations which contain as active substance any desired compound of general formula I:

Example A

Dry ampoule containing 75 mg of active substance per 10 ml

Composition:

Active substance 75.0 mg

Mannitol 50.0 mg water for injections ad 10.0 ml

Preparation: Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.

Example B

Drv ampoule containing 35 mg of active substance per 2 ml

Composition:

Active substance 35.0 mg

Mannitol 100.0 mg water for injections ad 2.0 ml

Preparation: Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.

Example C

Tablet containing 50 mg of active substance

Composition:

(1 ) Active substance 50 .0 mg

(2) Lactose 98 .0 mg

(3) Maize starch 50 .0 mg

(4) Polyvinylpyrrolidone 15. 0 mg

(5) Magnesium stearate 2. 0 mq 215.0 mg

Preparation:

(1 ), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm.

Example D

Tablet containing 350 mq of active substance

Composition:

(1 ) Active substance 350.0 mg

(2) Lactose 136 .0 mg

(3) Maize starch 80 .0 mg

(4) Polyvinylpyrrolidone 30. .0 mg

((55)) MMaaggnneessiiuumm sstteeaarraattee 4. 0 mq

600.0 mg

Preparation: (1 ), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm.

Example E

Capsules containing 50 mq of active substance

Composition:

(1 ) Active substance 50.0 mg

(2) Dried maize starch 58.0 mg

(3) Powdered lactose 50.0 mg

(4) Magnesium stearate 2.0 mq

160.0 mg Preparation:

(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.

Example F

Capsules containinq 350 mq of active substance

Composition:

(1 ) Active substance 350.0 mg

(2) Dried maize starch 46.0 mg

(3) Powdered lactose 30.0 mg

(4) Magnesium stearate 4.0 mq

430.0 mg

Preparation: (1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.

Example G

Suppositories containing 100 mg of active substance

1 suppository contains: Active substance 100.0 mg

Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg

2,000.0 mg Preparation:

The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40⁰C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.

Claims

Patent Claims

1. Compounds of general formula (I)

wherein

D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR 2a -CR^2bR^2c or a -C(O) group, and wherein

_R2a_/R2b_/R2c each independently of one another denote a fluorine atom, a hydroxy, Ci_-5-alkyloxy, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)- amino, Cs-s-cycloalkyleneimino, Ci_-5-alkylcarbonylamino group, a Ci-5-alkyl group which may be substituted by 1 -3 fluorine atoms, a hydroxy-Ci-₅-alkyl, Ci-s-alkyloxy-Ci-s-alkyl, amino-Ci_-5-alkyl, Ci-s-alkylamino-Ci-s-alkyl, di-(Ci-₅-alkyl)-amino-Ci-₅-alkyl, C_4-7- cycloalkyleneimino-Ci-₅-alkyl, carboxy-Co-₅-alkyl, Ci_-5- alkyloxycarbonyl-Co-₅-alkyl, aminocarbonyl-Co-₅-alkyl, Ci-s-alkylanninocarbonyl-Co-s-alkyl, di-(Ci_-5-alkyl)-anninocarbonyl- Co-₅-alkyl or a C_4-7-cycloalkyleneinninocarbonyl-Co-₅-alkyl group, while the two groups R^2b/R^2c cannot both simultaneously be bound to the cyclic carbon atom via a heteroatom, except where -C(R^2bR^2c)- corresponds to a -CF₂ group, or

R^2a denotes a phenyl or monocyclic heteroaryl group substituted by fluorine, chlorine, bromine, methyl, methoxy, amino or nitrogen, or

two groups R^2b/R^2c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetan, azetidine, thietan, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, pipehdine, pentamethylenesulphide, hexamethyleneimine, 1 ,3- dioxolane, 1 ,4-dioxane, hexahydropyridazine, piperazine, thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone, tetrahydro-2(1 H)-pyhmidinone or [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by 1 -2 Ci-₃-alkyl or CF₃- groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1 -2 fluorine atoms, and/or wherein a -CH₂ group besides an N atom may be replaced by a -CO group, and/or the imino groups of which may each be substituted by a Ci-

₃-alkyl or Ci-₃-alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to a sulphoxide or sulphone group,

K² and K³ each independently of one another denote a -CH₂, -CHR^6a, - C_R6b_R6c _{or a} __C(₀) _groupj wherein _R6a_/R6b_/R6c each independently of one another denote a Ci_-5-alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci_-5- alkyl, Ci-s-alkyloxy-Ci-s-alkyl, amino-Ci_-5-alkyl, Ci_-5-alkylamino-Ci-

₅-alkyl, di-(Ci-₅-alkyl)-amino-Ci-₅-alkyl, C_4-7-cycloalkyleneimino-Ci- ₅-alkyl, carboxy-Co-₅-alkyl, Ci-s-alkyloxycarbonyl-Co-s-alkyl, aminocarbonyl-Co-₅-alkyl, Ci-s-alkylaminocarbonyl-Co-s-alkyl, di- (Ci-₅-alkyl)-aminocarbonyl-C₀-₅-alkyl or a C_4-7- cycloalkyleneiminocarbonyl-Co-₅-alkyl group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or a cyclopentene, cyclohexene, oxetan, azetidine, thietan, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylenesulphide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2(1 H)-pyrimidinone, [1 ,3]oxazinan-2-one ring, while the methylene groups thereof may be substituted by 1 -2 Ci-₃-alkyl or CF₃- groups, and/or the methylene groups thereof, if they are not bound to a heteroatom, may be substituted by 1 -2 fluorine atoms, and/or wherein a -CH₂ group besides a nitrogen atom may be replaced by a -CO group, and/or the imino groups of which may each be substituted by a Ci- 3-alkyl or Ci-₃-alkylcarbonyl group, and/or wherein the sulphur atom may be oxidised to a sulphoxide or sulphone group, with the proviso that a heteroatom introduced by R^6b or R^6c cannot be only one carbon atom away from the cyclic nitrogen -N(R¹)- in formula (I), and in total in formula (II) a maximum of four groups selected from R^2a, R^2b, R^2c, R^6a, R^6b and R^6c may be present, and

R¹ denotes a hydrogen atom or a hydroxy, Ci-3-alkyloxy, amino, Ci-3-alkylamino, di-(Ci_-3-alkyl)-amino, a Ci_-5-alkyl, C_2-5-alkenyl- CH₂, C₂-5-alkynyl-CH₂, C_3-6-cycloalkyl, C_4-6-cycloalkenyl, Oxetan-3- yl, tetrahydrofuran-3-yl, benzyl, Ci_-5-alkyl-carbonyl, trifluoromethylcarbonyl, Cs-e-cycloalkyl-carbonyl, Ci_-5-alkyl- sulphonyl, Cs-β-cycloalkyl-sulphonyl, aminocarbonyl, Ci-₅-alkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, Ci_-5- alkyloxycarbonyl, C_4-7-cycloalkyleneiminocarbonyl group, while the methylene and methyl groups contained in the groups mentioned previously may additionally be substituted by a Ci_-3alkyl, carboxy, Ci_-5 - alkoxycarbonyl group, or by a hydroxy, Ci_-5-alkyloxy, amino, Ci_-5-alkylamino, Ci_-5-dialkylamino or C_4-7- cycloalkyleneimino group, provided that the methylene or methyl groups are not directly bound to a heteroatom selected from among O, N or S, and/or one to three hydrogen atoms may be replaced by fluorine atoms, provided that the methylene or methyl groups are not directly bound to a heteroatom selected from among O, N or S,

and wherein

A¹ denotes either N or CR⁹,

A² denotes either N or CR¹⁰, A³ denotes either N or CR¹¹ ,

while R⁹, R¹⁰ and R¹¹ each independently of one another denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a phenyl,

Ci-5-alkyl, CF₃, C2-5 -alkenyl, C2-5-alkynyl, a cyano, carboxy, Ci_-5- alkyloxycarbonyl, hydroxy, Ci_-3-alkyloxy, CF₃O, CHF₂O, CH₂FO, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)-amino or C_4-7- cycloalkyleneimino group, and

R⁴ and R⁵ each independently of one another denote

a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a Ci_-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group,

L denotes a 5-membered monocyclic heteroarylene group optionally substituted in the carbon skeleton by a group R⁶ and the two bonds shown in formula (I) may be provided by two carbon atoms or an imino group and a carbon atom of the heterocyclic group, while any -NH group present may be replaced by an -NR⁶ group, or

a group of general formula (III)

(Hi)₁

while if the bond is provided via an imino group the group D of general formula (I) is linked to the nitrogen atom of the group L, and R⁶ denotes a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a Ci_-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group, while the heteroatoms O or S optionally introduced as substituents are not separated by precisely one carbon atom from the nitrogen atom in the heterocyclic group substituted by R⁶,

B denotes a thiophene ring according to formula (IV),

which is bound to the carbonyl group in formula (I) via the 2 position and which is substituted in the 5 position by R⁷ and optionally additionally by

R⁸, where

R⁷ denotes a fluorine, chlorine, bromine or iodine atom, or a methoxy, Ci_-2-alkyl or ethynyl group,

R⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci-₂-alkyl or amino group,

while, unless stated otherwise, by the term "heteroaryl group" mentioned in the definitions hereinbefore is meant a monocyclic 5- or 6-membered heteroaryl group wherein

the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-nnennbered heteroaryl group contains an imino group optionally substituted according to the above description, or an oxygen or sulphur atom, or

an imino group optionally substituted according to the above description or an oxygen or sulphur atom and additionally one or two nitrogen atoms, or

an imino group optionally substituted according to the above description and three nitrogen atoms,

and furthermore, unless stated otherwise, a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a Ci-3-alkyl, hydroxy, Ci-3-alkyloxy group, amino, Ci_-3-alkylamino, di-(Ci_-3-alkyl)-amino or C3-6- cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms,

and the bond is provided in each case via a nitrogen atom or or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

while, unless stated otherwise, by the term "halogen atom" mentioned hereinbefore in the definitions is meant an atom selected from among fluorine, chlorine, bromine and iodine,

while unless stated otherwise the alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned previously which have more than two carbon atoms may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

2. Compounds of general formula (I) according to claim 1 , wherein

D, R⁴ \, RR⁵⁵ aanndd BB aarree ddeeffiinneedd aass ddeessccrriibbeedd in claim 1 and wherein denotes a group of general formula

while if the bond is provided via an imino group the group D of general formula (I) is linked to the nitrogen atom of the group L, and

R⁶ denotes a hydrogen atom or a straight-chain or branched Ci_-5-alkyl group, which may be wholly or partly substituted by fluorine atoms, and which may optionally be substituted by a hydroxy, Ci_-4-alkyloxy group, a Ci_-4-alkylsulphanyl, or a Ci_-4-alkylsulphonyl group, while the heteroatoms O or S optionally introduced as substituents are not separated by precisely one carbon atom from the nitrogen atom substituted by R⁶ in the heterocyclic group,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

3. Compounds of general formula (I) according to claim 1 or 2, wherein L, R⁴, R⁵ and B are defined as described in Claims 1 or 2 and wherein D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR^2a- or a -CR^2bR^2c group, and wherein

_R2a_/R2b_/R2c each independently of one another denote a fluorine atom, a methoxy or a methyl group, or two groups R^2b/R^2c together with the cyclic carbon atom may form a cyclopropyl ring, and

K² and K³ each independently of one another denote a -CH₂, -CHR^6a or -CR^6bR^6c- group, wherein

_R6a_/R6b_/R6c each independently of one another denote a methyl group, a CF₃ or a cyano group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a cyclopropyl ring, and

R¹ denotes a hydrogen atom or a Ci-₃-alkyl, or C₃-₆-cycloalkyl group, and

A¹ denotes CR⁹,

A² denotes CR¹⁰,

A³ denotes CR¹¹,

while R⁹, R¹⁰ and R¹¹ each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, methoxy, CF₃O, CHF₂O, CH₂FO- group,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

4. Compounds of general formula (I) according to one of Claims 1 , 2 or 3, wherein

D denotes a substituted bicyclic ring system of formula (II)

wherein

K¹ and K⁴ each independently of one another denote a bond, a -CH₂, -CHR^2a- or a -CR^2bR^2c group, and wherein _R2a_/R2b_/R2c each independently of one another denote a methyl group, or two groups R^2b/R^2c together with the cyclic carbon atom may form a cyclopropyl ring, and

K² and K³ each independently of one another denote a -CH₂, -CHR^6a or -CR^6bR^6c- group, wherein

R^6a/R^6b/R^6c each independently of one another denote a methyl group,

or two groups R^6b/R^6c together with the cyclic carbon atom may form a cyclopropyl ring, and

R¹ denotes a hydrogen atom or a Ci_-3-alkyl, or C_3-6-cycloalkyl group,

and

A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes CR¹²,

while R¹⁰, R¹¹, R¹² and R¹³ each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, methoxy, CF₃O, CHF₂O, CH₂FO- group, and enotes a group of general formula

while the group D of general formula (I) is linked to the nitrogen atom of the group L, and

R⁴ and R⁵ in each case represent a hydrogen atom, and

B denotes a thiophene ring according to formula (IV),

which is bound to the carbonyl group in formula (I) via the 2 position and which is substituted in the 5 position by R⁷, while

R⁷ denotes a chlorine or bromine atom, or an ethynyl group,

while unless stated otherwise the alkyl, alkenyl, alkynyl and alkoxy groups contained in the definitions mentioned previously which have more than two carbon atoms may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

5. Physiologically acceptable salts of the compounds according to one of claims 1 to 4.

6. Medicaments, containing a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, optionally in addition to one or more inert carriers and/or diluents.

7. Use of a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a medicament with an inhibitory effect on factor Xa and/or an inhibitory effect on related serine proteases.

8. Process for preparing a medicament according to claim 6, characterised in that a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.