WO2008135525A2 - Substituted azetidines, manufacturing and use thereof as medicaments - Google Patents

Abstract

The present invention relates to new substituted carboxylic acid amides of general formula (I), wherein D, L, E, G, M, R3, R4, R5 et R13 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 AZETIDINES, MANUFACTURING AND USE THEREOF AS

MEDICAMENTS

The present invention relates to new substituted azetidines of general formula (I)

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 1 st embodiment of the present invention includes those compounds of general formula (I) wherein

D denotes a substituted bicyclic ring system of formula

wherein

K¹ denotes a -CH₂, -CHR ₅7a , -CR ₃7'b^DoR7'c^C or a -C(O) group, and wherein

_R7a_/R7b_/R7c 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-C_0-5-alkyl group, while the two groups R^7b/R^7c cannot both simultaneously be bound via a heteroatom to the ring carbon atom, except where -C(R^7bR^7c)- corresponds to a-CF₂ group, or R^7a denotes a phenyl or monocyclic heteroaryl group substituted by fluorine, chlorine, bromine, methyl, methoxy, amino or nitro, or

two groups R^7b/R^7c together with the ring 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, pentamethylene sulphide, hexamethyleneimine, 1 ,3- dioxolan, 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 form a sulphoxide or sulphone group,

K² and K³ each independently of one another denote a -CH₂, -CHR 8a __CR8_bR8c _{or a} __{C(0) g rou pj wh j|e}

R^8a/R^8b/R^8c 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^8b/R^8c together with the ring 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, pentamethylene sulphide, hexamethyleneimine, hexahydropyridazine, tetrahydro-2(1 H)-pyrimidinone 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 a nitrogen atom, may be - A -

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 form a sulphoxide or sulphone group, with the proviso that a heteroatom introduced by R^8b or R^8c cannot be only one carbon atom away from X in formula (I), and

in all there may be not more than four groups selected from R^7a, R^7b, R^7c,

R^8a, R^8b and R^8c, and

X denotes an oxygen or sulphur atom, a CF₂, sulphene, sulphone or an NR¹ group, wherein

R¹ denotes a hydrogen atom or a hydroxy, Ci-3-alkyloxy, amino, Ci-3-alkylamino, di-(Ci_-3-alkyl)-amino, a Ci_-5-alkyl, C2-5-alkenyl-CH₂, C2-5-alkynyl-CH₂, Cs-β-cycloalkyl, C_4-6- cycloalkenyl, Oxetan-3-yl, tetrahydrofuran-3-yl, benzyl, Ci_-5- alkyl-carbonyl, thfluoromethylcarbonyl, C₃-₆-cycloalkyl- carbonyl, Ci_-5-alkyl-sulphonyl, Cs-e-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 present in the above-mentioned groups mayadditionally be substituted by a Ci_-3alkyl, carboxy, Ci_-5 - alkoxycarbonyl group, or may be substituted by a cyano, hydroxy, Ci_-5- alkyloxy, amino, Ci_-5-alkylamino, Ci_-5-dialkylamino or

C^-cycloalkyleneimino group, if 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, if 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 CR¹⁰,

A denotes either N or CR 1 1

A denotes either N or CR 12

while R > 10 , _O R1 1 and R >12 each independently denote

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

or

D denotes a group of formula

wherein

m denotes the number 1 or 2,

R )17 independently of one another denotes a hydrogen, fluorine, chlorine or bromine atom or a Ci-₃-alkyl group, R³ denotes a hydrogen atom or a Ci_-3-alkyl group, and

-L-E-G- denotes a -C-C-C- group, which may be substituted by R⁴ and R⁵, and

R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or C₂-₆-alkynyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or C_2-6-alkynyl group may optionally be wholly or partly replaced by fluorine atoms, and/or

the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or

C₂-₆-alkynyl group optionally each independently substituted by one to two substituents selected from a C_3-5-cycloalkyl group, a nitrile, hydroxy or Ci_-5-alkyloxy group, while the hydrogen atoms of the Ci-5-alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy,

Ci-5-alkylcarbonyloxy, Ci_-5-alkyloxycarbonyloxy, carboxy- Ci-5-alkyloxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyloxy, mercapto, Ci-₅-alkylsulphanyl, Ci_-5-alkylsulphinyl, Ci_-5-alkylsulphonyl, carboxy, Ci-₅-alkyloxycarbonyl, aminocarbonyl, Ci-₅-alkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, C_4-7- cycloalkyleneiminocarbonyl, aminosulphonyl, Ci-₅-alkylaminosulphonyl, di-(Ci_-5-alkyl)-aminosulphonyl, C_4-7- cycloalkyleneiminosulphonyl, amino, Ci_-5-alkylamino, di- (Ci-5-alkyl)-amino, Ci-5-alkylcarbonylamino, Ci_-5-alkyl- sulphonylamino, Λ/-(Ci-5-alkylsulphonyl)-Ci-5-alkylamino, C3-6- cycloalkylcarbonylamino group, or a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl group, while the above-mentioned carbo- and heterocyclic groups in the ring may each be substituted by 1 -4 Ci- ₃-alkyl or Ci_-3-alkylcarbonyl groups or by 1-2 oxo groups, and/or

the hydrogen atoms of the sp²-hybridised carbon atoms of the straight-chain or branched C2-6-alkenyl group may optionally be wholly or partly replaced by fluorine atoms, or

a nitrile, carboxy, aminocarbonyl, Ci_-5-alkylaminocarbonyl, C-3-6- cycloalkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl,

Ci-₅-alkyloxycarbonyl or a C_4-7-cycloalkyleneiminocarbonyl group wherein a methylene group may optionally be replaced by an oxygen, sulphur or Co-3-alkyl-substituted nitrogen atom, or

a phenyl, mono- or bicyclic heteroaryl, phenyl-Ci_-5-alkyl or mono- or bicyclic heteroaryl-Ci_-5-alkyl group, which may optionally be mono- to th-substituted in the phenyl or heteroaryl moiety by identical or different substituents selected from among fluorine, chlorine, bromo-and iodine atoms, and Ci-₅-alkyl, trifluoromethyl, amino, Ci_-5-alkyl-amino, di-(Ci_-5-alkyl)- amino, hydroxy, Ci_-5-alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and Ci_-5-alkyloxycarbonyl group, and

if R⁴ is bound to E, R⁴ may also denote a fluorine atom or a hydroxy, methoxy, C3_-5-alkenyl-oxy, C3_-5-alkynyl-oxy, C2-5-alkyl-oxy, C3-6- cycloalkyl-oxy, Ci-5-alkylaminocarbonyloxy, di(Ci_-5- alkyl)aminocarbonyloxy or C_4-7-cycloalkyleneiminocarbonyloxy, phenyl- Co-3-alkyloxy, heteroaryl-C_0-3-alkyloxy, amino, Ci_-5-alkylamino, di-(Ci_-5- alkyl)-amino, C^-cycloalkyleneimino, Ci-3-acylamino, (Ci-3-acyl)Ci-3- alkylamino, Ci-5-alkyloxycarbonylamino, Ci-5-alkylaminocarbonylamino, di(Ci-₅-alkyl)aminocarbonylamino or a C_4-7-cycloalkyleneiminocarbonyl- amino group, while the methyl or methylene groups present in the above- mentioned alkyl or cycloalkyl groups may each be substituted independently by a substituent selected from among morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dimethylaminocarbonyl, Ci_-5. alkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino, and the above-mentioned phenyl or heteroaryl groups may optionally be mono- to tri-substituted by identical or different substituents selected from among fluorine, chlorine, bromine and iodine atoms, and Ci_-5-alkyl, trifluoromethyl, amino, Ci-5-alkyl-annino, di-(Ci-5-alkyl)-annino, hydroxy, Ci_-5-alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and Ci_-5-alkyloxycarbonyl group,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group, and/or

two atoms form an -O-O or -S-O- bond,

is excluded, and

R⁵ denotes a hydrogen atom, a Ci_-5 alkyl, C₂-₅ alkenyl or C₂-₅ alkynyl or a phenyl-C₀-5 alkyl group, while the alkyl group may be substituted by a hydroxy, methoxy, hydroxycarbonyl or Ci_-5alkoxycarbonyl group, or if R⁵ is linked to E it may also denote a hydroxy or methoxy group, or

R⁴ and R⁵ if they are bound to the same carbon atom, may form, together with the carbon atom, a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form, together with the carbon atom or atoms a 3-7-membered carbocyclic group or a monounsaturated 5-7 membered carbocyclic group,

while one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or by a -NH, -N(Ci_-5-alkyl),

-N(Ci_-4-alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, and/or

two immediately adjacent carbon chain members of these C_4-7-carbocyclic groups may together be replaced by a -C(O)NH,

-C(O)N(Ci_-5-alkyl), -S(O)₂NH, or -S(O)₂N(Ci_-5-alkyl) group, and/or four directly adjacent carbon chain members of these C_5-7-carbocyclic groups may together be replaced by a -0-CH₂- CH₂-O group, and/or

1 to 3 carbon atoms of these 3-7-membered cyclic groups may optionally be substituted independently of one another by in each case one or two fluorine atoms or one or two Ci_-5-alkyl groups or a hydroxy, formyloxy, Ci_-5-alkyloxy, Ci_-5-alkylcarbonyloxy, amino, Ci-5-alkylamino, di-(Ci_-5-alkyl)-amino, C_4-7-cycloalkyleneimino, Ci-5-alkylcarbonylamino, Cs-β-cycloalkylcarbonylamino, nitrile, carboxy-Ci-₅-alkyl, Ci-s-alkyloxycarbonyl-Ci-s-alkyl, carboxy, Ci-₅-alkyloxycarbonyl, aminocarbonyl, Ci-₅-alkylaminocarbonyl, di- (Ci-₅-alkyl)-aminocarbonyl or C_4-7-cycloalkyleneiminocarbonyl group,

with the proviso that a cyclic group of this kind formed from R⁴ and R⁵ together,

wherein two nitrogen atoms or one nitrogen and one oxygen atom are separated from one another in the cyclic group by precisely one optionally substituted -CH₂ group, and/or

wherein two atoms in the ring form a -O-O or -S-O- bond,

is excluded,

R¹³ denotes a hydrogen atom or a Ci_-5 alkyl group,

M denotes a phenyl, thienyl or pyridyl ring optionally substituted by R² and R⁶, wherein

R² denotes a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano Or -C(O)NH₂ group, and

R⁶ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxy, methoxy, trifluoromethoxy, a Ci-3-alkyl, cyano, amino, or NH₂C(O) group optionally substituted by fluorine atoms, while, unless stated otherwise, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while

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

the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci-₃-alkyl group, or an oxygen or sulphur atom, or

an imino group optionally substituted by a Ci-3-alkyl group or an oxygen or sulphur atom and additionally one or two nitrogen atoms, or

an imino group optionally substituted by a Ci-3-alkyl group and three nitrogen atoms,

and moreover 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 effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

and, 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,

and the alkyl, alkenyl, alkynyl and alkyloxy groups with more than two carbon atoms contained in the previous definitions, unless stated otherwise, 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.

Examples of monocyclic heteroaryl groups are the pyridyl, /V-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1 ,2,3]triazinyl, [1 ,3,5]triazinyl, [1 ,2,4]triazinyl, pyrrolyl, imidazolyl, [1 ,2,4]triazolyl, [1 ,2,3]thazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1 ,2,3]oxadiazolyl, [1 ,2,4]oxadiazolyl, furazanyl, thienyl, thiazolyl, isothiazolyl, [1 ,2,3]thiadiazolyl, [1 ,2,4]thiadiazolyl or [1 ,2,5]thiadiazolyl group.

Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]- isothiazolyl, benzo[c/]isothiazolyl, benzooxazolyl, benzo[c] isoxazolyl, benzo[c/]- isoxazolyl, benzo[1 ,2,5]oxadiazolyl, benzo[1 ,2,5]thiadiazolyl, benzo[1 ,2,3]thia- diazolyl, benzo[c/][1 ,2,3]thazinyl, benzo[1 ,2,4]thazinyl, benzothazolyl, 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-6-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, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2- dimethyl-3-butyl or 2,3-dimethyl-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 E, G, L, M, R³-R⁵ and R¹³ are defined as described in embodiment 1 and wherein

D denotes a substituted bicyclic ring system of formula

wherein

K¹ denotes a -CH₂, -CHR ₅7'a^a, -CR 7'b^D _DR 7'c^C or a -C(O) group, and

_R7a_/R7b_/R7c each independently of one another denote a fluorine atom, a hydroxy, Ci_-5-alkyloxy, a Ci_-5-alkyl group, while the two groups R^7b/R^7c cannot simultaneously be bound to the ring carbon atom via a heteroatom, except where -C(R^7bR^7c)- corresponds to a -CF₂ group, or

two groups R^7b/R^7c together with the ring carbon atom may form a 3-membered carbocyclic group and

K² and K³ each independently of one another denote a -CH₂, -CHR^8a, - C_R ^8b _R ^8c _{or a} .Q(O). group, wherein

_R8a_/R8b_/R8c each independently of one another denote a Ci_-5-alkyl group, and/or two groups R^8b/R^8c together with the ring carbon atom may form a 3-membered saturated carbocyclic group and

in all there may be not more than four groups selected from R^7a, R^7b, R^7c, R^8a, R^8b and R^8c, and

X denotes an oxygen or sulphur atom, a sulphene, sulphone, -CF₂- or a NR¹ group, wherein

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 or a C_3-6-cycloalkyl group,

and wherein

A¹ denotes either N or CR¹⁰,

A² denotes either N or CR¹¹,

A³ denotes either N or CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci_-5- alkyl, CF₃, 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.

A 3rd embodiment of the present invention includes those compounds of embodiments 1 or 2 wherein E, G, L, M, R³-R⁵ , R¹³ , D, K¹, K² and K³ are defined as described in the first or second embodiment, and wherein

X denotes a NR¹ group, wherein

R¹ denotes a hydrogen atom or a Ci_-5-alkyl, allyl or cyclopropyl group , and

A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes either N or CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, carboxy, Ci-5-alkyloxycarbonyl, hydroxy, methoxy, CF₃O, CHF₂O, CH₂FO group.

A 4th embodiment of the present invention includes those compounds of general formula (I) wherein D, E, G, L, M, R³ and R¹³ are defined as described in embodiment 1 , 2 or 3, and wherein

R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci-₆-alkyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-6-alkyl group may optionally be wholly or partly replaced by fluorine atoms, and/or

the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl group may optionally each be substituted by a substituent selected from a hydroxy, Ci-₅-alkyloxy, carboxy, Ci_-5-alkyloxycarbonyl, aminocarbonyl, Ci-₅-alkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, C_4-7- cycloalkyleneiminocarbonyl, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)- amino, Ci-5-alkylcarbonylamino, Ci_-5-alkylsulphonylamino, Λ/-(Ci-5-alkylsulphonyl)-Ci-5-alkylamino, Cs-e-cycloalkylcarbonyl- amino group, or

a nitrile, carboxy, aminocarbonyl, Ci-s-alkylaminocarbonyl, C3-6- cycloalkylaminocarbonyl, di-(Ci-₅-alkyl)-aminocarbonyl, Ci-₅-alkyloxycarbonyl or a C_4-7-cycloalkyleneiminocarbonyl group wherein a methylene group may optionally be replaced by an oxygen, sulphur or Co-3-alkyl-substituted nitrogen atom, and

if R⁴ is bound to E, R⁴ may also denote a fluorine atom or a hydroxy, methoxy, C_3-5-alkenyloxy, C_3-5-alkynyloxy, C_2-5-alkyloxy, C_3-6-cycloalkyl- oxy, Ci-5-alkylaminocarbonyloxy, di(Ci_-5-alkyl)aminocarbonyloxy or C_4-7- cycloalkyleneiminocarbonyloxy, phenyl-Co-2-alkyloxy group which may be substituted in the phenyl ring by 1 -2 fluorine atoms or methoxy groups, or denote an amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)-amino, C_4-7- cycloalkyleneimino, Ci-3-acylamino, (Ci-s-acylJCi-s-alkylamino, Ci_-5- alkyloxycarbonylamino, Ci-5-alkylaminocarbonylamino, di(Ci_-5- alkyl)aminocarbonylamino or a C_4-7-cycloalkyleneiminocarbonylamino- group, while the methyl or methylene groups present in the above- mentioned alkyl or cycloalkyl groups may each be substituted independently by a substituents selected from among dimethylaminocarbonyl, Ci-salkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group, and/or

two atoms form a -O-O or -S-O- bond,

is excluded, and

denotes a hydrogen atom or a Ci_-5 alkyl, allyl, propargyl or benzyl group, or if R⁵ is linked to E, it may also denote a hydroxy or methoxy group or R⁴ and R⁵ if they are bound to the same carbon atom, may form together with the carbon atom a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form, together with the carbon atom or atoms, a 3-7-membered carbocyclic group,

while one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or by a -NH, -N(Ci_-5-alkyl),

-N(Ci_-4-alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, and/or

two immediately adjacent carbon chain members of these C_4-7-carbocyclic groups may together be replaced by a -C(O)NH,

-C(O)N(Ci_-5-alkyl), -S(O)₂NH, or -S(O)₂N(Ci_-5-alkyl) group, and/or

four directly adjacent carbon chain members of these C_5-7-carbocyclic groups may together be replaced by a -0-CH₂- CH₂O group,

with the proviso that a cyclic group of this kind formed from R⁴ and R⁵ together,

wherein two nitrogen atoms or one nitrogen and one oxygen atom in the cyclic group are separated from one another by precisely one optionally substituted -CH₂ group, and/or

wherein two atoms in the ring form a -O-O or -S-O- bond,

is excluded.

A 5th embodiment of the present invention includes those compounds of embodiments 1 , 2, 3, or 4, wherein

D denotes a substituted bicyclic ring system of general formula

wherein

K¹ denotes a -CH₂, -CHR^7a, -CR^7bR^7c or a -C(O) group, wherein

R^7a denotes a Ci_-2-alkyl group and

R^7b/R^7c each independently of one another denote a hydroxy, methoxy or a Ci_-3-alkyl group while the two groups R^7b/R^7c cannot simultaneously be bound to the ring carbon atom through an oxygen atom, or two groups R^7b/R^7c together with the ring carbon atom may form a 3-membered carbocyclic group, and

K² and K³ in each case independently of one another denote a -CH₂, - CHR^8a or a -CR^8bR^8c group, wherein

_R8a_/R8b_/R8c each independently of one another denote a Ci-₃-alkyl group, and/or two groups R^8b/R^8c together with the ring carbon atom may form a

3-membered saturated carbocyclic group and

in all there may be not more than four groups selected from R 7a , o R7b , o R7c , R^8a, R^8b and R^8c, and

X denotes an NR¹ group, wherein

R¹ denotes a hydrogen atom or a Ci_-3-alkyl, allyl or cyclopropyl group, and A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, hydroxy, methoxy, CF₃O, CHF₂O, CH₂FO group, and

-L-E-G- denotes a -C-C-C group which may be substituted by R⁴ and R⁵, and

R³ denotes a hydrogen atom, and

R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci_-3-alkyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-6-alkyl group may optionally be substituted independently of one another by a substituent selected from a hydroxy, Ci_-5-alkyloxy, carboxy, Ci-₅-alkyloxycarbonyl group, or

if R⁴ is bound to E, may also denote a fluorine atom or a hydroxy, methoxy, C_3-5-alkenyl-oxy, C_2-5-alkyl-oxy, Cs-6-cycloalkyl-oxy, Ci_-5- alkylaminocarbonyloxy, di(Ci_-5-alkyl)aminocarbonyloxy or C_4-7- cycloalkyleneiminocarbonyloxy group,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group, is excluded, and

R⁵ denotes a hydrogen atom or a Ci_-5 alkyl, allyl or benzyl group, or if R⁵ is linked to E it may also denote a hydroxy or methoxy group, or

R⁴ and R⁵ if they are bound to the same carbon atom, may form together with the carbon atom a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form together with the carbon atom or atoms a

3-6-membered carbocyclic group,

while four directly adjacent carbon chain members of these C_5-6-carbocyclic groups may together be replaced by a -0-CH₂- CH₂O group,

R¹³ denotes a hydrogen atom,

M denotes a phenyl substituted by R² in the 4-position or a pyridyl ring substituted by R² in the 5-position, wherein

R² denotes a fluorine, chlorine, bromine atom, a methoxy or ethynyl group, and

R⁶ denotes a hydrogen or fluorine atom.

A 6th embodiment of the present invention includes those compounds of embodiments 1 , 2, 3, 4 or 5 wherein

D denotes a substituted bicyclic ring system of general formula

A 7th embodiment of the present invention includes those compounds of embodiments 1 , 2, 3, 4, 5 or 6 which are in the R configuration at the chain members E and L of the 4-membered central ring.

An 8th embodiment of the present invention encompasses the following compounds:

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

c/s-(2RS,3RS)-3-(2-methoxy-ethoxy)-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -

[(4-bromo-phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- amide]

c/s-(2RS,3RS)-2-methyl-3-phenoxy-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

c/s-(2RS,3RS)-2-methyl-3-propyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2,3,3-thmethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-amide]

(2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(1 R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

(2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2,3,3-thmethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

and the salts thereof.

According to the invention the compounds of general formula (I) are obtained by methods known per se, for example by the following methods:

(a) The preparation of a compound of general formula (Ma) or (Mb)

wherein A¹ to A³, K¹ to K³, M and R¹ to R⁶ are defined as mentioned in embodiment 1 , and which may optionally be protected at any amino, hydroxy, carboxy or thiol groups durch common protective groups such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which may be cleaved by methods known from the literature, is described in the examples or may be carried out for example according to one of the following formula schemes 1 and 2 or analogously to the methods of synthesis described in WO2004/87695, WO2004/87646 or in WO2003/45912.

Scheme 1

(IVa) (V) i) Acylation

Compound of formula (Ma)

Scheme 2

= amino protecting group )

iv) urea synthesis with

Compound of formula (Na)

(Ilia) wherein

Q/Q¹ denotes a leaving group or a group which may be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy, Ci_-4-alkyloxy, alkyloxycarbonyloxy, 4-nitrophenyloxy, a trichloromethyl or acyloxy group, and

PG denotes a protective group for the amino function known from the literature, such as for example a benzyl, methoxybenzyl, tert.- butoxycarbonyl, benzyloxycarbonyl or a trifluoroacetyl group.

The reaction steps i) -iv) shown in Schemes 1 and 2 may be carried out in the manner described in the Examples or according to the conditions known from the literature, for example as follows:

i) acylation of an amine (IVa) with an optionally activated carboxylic acid (V) or (Vl) :

The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethylsulphoxide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200⁰C, but preferably at temperatures between -10 and 100°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, for example in the presence of ethyl-1 - ethoxy-1 ,2-dihydroquinoline-1 -carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, propanphosphonic acid cycloanhydride, Λ/./V-dicyclohexylcarbodiimide,

A/./V-dicyclohexylcarbodiimide/camphorsulphonic acid, Λ/,Λ/'-dicyclohexylcarbodiimide/Λ/-hydroxysuccinimide or 1 -hydroxy-benzotriazole, Λ/./V-carbonyldiimidazole, O-(benzotriazol-1 -yl)-/V,/V,ΛΛ/V-tetramethyl-uronium tetrafluoroborate/Λ/-nnethylnnorpholine, O-(benzotriazol-1 -yl)- A/./V./V./V-tetrannethyl-uroniunn tetrafluoroborate//V-

5 ethyldiisopropylamine, O-(7-azabenzotriazol-1-yl)-

/V,/V,/V',/V'-tetramethyluronium-hexafluorophosphate//V- methylnnorpholine, O-pentafluorophenyl-Λ/,Λ/,Λ/',Λ/'- tetramethyluronium-hexafluorophosphate/triethylamine, Λ/./V-thionyldiimidazole or triphenylphosphine/carbon io tetrachloride, optionally with the addition of an auxiliary base such as sodium hydroxide solution, caesium, potassium or sodium carbonate or hydrogen carbonate or an amine base such as pyridine, thethylamine, N- methylmorpholine or diisopropylethylamine at temperatures is between -20 and 200⁰C, but preferably at temperatures between -10 and 160⁰C.

The acylation may also be carried out with a carboxylic acid ester (V) or (Vl) and the amine (IVa) by activation with 20 trimethylaluminium.

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.,

25 Pergamon 1995, or in the Houben-Weyl Supplementary

Volume 22, published by Thieme, 2003, and the literature cited therein.

ii) and iii) Cleaving a protective group

30

Any protecting 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

35 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 iodotrimethylsilane, 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 tetrahydrofuran, 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.

However, a protective group may also be cleaved by the methods described by T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

iv) Synthesis of a urea

The reaction of a derivative (Vila) with an isocyanate (VIII) or an optionally activated carbamic acid IX - such as for example a 4-nitrophenylcarbamic acid ester - is carried out in a solvent such as for example water, methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethylsulphoxide or sulpholane or a mixture of these solvents, optionally with the addition of an auxiliary base such as sodium hydroxide solution, caesium, potassium or sodium carbonate or sodium hydrogen carbonate or an amine base such as pyridine, thethylamine, N- methylmorpholine or diisopropylethylamine at temperatures between -20 and 200⁰C, but preferably at temperatures between -10 and 160°C. The compounds of general formula (lib) may be synthesised analogously to Schemes 1 and 2 starting from component (IVb).

(b) The components of general formula (IVa) and (IVb)

wherein A¹, A², A³, K¹, K², K³, X and R³ are defined as in embodiment 1 , and which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups, such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which can be cleaved by methods known from the literature in the course of the synthesis sequence to produce compounds of formula (I), are known from the literature, or their synthesis is described in the embodiments by way of example, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example in WO2006/108709; S. Durand-Henchoz et al. Bull. Soc. Chim. France

1966, 11 , 3413; J. P. Deer et al. Synth. Commun. 2002, 32, 2555; G. J. Quallich et al., J. Org. Chem. 1998, 63, 4116 or in J. D. Harling et al. Synth. Commun. 2001 , 31 , 787.

For example, compounds of general formula (IVa) and (IVb), wherein R³ denotes a hydrogen atom and A¹, A², A³, K¹, K², K³ and X are defined as in embodiment 1 , may be prepared by reduction of the nitro group of compounds of general formula (Xa) and (Xb)

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

The reduction of the nitro group is conveniently carried out for example in a solvent or mixture of solvents such as water, aqueous ammonium chloride solution, hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, acetanhydride with 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 under a pressure of 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, glycoldimethyl ether, diethyleneglycol dimethyl ether, dioxane, tetrahydrofuran, /V-methylpyrrolidinone, or /V-ethyl-diisopropylamine, /V-Ci-5-alkylmorpholine, A/-Ci-₅-alkylpipendine, /V-Ci-s-alkylpyrrolidine, thethylamine, pyridine, for example at temperatures between -30 and 250⁰C, but preferably between 0 and 150⁰C.

(c) The components of general formula

(V), (Vl) wherein R*. R³ R⁶ and R² are defined as mentioned in embodiment 1 , and wherein

Q denotes for example a hydroxy or Ci_-4-alkyloxy group, a halogen atom, an alkyloxycarbonyloxy or acyloxy group, which may optionally be protected at any amino, hydroxy, carboxy or thiol groups by common protective groups such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which may be cleaved in a manner known from the literature during the sequence of synthesis for preparing compounds of formula (I), and PG denotes a protective group for the amino function known from the literature, such as for example a benzyl, methoxybenzyl, tert.- butoxycarbonyl, benzyloxycarbonyl or a trifluoroacetyl group,

are known in the literature, or their synthesis is described in the embodiments by way of example, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example by G. Gerona-Navarro et al., Tet. Lett. 2004, 45, 2193-2196 or C. Palorno et al., Bioorg. Med. Chem. Lett. 1993, 3, 2461-2466.

The components of general formula

(VIII) (IX) wherein R and R are defined as in embodiment 1 , and wherein

Q¹ denotes for example a hydroxy or Ci_-4-alkyloxy group, a halogen atom, an alkyloxycarbonyloxy or acyloxy group which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups, such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which can be cleaved by methods known from the literature in the course of the synthesis sequence to produce compounds of formula (I), are known from the literature, or their synthesis is described in the embodiments by way of example, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example in WO2004/87646, WO2003/45912, WO06/32342 or US2007/0015812.

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.

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.

For example, a suitable protective group for an ethynyl group may be a trimethylsilyl, diphenylmethylsilyl, tert.butyldimethylsilyl or a 1 -hydroxy- 1 -methyl - ethyl group.

Other protective groups which may be used 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 iodotrimethylsilane, 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 anisol.

A te/t.butyl or te/t.butyloxycarbonyl 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 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-tolyltartahc 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 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 may be 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 (10O mMoI) 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, thrombophlebitis, 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.

The compounds specified may also be used as anticoagulants in connection with the preparation, storage, fractionation or use of whole blood or in invasive therapies, e.g. for coating prostheses, artificial heart valves and catheters for reducing the risk of thrombosis.

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 peripoheral 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 new compounds and the physiologically acceptable salts thereof can also be used for the prevention and treatment of arterial vascular diseases in combination therapy with lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, particularly ACE inhibitors, angiotensin Il antagonists, renin inhibitors, β-receptor antagonists, α-receptor antagonists, diuretics, Ca-channel blockers, or stimulators of soluble guanylate cyclase.

By increasing the antithrombotic activity the new compounds and the physiologically acceptable salts thereof can also be used in combination therapy with other anticoagulants such as, for example, unfractionated heparin, low-molecular heparin, fondapahnux or direct thrombin inhibitors, for example recombinant hirudine or "active-site" thrombin inhibitors.

The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, prasugrel, ticlopidine), with P₂T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

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.

Experimental section

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

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 F₂S₄ 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.

The HPLC-MS data were obtained under the following conditions: Method A:

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

The mobile phase used was:

A: water with 0.13% TFA B: acetonitrile

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

0.00 95 5 6.00

0.01 95 5 6.00

0.89 2 98 6.00

0.90 2 98 6.00

0.95 95 5 6.00 1.05 95 5 6.00

1.10 95 5 0.10

The stationary phase used was a Varian MS 100 C18 column, 3 μm, 4.6 mm x 20 mm.

The diode array detection took place in the wavelength range 210-380 nm.

Method B:

Waters Alliance 2695, Waters Micromass ZQ Mass spectrometer with diode array detector 2996. The mobile phase used was:

A: water with 0.13% TFA

B: acetonitrile

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

0.00 95 5 3.50

0.18 95 5 3.50

2.00 2 98 3.50 2.20 2 98 3.50

2,30 95 5 3.50

2.50 95 5 3.50

2.60 95 5 0.10

The stationary phase used was a Varian MS 100 C18 column, 3 μm, 4.6 mm x 30 mm. The diode array detection took place in the wavelength range 210-380 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

time in min %A %B flow rate in ml/min 0.00 95 5 3.50

0.18 95 5 3.50

2.00 2 98 3.50

2.20 2 98 3.50

2,30 95 5 3.50

2.50 95 5 3.50

2.60 95 5 0.50

The stationary phase used was a Varian MS 100 C18 column, 3 μm, 4.6 mm x 30 mm.

The diode array detection took place in the wavelength range 210-380 nm.

Method D

Waters Alliance 2695, Waters Micromass ZQ Mass spectrometer with diode array detector 2996. The mobile phase used was: A: water with 0.1 % ammonia

B: acetonitrile

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

0.00 95 5 4.00

0.01 95 5 4.00

0.89 2 98 4.00

0.90 2 98 4.00

0.95 95 5 4.00

1.05 95 5 4.00

1.10 95 5 0.50

The stationary phase used was a Waters Xbridge C18 column, 3.5 μm, 4.6 mm x 20 mm.

The diode array detection took place in the wavelength range 210-380 nm. The following abbreviations are used in the descriptions of the experiments.

DCM dichloromethane

DIPEA /V-ethyl-diisopropylamine

DMF N, N-ύ imethylformam ide

DMSO dimethylsulphoxide

EtOH ethanol sat. saturated h hour(s)

HATU O-(7-azabenzotriazol-1 -yl)-/V,/V,/V',/V'-tetramethyluronium- hexafluorophosphate i. vac. in vacuo cone. concentrated

MeOH methanol min minute(s)

NMM /V-methyl-morpholine

Rf retention factor

Rt retention time

TBTU O-(benzothazol-1 -yl)-/V,/V,/V, /V- tetramethyluroniumtetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Example 1

Azetidine-1 ,2-dicarboxylic acid-1-[(4-chloro-phenyl)-amide]-2-[(2-nnethyl-1 ,2,3,4- tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

(a) tert. butyl 2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-ylcarbamoyl)- azetidine-1-carboxylate (as the trifluoroacetate salt)

127 mg (631 μmol) 1 -tert. butyl azetidine-1 ,2-dicarboxylate are dissolved in 4 ml THF, combined successively with 0.39 ml DIPEA (2.2 mmol) and 269 mg (0.71 mmol) HATU and stirred for one hour at RT. Then 102 mg (631 μmol) 2-methyl- 1 ,2,3,4-tetrahydro-isoquinolin-6-ylamine are added. The reaction mixture is stirred for a further hour and then evaporated to dryness i.vac. The residue is purified by RP-HPLC.

Rt value: 0.42 min (Method A) Ci₉H₂₇N₃O₃ (345.45) x CF₃CO₂H Mass spectrum: (M+H)⁺ = 346

(b) azetidine-1 , 2-dicarboxylic acid-1 -[(4-chloro-phenyl)-amide]-2-[(2-methyl- 1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

105 mg (229 μmol) tert. butyl 2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6- ylcarbamoyl)-azetidine-1-carboxylate (as the trifluoroacetate salt) are dissolved in 2 ml DCM/TFA mixture and stirred for 30 minutes at RT. Then 1 ml NMM and 40 mg (260 μmol) 4-chloro-phenylisocyanate are added and the mixture is stirred for 1.5 hours. The reaction mixture is evaporated to dryness i.vac. The residue is purified by RP-HPLC.

Rt value: 0.47 min (Method A) C_2IH₂₃CIN₄O₂ (398.90) x CF₃CO₂H

Mass spectrum: (M+H)⁺ = 399/401 (chlorine isotope)

The following compounds may be prepared analogously:

Example 3

Azetidine-1 , 2-dicarboxylic acid-1 -[(5-chloro-pyridin-2-yl)-amide]-2-[(2-methyl- 1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

(a) azetidine-1 , 2-dicarboxylic acid-1 -[(5-chloro-pyridin-2-yl)-amide]-2-[(2- methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

259 mg (1.28 mmol) 4-nitrophenyl chloroformate are added to a solution of 150 mg (1.17 mmol) 2-amino-5-chloro-pyridine in 5 ml DCM and 141 μl (1.75 mmol) pyridine and stirred for 2.5 hours. Then one-third of this reaction mixture is added to a solution of 50 mg (106 μmol) tert. butyl 2-(2-methyl-1 , 2,3,4- tetrahydro-isoquinolin-6-ylcarbamoyl)-azetidine-1 -carboxylate (as the trifluoroacetate salt) and 46 μl (327 μmol) TEA in 2 ml DCM. The reaction mixture is stirred for 16 hours at RT and then combined with 0.5 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are washed with sat. sodium hydrogen carbonate solution and then dried on sodium sulphate, filtered and evaporated down i.vaα. The residue is combined with water/acetonitrile. A solid is precipitated, which is rinsed with a little acetonitrile and dried. Rt value: 1.01 min (Method B) C₂₀H₂₂CIN₅O₂ (399.87) Mass spectrum: (M+H)⁺ = 400/402 (chlorine isotope) Example 4

2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo-phenyl)-annide]-2-[(2- methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-annide] (as the trifluoroacetate salt)

(a) methyl 1 -benzyl-2-methyl-azetidine-2-carboxylate (as the trifluoroacetate salt)

311.0 mg (1.3 mmol) methyl 1 -benzyl-2-methyl-4-oxo-azetidine-2-carboxylate (prepared analogously to G. Gerona-Navarro et al. J. Org. Chem. 2001, 66, 3538) are dissolved in 2 ml THF and combined successively with 491 μl (2.6 mmol) diphenylsilane and 13 mg (14 μmol) of carbonylhydridotris(thphenylphosphine)rhodium(l). The reaction mixture is stirred for 1.5 hours at RT and then evaporated down i. vac. The residue is purified by RP-HPLC. Rt value: 0.84 min (Method B) Ci₃Hi₇NO₂ x CF₃CO₂H (219.29)

Mass spectrum: (M+H)⁺ = 220

(b) 1 -benzyl-2-methyl-azetidine-2-carboxylic acid-(2-methyl-1 ,2,3,4- tetrahydro-isoquinolin-6-yl)-amide (as the bis-trifluoroacetate salt)

240 mg (720 μmol) methyl 1 -benzyl-2-methyl-azetidine-2-carboxylate (as the trifluoroacetate salt) are dissolved in 2 ml of methanol and combined with 4 ml (10 mmol) lithium hydroxide solution (8% in water). The reaction mixture is stirred for three hours at RT, then acidified with hydrochloric acid and freed from methanol i. vac. The aqueous phase is lyophilised. The crude product thus obtained is dissolved in 5 ml DMF and combined with 407 mg (1.1 mmol) HATU and 0.5 ml (3,3 mmol) NMM. The mixture is stirred for 15 minutes and then 174 mg (1.1 mmol) 2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-ylamine are added. The reaction mixture is stirred for three hours at RT and then purified by RP-HPLC. Rt value: 0.88 min (Method B) C₂₂H₂₇N₃O x 2 CF₃CO₂H (349.48) Mass spectrum: (M+H)⁺ = 350

(c) 2-methyl-azetidine-2-carboxylic acid-(2-methyl-1 ,2,3,4-tetrahydro- isoquinolin-6-yl)-amide (as the bis-trifluoroacetate salt)

200 mg (346 μmol) 1 -benzyl-2-methyl-azetidine-2-carboxylic acid-(2-methyl-

1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-annide (as the bis-trifluoroacetate salt) are dissolved in 10 ml of methanol, combined with 50 mg palladium/charcoal and hydrogenated at 3 bar hydrogen and RT for 4.5 hours. Then the catalyst is filtered off and the residue is evaporated down i. vac.

Rt value: 0.25 min (Method B)

Ci₅H₂I N₃O x 2 CF₃CO₂H (259,35) Mass spectrum: (M+H)⁺ = 260

(d) 2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo-phenyl)-amide]-2- [(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

74 mg (152 μmol) 2-methyl-azetidine-2-carboxylic acid-(2-methyl-1 , 2,3,4- tetrahydro-isoquinolin-6-yl)-amide (as the bis-trifluoroacetate salt) are dissolved in 1 ml DMF and combined with 105 μl (748 μmol) TEA and 30 mg (152 μmol) 4-bromo-phenylisocyanate. The reaction mixture is stirred for three hours at RT and then purified by RP-HPLC. Rt value: 1.33 min (Method B) C₂₂H₂₅BrN₄O₂ x CF₃CO₂H (457,37) Mass spectrum: (M+H)⁺ = 457/459 (bromine isotope)

The following compounds may be prepared analogously:

Example 5

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

(a) methyl c/s-(2RS,3RS)-1 -benzyl-3-methoxy-2-methyl-4-oxo-azetidine-2- carboxylate

4.0 ml (43.4 mmol) methyl pyruvate and 4.7 ml (43.4 mmol) benzylamine are dissolved in 200 ml of toluene and the mixture is boiled for 1.5 hours using the water separator. Then 30.8 g (216.8 mmol) sodium sulphate are added, the mixture is cooled to 0⁰C and 24 ml (173 mmol) TEA are added. Then 12.0 ml (131.3 mmol) methoxyacetic acid chloride are slowly added dropwise. After the addition has ended the reaction mixture is refluxed for 1.5 hours. It is filtered to remove insoluble matter and evaporated down i. vac. The residue is purified by RP-HPLC.

Rt value: 1.26 min (Method B) Ci₄Hi₇NO₄ (263.29) Mass spectrum: (M+H)⁺ = 264 (b) methyl c/s-(2RS,3RS)-1 -benzyl-S-methoxy^-methyl-azetidine^- carboxylate

Prepared analogously to Example 4a starting from methyl c/s-(2RS,3RS)-1 - benzyl-3-methoxy-2-methyl-4-oxo-azetidine-2-carboxylate. 5 Rt value: 0.96 min (Method B) Ci₄Hi₉NO₄ (249,31 ) Mass spectrum: (M+H)⁺ = 250

(c) c/s-(2RS,3RS)-1 -benzyl-3-methoxy-2-methyl-azetidine-2-carboxylic acid- io (2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (as the bis- trifluoroacetate salt)

Prepared analogously to Example 4b starting from methyl c/s-(2RS,3RS)-1 - benzyl-3-methoxy-2-methyl-azetidine-2-carboxylate. Rt value: 0.94 min (Method B) is C₂₃H₂₉N₃O₂ x 2 CF₃CO₂H (379.51 )

Mass spectrum: (M+H)⁺ = 380

(d) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-2-carboxylic acid-(2- methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (as the bis-

20 trifluoroacetate salt)

Prepared analogously to Example 4c starting from c/s-(2RS,3RS)-1 -benzyl-3- methoxy-2-methyl-azetidine-2-carboxylic acid-(2-methyl-1 ,2,3,4-tetrahydro- isoquinolin-6-yl)-amide (as the bis-thfluoroacetate salt).

Rt value: 0,35 min (Method B) 25 Ci₆H₂₃N₃O₂ x 2 CF₃CO₂H (289,38)

Mass spectrum: (M+H)⁺ = 290

(e) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4- bromo-phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-

₃o amide] (as the trifluoroacetate salt)

Prepared analogously to Example 4d starting from c/s-(2RS,3RS)-3-methoxy-2- methyl-azetidine-2-carboxylic acid-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6- yl)-amide (as the bis-thfluoroacetate salt).

Rt value: 1.29 min (Method B) S5 C₂₃H₂₇BrN₄O₃ x CF₃CO₂H (487.40)

Mass spectrum: (M+H)⁺ = 487/489 (bromine isotope) The following compounds may be prepared analogously:

N^c Structural formula Mass peak(s) Rf value or R_t

Name c/s-(2RS,3RS)-3-methoxy-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-nnethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-annide] (as the trifluoroacetate salt)

18 V-, (M+H)⁺ = 515/517 R_t = 1.29 min (bromine isotope) (Method C) c/s-(2RS,3RS)-3-methoxy-2-nnethyl-azetidine-1 ,2-dicarboxylic acid-1 ^■ [(4-bromo-phenyl)-amide]-2-[(2,3,3-trimethyl-1 ,2,3,4-tetrahydro- isoquinolin-7-yl)-amide] (as the trifluoroacetate salt

22 (M+H)⁺ = 573/575 Rt = 0.88 min (bromine isotope) (Method D)

c/s-(2RS,3RS)-6-{[1 -(4-bromo-phenylcarbamoyl)-3-methoxy-2-methyl- azetidine-2-carbonyl]-amino}-3,4-dihydro-1 H-isoquinolin-2-carboxylate tert. butyl

Example 19

(2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(1 R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

(a) 3-amino-phenyl-acetonitrile

Palladium/charcoal 10% (4.5g) is added to a solution of 3-nitro-phenyl- acetonitrile (46 g, 284 mmol) in methanol (644 ml_). The mixture is hydrogenated at 1.1 bar hydrogen atmosphere and at 20⁰C for 35 minutes. Then it is filtered to remove the catalyst and evaporated down i.vaα. Rt value: 0.22 min (Method C) C₈H₈N₂ (132.16)

Mass spectrum: (M+H)⁺ = 133

(b) methyl (3-cyanomethyl-phenyl)-carbamate A solution of 3-amino-phenyl-acetonitrile (81 g, 613 mmol) and DIPEA (151.6 ml_, 885 mmol) in dichloromethane (1 L) is cooled to 2°C in an ice bath and within one hour combined with a solution of methyl chloroformate (59 ml_, 767 mmol) in dichloromethane (100 ml_). Then the reaction mixture is heated to RT and stirred for 16 hours. The mixture is then poured into 1.5 L water and the organic phase is separated off. The organic phase is washed successively with sat. aqueous citric acid solution (1 L), sat. aqueous sodium hydrogen carbonate solution and with sat. aqueous saline solution. Then the organic phase is stirred with activated charcoal, dried on sodium sulphate and concentrated i.vaα. Rt value: 1.08 min (Method C)

Mass spectrum: (M+H)⁺ = 191

(c) methyl [3-(2-amino-ethyl)-phenyl]-carbamate Raney nickel (60 g) is added to a solution of methyl (3-cyanomethyl-phenyl)- carbamate (119 g, 626 mmol) in methanolic ammonia solution (7 M, 600 mL). The mixture is hydrogenated with 5 bar hydrogen atmosphere for three hours at 6O⁰C. Then it is filtered to remove the catalyst and evaporated down i.vaα. Rt value: 0.74 min (Method C) Ci₀Hi₄N₂O₂ (194.23)

Mass spectrum: (M+H)⁺ = 195

(d) methyl [3-(2-acetylamino-ethyl)-phenyl]-carbamate

A solution of methyl [3-(2-amino-ethyl)-phenyl]-carbamate (121 g, 623 mmol) and triethylamine (175 ml, 1246 mmol) in dichloromethane (1 L) is cooled to 2°C using an ice bath and then a solution of acetanhydride (88,3 ml, 935 mmol) in dichloromethane (100 ml) is added slowly, so that the temperature does not rise above 10⁰C. The reaction mixture is then heated to RT within one hour and then poured into sat. sodium hydrogen carbonate solution. The organic phase is separated off, washed with sat. saline solution, dried on sodium sulphate and evaporated down i.vaα. Rt value: 0.97 min (Method C) Ci₂Hi₆N₂O₃ (236.27)

Mass spectrum: (M+H)⁺ = 237

(e) methyl (1 -methyl-3,4-dihydro-isoquinoline-6-yl)-carbamate A solution of methyl [3-(2-acetamino-ethyl)-phenyl]-carbamate (135 g, 573 mmol) in chloroform (2.2 L) is cooled to <1 °C in the ice bath and then within two hours a suspension of phosphorus pentachloride (250.4 g, 1.2 mol) in chloroform (1.8 L) is added batchwise so that the temperature does not rise above 9°C. The reaction mixture is heated to RT and stirred for 16 hours. The precipitate formed is filtered off, washed with 1 L chloroform and dissolved in 2 L ice water. Solid potassium hydroxide is added until the pH is about 8. The solid then precipitated is filtered off, washed thoroughly with ice water and then dried at 40⁰C under a slight vacuum (20 mbar). Rt value: 0.81 min (Method C) Ci₂Hi₄N₂O₂ (218.25)

Mass spectrum: (M+H)⁺ = 219

(f) methyl (f?)-(1 -methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-carbamate (as the formate salt) Dichloro-(p-cymene)-ruthenium(ll)-dimer (166 mg, 271 μmol) and (1 S,2S)-(+)- N-p-tosyl-1 ,2-diphenylene-diamine (202 mg, 551 μmol) are dissolved in formic acid-thethylamine complex (50 ml) under an argon atmosphere and within 30 minutes combined with a solution of methyl (1 -methyl-3,4-dihydro-isoquinolin-6- yl)-carbamate (21.8 g, 100 mmol) in warm DMSO (200 ml). The reaction mixture is stirred for 17 hours at RT. A precipitate is formed which is filtered off, washed with dichloromethane and then dried. Rt Wert: 0.79 min (Method C) Ci₂Hi₆N₂O₂ x HCO₂H (220.27) Mass spectrum: (M+H)⁺ = 221

A conventional HPLC system with a DAICEL OJ-H 250 mm x 4.6 mm chiral column with a particle size of 5 μm is used to determine the enantiomeric excess. Elution is carried out with (hexane + 0.2% diethylamine)/isopropanol mixture 70:30 as the liquid phase with a flow rate of 1 ml/min at 10⁰C. The following retention times were obtained accordingly for the enantiomers: (R)-enantiomer (main isomer): R_t Wert: 8.69 min (S)-enantiomer: R_t Wert: 9.40 min

An enantiomeric excess of >98% is determined, in favour of the desired (R)- enantiomer. The stereochemistry is assigned analogously to the process described in the literature for the reagent.

(g) methyl (R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-carbamate Methyl (R)-(I -methyl-1 , 2, 3,4-tetrahydro-isoquinolin-6-yl)-carbamate (as the formate salt) (10.0 g, 37.6 mmol) is dissolved in 400 ml of methanol and combined with 8.4 ml formaldehyde (37% in water, 112.7 mmol). Then 15.9 g (75.1 mmol) sodium triacetoxyborohydride are added to the mixture batchwise, and the mixture is stirred for two hours at RT. Then the mixture is concentrated i.vaα, taken up in ice water and made alkaline by the addition of 4N sodium hydroxide solution. The precipitate formed is filtered off, washed with cold water and dried.

Rt value: 0.48 min (Method D)

CnHi₆N₂ (234.29)

Mass spectrum: (M+H)⁺ = 235

(h) (R)-1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-ylamine

Methyl (R)-(1 ,2-dimethyl-1 , 2, 3,4-tetrahydro-isoquinolin-6-yl)-carbamate (7.2 g, 30.7 mmol) is dissolved in 19 ml of methanol and combined with 41 ml (123 mmol) 3N potassium hydroxide solution. The mixture is refluxed for 75 minutes, then cooled and concentrated i.vac. The residue is mixed with ice water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered off and evaporated to dryness. Rt Wert: 0.48 min (Method D) CnHi₆N₂ (176.26) Mass spectrum: (M+H)⁺ = 177

(i) methyl (2R,3R)-1 -benzyl-S-methoxy^-methyM-oxo-azetidine^- carboxylate

For preparative separation of the racemate methyl c/s-(2RS,3RS)-1 -benzyl-3- methoxy-2-methyl-4-oxo-azetidine-2-carboxylate into its corresponding enantiomers a conventional HPLC system with a DAICEL AS-H 250 mm x 20 mm chiral column with a particle size of 5 μm is used. Elution is carried out with liquid carbon dioxide/(isopropanol+0.2% diethylamine) mixture 70:30 as the liquid phase with a flow rate of 70 ml/min.

For analytical separation of the racemate methyl c/s-(2RS,3RS)-1-benzyl-3- methoxy-2-methyl-4-oxo-azetidine-2-carboxylate into its corresponding enantiomers a conventional HPLC system with a DAICEL AS-H 250 mm x 4.6 mm chiral column with a particle size of 5 μm is used. Elution is carried out with liquid carbon dioxide/(isopropanol) mixture 90:10 as the liquid phase with a flow rate of 5 ml/min. Accordingly, the following retention times are obtained for the enantiomers: enantiomer 1 : methyl (2R,3R)-1 -benzyl-3-methoxy-2-methyl-4-oxo-azetidine-2- carboxylate

Rt value: 1.45 min

Ci₄Hi₇NO₄ (263.29)

Mass spectrum: (M+H)⁺ = 264

enantiomer 2: methyl (2S,3S)-1-benzyl-3-methoxy-2-methyl-4-oxo-azetidine-2- carboxylate Rt value: 2.77 min Ci₄Hi₇NO₄ (263.29) Mass spectrum: (M+H)⁺ = 264

(i) (2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(1 R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- amide] (as the trifluoroacetate salt)

Prepared analogously to the reaction sequence of Example 5 b-e starting from methyl (2R,3R)-1 -benzyl-3-methoxy-2-methyl-4-oxo-azetidine-2-carboxylate (silane reduction, hydrolysis and amide coupling, hydrogenation and urea formation). Rt value: 1.22 min (Method C) C₂₄H₂₉BrN₄O₃ x CF₃CO₂H (501.43)

Mass spectrum: (M+H)⁺ = 501/503 (bromine isotope)

The following compounds may be prepared analogously:

Example 23

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

(a) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4- bromo-phenyl)-amide]-2-[(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

320 mg (558 μmol) tert. butyl c/s-(2RS,3RS)-6-{[1-(4-bromo-phenylcarbamoyl)-

3-methoxy-2-methyl-azetidine-2-carbonyl]-amino}-3,4-dihydro-1 H-isoquinolin-2- carboxylate are dissolved in 5 ml of a mixture of trifluoroacetic acid/dichloromethane (v/v 1 :1 ) and stirred for one hour at RT. Then the mixture is evaporated to dryness and purified by preparative HPLC (eluant acetonitrile, water, cone, ammonia).

Rt value: 0.69 min (Method D) C₂₂H₂₅BrN₄O₃ (473,36) Mass spectrum: (M+H)⁺ = 473/475 (bromine isotope)

(b) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4- bromo-phenyl)-amide]-2-[(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- amide] (as the trifluoroacetate salt)

50 mg (106 μmol) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo-phenyl)-amide]-2-[(1 , 2, 3,4-tetrahydro-isoquinolin-6-yl)-amide] are suspended in 0.5 ml_ dichloromethane and combined with 11.0 μl_ (211 μmol) acetaldehyde and 16.9 μl_ (306 μmol) glacial acetic acid. The mixture is stirred for 30 minutes at RT, then 10.6 mg (169 μmol) sodium cyanoborohydride are added and the reaction mixture is stirred for four days at RT. Then the mixture is taken up in a mixture of methanol, DMF and water and purified by preparative HPLC.

Rt value: 0.76 min (Method D)

C₂₄H₂₉BrN₄O₃ (501.42)

Mass spectrum: (M+H)⁺ = 501/503 (bromine isotope)

The following compounds may be prepared analogously:

Example 27

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-cyanomethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide] (as the trifluoroacetate salt)

(a) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4- bromo-phenyl)-amide]-2-[(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide]

50 mg (106 μmol) c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo-phenyl)-amide]-2-[(1 , 2, 3,4-tetrahydro-isoquinolin-6-yl)-amide] are suspended in 0.5 ml_ dichloromethane and combined with 30 μl_ (211 μmol) triethylamine and 7 μl_ (106 μmol) bromoacetonitrile. The reaction mixture is stirred for four days at RT. Then the mixture is taken up in a mixture of methanol, DMF and water and purified by preparative HPLC. Rt value: 0.74 min (Method D) C₂₄H₂₆BrN₅O₃ (512.40)

Mass spectrum: (M+H)⁺ = 512/514 (bromine isotope) 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 containinq 35 mq 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 containinq 50 mq of active substance

5 Composition:

(1 ) Active substance 50.0 mg

(2) Lactose 98.0 mg

(3) Maize starch 50.0 mg o (4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mq

215.0 mg

Preparation: s (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. 0 Example D

Tablet containinq 350 mq of active substance

Composition: 5

(1 ) Active substance 350 .0 mg

(2) Lactose 136 .0 mg

(3) Maize starch 80 .0 mg

(4) Polyvinylpyrrolidone 30. .0 mg 0 (5) Magnesium stearate 4. 0 mq

600.0 mg

Preparation:

(1 ), (2) and (3) are mixed together and granulated with an aqueous solution of5 (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

wherein

K¹ denotes a -CH₂, -CHR i7a , -CR ^■>7bi R->7c or a -C(O) group, and wherein

_R7a_/R7b_/R7c 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_-5-alkyloxy-Ci-₅-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^7b/R^7c cannot both simultaneously be bound via a heteroatom to the ring carbon atom, except where -C(R^7bR^7c)- corresponds to a-CF₂ group, or R^7a denotes a phenyl or monocyclic heteroaryl group substituted by fluorine, chlorine, bromine, methyl, methoxy, amino or nitro, or

two groups R^7b/R^7c together with the ring 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, pentamethylene sulphide, hexamethyleneimine, 1 ,3- dioxolan, 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 form a sulphoxide or sulphone group,

K² and K³ each independently of one another denote a -CH₂, -CHR^8a, __CR8_bR8c _{or a} __{C(0) g rou pj wh j|e}

R^8a/R^8b/R^8c 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^8b/R^8c together with the ring 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, pentamethylene sulphide, hexamethyleneimine, hexahydropyridazine, 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 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 form a sulphoxide or sulphone group, with the proviso that a heteroatom introduced by R^8b or R^8c cannot be only one carbon atom away from X in formula (I), and

in all there may be not more than four groups selected from R^7a, R^7b, R^7c, R^8a, R^8b and R^8c, and

X denotes an oxygen or sulphur atom, a CF₂, sulphene, sulphone or an NR¹ group, wherein

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, Cs-β-cycloalkyl, C_4-6- cycloalkenyl, Oxetan-3-yl, tetrahydrofuran-3-yl, benzyl, Ci_-5- alkyl-carbonyl, thfluoromethylcarbonyl, C₃-₆-cycloalkyl- carbonyl, Ci_-5-alkyl-sulphonyl, C_3-6-cycloalkyl-sulphonyl, aminocarbonyl, Ci-₅-alkylanninocarbonyl, di-(Ci_-5-alkyl)- aminocarbonyl, Ci-₅-alkyloxycarbonyl, C_4-7- cycloalkyleneiminocarbonyl group, while the methylene and methyl groups present in the above-mentioned groups may additionally be substituted by a Ci-3-alkyl, carboxy, Ci_-5 - alkoxycarbonyl group, or may be substituted by a hydroxy, Ci_-5-alkyloxy, amino, Ci_-5-alkylamino, Ci_-5-dialkylamino or C_4-7- cycloalkyleneimino group, if 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, if 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 CR¹⁰,

A² denotes either N or CR¹¹ ,

A³ denotes either N or CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

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

or

D denotes a group of formula

wherein

m denotes the number 1 or 2,

R¹⁷ independently of one another denotes a hydrogen, fluorine, chlorine or bromine atom or a Ci_-3-alkyl group,

R³ denotes a hydrogen atom or a Ci_-3-alkyl group, and

-L-E-G- denotes a -C-C-C- group, which may be substituted by R⁴ and R⁵, and

R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or C₂-₆-alkynyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or C_2-6-alkynyl group may optionally be wholly or partly replaced by fluorine atoms, and/or

the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl, C₂-₆-alkenyl or C₂-₆-alkynyl group optionally each independently substituted by one to two substituents selected from a C_3-5-cycloalkyl group, a nitrile, hydroxy or Ci_-5-alkyloxy group, while the hydrogen atoms of the Ci-5-alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, Ci-5-alkylcarbonyloxy, Ci_-5-alkyloxycarbonyloxy, carboxy- Ci-5-alkyloxy, Ci-s-alkyloxycarbonyl-Ci-s-alkyloxy, mercapto, Ci-₅-alkylsulphanyl, Ci_-5-alkylsulphinyl, Ci_-5-alkylsulphonyl, carboxy, Ci-₅-alkyloxycarbonyl, aminocarbonyl, Ci-₅-alkylanninocarbonyl, di-(Ci-₅-alkyl)-anninocarbonyl, C_4-7- cycloalkyleneiminocarbonyl, aminosulphonyl,

Ci-₅-alkylanninosulphonyl, di-(Ci_-5-alkyl)-annirιosulphonyl, C_4-7- cycloalkyleneiminosulphonyl, amino, Ci_-5-alkylannino, di- (Ci-5-alkyl)-annino, Ci-5-alkylcarbonylannino, Ci_-5-alkyl- sulphonylamino, W-(Ci_-5-alkylsulphonyl)-Ci-5-alkylannino, C3-6- cycloalkylcarbonylamino group, or einer morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl group, while the above- mentioned carbo- and heterocyclic groups in the ring may each be substituted by 1 -4 Ci-₃-alkyl or Ci-₃-alkylcarbonyl groups or by 1 -2 oxo groups, and/or

the hydrogen atoms of the sp²-hybhdised carbon atoms of the straight-chain or branched C2-6-alkenyl group may optionally be wholly or partly replaced by fluorine atoms, or

a nitrile, carboxy, aminocarbonyl, Ci-5-alkylaminocarbonyl, C3-6- cycloalkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, Ci-₅-alkyloxycarbonyl or a C_4-7-cycloalkyleneiminocarbonyl group wherein a methylene group may optionally be replaced by an oxygen, sulphur or Co-3-alkyl-substituted nitrogen atom, or

a phenyl, mono- or bicyclic heteroaryl, phenyl-Ci_-5-alkyl or mono- or bicyclic heteroaryl-Ci_-5-alkyl group, which may optionally be mono- to th-substituted in the phenyl or heteroaryl moiety by identical or different substituents selected from among fluorine, chlorine, bromo-and iodine atoms, and Ci-₅-alkyl, trifluoromethyl, amino, Ci_-5-alkyl-amino, di-(Ci_-5-alkyl)- amino, hydroxy, Ci_-5-alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and Ci_-5-alkyloxycarbonyl group, and

if R⁴ is bound to E, R⁴ may also denote a fluorine atom or a hydroxy, methoxy, C_3-5-alkenyl-oxy, C_3-5-alkynyl-oxy, C_2-5-alkyl-oxy, C3-6- cycloalkyl-oxy, Ci-s-alkylaminocarbonyloxy, di(Ci_-5- alkyl)aminocarbonyloxy or C_4-7-cycloalkyleneinninocarbonyloxy, phenyl- Co-3-alkyloxy, heteroaryl-Co-3-alkyloxy, amino, Ci_-5-alkylannino, di-(Ci_-5- alkyl)-amino, C^-cycloalkyleneimino, Ci-3-acylannino, (Ci-3-acyl)Ci-3- alkylamino, Ci-5-alkyloxycarbonylannino, Ci-5-alkylanninocarbonylannino, di(Ci-5-alkyl)anninocarbonylannino or a C_4-7-cycloalkyleneiminocarbonyl- amino group, while the methyl or methylene groups present in the above- mentioned alkyl or cycloalkyl groups may each be substituted independently by a substituent selected from among morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dimethylaminocarbonyl, Ci_-5. alkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino, and the above-mentioned phenyl or heteroaryl groups may optionally be mono- to tri-substituted by identical or different substituents selected from among fluorine, chlorine, bromine and iodine atoms, and Ci_-5-alkyl, trifluoromethyl, amino, Ci_-5-alkyl-amino, di-(Ci-5-alkyl)-amino, hydroxy, Ci_-5-alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and Ci_-5-alkyloxycarbonyl group,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group, and/or

two atoms form an -O-O or -S-O- bond,

is excluded, and

R⁵ denotes a hydrogen atom, a Ci_-5 alkyl, C₂-s alkenyl or C₂-s alkynyl or a phenyl-Co-5 alkyl group, while the alkyl group may be substituted by a hydroxy, methoxy, hydroxycarbonyl or Ci_-5alkoxycarbonyl group, or if R⁵ is linked to E it may also denote a hydroxy or methoxy group, or

R⁴ and R⁵ if they are bound to the same carbon atom, may form, together with the carbon atom, a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form, together with the carbon atom or atoms a 3-7-membered carbocyclic group or a monounsaturated 5-7 membered carbocyclic group,

while one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or by a -NH, -N(Ci_-5-alkyl), -N(Ci_-4-alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, and/or

two immediately adjacent carbon chain members of these C_4-7-carbocyclic groups may together be replaced by a -C(O)NH, -C(O)N(Ci_-5-alkyl), -S(O)₂NH, or -S(O)₂N(Ci_-5-alkyl) group, and/or

four directly adjacent carbon chain members of these C_5-7-carbocyclic groups may together be replaced by a -0-CH₂- CH₂-O group, and/or

1 to 3 carbon atoms of these 3-7-membered cyclic groups may optionally be substituted independently of one another by in each case one or two fluorine atoms or one or two Ci_-5-alkyl groups or a hydroxy, formyloxy, Ci_-5-alkyloxy, Ci_-5-alkylcarbonyloxy, amino, Ci-5-alkylamino, di-(Ci_-5-alkyl)-amino, C_4-7-cycloalkyleneimino,

Ci-5-alkylcarbonylamino, Cs-β-cycloalkylcarbonylamino, nitrile, carboxy-Ci-₅-alkyl, Ci-s-alkyloxycarbonyl-Ci-s-alkyl, carboxy, Ci-₅-alkyloxycarbonyl, aminocarbonyl, Ci-₅-alkylaminocarbonyl, di- (Ci-₅-alkyl)-aminocarbonyl or C_4-7-cycloalkyleneiminocarbonyl group,

with the proviso that a cyclic group of this kind formed from R⁴ and R⁵ together,

wherein two nitrogen atoms or one nitrogen and one oxygen atom are separated from one another in the cyclic group by precisely one optionally substituted -CH₂ group, and/or wherein two atoms in the ring form a -O-O or -S-O- bond,

is excluded,

R >1ⁱ3^ό denotes a hydrogen atom or a Ci_₅ alkyl group,

M denotes a phenyl, thienyl or pyridyl ring optionally substituted by R² and R⁶, wherein

R² denotes a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano Or -C(O)NH₂ group, and

R⁶ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxy, methoxy, trifluoromethoxy, a Ci-3-alkyl, cyano, amino, or

NH₂C(O) group optionally substituted by fluorine atoms,

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

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

the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci-₃-alkyl group, or an oxygen or sulphur atom, or

an imino group optionally substituted by a Ci-3-alkyl group or an oxygen or sulphur atom and additionally one or two nitrogen atoms, or

an imino group optionally substituted by a Ci-3-alkyl group and three nitrogen atoms,

and moreover 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 effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,

and, 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,

and the alkyl, alkenyl, alkynyl and alkyloxy groups with more than two carbon atoms contained in the previous definitions, unless stated otherwise, 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 E, G, L, M, R³-R⁵ and R¹³ are defined as described in claim 1 , and wherein

D denotes a substituted bicyclic ring system of formula

wherein

K¹ denotes a -CH₂, -CHR^7a, -CR^7bR^7c or a -C(O) group, and

_R7a_/R7b_/R7c each independently of one another denote a fluorine atom, a hydroxy, Ci_-5-alkyloxy, a Ci_-5-alkyl group, while the two groups R^7b/R^7c cannot simultaneously be bound to the ring carbon atom via a heteroatom, except where -C(R^7bR^7c)- corresponds to a -CF₂ group, or

two groups R^7b/R^7c together with the ring carbon atom may form a

3-membered carbocyclic group and

K² and K³ each independently of one another denote a -CH₂, -CHR ,8a , - CR^8bR^8c or a -C(O)- group, wherein

_R8a_/R8b_/R8c each independently of one another denote a Ci_-5-alkyl group, and/or two groups R^8b/R^8c together with the ring carbon atom may form a

3-membered saturated carbocyclic group and

in all there may be not more than four groups selected from R^7a, R^7b, R^7c, R^8a, R^8b and R^8c, and

X denotes an oxygen or sulphur atom, a sulphene, sulphone, -CF₂- or a NR¹ group, wherein

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 or a C₃-₆-cycloalkyl group,

and wherein

A¹ denotes either N or CR¹⁰, A² denotes either N or CR¹¹ ,

A³ denotes either N or CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci_-5-alkyl, CF₃, 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,

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 E, G, L, M, R³-R⁵ , R¹³ , D, K¹, K² and K³ are defined as described in the first or second claims, and wherein

X denotes a NR¹ group, wherein

R¹ denotes a hydrogen atom or a Ci_-5-alkyl, allyl or cyclopropyl group , and

A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes either N or CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, cyano, carboxy, Ci_-5- alkyloxycarbonyl, hydroxy, 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 to 3, wherein D, E, G, L, M, R³ and R¹³ are defined as described in claims 1 , 2 or 3, and wherein

R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci_-6-alkyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-6-alkyl group may optionally be wholly or partly replaced by fluorine atoms, and/or

the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-₆-alkyl group may optionally each be substituted by a substituent selected from a hydroxy, Ci-₅-alkyloxy, carboxy, Ci_-5-alkyloxycarbonyl, aminocarbonyl,

Ci-₅-alkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, C_4-7- cycloalkyleneiminocarbonyl, amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)- amino, Ci-5-alkylcarbonylamino, Ci_-5-alkylsulphonylamino, Λ/-(Ci-5-alkylsulphonyl)-Ci-5-alkylamino, C_3-6-cycloalkylcarbonyl- amino group, or

a nitrile, carboxy, aminocarbonyl, Ci_-5-alkylaminocarbonyl, C-3-6- cycloalkylaminocarbonyl, di-(Ci_-5-alkyl)-aminocarbonyl, Ci-₅-alkyloxycarbonyl or a C_4-7-cycloalkyleneiminocarbonyl group wherein a methylene group may optionally be replaced by an oxygen, sulphur or

Co-3-alkyl-substituted nitrogen atom, and

if R⁴ is bound to E, R⁴ may also denote a fluorine atom or a hydroxy, methoxy, C3_-5-alkenyloxy, C3_-5-alkynyloxy, C2-5-alkyloxy, C3-6-cycloalkyl- oxy, Ci-5-alkylaminocarbonyloxy, di(Ci_-5-alkyl)aminocarbonyloxy or C_4-7- cycloalkyleneiminocarbonyloxy, phenyl-Co-2-alkyloxy group which may be substituted in the phenyl ring by 1 -2 fluorine atoms or methoxy groups, or denote an amino, Ci_-5-alkylamino, di-(Ci_-5-alkyl)-amino, C_4-7- cycloalkyleneimino, Ci_-3-acylamino, (Ci-s-acyOCi-s-alkylamino, Ci_-5- alkyloxycarbonylamino, Ci-5-alkylaminocarbonylamino, di(Ci_-5- alkyl)aminocarbonylamino or a C_4-7-cycloalkyleneiminocarbonylamino- group, while the methyl or methylene groups present in the above- mentioned alkyl or cycloalkyl groups may each be substituted independently by a substituents selected from among dimethylaminocarbonyl, Ci-salkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group, and/or

two atoms form a -O-O or -S-O- bond,

is excluded, and

R⁵ denotes a hydrogen atom or a Ci_-5 alkyl, allyl, propargyl or benzyl group, or if R⁵ is linked to E, it may also denote a hydroxy or methoxy group or

R⁴ and R⁵ if they are bound to the same carbon atom, may form together with the carbon atom a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form, together with the carbon atom or atoms, a 3-7-membered carbocyclic group,

while one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or by a -NH, -N(Ci_-5-alkyl), -N(Ci_-4-alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, and/or

two immediately adjacent carbon chain members of these C_4-7-carbocyclic groups may together be replaced by a -C(O)NH, -C(O)N(Ci_-5-alkyl), -S(O)₂NH, or -S(O)₂N(Ci_-5-alkyl) group, and/or

four directly adjacent carbon chain members of these C_5-7-carbocyclic groups may together be replaced by a -0-CH₂- CH₂O group,

with the proviso that a cyclic group of this kind formed from R⁴ and R⁵ together,

wherein two nitrogen atoms or one nitrogen and one oxygen atom in the cyclic group are separated from one another by precisely one optionally substituted -CH₂ group, and/or

wherein two atoms in the ring form a -O-O or -S-O- bond,

is excluded,

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

5. Compounds of general formula (I) according to one of claims 1 to 4, wherein

D denotes a substituted bicyclic ring system of general formula

wherein

K¹ denotes a -CH₂, -CHR^7a, -CR^7bR^7c or a -C(O) group, wherein

R^7a denotes a Ci_-2-alkyl group and R^7b/R^7c each independently of one another denote a hydroxy, methoxy or a Ci-3-alkyl group while the two groups R^7b/R^7c cannot simultaneously be bound to the ring carbon atom through an oxygen atom, or two groups R^7b/R^7c together with the ring carbon atom may form a 3-nnennbered carbocyclic group, and

K² and K³ in each case independently of one another denote a -CH₂, - CHR^8a or a -CR^8bR^8c group, wherein

_R8a_/R8b_/R8c each independently of one another denote a Ci-₃-alkyl group, and/or two groups R^8b/R^8c together with the ring carbon atom may form a

3-membered saturated carbocyclic group and

in all there may be not more than four groups selected from R^7a, R^7b, R^7c, R^8a, R^8b and R^8c, and

X denotes an NR¹ group, wherein

R¹ denotes a hydrogen atom or a Ci_-3-alkyl, allyl or cyclopropyl group, and

A¹ denotes CR¹⁰,

A² denotes CR¹¹,

A³ denotes CR¹²,

while R¹⁰, R¹¹ and R¹² each independently denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF₃, hydroxy, methoxy, CF₃O, CHF₂O, CH₂FO group, and

-L-E-G- denotes a -C-C-C group which may be substituted by R⁴ and R⁵, and

R³ denotes a hydrogen atom, and R⁴ denotes a hydrogen atom or

a straight-chain or branched Ci-₃-alkyl group, while the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched Ci-6-alkyl group may optionally be substituted independently of one another by a substituent selected from a hydroxy, Ci_-5-alkyloxy, carboxy, Ci-₅-alkyloxycarbonyl group, or

if R⁴ is bound to E, may also denote a fluorine atom or a hydroxy, methoxy, C3_-5-alkenyl-oxy, C2-5-alkyl-oxy, Cs-β-cycloalkyl-oxy, Ci_-5- alkylaminocarbonyloxy, di(Ci_-5-alkyl)aminocarbonyloxy or C_4-7- cycloalkyleneiminocarbonyloxy group,

with the proviso that

two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted -CH₂ group,

is excluded, and

R⁵ denotes a hydrogen atom or a Ci_-5 alkyl, allyl or benzyl group, or if R⁵ is linked to E it may also denote a hydroxy or methoxy group, or

R⁴ and R⁵ if they are bound to the same carbon atom, may form together with the carbon atom a -C=O group, or a - CF₂- group, or

R⁴ and R⁵ if they are bound to the same carbon atom or to two adjacent carbon atoms, may form together with the carbon atom or atoms a 3-6-membered carbocyclic group,

while four directly adjacent carbon chain members of these C_5-6-carbocyclic groups may together be replaced by a -0-CH₂-

CH₂O group, R¹³ denotes a hydrogen atom,

M denotes a phenyl substituted by R² in the 4-position or a pyridyl ring substituted by R² in the 5-position, wherein

R² denotes a fluorine, chlorine, bromine atom, a methoxy or ethynyl group, and

R⁶ denotes a hydrogen or fluorine atom,

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

6. Compounds of general formula (I) according to one of claims 1 to 5, wherein

D denotes a substituted bicyclic ring system of general formula

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

7. Compounds of general formula (I) according to one of claims 1 to 6, which are in the R-configuration at the chain members E and L of the 4- membered central ring,

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

8. The following compounds of general formula (I) according to claim 1 :

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide];

c/s-(2RS,3RS)-3-(2-methoxy-ethoxy)-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -

[(4-bromo-phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- amide];

c/s-(2RS,3RS)-2-methyl-3-phenoxy-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide];

c/s-(2RS,3RS)-2-methyl-3-propyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide];

c/s-(2RS,3RS)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2,3,3-thmethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-amide];

(2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(1 R)-(1 ,2-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide];

(2R,3R)-3-methoxy-2-methyl-azetidine-1 ,2-dicarboxylic acid-1 -[(4-bromo- phenyl)-amide]-2-[(2,3,3-thmethyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-amide];

and the salts thereof.

9. Physiologically acceptable salts of the compounds according to one of claims 1 to 8.

10. Medicaments, containing a compound according to at least one of claims 1 to 8 or a physiologically acceptable salt according to claim 9, optionally in addition to one or more inert carriers and/or diluents.

11. Use of a compound according to at least one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 for preparing a medicament with an inhibitory effect on factor Xa and/or an inhibitory effect on related serine proteases.

12. Method of preparing a medicament according to claim 10, characterised in that a compound according to at least one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.