SUBSTITUTED OXAZOLIDINONES AND THEIR USE IN THE FIELD OF BLOOD COAGULATION

• US 20100137274A1
• Filed: 06/30/2009
• Published: 06/03/2010
• Est. Priority Date: 12/24/1999
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Lampe, Thomas, Pernerstorfer, Joseph, Rohrig, Susanne, Perzborn, Elisabeth, Schlemmer, Karl-Heinz, Straub, Alexander, Pohlmann, Jens
• Granted Patent: US 8,129,378 B2
• Time in Patent Office: Days
• US Class Current: 514/210.200
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I)

processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.

Claims

1. Compounds of the general formula (I)

in which:

R¹ represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted;

R² represents any organic radical;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₆)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

except for compounds of the general formula (I) in which the radical R¹ is an unsubstituted 2-thiophene radical and the radical R² is simultaneously a mono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

2. Compounds of the general formula (I) according to claim 1, characterized in that

R¹ represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen;

cyano;

nitro;

amino;

aminomethyl;

(C₁-C₈)-alkyl which for its part may optionally be mono- or polysubstituted by halogen;

(C₃-C₇)-cycloalkyl;

(C₁-C₈)-alkoxy;

imidazolinyl;

—

C(═

NH)NH₂;

carbamoyl; and

mono- and di-(C₁-C₄)-alkyl-aminocarbonyl,

R² represents one of the groups below;

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where;

the radical “

A”

represents (C₆-C₁₄)-aryl, preferably (C₆-C₁₀)-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;

the radical “

B”

represents a 5- or 6-membered aromatic heterocycle which contains up to 3 heteroatoms and/or hetero chain members, in particular up to 2 heteroatoms and/or hetero chain members, from the group consisting of S, N, NO(N-oxide) and O;

the radical “

D”

represents a saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused 4- to 9-membered hetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

the radical “

M”

represents —

NH—

, —

CH₂—

, —

CH₂CH₂—

, —

O—

, —

NH—

CH₂—

, —

CH₂—

NH—

, —

OCH₂—

, —

CH₂O—

, —

CONH—

, —

NHCO—

, —

COO—

, —

OOC—

, —

S—

, —

SO₂—

or represents a covalent bond;

where

the groups “

A”

, “

B” and

“

D”

defined above may each optionally be mono- or polysubstituted by a radical from the group consisting of halogen;

trifluoromethyl;

oxo;

cyano;

nitro;

carbamoyl;

pyridyl;

(C₁-C₆)-alkanoyl;

(C₃-C₇)-cycloalkanoyl;

(C₆-C₁₄)-arylcarbonyl;

(C₅-C₁₀)-heteroarylcarbonyl;

(C₁-C₆)-alkanoyloxymethyloxy;

(C₁-C₄)-hydroxyalkylcarbonyl;

—

COOR²⁷;

—

SO₂R²⁷;

—

C(NR²⁷R²⁸)═

NR²⁹;

—

CONR²⁸R²⁹;

—

SO₂NR²⁸R²⁹;

—

OR³⁰;

—

NR³⁰R³¹, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,

where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano;

—

OR²⁷;

—

NR²⁸R²⁹;

—

CO(NH)_v(NR²⁷R²⁸) and —

C(NR²⁷R²⁸)═

NR²⁹,

where;

v is either 0 or 1 and

R²⁷, R²⁸ and R²⁹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, O and S, and

R³⁰ and R³¹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, —

CH₂C(NR²⁷R²⁸)═

NR²⁹ or —

COR³³,

where

R³³ represents (C₁-C₆)-alkoxy, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl-(C₁-C₄)-alkyl, (C₁-C₄)-aminoalkyl, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkanoyl-(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkenyl, (C₁-C₈)-alkyl, which may optionally be substituted by phenyl or acetyl, (C₆-C₁₄)-aryl, (C₅-C₁₀)-heteroaryl, trifluoromethyl, tetrahydrofuranyl or butyrolactone,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₆)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

except for compounds of the general formula (I) in which the radical R¹ is an unsubstituted 2-thiophene radical and the radical R² is simultaneously a mono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

3. Compounds of the general formula (I) according to claim 1, characterized in that

R¹ represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, by amino, aminomethyl or (C₁-C₈)-alkyl, preferably methyl, where the (C₁-C₈)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,

R² represents one of the groups below:

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where;

the radical “

A”

represents (C₆-C₁₄)-aryl, preferably (C₆-C₁₀)-aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;

the radical “

B”

represents a 5- or 6-membered aromatic heterocycle which contains up to 3 heteroatoms and/or hetero chain members, in particular up to 2 heteroatoms and/or hetero chain members, from the group consisting of S, N, NO(N-oxide) and O;

the radical “

D”

represents a saturated or partially unsaturated 4- to 7-membered heterocycle which contains up to three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

the radical “

M”

represents —

NH—

, —

CH₂—

, —

CH₂CH₂—

, —

O—

, —

NH—

CH₂—

, —

CH₂—

NH—

, —

OCH₂—

, —

CH₂O—

, —

CONH—

, —

NHCO—

, —

COO—

, —

OOC—

, —

S—

or represents a covalent bond;

where

the groups “

A”

, “

B” and

“

D”

defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen;

trifluoromethyl;

oxo;

cyano;

nitro;

carbamoyl;

pyridyl;

(C₁-C₆)-alkanoyl;

(C₃-C₇)-cycloalkanoyl;

(C₆-C₁₄)-arylcarbonyl;

(C₅-C₁₀)-heteroarylcarbonyl;

(C₁-C₆)-alkanoyloxymethyloxy;

—

COOR²⁷;

—

SO₂R²⁷;

—

C(NR²⁷R²⁸)═

NR²⁹;

—

CONR²⁸R²⁹;

—

SO₂NR²⁸R²⁹;

—

OR³⁰;

—

NR³⁰R³¹, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,

where (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl for their part may optionally be substituted by a radical from the group consisting of cyano;

—

OR²⁷;

—

NR²⁸R²⁹;

—

CO(NH)_v(NR²⁷R²⁸) and —

C(NR²⁷R²⁸)═

NR²⁹,

where;

v is either 0 or 1 and

R²⁷, R²⁸ and R²⁹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl, and/or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, O and S, and

R³⁰ and R³¹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, (C₆-C₁₄)-arylcarbonyl, (C₅-C₁₀)-heteroarylcarbonyl, (C₁-C₄)-alkylaminocarbonyl or —

CH₂C(NR²⁷R²⁸)═

NR²⁹,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₆)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

except for compounds of the general formula (I) in which the radical R¹ is an unsubstituted 2-thiophene radical and the radical R² is simultaneously a mono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

4. Compounds of the general formula (I) according to claim 1, characterized in that

R¹ represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (C₁-C₆)-alkyl, preferably methyl, where the (C₁-C₈)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, preferably fluorine,

R² represents one of the groups below:

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where;

the radical “

A”

represents phenyl or naphthyl, in particular phenyl;

the radical “

B”

represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO(N-oxide) and O;

the radical “

D”

represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO₂, N, NO(N-oxide) and O;

the radical “

M”

represents —

NH—

, —

O—

, —

NH—

CH₂—

, —

CH₂—

NH—

, —

OCH₂—

, —

CH₂O—

, —

CONH—

, —

NHCO—

or represents a covalent bond;

where

the groups “

A”

, “

B” and

“

D”

defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen;

trifluoromethyl;

oxo;

cyano;

pyridyl;

(C₁-C₃)-alkanoyl;

(C₆-C₁₀)-arylcarbonyl;

(C₅-C₆)-heteroarylcarbonyl;

(C₁-C₃)-alkanoyloxymethyloxy;

—

C(NR²⁷R²⁸)═

NR²⁹;

—

CONR²⁸R²⁹;

—

SO₂NR²⁸R²⁹;

—

OH;

—

NR³⁰R³¹;

(C₁-C₄)-alkyl; and

cyclopropyl, cyclopentyl or cyclohexyl,

where (C₁-C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano;

—

OH;

—

OCH₃;

—

NR²⁸R²⁹;

—

CO(NH)_v(NR²⁷R²⁸) and —

C(NR²⁷R²⁸)═

NR²⁹,

where;

v is either 0 or 1, preferably 0, and

R²⁷, R²⁸ and R²⁹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and

R³⁰ and R³¹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₃)-alkanoyl or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₆)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

except for compounds of the general formula (I) in which the radical R¹ is an unsubstituted 2-thiophene radical and the radical R² is simultaneously a mono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

5. Compounds of the general formula (I) according to claim 1, characterized in that

R¹ represents 2-thiophene which may optionally be substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl or trifluoromethyl,

R² represents one of the groups below:

A-,

A-M-,

D-M-A-,

B-M-A-,

B-,

B-M-,

B-M-B-,

D-M-B-,

where;

the radical “

A”

represents phenyl or naphthyl, in particular phenyl;

the radical “

B”

represents a 5- or 6-membered aromatic heterocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO(N-oxide) and O;

the radical “

D”

represents a saturated or partially unsaturated 5- or 6-membered heterocycle which contains a nitrogen atom and optionally a further heteroatom and/or hetero chain member from the group consisting of S, SO, SO₂ and O;

or contains up to two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO₂ and O;

the radical “

M”

represents —

NH—

, —

O—

, —

NH—

CH₂—

, —

CH₂—

NH—

, —

OCH₂—

, —

CH₂O—

, —

CONH—

, —

NHCO—

or represents a covalent bond;

where

the groups “

A”

, “

B” and

“

D”

defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen;

trifluoromethyl;

oxo;

cyano;

pyridyl;

(C₁-C₃)-alkanoyl;

(C₆-C₁₀)-arylcarbonyl;

(C₅-C₆)-heteroarylcarbonyl;

(C₁-C₃)-alkanoyloxymethyloxy;

—

CONR²⁸R²⁹;

—

SO₂NR²⁸R²⁹;

—

OH;

—

NR³⁰R³¹;

(C₁-C₄)-alkyl;

where (C₁-C₄)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano;

—

OH;

—

OCH₃;

—

NR²⁸R²⁹;

—

CO(NH)_v(NR²⁷R²⁸) and —

C(NR²⁷R²⁸)═

NR²⁹,

where;

v is either 0 or 1, preferably 0, and

R²⁷, R²⁸ and R²⁹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or

R²⁷ and R²⁸ or R²⁷ and R²⁹ together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N, O and S, and

R³⁰ and R³¹ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₄)-alkylsulphonyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-aminoalkyl, di-(C₁-C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁-C₃)-alkanoyl or phenylcarbonyl,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₄)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

except for compounds of the general formula (I) in which the radical R¹ is an unsubstituted 2-thiophene radical and the radical R² is simultaneously a mono- or polysubstituted phenyl radical and the radicals R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each simultaneously hydrogen.

6. Compounds of the general formula (I) according to claim 1, characterized in that

R¹ represents 2-thiophene which is substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl and trifluoromethyl,

R² represents D-A-:

where;

the radical “

A”

represents phenylene;

the radical “

D”

represents a saturated 5- or 6-membered heterocycle,

which is attached to “

A”

via a nitrogen atom,

which has a carbonyl group directly adjacent to the linking nitrogen atom and

in which one carbon ring member may be replaced by a heteroatom from the group consisting of S, N and O;

where

the group “

A”

defined above may optionally be mono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a radical from the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano,

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ each represent hydrogen

and their pharmaceutically acceptable salts, hydrates and prodrugs.

7. Compound according to claim 1 having the following formula

and its pharmaceutically acceptable salts, hydrates and prodrugs.

8. Process for preparing substituted oxazolidinones according to claim 1, where either according to a process alternative

[A] compounds of the general formula (II)

in which

the radicals R², R³, R⁴, R⁵, R⁶ and R⁷ are each as defined in claim 1 are reacted with carboxylic acids of the general formula (III)

in which

the radical R¹ is as defined in claim 1,

or else with the corresponding carbonyl halides, preferably carbonyl chlorides, or else with the corresponding symmetric or mixed carboxylic anhydrides of the carboxylic acids of the general formula (III) defined above

in inert solvents, if appropriate in the presence of an activating or coupling agent and/or a base, to give compounds of the general formula (I)

in which

the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined in claim 1,

or else according to a process alternative

[B] compounds of the general formula (IV)

in which

the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined in claim 1,

are converted, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the general formula (V)

in which

the radicals R¹, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined in claim 1,

and, by reaction in an inert solvent, if appropriate in the presence of a catalyst, with an amine of the general formula (VI)

R²—

NH₂ 

 

(VI),

in which

the radical R² is as defined in claim 1,

the compounds of the general formula (VII)

in which

the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined in claim 1,

are initially prepared and,

subsequently, in an inert solvent in the presence of phosgene or phosgene equivalents, such as, for example, carbonyldiimidazole (CDI), cyclized to give the compounds of the general formula (I)

in which

the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each as defined in claim 1,

where—

both for process alternative [A] and for process alternative [B]—

in the case where R² contains a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical having one or more identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the corresponding sulphone, sulphoxide or N-oxide may follow

and/or

where—

both for process alternative [A] and for process alternative [B]—

in the case where the compound prepared in this manner has a cyano group in the molecule, an amidination of this cyano group by customary methods may follow

and/or

where—

both for process alternative [A] and for process alternative [B]—

in the case where the compound prepared in this manner has a BOC amino protective group in the molecule, removal of this BOC amino protective group by customary methods may follow

and/or

where—

both for process alternative [A] and for process alternative [B]—

in the case where the compound prepared in this manner has an aniline or benzylamine radical in the molecule, a reaction of this amino group with various reagents such as carboxylic acids, carboxylic anhydrides, carbonyl chlorides, isocyanates, sulphonyl chlorides or alkyl halides to give the corresponding derivatives may follow

and/or

where—

both for process alternative [A] and for process alternative [B]—

in the case where the compound prepared in this manner has a phenyl ring in the molecule, a reaction with chlorosulphonic acid and subsequent reaction with amines to give the corresponding sulphonamides may follow.

9. Medicaments, comprising at least one compound of the general formula (I) according to claim 1 and one or more pharmacologically acceptable auxiliaries or excipients.

10. Use of compounds of the general formula (I)

in which:

R¹ represents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted;

R² represents any organic radical;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each represents hydrogen or represents (C₁-C₆)-alkyl

and their pharmaceutically acceptable salts, hydrates and prodrugs,

for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aorto-coronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.

11. Use of compounds of the general formula (I) according to claim 10 for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of disorders which are influenced positively by inhibition of factor Xa.

12. Use of compounds of the general formula (I) according to claim 10 for preparing medicaments or pharmaceutical compositions for the treatment of disseminated intravascular coagulation (DIC).

13. Use of compounds of the general formula (I) according to claim 10 for preparing medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of disorders such as atherosclerosis;

arthritis;

Alzheimer'"'"'s disease or cancer.

14. Use of compounds of the general formula (I) according to claim 10 for preparing medicaments or pharmaceutical compositions for the inhibition of factor Xa.

15. Method for preventing the coagulation of blood in vitro, in particular in the case of banked blood or biological samples containing factor Xa, characterized in that compounds of the general formula (I) according to claim 10 are added.