Guanidine and amidine derivatives as factor Xa inhibitors

A compound of the formula I,

• 21
• wherein
• R0 is
• 1. phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R2 or
• 2. a mono- or bicyclic 5- to 10-membered heteroaryl containing one or two nitrogen atoms as ring heteroatoms, wherein heteroaryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R2,
• R2is
• 1. —NO2,
• 2. halogen,
• 3. —CN,
• 4. —OH,
• 5. —NH2,
• 6. (C1-C8)-alkyloxy-, wherein alkyloxy is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, amino group, hydroxy group or methoxy group, or
• 7. —(C1-C8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, amino group, hydroxy group or methoxy group,
• Q and Q′ are independently of one another identical or different and are a direct bond, —O—, —S—, —NR10—, —C(O)NR10—, —NR10C(O)—, —S(O)—, —SO2—, —NR10—SO2—, —SO2—NR10— oder —C(O)—;
• R10 is hydrogen atom or (C1-C4)-alkyl-,
• X is
• 1. a direct bond,
• 2. (C1-C6)-alkylen, wherein alkylen is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, amino group or a hydroxy group,
• 3. (C3-C6)-cycloalkylen, wherein cycloalkylen is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, amino group or a hydroxy group,
• provided that at least one of Q, X and Q′ is not a direct bond,
• D is an atom out of the group carbon, oxygen, sulfur and nitrogen, the substructure of formula III
• 22
• is
• 1. a mono- or bicyclic 5- to 10-membered carbocyclic aryl group, wherein said 5- to 10-membered carbocyclic aryl group is unsubstituted or mono-, di- or trisubstituted independently of one another by R1,
• 2. phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R1,
• 3. a mono- or bicyclic 5-to 10-membered heterocyclic group (Het), containing one or more heteroatoms as ring heteroatoms, such as nitrogen, sulfur or oxygen, wherein said Het group is unsubstituted or mono-, di- or trisubstituted independently of one another by R1, or
• 4. pyridyl, wherein pyridyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R1,
• R1 is
• 1. halogen,
• 2. —NO2,
• 3. —CN,
• 4. R11R12N—, wherein R11R12 independently of one another are hydrogen atom, (C1-C4)-alkyl- or (C1-C6)-acyl-,
• 5. (C1-C8)-alkylamino-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 6. —OH,
• 7. —SO2—NH2,
• 8. (C1-C8)-alkyloxy-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 9. (C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 10. (C1-C8)-alkyl-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 11. hydroxycarbonyl-(C1-C8)-alkylureido-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 12. (C1-C8)-alkyloxycarbonyl-(C1-C8)-alkylureido-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• 13. (C1-C8)-alkylsulfonyl-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, or
• 14. —C(O)—NR14R15, wherein R4R15 independently of one another are hydrogen atom or (C1-C4)-alkyl-, or
• two R1 residues bonded to adjacent ring carbon atoms together with the carbon atoms to which they are bonded form an aromatic ring condensed to the ring depicted in formula I, where the ring formed by the two R1 residues is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• R11 and R12 together with the nitrogen atom to which they are bonded form a saturated or unsaturated 5- to 6-membered monocyclic heterocyclic ring which in addition to the nitrogen atom carrying R11 and R12 can contain one or two identical or different ring heteroatoms chosen from oxygen, sulfur and nitrogen, and in which one or two of the ring carbon atoms can be substituted by oxo to form —C(O)— residue(s),
• R13 is
• 1. halogen,
• 2. —NO2,
• 3. —CN,
• 4. —OH,
• 5. (C1-C8)-alkyl-,
• 6. (C1-C8)-alkyloxy-,
• 7. —CF3 or
• 8. —NH2,
• V is a residue of the formulae IIa, IIb, IIc, IId, IIe or IIf,
• 23
• wherein
• L is is a direct bond or (C1-C3)-alkylene, wherein alkylene is unsubstituted or mono-, di- or trisubstituted independently of one another by A,
• A is
• 1. hydrogen atom,
• 2. —C(O)—OH,
• 3. —C(O)—O—(C1-C4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or tri-substituted independently of one another by —OH, —NH2 or —(C1-C4)-alkoxy,
• 4. —C(O)—NR4R5,
• 5. (C1-C4)-alkyl-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by —OH, —NH2 or —(C1-C4)-alkoxy,
• 6. —SO2—NH2 or
• 7. —SO2—CH3,
• U is —NH2, (C1-C4)-alkyl-,—NH—C(O)—O—(C1-C4)-alkyl or —NH—C(O)—O—(C1-C4)-alkyl-aryl,
• M is hydrogen atom, (C1-C3)-alkyl- or —OH,
• R4 and R5 are independently of one another identical or different and are
• 1. hydrogen atom,
• 2. (C1-C12)-alkyl-, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13 as defined above,
• 3. (C6-C14)-aryl-(C1-C4)-alkyl-, wherein alkyl and aryl are unsubstituted or mono-, di- or trisubstituted independently of one another by R13 as defined above,
• 4. (C6-C14)-aryl-, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13 as defined above,
• 5. Het-, wherein Het- is unsubstituted or mono-, di- or trisubstituted independently of one another by R13 as defined above, or
• 6. Het-(C1-C4)-alkyl-, wherein alkyl and Het- are unsubstituted or mono-, di- or trisubstituted independently of one another by R13 as defined above, or
• R4 and R5 together with the nitrogen atom to which they are bonded form a saturated 3- to 8-membered monocyclic heterocyclic ring which in addition to the nitrogen atom carrying R4 and R5 can contain one or two identical or different ring heteroatoms chosen from oxygen, sulfur and nitrogen;
• in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts.