Base-substituted benzylamine analogs for use as coagulation factor Xa inhibitors, the production and use thereof

1. A compound of the general formula I

where

A is P 2 -P 1 with

R 1 is H;

R 2 is —CH 2 —OR 7 or —CH 2 —OCOOR 7 , where R 7 is H or a branched or unbranched alkyl radical having 1-5 C atoms, or R 2 is a —CH 2 —CH 2 —COOR 7* or —CH 2 —CH 2 —CH 2 —COOR 7* , where R 7* is H or a branched or unbranched alkyl radical having 1-5 C atoms;

R 3 is H;

R 4 is —(CH 2 ) f —R 8 with f=0 or 2 or —CH═CH—R 8 , where R 8 is a mono- or polysubstituted or unsubstituted phenyl ring that is attached to —(CH 2 ) f — or —CH═CH— at a carbon of said phenyl ring or a mono- or polysubstituted or unsubstituted pyridyl radical that is attached to —(CH 2 ) f — or —CH═CH— at a carbon of the pyridyl ring, and where P 2 in the structure A of the general formula I is in the D or L configuration;

R 5 is —SO 2 R 9* or —SO 2 —NH—R 9* , where R 9* is a mono- or polysubstituted or unsubstituted aralkyl or heteroaralkyl radical, where the optional substituent is selected from —OH, —O—COOR 7 , —CH 2 —OCOOR 7 , with R 7 as defined above, —NH 2 , —NO 2 , —COOR 10 , —CH 2 —COOR 10 group or a CI, F or Br atom, and where R 10 is an H or an alkyl radical having 1 to 6 C atoms;

U is a phenyl or pyridyl radical;

V is (CH 2 ) n with n=0 or 1;

X is CH;

Y is CH; and

z occurs in position 2, 3 or 4, and is an aminomethyl, a guanidino group or an amidino group

where R 11 is H, OH, NH 2 , —COR 12 or —COOR 12 , where R 12 is a branched or unbranched alkyl radical having 1 to 8 C atoms or a mono- or polysubstituted or unsubstituted aryl or heteroaryl, aralkyl or heteroaralkyl radical, where the alkyl radical has 1 to 16 C atoms and the aryl or heteroaryl radical has 4 to 14 C atoms;

or a compound of the general formula I in the form of its salt.

2. The compound as claimed in claim 1 , characterized in that the structural element

of the formula I is a —CH 2 — or —NH— group.

3. The compound as claimed in claim 1 , characterized in that R 2 is —CH 2 —CH 2 —COOH, —CH 2 —CH 2 —COOCH 2 CH 3 or —CH 2 OH;

R 4 is —(CH 2 ) 2 —R 8 ;

R 5 is a benzylsulfonyl, aminobenzylsulfonyl, hydroxybenzylsulfonyl, chlorobenzylsulfonyl, fluorobenzylsulfonyl, carboxybenzylsulfonyl, ethyloxycarbonylbenzylsulfonyl, carboxymethylbenzyl-sulfonyl, ethyloxycarbonylmethylbenzylsulfonyl, pyridylmethylsulfonyl, or N-(oxide)-pyridylmethylsulfonyl radical;

U is a phenyl radical;

V is (CH 2 ) n with n=0; and

z is present in position 4 and is an amidino group

where R 11 is H, OH or —COOR 12 with R 12 a branched or unbranched alkyl radical having 2, 4, or 6 C atoms.

4. The compound as claimed in claim 1 , characterized in that R 4 is a —CH 2 —CH 2 —R 8 radical, where R 8 is optionally substituted by one or more —NH 2 and/or —OH groups.

5. The compound as claimed in claim 1 , characterized in that the substituent is —OH, —NH 2 , —NO 2 , —COOH, —COOCH 2 CH 3 , or a halogen.

6. A compound selected from the following structures:

where the radical R is selected from the radicals

where the linkage of the group R to the Cγ carbon atom of the radical P 2 originates from the atom labeled with an asterisk, and the amino acid on which the radical R is located is optionally in the D or the L configuration.

7. The compound as claimed in claim 1 , characterized in that the compound is selected from a structure as claimed in claim 9 , where, in the structures mentioned, the glycine residue with the structural element

is in each case replaced by a serine residue with the structural element

or by a glutamic acid residue with the structural element

or by a glutamine y-ethyl ester with the structural element

8. The compound as claimed in claim 1 , characterized in that the compounds are in the form of salts.

9. A medicament comprising a compound as claimed in claim 1 and pharmaceutically suitable excipients and/or additives.

10. The medicament as claimed in claim 9 , where the medicament is employed in the form of a tablet, of a coated tablet, of a capsule, of a pellet, suppository, of a solution, of eyedrops, nose and ear drops, of a syrup, of an emulsion or suspension, of a pessary, stick, aerosol, dusting powder, of a paste, cream or ointment.

11. The compound of claim 1 , wherein

R 7 is an H or a branched or unbranched alkyl radical having 1-3 C atoms; or

R 7* is ethyl; or

f is 2; or

P 2 is in the D configuration; or

R 9* is benzyl; or

R 10 is an alkyl radical having 1 to 4 C atoms; or

V is (CH 2 ) n , and n=0; or

z occurs in position 4; or

R 12 is a branched or unbranched alkyl radical having 1 to 6 C atoms, or R 12 is a mono- or polysubstituted or unsubstituted aryl or heteroaryl, aralkyl or heteroaralkyl radical, where the alkyl radical has 1 to 8 C atoms, or the aryl or heteroaryl has 6 to 10 C atoms, or where the heteroaryl has 1-3 N as heteroatoms.

12. The compound of claim 11 , wherein R 12 is a mono- or polysubstituted or unsubstituted aryl or heteroaryl, aralkyl or heteroaralkyl radical, where the alkyl radical has 1 to 4 C atoms or the aryl or heteroaryl has 6 C atoms.

13. The compound of claim 12 , wherein R 12 is a mono- or polysubstituted or unsubstituted aryl or heteroaryl, aralkyl or heteroaralkyl radical, where the alkyl radical has 1 to 2 C atoms.

14. The compound of claim 2 , wherein said structural element of the formula I is a —CH 2 — group.

15. The compound of claim 3 , wherein R 8 is phenyl, hydroxyphenyl, pyridyl, or aminopyridyl radical.

16. The compound of claim 4 , wherein

R 8 is pyridyl, or

P 2 in the structure A of the general formula I is homophenylalanine, homotyrosine, indanylglycine or 4-pyridylhomoalanine.

17. The compound of claim 16 , wherein the P2 amino acid is in the D configuration.

18. The compound of claim 6 , wherein the amino acid on which the radical R is located is in the D configuration.

19. The compound of claim 8 , wherein said salts are with mineral acids or suitable organic acids.

20. The compound of claim 19 , wherein said mineral acids or suitable organic acids are selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, formic acid, methylsulfonic acid, succinic acid, malic acid, and trifluoroacetic acid.

21. The compound of claim 19 , wherein said compounds are in the form of their hydrochlorides, sulfates, or acetates.

22. The medicament of claim 10 , wherein said medicament is employed in the form of a solution for injection or infusion.

23. The compound of claim 1 , wherein R 9* comprises a mono- or polysubstituted or unsubstituted phenyl or pyridyl ring.

24. The compound of claim 6 , wherein R 9* is unsubstituted or comprises a substituent selected from —OH, —NH 2 , —NO 2 , —COOR 10 , or a —CH 2 —COOR 10 group, or a CI, F or Br atom, and where R 10 is an H or an alkyl radical having 1 to 6 C atoms.

25. A compound selected from the group consisting of:

26. The compound of claim 1 , wherein

R 2 is —CH 2 —CH 2 —COOH, —CH 2 —CH 2 —COOCH 2 CH 3 or —CH 2 OH;

R 4 is —(CH 2 ) 2 —R 8 , where R 8 is a mono-substituted or unsubstituted phenyl or pyridyl attached to —(CH 2 ) 2 — at a carbon of said phenyl or pyridyl ring

R 5 is —SO 2 R 9* , where R 9* is a mono-substituted or unsubstituted benzyl or heteroaralkyl, where heteroaralkyl is aralkyl in which 1 ring C atom is replaced with N;

U is a phenyl radical;

V is (CH 2 ) n with n=0; and

z is present in position 4 and is an amidino group

where R 11 is H; and

where each substituent is independently —OH, —NH 2 , —NO 2 , —COOH, —COOCH 2 CH 3 , or a halogen.

27. The compound of claim 26 , wherein R 2 is —CH 2 —CH 2 —COOH or —CH 2 —CH 2 —COOCH 2 CH 3 .

28. The compound of claim 26 , wherein R 9* is benzylsulfonyl, aminobenzylsulfonyl, hydroxybenzylsulfonyl, chlorobenzylsulfonyl, fluorobenzylsulfonyl, carboxybenzylsulfonyl, ethyloxycarbonylbenzylsulfonyl, pyridylmethylsulfonyl, or N-(oxide)-pyridylmethylsulfonyl.

29. The compound of claim 28 , wherein R 9* is benzylsulfonyl, aminobenzylsulfonyl, hydroxybenzylsulfonyl, chlorobenzylsulfonyl, fluorobenzylsulfonyl, or pyridylmethylsulfonyl.