2-(aminomethyl)-5-chlorobenzylamide derivatives and their use as inhibitors of the clotting factor Xa
2-(Aminomethyl)-5-chlorobenzylamide derivatives and their use as inhibitors of coagulation factor Xa are provided. The compounds are suitable for the treatment and prophylaxis of cardiovascular and thrombotic events.
1. A compound of the formula I:
and pharmaceutically suitable salts of this compound, in which
XR 1 =—OH, —OCH 2 —COOR 4 , —OSO 2 —R 5 , —OCOOR 5 , —OCO—R 6 , —NR 3 CH 2 —COOR 4 , —NR 3 SO 2 —R 5 , —NR 3 COOR 5 , or —NR 3 CO—R 6 ;
R 3 =H or a branched or unbranched alkyl group having 1-6 C atoms,
n=0, 1, 2, 3 or 4,
R 4 =H or a branched or unbranched alkyl group having 1-6 C atoms,
R 5 =a branched or unbranched alkyl group having 1-7 C atoms which is unsubstituted or substituted by R 7 , or an aryl or heteroaryl group which is unsubstituted or substituted by R 7 , or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 , or a cyclohexylmethyl group
R 7 =halogen, CN, NHR 3 , NHCO—R 3 , —CH 2 —NHR 3 , NO 2 , OR 3 , SR 3 , —COOR 4 or —CH 2 —COOR 4 and R 3 and R 4 as defined above
R 6 =a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 , or cycloalkyl or a cyclohexylmethyl, but also —COOR 4 , where R 4 is as defined above; and R 6 may also be substituted by R 7 which is as defined above, and
R 2 =a group selected from
P2=any natural or unnatural α-amino acid, that is glycine or has the following structure
with
R 3 as defined above,
Y=CH or N, and, in the case of R 8 ═H, may only be N,
R 8 =H or a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 , or an aryl or heteroaryl group which is unsubstituted or substituted by R 7 , or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 , or a cyclohexylmethyl group, and where R 7 is defined as described above, or
P2=any α-azaimino acid of the following structure
q=0, 1 or 2, and a carbon atom of the ring may be substituted by R 7 which is as defined above; and
wherein P2 is not glycine alkylated on the nitrogen atom.
2. The compound as claimed in claim 1 , wherein XR 1 is O—CH 2 —COOH, O—CH 2 —COOCH 2 CH 3 , O(benzylsulfonyl), O(methylsulfonyl), O(ethylsulfonyl), O(n-propylsulfonyl), O(n-butylsulfonyl), NR 3 —CH 2 —COOCH 2 CH 3 , NR 3 (benzylsulfonyl), NR 3 (methylsulfonyl), NR 3 (ethylsulfonyl), NR 3 (n-propylsulfonyl), or NR 3 (n-butylsulfonyl).
3. The compound as claimed in claim 1 , wherein the amino acid with X and R 2 has the following structure:
4. The compound as claimed in claim 1 , wherein the amino or imino acid with X and R 2 is in the D configuration.
5. The compound as claimed in claim 1 , wherein P2 is azaglycine, azaproline, serine, glutamic acid, ethyl glutamate, methyl glutamate, or α,β-diaminopropionic acid.
6. The compound as claimed in claim 1 , wherein R 7 is an OH, an NH 2 , a —COOH, a —COOCH 2 CH 3 , a —CH 2 —COOH, or a —CH 2 —COOCH 2 CH 3 group.
7. The compound as claimed in claim 1 , wherein XR 1 =O—CH 2 —COOR 4 or NR 3 —CH 2 —COOR 4 , and n=2.
8. The compound as claimed in claim 1 , wherein XR 1 is O—CH 2 COOC 6 H 11 or NR 3 —CH 2 COOC 6 H 11 , and/or P2 is alanine.
9. The compound as claimed in claim 1 , wherein
XR 1 =OH, O—CH 2 —COOR 4 , O—SO 2 —R 5 , O—COOR 5 , OCO—R 6 ; NR 3 —CH 2 —COOR 4 , NR 3 —SO 2 —R 5 , NR 3 —COOR 5 or NR 3 CO—R 6 ;
R 3 =H,
n=2
R 4 =H or a branched or unbranched alkyl group having 1-6 C atoms,
R 5 =a branched or unbranched alkyl group having 1-7 C atoms which is unsubstituted or substituted by R 7 , or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 ,
R 7 =NHR 3 , OR 3 or —COOR 4 , and R 3 and R 4 are as described above
R 6 =—COOR 4 , where R 4 is as described above, and
P2=any natural or unnatural α-amino acid that is glycine or has the following structure
with
R 3 as defined above,
Y=CH or N, and, in the case of R 8 =H, may only be N,
R 8 =H or a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 ; and
wherein P2 is not glycine alkylated on the nitrogen atom.
10. The compound as claimed in claim 1 , wherein
XR 1 =NR 3 —CH 2 —COOR 4 or NR 3 —SO 2 —R 5 ,
R 3 ═H,
n=2
R 4 =H or ethyl,
R 5 =branched or unbranched alkyl group having 1-4 C atoms, or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 ,
R 7 =OR 3 or —COOR 4 and R 3 and R 4 as defined above
P2=any natural or unnatural α-amino acid that is glycine or has the following structure
with
R 3 as defined above,
Y=CH or N and, in the case of R 8 =H, may only be N,
R 8 =H or a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 ; and
wherein P2 is not glycine alkylated on the nitrogen atom.
11. A method of inhibiting coagulation factor Xa, comprising administering to a patient in need thereof a compound of the general formula I:
or pharmaceutically suitable salts of these compounds as inhibitors of coagulation factor Xa, where
XR 1 =—OH, —OCH 2 —COOR 4 , —OSO 2 —R 5 , —OCOOR 5 , —OCO—R 6 —NR 3 CH 2 —COOR 4 , —NR 3 SO 2 —R 5 , —NR 3 COOR 5 , or —NR 3 CO—R 6 ;
R 3 is H or a branched or unbranched alkyl group having 1-6 C atoms,
n=0, 1, 2, 3 or 4,
R 4 =H or a branched or unbranched alkyl group having 1-6 C atoms,
R 5 =a branched or unbranched alkyl group having 1-7 C atoms, which is unsubstituted or substituted by R 7 , or R 5 is an aryl or heteroaryl group which is unsubstituted or substituted by R 7 , or R 5 is an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 , or a cyclohexylmethyl group
R 7 =halogen, CN, NHR 3 , NHCO—R 3 , —CH 2 —NHR 3 , NO 2 , OR 3 , SR 3 , —COOR 4 or —CH 2 —COOR 4 and R 3 and R 4 as defined above
R 6 =a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 , or cycloalkyl or a cyclohexylmethyl, but also —COOR 4 , where R 4 is as defined above; and R 6 may also be substituted by R 7 which is as defined above, and
R 2 =a group selected from
P2=any natural or unnatural α-amino acid or α-azaamino acid of the following structure
with
R 3 and R 8 as defined above, and
Y=CH or N, or
P2=any α-imino acid or α-azaimino acid of the following structures
or
with R 7 and Y as defined above, and
q=0, 1 or 2, and one carbon atom of the ring may be substituted by R 7 which is as defined above.
12. The method as claimed in claim 11 , wherein XR 1 =O—CH 7 —COOR 4 or NR 3 —CH 2 —COOR 4 , and n=2.
13. The method according to claim 11 , wherein R 1 is —CH 2 COOC 6 H 11 and/or P2 is an alanine.
14. The method as claimed in claim 11 , wherein
XR 1 =OH, O—CH 2 —COOR 4 , O—SO 7 —R 5 , O—COOR 5 , OCO—R 6 , NR 3 —CH 2 —COOR 4 , NR 3 —SO 2 —R 5 , NR 3 —COOR 5 or NR 3 CO—R 6 ;
R 3 =H,
n=2
R 4 =H or a branched or unbranched alkyl group having 1-6 C atoms,
R 5 =a branched or unbranched alkyl group having 1-7 C atoms which is unsubstituted or substituted by R 7 , or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 ,
R 7 =NHR 3 , OR 3 or —COOR 4 and R 3 and R 4 as defined above
R 6 =—COOR 4 , where R 4 is as defined above, and
P2=any natural or unnatural α-amino acid of the following structure
with
R 3 as defined above, or a branched or unbranched alkyl group having 1-6 C atoms,
or proline
Y=CH or N,
R 8 =a branched or unbranched group having 1-8 C atoms, which is unsubstituted or substituted by R 7 .
15. The method as claimed in claim 11 , wherein
XR 1 =NR 3 —CH 2 —COOR 4 or NR 3 —SO 2 —R 5 ,
R 3 =H,
n=2
R 4 =H or ethyl,
R 5 =branched or unbranched alkyl group having 1-4 C atoms, or an aralkyl or heteroaralkyl group which is unsubstituted or substituted by R 7 ,
R 7 =OR 3 or —COOR 4 and R 3 and R 4 as defined above
P2=any natural or unnatural α-amino acid that is glycine or has the following structure
with
R 3 as defined above,
Y=CH or N and, in the case of R 8 ═H, may only be N,
R 8 ═H or a branched or unbranched alkyl group having 1-8 C atoms, which is unsubstituted or substituted by R 7 ;
wherein P2 is not glycine alkylated on the nitrogen atom.
16. A pharmaceutical composition comprising a compound of the general formula (I) as claimed in claim 1 and at least one suitable carrier or excipient.
17. The pharmaceutical composition as claimed in claim 16 for oral, subcutaneous, intravenous or transdermal administration for treating thromboembolic disorders.
18. The pharmaceutical composition as claimed in claim 16 , wherein the preparation is formulated in the form of tablets, coated tablets, capsules, pellets, suppositories, solutions or patches.
19. A process for producing a pharmaceutical composition comprising mixing a compound of the general formula (I) as claimed in claim 1 and at least one carrier or excipient.
20. The compound of claim 1 , wherein
n=2, or
R 7 =Cl or F, or
R 6 is a branched or unbranched alkyl group having 1-4 C atoms; or
R 8 is a branched or unbranched alkyl group having 1-4 C atoms.
21. The compound of claim 7 , wherein XR 1 =O—CH 2 —COOC 2 H 5 or NR 3 —CH 2 —COOC 2 H 5 .
22. The compound of claim 9 , wherein R 8 =a branched or unbranched alkyl group having 1-4 C atoms.
23. The compound of claim 10 , wherein R 8 is a branched or unbranched alkyl group having 1-4 C atoms.
24. The compound of claim 1 , wherein P2 is glycine, serine, glutamic acid, ethyl glutamate, or methyl glutamate.
25. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or any pharmaceutically suitable salts thereof.
26. A compound selected from the group consisting of:
or any pharmaceutically suitable salts thereof.
27. The method of claim 11 , wherein
R 3 is H or methyl; or
n=2; or
R 4 =ethyl; or
R 5 =a branched or unbranched alkyl group having 1-4 C atoms; or
R 7 =Cl or F; or
R 6 =a branched or unbranched alkyl group having 1-4 C atoms; or
P2=
28. The method of claim 12 , wherein XR 1 is O—CH 2 —COOC 2 H 5 or NR 3 —CH 2 —COOC 2 H 5 .
29. The method of claim 14 , wherein R 8 is a branched or unbranched alkyl group having 1-4 C atoms.
30. The method of claim 15 , wherein R 8 =a branched or unbranched alkyl group having 1-4 C atoms.
31. The compound of claim 1 , wherein P2 is glycine or has the following structure,
wherein P2 is not glycine alkylated on the nitrogen atom.