Urokinase inhibitors, production and use thereof

1. A compound of the general formula I

wherein

A is P 2 —P 1 in which

R 1 is H or —(CH 2 ) a COOR 6 , in which a=0, 1, 2, 3, 4, or 5, and where R 6 is a branched or unbranched alkyl radical having from 1 to 6 C atoms

R 2 is an H, a branched or unbranched alkyl radical having from 1 to 8 C atoms, or

—(CH 2 ) c COOR 8 , in which c=1, 2, 3, or 4, where R 8 is H or a branched or unbranched alkyl radical having from 1 to 6 C atoms or

—(CH 2 ) d —OR 9 , in which d=1, 2, 3, or 4, where R 9 is H, or

—(CH 2 ) e R 10 , —(CH 2 ) e —OR 10 , —(CH 2 ) e —SR 10 , —(CH 2 ) e -guanidino, —(CH 2 ) e -imidazole or —(CH 2 ) e NHR 10 , in which e=1, 2, 3, 4, or 5, where R 10 is H, a branched or unbranched alkyl radical having 1-16 C atoms, or a substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroaralkyl radical, where the alkyl radical possesses from 1 to 16 C atoms, and the aryl or heteroaryl radical possesses from 4 to 14 C atoms, and from 1 to 3 N as heteroatom, or —(CH 2 ) k O—CO—OR 16 , in which k=1, 2, 3, 4, 5, 6, 7, or 8, where R 16 is a branched or unbranched alkyl having 1-16 C atoms, a substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroaralkyl radical, or an adamantyl, a camphor, or a cyclohexylmethyl radical; and

R 5 is —(CH 2 ) g (CH 3 ) h , in which g+h=1, 2, or 3, —(CH 2 ) i -aryl, in which i=0, 1, 2, or 3, —SO 2 R 12 , —COR 12 or —COOR 12 , where R 12 is a branched or unbranched alkyl having 1-16, C atoms, a substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroaralkyl radical, or an adamantyl, a camphor, or a cyclohexylmethyl radical, where R 5 is optionally modified with a —(CH 2 ) j COOR 13 , —(CH 2 ) j SO 2 R 13 , —(CH 2 ) j NH 2 , —(CH 2 ) j -amidino, —(CH 2 ) j -hydroxyamidino, or —(CH 2 ) j -guanidino group in which j=0, 1, or 2, where R 13 is H or an alkyl radical having from 1 to 6 C atoms; or

R 3 is H or —(CH 2 ) b R 7 , in which b=1, 2, 3, 4, 5, 6, 7, or 8, where R 7 is H, a branched or unbranched alkyl radical having from 1 to 10 C atoms or a —(CH 2 ) j COOR 13 , —(CH 2 ) j SO 2 R 13 , or —(CH 2 ) j NH 2 , or —(CH 2 ) j -amidino, —(CH 2 ) j hydroxyamidino, or —(CH 2 ) j -guanidino group in which j=0, 1, or 2, where R 13 is H or an alkyl radical having from 1 to 6 C atoms, and with P 1 being present in the L configuration in the structure A;

R 4 is a branched or unbranched alkyl radical having from 1 to 8 C atoms, —(CH 2 ) f OR 11 , —(CH 2 ) f SR 11 , or —(CH 2 ) f NHR 11 in which f=1, 2, 3, 4, 5, 6, 7, or 8, where R 11 is H or —CO—OR 17 , where R 17 is a branched or unbranched alkyl having 1-16 C atoms, a substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroaralkyl radical, or an adamantyl, a camphor, or a cyclohexylmethyl radical and with P 2 being present in the D configuration in the structure A;

U is a phenyl or cyclohexyl radical or a heterophenyl or heterocyclohexyl radical having at least one N, S, or O as heteroatom;

V is (CH 2 ) n in which n is 0, 1, 2, or 3;

X is N or CH;

Y is N or (CH) m in which m=0 or 1;

Z occurs in the 3 or 4 position and is an aminomethyl, a guanidine, or an amidino group

 where R 14 is H, OH, NH 2 , —COR 15 or —COOR 15 , where R 15 is a branched or unbranched alkyl radical having from 1 to 16 C atoms or a substituted or unsubstituted aryl or heteroaryl, aralkyl, or heteroaralkyl radical, where the alkyl radical possesses from 1 to 16 C atoms and the aryl or heteroaryl radical possesses from 4 to 14 C atoms and from 1 to 3 N as heteroatom;

characterized in that one or more radicals, selected from —COOH, —CH(COOH) 2 , —SO 2 H, NH 2 , an amidino, hydroxyamidino, amidrazono, or guanidino group, or a salt thereof, are present in the radicals R 1 , R 2 , R 3 or R 5 ;

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

2. The compound as claimed in claim 1 , in which an amino group-functionalized or carboxyl group-functionalized oligo- or polyalkylene glycol chain is coupled directly to a functional group of R 2 , with the formation of an amide bond at R 2 , with the oligo- or polyalkylene glycol chain possessing a substituted or unsubstituted amino group and/or carboxyl group, at least at both ends, or with the oligo- or polyalkylene glycol chain possessing a substituted or unsubstituted amino group and/or carboxyl group, at one end and being present, at the other end, as an alkyl ether having 1-4 C atoms,

with R 2 being

(a) —(CH 2 ) n —NH 2 in which n is 1-5, or

(b) —(CH 2 ) n —COOH in which n is 1-5.

3. The compound as claimed in claim 2 , wherein, after coupling the oligo- or polyalkylene glycol, P 1 has the general formula II

 where q is 0, 1, 2, 3, 4, or 5 and D is formula III

E-F-G-  (III)

where, when E is an H 2 N, HOOC—(CH 2 ) n —CO—NH, HOOC, or H 2 N—(CH 2 ) n —NH—CO group, F is an oligo- or polyalkylene glycol of the general formula —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, in which d=1, 2, 3, or 4, v=an integer from 1 to 1000 m=0, 1, 2, 3, or 4, and k=0 or 1, or, when E is a CH 3 —O group, F is an oligo- or polyalkylene glycol chain of the general formula —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, in which d=1, 2, 3, or 4, v=an integer from 1 to 1000 m=0, 1, 2, 3, or 4, and k=0 or 1;

and G is —CO—NH— or —NH—CO—.

4. The compound as claimed in claim 1 , wherein U is substituted at 1, 2, or 3 positions by a halogen, or a methyl, ethyl, propyl, methoxy, ethoxy, or propoxy radical.

5. The compound as claimed in claim 1 , wherein a carboxyl group is protected as an ester.

6. The compound as claimed in claim 1 , in the form of a prodrug, with R 9 and/or R 11 in this case being an alkylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, or aralkoxycarbonyl radical, with the alkyl radical having from 1 to 6 C atoms and the aryl radical having from 5 to 8 C atoms.

7. The compound as claimed in claim 1 , characterized in that the amidino group is in the 4 position in the amidinobenzylamide radical and in that P 2 is derived from the amino acid D-Ser and P 1 is derived from glycine, alanine, serine, aspartic acid or glutamic acid, and in that R 5 is an unsubstituted aryl- or aralkylsulfonyl radical, or such a radical provided with a carboxyl group or carboxyalkyl group, having from 1 to 16 C atoms in the alkyl radical and from 6 to 14 C atoms in the aryl radical.

8. The compound as claimed in claim 1 , characterized in that the amidino group is in the 4 position in the amidinobenzylamide radical and in that P2 is the amino acid D-Ser and P1 is a natural or artificial, unsubstituted or substituted, basic amino acid in the L configuration selected from the group consisting of Lys, homoLys, Arg, norArg, homoArg, His, Orn, Orn(2-imidazolinyl), Dab, 4-[(2-amino)pyrimidinyl]butyric acid, Dap, Ala[3-(2-pyrrolidinyl)], Ala[3-pyrrolidinyl-(2-N-amidino)], Ala[3-(N-piperazine-4-N-amidino], Ala(4-Pip), Ala[4-Pip(N-amidino)], homoAla(4-Pip), Ala[3-Pip(N-amidino)], homoAla(3-Pip), homoAla[4-Pip(N-amidino) ], Ala-(3-guanidino), Phe(3-amidino), Phe(4-amidino), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(3-guanidino), Phe(4-guanidino), Phe[4-(2-imidazolinyl)], Phe[3-CH 2 -(guanidine)], Phe[4-CH 2 -(guanidino)], homoPhe(3-amidino), homoPhe(4-amidino), hPhe(3-NH 2 ), hPhe(4-NH 2 ), hPhe(3-guanidino), hPhe(4-guanidino), cis-Cha(4-NH 2 ), trans-Cha(4-NH 2 ), cis-homoCha(4-NH 2 ), trans-homoCha(4-NH 2 ), trans-Cha (4-CH 2 NH 2 ), and trans-homoCha(4-CH 2 NH 2 ), and in that R 5 is a sulfonyl group-provided aryl- or aralkylsulfonyl radical having from 1 to 16 C atoms in the alkyl radical and from 6 to 14 C atoms in the aryl radical, which is bonded to the amino group of the D-Ser.

9. The compound as claimed in claim 8 , characterized in that P1 is the amino acid Lys or Arg.

10. The compound as claimed in claim 1 , characterized in that the substituent on the substituted aryl, heteroaryl, aralkyl, or heteroaralkyl radical is a halogen.

11. The compound as claimed in claim 1 , characterized in that a compound of the general formula I has the following structure:

 in which R is COOH, HOOC—(CH 2 ) p — or R 18 OOC—(CH 2 ) p — in which p=1 and 2 and R 18 =methyl or ethyl, or COOMe in ortho, meta or para, or H, and X is CH and R 1 is H; or

R is 4-COOH or 3-COOH, with X being CH and R 1 being H, CH 3 or CH 2 —OH; or

R is 4-CN, with X being CH and R 1 being CH 3 ; or

R is 4-(NH 2 —CH 2 ), with X being CH and R 1 being H; or

R is 4-COOMe, with X being CH and R 1 being CH 2 —OH.

12. The compound as claimed in claim 1 , characterized in that a compound of the general formula I has one of the following structures:

13. The compound as claimed in claim 1 , characterized in that a compound of the general formula I has one of the following structures:

in which n=2 to 250.

14. The compound as claimed in claim 1 , characterized in that the compounds are mineral acid or organic acid salts.

15. The compound as claimed in claim 14 , characterized in that said salts are sulfates, acetic acid, formic acid, methylsulfonic acid, succinic acid, malic acid, or trifluoroacetic acid.

16. A process for preparing a compound as claimed in claim 1 , the process comprising sequentially coupling the appropriate amino acids to a 4-acetyloxamidinobenzylamine, with either the N-terminal amino acid already carrying the R 5 radical or with this radical subsequently being bonded to it.

17. A pharmaceutical composition comprising a compound as claimed in claim 1 and pharmaceutically suitable auxiliary substances and/or additives.

18. The pharmaceutical composition as claimed in claim 17 , wherein the pharmaceutical composition is used in the form of a tablet, a sugar-coated tablet, a capsule, a pellet, a suppository, a solution, an injection solution or infusion solution, eyedrops, nose drops and ear drops, a juice, an emulsion or suspension, a globule, a stylus, an aerosol, a powder, a paste, a cream or an ointment.

19. The compound as claimed in claim 1 being benzylsulfonyl-dSer-Arg-4-amidinobenzylamide.

20. The compound of claim 1 , wherein characterized in that one or more radicals selected from —COOH, —CH(COOH) 2 , —SO 2 H, NH 2 , an amidino, hydroxyamidino, amidrazono, or guanidino group, is present in the radicals R 1 , R 2 , R 3 or R 5 .

21. The compound of claim 1 , wherein the salt of one or more radicals selected from —COOH, —CH(COOH) 2 , —SO 2 H, NH 2 , an amidino, hydroxyamidino, amidrazono, or guanidino group, is present in the radicals R 1 , R 2 , R 3 or R 5 .