Highly selective inhibitors of the urokinase plasminogen activator
View Patent ↗A method is described for inhibiting urokinase plasminogen activator in a human or animal patient. The method involves administering to the patient a urokinase plasminogen activator inhibiting effective amount of a compound of the formula (I):
1. A method of inhibiting urokinase plasminogen activator in a human or animal patient, comprising: administering to the patient a selective urokinase plasminogen activator inhibiting effective amount of a compound of the formula (I):
wherein,
Ar is an aromatic or heteroaromatic ring system,
X 1 is a radical of the formula (IIa), (IIb) or (IIc):
R 1 is H, an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl radical,
R 2 is halogen, C(R 3 ) 3 , C 2 (R 3 ) 5 , OC(R 3 ) 3 or OC 2 (R 3 ) 5 ,
R 3 is in each case independently H or halogen,
R 4 and R 5 are H or an unsubstituted or substituted alkyl, alkenyl or alkynyl radical, where at least one of the radicals R 4 and R 5 contain a hydrogen bond donor group, where the hydrogen bond donor group provides a hydrogen atom or/and an electron pair for a hydrogen bond,
R 6 and R 7 are H or an unsubstituted or substituted alkyl, alkenyl or alkynyl radical, where at least one of the radicals R 6 and R 7 contains a hydrogen bond donor group, where the hydrogen bond donor group provides a hydrogen atom or/and an electron pair for a hydrogen bond and where R 4 or R 5 may be bridged with R 6 or R 7 ,
R 8 is H or an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl radical or —SO 2 —R 9 , where R 8 may or may not be bridged with R 6 or R 7 ,
R 9 is H or an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl radical,
X 2 is a hydrogen bond acceptor group, which is NH, NR 10 , O or S,
R 10 is an unsubstituted or substituted alkyl, alkenyl or alkynyl radical, and
m is an integer from 0 to 4,
or a salt thereof.
2. The method of claim 1 , wherein the compound is administered to the patient to treat a disorder associated with overexpression of urokinase plasminogen activator, or a receptor for it.
3. The method of claim 1 , wherein the compound is administered to inhibit malignant tumor growth in a patient.
4. The method of claim 1 , wherein the compound is administered to inhibit tumor metastasis in a patient.
5. The method of claim 1 , wherein the compound is administered in a dose of 0.01 to 100 mg/kg of patient body weight per day.
6. The method of claim 1 , wherein the compound is administered together with at least one other urokinase inhibitor.
7. The method of claim 1 , wherein in the compound of formula (I), Ar is a benzene ring.
8. The method of claim 1 , wherein in the compound of formula (I), the substituents
—CHX 1 R 1 and
are
arranged on the benzene ring in para position in relation to one another.
9. The method of claim 1 , wherein in the compound of formula (I), for R 4 , R 5 , R 6 and R 7 , the hydrogen bond donor groups are selected from OH, OR 1 , NH 2 , NHR 1 , N(R 1 ) 2 , SH and SR 1 .
10. The method of claim 1 , wherein in the compound of formula (I), the hydrogen bond donor group is contained in a group selected from —CH 2 OH, —CH 2 CH 2 OH, —CO 2 H, —CO 2 R 1 , —CONH 2 , —CONHR 1 , —CON(R 11 ) 2 , —COSH, —COSR 1 , —CSOH, —COSR 1 , —COR 1 and —CSR 1 .
11. The method of claim 1 , wherein in the compound of formula (I), the hydrogen bond acceptor groups for X 2 are selected from O and NH.
12. The method of claim 1 , wherein in the compound of formula (I), R 8 and R 9 are selected from the group consisting of unsubstituted or substituted aryl radicals, unsubstituted or substituted tertiary alkyl radicals and cycloalkyl radicals.
13. The method of claim 1 , wherein in the compound is administered in the form of a tablet, coated tablet, capsule, pellet, suppository, solution or transdermal system.
14. The method of claim 1 , wherein in the compound of formula (I), R 8 and R 9 are selected from the group consisting of phenyl and substituted phenyl radicals, unsubstituted or substituted tertiary alkyl radicals and bicycloalkyl radicals.
15. The method of claim 1 , wherein in the compound of formula (I), R 8 and R 9 are selected from the group consisting of phenyl and substituted phenyl radicals, unsubstituted or substituted tertiary alkyl radicals and an adamantyl radical.