Selective inhibitors of the urokinase plasminogen activator

1. A pharmaceutical composition comprising at least one compound of the formula (I)

in which

the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other;

Ar is an aromatic or heteroaromatic ring system having a single ring;

X 1 is NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is H or a group of the formula II, IIIa, IIIb or IIIc:

where

X 2 is NH, NR 4 , O or S,

X 3 is NH, NR 4 , O, S, CO, COO, CONH OR CONR 4 ,

Y is C(R 8 ) 2 ,

R 4 is H or an alkyl, alkenyl or alkynyl radical,

R 7 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical or —SO 2 —R 9 ,

R 8 is in each case independently H, halogen or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical,

R 9 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical and

n is an integer from 0 to 2,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is halogen, C(R 6 ) 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5 ,

where

R 6 is in each case independently H or halogen and

m is an integer from 0 to 4;

or a salts of said at least one compound, and a pharmaceutically acceptable carrier therefor.

2. A pharmaceutical composition according to claim 1 , in which Ar is a benzene ring.

3. A pharmaceutical composition according to claim 1 , in which R 7 and R 9 are each independently an aryl, tertiary alkyl or cycloalkyl radical.

4. A pharmaceutical composition comprising at least one compound of the formula (IV)

in which

X 1 is in each case independently NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is in each case independently H or any organic radical,

R 4 is in each case independently H or an alkyl, alkenyl or alkynyl radical;

Ar is in each case independently an aromatic or heteroaromatic ring system,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is in each case independently halogen, C(R 6 ) 3 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5 ,

where

R 6 is in each case independently H or halogen; and

m is an integer from 0 to 4;

or salts of said at least one compound, and a pharmaceutically acceptable carrier therefor.

5. A pharmaceutical composition according to claim 1 wherein said composition is adapted to be administered orally, topically, rectally or parenterally.

6. A pharmaceutical composition according to claim 1 wherein said composition is adapted to be administered in the form of tablets, coated tablets, capsules, pellets, suppositories, solutions or transdermal systems.

7. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I has a K i that is at least two times lower for uPA than for tPA.

8. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I has a K i that is at least five times lower for uPA than for tPA.

9. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I has a K i that is at least 10 times lower for uPA than for tPA.

10. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I has a K i that is at least 1000 times lower for uPA than for tPA.

11. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I is conjugated with at least one physiological effective substance, wherein said substance is at least one radiolabelled substance.

12. A pharmaceutical composition according to claim 1 , wherein said compound of the formula I is incorporated into a carrier vesicle.

13. A pharmaceutical composition according to claim 1 , wherein R 6 in said compound of formula I is F.

14. A pharmaceutical composition according to claim 3 , wherein said at least one aryl radical is a phenyl radical.

15. A pharmaceutical composition according to claim 3 , wherein said at least one cycloalkyl radical is a bicycloalkyl radical.

16. A pharmaceutical composition according to claim 15 , wherein said bicycloalkyl radical is an adamantyl radical.

17. A pharmaceutical composition according to claim 4 , wherein R 6 in said compound of formula I is F.

18. A compound of the formula (I)

in which

the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other;

Ar is an aromatic or heteroaromatic ring system having a single ring;

X 1 is NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is H or a group of the formula II, IIIa, IIIb or IIIc:

where

X 2 is NH, NR 4 , O or S,

X 3 is NH, NR 4 , O, S, CO, COO, CONH OR CONR 4 ,

Y is C(R 8 ) 2 ,

R 4 is H or an alkyl, alkenyl or alkynyl radical,

R 7 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical or —SO 2 —R 9 ,

R 8 is in each case independently H, halogen or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical,

R 9 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical and

n is an integer from 0 to 2,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is halogen, C(R 6 ) 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5 ,

where

R 6 is in each case independently H or halogen; and

m is an integer from 0 to 4, with the provisos that

when Ar=phenyl, m=O, CH 2 X 1 is not CH 2 COOH,

when Ar=phenyl, m=0, X 1 =NR 3 R 4 with R 4 =H and R 3 =—COOR 7 with R 7 =tertbutyl and m=0, the compound of formula (I) is not in the hydrochloride salt form, and

when Ar=phenyl, m=0 and X 1 =NH 2 the compound of formula (I) is not in the bistrifluoroacetate salt form.

19. The compound of claim 18 , in which Ar is a benzene ring.

20. A compound of the formula (I)

in which

Ar is an aromatic or heteroaromatic ring system having a single ring:

X 1 is NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is H or a group of the formula II, IIIa, IIIb or IIIc:

where

X 2 is NH, NR 4 , O or S,

X 3 is NH, NR 4 , O, S, CO, COO, CONH OR CONR 4 ,

Y is C(R 8 ) 2 ,

R 4 is H or an alkyl, alkenyl or alkynyl radical,

R 7 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical or —SO 2 —R 9 ,

R 8 is in each case independently H, halogen or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical,

R 9 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical and

n is an integer from 0 to 2,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is halogen, C(R 6 ) 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5a

where

R 6 is in each case independently H or halogen; and

m is an integer from 0 to 4, with the provisos that

when Ar=phenyl, m=O, CH 2 X 1 is not CH 2 COOH,

when Ar=phenyl, m=0, X 1 =NR 3 R 4 with R 4 =H and R 3 =—COOR 7 with R 7 =tertbutyl and m=0, the compound of formula (I) is not in the hydrochloride salt form, and

when Ar=phenyl, m=0 and X 1 =NH 2 the compound of formula (I) is not in the bistrifluoroacetate salt form, in which R 7 and R 9 are at least one aryl radical, at least one tertiary alkyl radical or at least one cycloalkyl radical.

21. A compound according to claim 20 , wherein said at least one aryl radical is a phenyl radical.

22. A compound according to claim 20 , wherein said at least one cycloalkyl radical is a bicycloalkyl radical.

23. A compound according to claim 22 , wherein said bicycloalkyl radical is an adamantyl radical.

24. A compound according to claim 18 wherein R 6 in said compound of formula I is F.

25. A compound of the formula (IV)

in which

X 1 is in each case independently NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is in each case independently H or any organic radical,

R 4 is in each case independently H or an alkyl, alkenyl or alkynyl radical;

Ar is in each case independently an aromatic or heteroaromatic ring system,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is in each case independently halogen, C(R 6 ) 3 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5 ,

where

R 6 is in each case independently H or halogen; and

m is an integer from 0 to 4;

or salts of said compound.

26. A pharmaceutical composition comprising at least one compound of the formula (I)

in which

Ar is an aromatic or heteroaromatic ring system having a single ring;

X 1 is NR 3 R 4 , OR 3 , SR 3 , COOR 3 , CONR 3 R 4 or COR 5 ,

where

R 3 is a group of the formula II, IIIa, IIIb or IIIc:

where

X 2 is NH, NR 4 , O or S,

X 3 is NH, NR 4 , O, S, CO, COO, CONH OR CONR 4 ,

Y is C(R 8 ) 2 ,

R 4 is H or an alkyl, alkenyl or alkynyl radical,

R 7 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical or —SO 2 —R 9

when R 3 is H or a group of the formula II, IIIb or IIIc and,

is an aryl or cycloalkyl radical when R 3 is a group of the formula IIIa,

R 8 is in each case independently H, halogen or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical,

R 9 is H or an alkyl, alkenyl, alkynyl, aryl or/and heteroaryl radical and

n is an integer from 0 to 2,

R 5 is H, an alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl or carboxyheteroaryl radical;

R 2 is halogen, C(R 6 ) 3 , C 2 (R 6 ) 5 , OC(R 6 ) 3 or OC 2 (R 6 ) 5 ,

where

R 6 is in each case independently H or halogen and

m is an integer from 0 to 4;

or salts of said at least one compound, and a pharmaceutically acceptable carrier therefor.

27. A compound of the formula:

or a salt thereof.

28. A compound of the formula:

or a salt thereof.

29. A compound of the formula:

or a salt thereof.

30. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutical acceptable carrier therefor.

31. A pharmaceutical composition comprising the compound of claim 28 and a pharmaceutical acceptable carrier therefor.

32. A pharmaceutical composition comprising the compound of claim 29 and a pharmaceutical acceptable carrier therefor.