Selective inhibitors of the urokinase plasminogen activator
View Patent ↗The present invention relates to novel selective inhibitors of the urokinase plasminogene activator (uPA, EC3,4.21.31) of the aryl guanidine type.
1. A method for the treatment of breast cancer, comprising administering to a patient in need of such treatment an effective amount of 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 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 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.
2. The method according to claim 1 , wherein the treatment comprises controlling pathological overexpression of urokinase and/or urokinase receptor in a patient.
3. The method according to claim 1 , wherein the treatment comprises controlling the formation of metastases in a patient.
4. A pharmaceutical kit for the treatment of breast cancer comprising the following components:
(a) at least one first anti-tumor agent 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 salts of said at least one compound, and a second anti-tumor agent, wherein said first anti-tumor agent and said second anti-tumor agent are in separate containers.
5. A kit according to claim 4 , wherein the halogen of R 6 in said compound of formula I is F.
6. A kit according to claim 4 , wherein said second anti-tumor agent is cisplatin, 5-fluorouracil or a peptide.
7. A method for the treatment of breast cancer comprising administering to a patient in need of such treatment an effective amount of 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, then 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 =—C00R 7 with R 7 =tertbutyl
and m=0, then the compound of formula (I) is not in the hydrochloride salt form,
and
when Ar=phenyl, m=0 and X 1 =NH 2 , then the compound of formula (I) is not in
the bistrifluoroacetate salt form.
8. The method of claim 7 , wherein Ar is a benzene ring.
9. The method of claim 8 , in which the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other.
10. The method of claim 7 , in which R 7 and R 9 are at least one aryl, at least one tertiary alkyl radical or at least one cycloalkyl radical.
11. The method of claim 10 , in which R 7 and R 9 are phenyl radicals.
12. The method of claim 10 , in which R 7 and R 9 are bicyloalkyl radicals.
13. The method of claim 10 , in which R 7 and R 9 are adamantyl.
14. A method according to claim 7 , wherein 0.01 to 100 mg of said compound is administered per kg of body weight per day.
15. A method according to claim 14 , wherein 0.1 to 100 mg of said compound is administered per kg of body weight per day.
16. The method according to claim 7 , wherein the halogen of R 6 in said compound of formula I is F.
17. The method according to claim 1 , wherein the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other, and with the provisos that
when Ar=phenyl, m=O, then 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 =—C00R 7 with R 7 =tertbutyl and
m=0, then the compound of formula (I) is not in the hydrochloride salt form, and
when Ar=phenyl, m0 and X 1 =NH 2 , then the compound of formula (I) is not in the bistrifluoroacetate salt form.
18. The method of claim 17 , in which Ar is a benzene ring.
19. The method of claim 18 , in which the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other.
20. The method of claim 17 , 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. The method of claim 20 , in which R 7 and R 9 are phenyl radicals.
22. The method of claim 20 , in which R 7 and R 9 are bicyloalkyl radicals.
23. The method of claim 20 , in which R 7 and R 9 are adamantyl.
24. The method according to claim 17 , wherein the halogen of R 6 in said compound of formula I is F.
25. The method according to claim 17 , wherein the treatment comprises controlling the formation of metastasis in a patient.
26. The method of claim 25 , wherein Ar is a benzene ring.
27. The method of claim 26 , in which the substituents —CH 2 X 1 and —NHC(NH)NH 2 are arranged in a para position to each other.
28. The method of claim 25 , in which R 7 and R 9 are at least one aryl, at least one tertiary alkyl radical or at least one cycloalkyl radical.
29. The method of claim 28 , in which R 7 and R 9 are phenyl radicals.
30. The method of claim 28 , in which R 7 and R 9 are bicyloalkyl radicals.
31. The method of claim 30 , in which R 7 and R 9 are adamantyl.
32. A method for the treatment of breast cancer comprising administering to a patient in need of such treatment an effective amount of 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 compound.
33. A method for the treatment of breast cancer, comprising administering to a patient in need of such treatment an effective amount of 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, carbokyalkyl, 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.
34. The method according to claim 33 , wherein the treatment comprises controlling pathological overexpression of urokinase or/and urokinase receptor in a patient.
35. The method according to claim 33 , wherein the treatment comprises controlling the formation of metastases in a patient.
36. The method of claim 7 comprising administering to said patient the compound of formula
or a salt thereof.
37. The method of claim 7 comprising administering to said patient the compound of
formula
or a salt thereof.
38. The method of claim 29 comprising administering to said patient the compound of formula
or a salt thereof.