Compounds and methods for treating cancer by inhibiting the urokinase receptor

Patent metadata

Field	Value
Publication number	US-9745288-B2
Application number	US-201214238504-A
Country	US
Kind code	B2
Filing date	Aug 16, 2012
Priority date	Aug 16, 2011
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

Compounds and methods for treating or preventing cancer associated with binding to the urokinase receptor are provided. Biological processes affected by the compounds include cell migration, cell growth, cell adhesion, angiogenesis, cancer cell invasion, apoptosis, tumor formation, tumor progression, metastasis, degradation of the extracellular matrix, pericellular proteolysis, activation of plasminogen, changes in the levels of an extracellular protease, and changes in the levels of a VEGF receptor.

First claim

What is claimed is:

1. A method for inhibiting binding of urokinase-type plasminogen activator to a urokinase receptor in a subject comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula (I), (II), (III), or (IV):

or a pharmaceutically acceptable salt of Formula (I), (II), (III), or (IV);
wherein:
n is an integer selected from the group consisting of 0 and 1;
m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
Ar 1 , Ar 2 , and Ar 3 are each independently selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted fused ring cycloalkyl or cycloheteroalkyl systems, substituted or unsubstituted fused ring aryl or heteroaryl systems, and substituted or unsubstituted fused ring cycloalkyl or cycloheteroalkyl/aryl or heteroaryl systems; each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, and hydroxyl;

wherein the compound binds to a urokinase receptor (uPAR); and
wherein the subject has cancer.

2. The method of claim 1 , wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I),
wherein
Ar 1 is selected from the group consisting of 4-isopropylphenyl and 3,4-dimethylphenyl; and
Ar 2 is selected from the group consisting of 3,5-dimethylphenyl; 2-aminophenethylalcohol; 2-amino-3-methylbenzylalcohol; 3′-aminoacetanilide; 3-aminophenol; 4-amino-2,5-dimethylphenol; 2-aminobenzylalcohol; 2′-aminoacetanilide; 8-aminoquinoline; 3-methoxy-5-trifluoromethylbenzyl; 5-methoxy-2-methylbenzyl; 2-benzyloxy; 3-methylbenzyl; 2-(p-tolyl)ethyl; 3-fluorophenethyl; 2-fluorophenethyl; 4-fluorophenethyl; 4-isopropylbenzyl; 4-propylbenzyl; 4-tert-butylbenzyl; 4-bromophenylbenzyl; 5-chloro-2-methoxybenzyl; 4-methoxy-2-methylbenzyl; and 2,4-dimethylbenzyl.

3. The method of claim 2 , wherein the compound of Formula (I) has the following structure:

4. The method of claim 1 , wherein the compound is a compound of Formula (II) and:
n=0;
Ar 1 is 4-methoxyphenyl;
Ar 2 is 2-ethoxylphenyl; and
Ar 3 is 4-methoxyphenyl.

5. The method of claim 4 , wherein the compound has the following structure:

6. The method of claim 1 , wherein the compound is a compound of Formula (II) and;
n=1;
Ar 1 is selected from the group consisting of benzo[d][1,3]dioxol-5-yl, 3-chloro-4-methoxyphenyl, and 4-methoxyphenyl;
Ar 2 is selected from the group consisting of 3,4-dimethoxyphenyl, 3-fluoro-4-methylphenyl, and 2,4-dimethoxyphenyl; and
Ar 3 is 4-methoxyphenyl and 4-fluorophenyl.

7. The method of claim 6 , wherein the compound of Formula (II) is selected from the group consisting of:

8. The method of claim 1 , wherein the compound is a compound of Formula (III) and:
Ar 1 is benzo[d][1,3]dioxol-5-yl;
Ar 2 is benzyl; and
Ar 3 is selected from the group consisting of benzyl and 2-methoxyphenyl.

9. The method of claim 8 , wherein the compound of Formula (III) is selected from the group consisting of:

10. The method of claim 1 , wherein the compound is a compound of Formula (IV) and has the following structure:

11. The method of claim 1 , wherein the cancer comprises breast cancer.

12. The method of claim 1 , wherein the cancer comprises pancreatic cancer.

13. A method for treating a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
Ar 1 is selected from the group consisting of 4-isopropylphenyl and 3,4-dimethylphenyl; and
Ar 2 is selected from the group consisting of 3,5-dimethylphenyl; 2-aminophenethylalcohol; 2-amino-3-methylbenzylalcohol; 3′-aminoacetanilide; 3-aminophenol; 4-amino-2,5-dimethylphenol; 2-aminobenzylalcohol; 2′-aminoacetanilide; 8-aminoquinoline; 3-methoxy-5-trifluoromethylbenzyl; 5-methoxy-2-methylbenzyl; 2-benzyloxy; 3-methylbenzyl; 2-(p-tolyl)ethyl; 3-fluorophenethyl; 2-fluorophenethyl; 4-fluorophenethyl; 4-isopropylbenzyl; 4-propylbenzyl; 4-tert-butylbenzyl; 4-bromophenylbenzyl; 5-chloro-2-methoxybenzyl; 4-methoxy-2-methylbenzyl; and 2,4-dimethylbenzyl; and

wherein the compound of Formula (I) or the pharmaceutically acceptable salt thereof binds to a urokinase receptor (uPAR); and wherein the cancer is selected from the group consisting of: breast cancer and pancreatic cancer.

14. The method of claim 13 , wherein the therapeutically effective amount of the composition inhibits invasion and/or metastasis of the cancer in the subject.

15. The method of claim 1 , wherein the compound has the following structure:

16. The method of claim 1 , wherein the compound has the following structure:

17. The method of claim 1 , wherein the therapeutically effective amount of the composition is administered to the subject in combination with an additional anti-angiogenic agent to the subject.

18. The method of claim 13 , the compound has the following structure:

19. The method of claim 13 , the compound has the following structure:

20. The method of claim 13 , wherein the therapeutically effective amount of the composition is administered to the subject orally.

21. The method of claim 13 , wherein the therapeutically effective amount of the composition is administered to the subject in combination with an additional anti-angiogenic agent to the subject.

22. The method of claim 13 , wherein the therapeutically effective amount of the compound is administered to the subject at a daily dose of about 150 mg/kg.

23. The method of claim 13 , wherein the therapeutically effective amount of the compound is administered to the subject at a daily dose of about 50 mg/kg.

24. The method of claim 13 , wherein the compound is administered to the subject in a formulation comprising 0.5% (w/v) of methylcellulose and 0.1% of tween-20.

25. The method of claim 13 , wherein the subject has breast cancer.

Assignees

• Meroueh Samy O
• Univ Indiana Res & Tech Corp

Inventors

• Meroueh Samy O

Classifications

• A61K31/453

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/36

  Compounds containing methylenedioxyphenyl groups, e.g. sesamin · CPC title

• A61K31/402

  1-aryl substituted, e.g. piretanide · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D207/277

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title