Plasminogen activator inhibitor antagonists

• US 6,677,473 B1
• Filed: 11/17/2000
• Issued: 01/13/2004
• Est. Priority Date: 11/19/1999
• Status: Expired due to Term

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Corvas International, Inc. (Bausch Health Cos., Inc.)
• Inventors: Madison, Edwin L., Lim-Wilby, Marguerita, Duncan, David F., Semple, Joseph Edward, Pryor, Kent E., Brunck, Terence K., Lawrence, C. Maxwell, Lewis, Ronald D. II
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US09/716,036
• Time in Patent Office: 1,152 Days
• Field of Search: 560/52, 560/9, 560/11, 562/426, 562/429, 562/460, 564/162, 564/163, 568/362
• US Class Current: 560/52
• CPC Class Codes: C07C 59/68 the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 59/72 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 59/90 containing singly bound oxygen-containing groups
• CPC Class Codes: C07C 65/24 polycyclic

Abstract

Compounds and pharmaceutical compositions useful as plasminogen activator inhibitor (PAI) antagonists are provided. In particular, methods of antagonizing PAI with substituted and unsubstituted aryl and heteroaryl ethers and thioethers, benzils, benzyl ethers, benzoate esters, sulfones and benzophenones are provided.

Claims

1. A compound that has the formula (XIc):

or a pharmaceutically acceptable derivative thereof, wherein;

each X¹ is independently selected from halo, pseudohalo, nitro, cyano, alkyl, haloalkyl, aryl or heteroaryl;

Q¹ is O, S, S(O), SO₂ or S(O)₂O;

Q² is O, S, S(O), SO₂, S(O)₂O or NR¹⁷;

L is a direct link, CH₂, (CH₂)_pC(O), (CH₂)_pC(O)O or (CH₂)_pC(O)NR¹⁷, where p is an integer from 0 to 6;

u is an integer from 0 to 4;

v is an integer from 0 to 4;

where u+v is not 0;

each R¹⁷ is independently selected from the group consisting of hydrogen, halo, pseudohalo, cyano, azido, nitro, SiR²⁷R²⁸R²⁵, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, hydroxy, alkoxy, aryloxy, aralkoxy, heteroaralkoxy and NR¹⁹R²⁰;

R¹⁹ and R²⁰ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and heterocyclyl;

R²⁵, R²⁷ and R²⁸ are each independently a monovalent group selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, hydroxy, alkoxy, aryloxy, aralkoxy, heteroaralkoxy and NR¹⁹R²⁰;

R¹⁷, R¹⁹, R²⁰, R²⁵, R²⁷ and R²⁸ may be substituted with one or more substituents each independently selected from Z², wherein Z² is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, S(O)_hR³⁵, NR³⁵R³⁶, COOR³⁵, COR³⁵, CONR³⁵R³⁶, OC(O)NR³⁵R³⁶, N(R³⁵)C(O)R³⁶, alkoxy, aryloxy, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, aralkoxy, heteroaralkoxy, alkoxycarbonyl, carbamoyl, thiocarbamoyl, alkoxycarbonyl, carboxyaryl, halo, pseudohalo, haloalkyl and carboxamido;

R³⁵ and R³⁶ are each independently selected from among hydrogen, halo, pseudohalo, cyano, azido, nitro, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, hydroxy, alkoxy, aryloxy, aralkoxy, heteroaralkoxy, amino, amido, alkylamino, dialkylamino, alkylarylamino, diarylamino and arylamino;

R⁷⁹ is selected as in either (i) or (ii) below;

(i) when L is not a direct link or CH₂, R⁷⁹ is hydrogen, alkenyl, alkynyl, Q²H, aryl or heteroaryl;

or

(ii) when L is a direct link or CH₂, R⁷⁹ is aryl excluding unsubstituted phenyl, heteroaryl, alkenyl or alkynyl.

2. The compound of claim 1 that has formula (XId):

3. The compound of claim 2, wherein Q²-L-R⁷⁹ is 3-iodobenzyloxy, phenoxycarbonylmethoxy, benzyloxycarbonyloxy or 9-fluorenyloxy.

4. The compound of claim 2, wherein each X¹ is independently halo, pseudohalo or nitro.

5. The compound of claim 2, wherein Q¹H is OH.

6. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 that is formulated for single dosage administration.

8. An article of manufacture, comprising packaging material, a compound of claim 1 or a pharmaceutically acceptable derivative thereof, which is effective for antagonizing a plasminogen activator inhibitor (PAI) or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders, unstable angina or cancer, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for antagonizing PAI, or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders, unstable angina or cancer.

9. A method of antagonizing a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of claim 1, or pharmaceutically acceptable derivatives thereof.

10. A method for treating, preventing, or ameliorating one or more symptoms of a plasminogen activator inhibitor (PAI) mediated disorder, comprising administering a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

11. The method of claim 10, wherein the disorder is cancer or a symptom thereof.

12. The method of claim 11 wherein the cancer is selected from the group consisting of tumors, solid tumors, metastatic solid tumors and breast cancer.

13. The method of claim 10, wherein the disorder is a thrombotic disorder, unstable angina or haemostatic disorder.

14. The method of claim 10 that is a method of modulating angiogenesis.

15. The method of claim 10 that is a method of attenuating metastasis.

16. A method of modulating the activity of a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of claim 1, or pharmaceutically acceptable derivatives thereof.

17. A method of modulating the interaction of a plasminogen activator (PA) with a plasminogen activator inhibitor (PAI), comprising contacting the PA or PAI with a compound of claim 1, or pharmaceutically acceptable derivatives thereof, wherein the contacting is effected simultaneously with, prior to, or subsequent to contacting the PA with the PAI.

18. The method of claim 13, wherein the thrombotic disorder or haemostatic disorder is selected from myocardial infarction, thrombosis associated with diabetes or obesity, reocclusion following thrombolytic therapy, deep vein thrombosis, or disseminated intravascular coagulation.

19. The method of claim 13, further comprising administration of tissue plasminogen activator (tPA), wherein the tPA is administered prior to, concurrently with, or subsequent to administration of the compound.

20. The compound [4-(4-hydroxy-3,5-diiodobenzoyl)-2,6-diiodophenoxy]acetic acid benzyl ester, or a pharmaceutically acceptable derivative thereof.

21. A pharmaceutical composition, comprising the compound of claim 20, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21 that is formulated for single dosage administration.

23. An article of manufacture, comprising packaging material, a compound of claim 20 or a pharmaceutically acceptable derivative thereof, which is effective for antagonizing a plasminogen activator inhibitor (PAI) or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders, unstable angina or cancer, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for antagonizing PAI, or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders, unstable angina or cancer.

24. A method of antagonizing a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of claim 20, or pharmaceutically acceptable derivatives thereof.

25. A method for treating, preventing, or ameliorating one or more symptoms of a plasminogen activator inhibitor (PAI) mediated disorder, comprising administering a compound of claim 20 or a pharmaceutically acceptable derivative thereof.

26. The method of claim 25, wherein the disorder is cancer or a symptom thereof.

27. The method of claim 26, wherein the cancer is selected from the group consisting of tumors, solid tumors, metastatic solid tumors and breast cancer.

28. The method of claim 25, wherein the disorder is a thrombotic disorder, unstable angina or haemostatic disorder.

29. The method of claim 25 that is a method of modulating angiogenesis.

30. The method of claim 25 that is a method of attenuating metastasis.

31. A method of modulating the activity of a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of claim 20, or pharmaceutically acceptable derivatives thereof.

32. A method of modulating the interaction of a plasminogen activator (PA) with a plasminogen activator inhibitor (PAI), comprising contacting the PA or PAI with a compound of claim 20, or pharmaceutically acceptable derivatives thereof, wherein the contacting is effected simultaneously with, prior to, or subsequent to contacting the PA with the PAI.

33. The method of claim 28, wherein the thrombotic disorder or haemostatic disorder is selected from myocardial infarction, thrombosis associated with diabetes or obesity, reocclusion following thrombolytic therapy, deep vein thrombosis, or disseminated intravascular coagulation.

34. The method of claim 28, further comprising administration of tissue plasminogen activator (tPA), wherein the tPA is administered prior to, concurrently with, or subsequent to administration of the compound.