Trihydroxy polyunsaturated eicosanoid derivatives

• US 20050228047A1
• Filed: 03/29/2005
• Published: 10/13/2005
• Est. Priority Date: 04/01/2002
• Status: Active Grant

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Petasis, Nicos A.
• Granted Patent: US 7,582,785 B2
• Time in Patent Office: Days
• US Class Current: 514/560
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 67/303 by hydrogenation of unsaturated carbon-to-carbon bonds
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07F 7/081 comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The invention features methods for the preparation of naturally occurring trihydroxy polyunsaturated eicosanoids and their structural analogs. The invention further provides new derivatives and analogs of trihydroxy polyunsaturated eicosanoids that can be prepared according to these methods. The invention also provides compositions and methods using trihydroxy polyunsaturated eicosanoid derivatives for the prevention, amelioration and treatment of a variety of diseases or conditions associated with inflammation or inflammatory response, autoimmune diseases, rheumatoid arthritis, cardiovascular diseases, or abnormal cell proliferation or cancer.

Claims

1. A method of preparing a compound of formula 27,

2. A method of claim 1, where the compound of formula 29, is prepared according to a method comprising:

(a) providing a compound of formula 30 and a compound of formula 31

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;

R^a and R^b are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; and

R^d is alkyl or aryl; and

each of the three R groups in SiR₃ is independently selected from a group consisting of alkyl, aryl and alkoxy; and

(b) performing a Wittig-type coupling among 30 and 31, followed by alkyne desilylation to form 29.

3. A method of claim 1, where the compound of formula 29, is prepared according to a method comprising:

(a) providing a compound of formula 33 and a compound of formula 34,

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;

R^a and R^b are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;

X is Cl, Br or I; and

each of the three R groups in SiR₃ is independently selected from a group consisting of alkyl, aryl and alkoxy; and

(b) performing a Sonogashira coupling among 33 and 34, followed by alkyne desilylation to form 29.

4. A method of claim 1, where the compound of formula 29 is prepared according to a method comprising:

(a) providing a compound of formula 35 and a compound of formula 36,

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;

R^a and R^b are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; and

X is Cl, Br or I;

R^e is hydrogen, alkyl or aryl; and

each of the three R groups in SiR₃ is independently selected from a group consisting of alkyl, aryl and alkoxy; and

(b) performing a Suzuki-type coupling among 35 and 36, followed by alkyne desilylation to form 29.

5. A method of claim 1, where the compound of formula 29, is prepared according to a method comprising:

(a) providing a compound of formula 11 and a compound of formula 38

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;

R^a is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; and

M² is magnesium zinc, copper, tin, silicon or boron; and

(b) performing addition of 11 to 38 to form 29.

6. A method of claim 3, where the compound of formula 34, is prepared according to a method comprising:

(a) providing a compound of formula 30 and a compound of formula 32,

wherein;

R^b is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;

R^d is alkyl or aryl; and

X is Cl, Br or I;

each of the three R groups in SiR₃ is independently selected from a group consisting of alkyl, aryl and alkoxy; and

(b) performing a Wittig-type coupling among 30 and 32 to form 34 directly or after isomerization.

7. A method of claim 3, where the compound of formula 34, is prepared according to a method comprising:

(a) providing a compound of formula 35 and a compound of formula 15,

wherein;

R^b is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;

X¹ and X² are each independently Cl, Br or I; and

each of the three R groups in SiR₃ is independently selected from a group consisting of alkyl, aryl and alkoxy; and

(b) performing a Negishi-type coupling among 15 and a zinc derivative generated from 35, to form 34.

8. A method of preparing a compound of formula 24,

9. A method of preparing a compound of formula 27,

10. A method of claim 9, where the activated zinc is prepared from zinc, a copper salt and a silver salt.

11. A method of preparing a compound of formula 23,

12. A method of preparing a compound of formula 39,

13. The method of claim 12 where the selective hydrogenation is performed by hydrogen and Lindlar catalyst.

14. The method of claim 12 where the selective hydrogenation is performed with a reagent prepared from zinc, a copper salt and a silver salt.

15. A method of preparing a compound of formula 41,

16. The method of claim 15 where the selective hydrogenation is performed by hydrogen and Lindlar catalyst.

17. The method of claim 15 where the selective hydrogenation is performed with a reagent prepared from zinc, a copper salt and a silver salt.

18. A compound having the formula 23,

19. A pharmaceutical composition, comprising a compound according to claim 18;

and a pharmaceutically acceptable carrier.

20. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a compound according to claim 18.

21. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a pharmaceutical composition according to claim 19.

22. A compound having a formula 39 or a formula 41,

23. A pharmaceutical composition, comprising a compound according to claim 22;

and a pharmaceutically acceptable carrier.

24. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a compound according to claim 22.

25. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a pharmaceutical composition according to claim 23.

26. A compound having a formula 40 or a formula 42,

27. A pharmaceutical composition, comprising a compound according to claim 26;

and a pharmaceutically acceptable carrier.

28. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a compound according to claim 26.

29. A method of ameliorating or treating a disease or condition associated with inflammatory response, cardiovascular disease and abnormal cell proliferation or cancer, the method comprising administering to a subject an effective amount of a pharmaceutical composition according to claim 27.

30. A compound selected from a group consisting of compounds having the general formulas 29 or 43-47:

31. A method for the preparation of an isotopically labeled compound of formula 49:

32. A method for the preparation of an isotopically labeled compound of formula 50: