Trihydroxy polyunsaturated eicosanoids

• US 6,949,664 B2
• Filed: 04/01/2003
• Issued: 09/27/2005
• 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.
• Primary Examiner(s): Carr, Deborah D.
• Application Number:
  US10/405,924
• Publication Number:
  US 20030236423A1
• Time in Patent Office: 910 Days
• Field of Search: 554/224, 514/549
• US Class Current: 554/224
• 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: C07C 59/42 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• 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 of trihydroxy polyunsaturated eicosanoids that can be prepared according to these methods. The invention also provides trihydroxy polyunsaturated eicosanoids and their use in pharmaceutical compositions.

Claims

1. A method of preparing an eicosanoid compound of formula 21,

the method comprising:

providing a compound of formula 22

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, or Zn; and

Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; and

performing selective hydrogenation on compound 22 to give compound 21.

2. A method of claim 1 where the selective hydrogenation is performed by hydrogen and Lindlar catalyst.

3. A method of claim 1, where Ra, Rb and Rc are H and A is OR, where R is selected from a group consisting of hydrogen, alkyl and aryl.

4. A method of preparing a compound of formula 22,

the method comprising:

(a) providing a compound of formula 25 and a compound of formula 4

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, or Zn;

Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; and

X is Br or I; and

(b) performing Sonogashira coupling among compound 25 and compound 4 to form compound 22.

5. A method of preparing an eicosanoid analog of formula 23,

the method comprising:

(a) providing a compound of formula 24

wherein;

Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;

R¹, R² and R³ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

X is selected from the group consisting of;

—

C(O)-A, —

SO2-A, —

PO(OR)-A, where A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —

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

Y, Z and W are linkers independently selected from the group consisting of a ring containing up to 20 atoms and a chain of up to 20 atoms, provided that Y, Z and W can independently include one or more nitrogen, oxygen, sulfur or phosphorous atoms, and further provided that Y, Z and W can independently include one or more substituents selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and further provided that Y, Z and W can also contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and provided that all linkers Y are connected to the adjacent C(R)OR group via a carbon atom; and

G is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, and carboxamido; and

(b) performing selective hydrogenation on compound 24 to give compound 23.

6. A compound having the formula 22 or 24

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;

Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;

R¹, R² and R³ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

X is selected from the group consisting of;

—

C(O)-A, —

SO2-A, —

PO(OR)-A, where 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, and R is hydroxyl or alkoxy;

Y, Z and W are linkers independently selected from the group consisting of a ring containing up to 20 atoms and a chain of up to 20 atoms, provided that Y, Z and W can independently include one or more nitrogen, oxygen, sulfur or phosphorous atoms, and further provided that Y, Z and W can independently include one or more substituents selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and further provided that Y, Z and W can also contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and provided that all linkers Y are connected to the adjacent C(R)OR group via a carbon atom; and

G is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, and carboxamido.

7. A pharmaceutical composition, comprising:

a compound according to claim 6; and

a pharmaceutically acceptable carrier.

8. 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 6.

9. 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 7.