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US 7,582,785 B2Granted
Trihydroxy polyunsaturated eicosanoid derivatives
AssigneeUniversity of Southern California
InventorNicos A. Petasis
Life of this patent
Estimating the term…
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.
Claims18
A compound having the formula 23,
- 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, perfluoroalkyl, aryl and heteroaryl;
- Q is selected from the group consisting of:
- —C(O)-A, —SO2-A, —PO(OR)-A, where A is hydroxyl, 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, hydroxyl, 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, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxyl, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, and carboxamido.
5 more elements
A compound having a formula 39 or a formula 41,
- wherein:
- A is hydroxyl, 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
- Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, aryl and heteroaryl;
- R4 is selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, hydroxyl, alkoxy, aryloxy,
- R5 is selected from the group consisting of (i)-(iv) as follows:
- i) CH2CH(R6)CH2, where R6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy;
- ii) CH2C(R6R7)CH2, where R6 and R7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R6 and R7 are connected together to form a carbocyclic or heterocyclic ring;
- iii) CH2OCH2, CH2C(O)CH2, or CH2CH2;
- and
- iv) R5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring;
- and
- R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R8 and R9 are connected together to form a carbocyclic or heterocyclic ring;
- and
- provided that the compound of formula 39 or formula 41 is not a compound of formula 27,
- wherein:
- A is hydroxyl, 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.
16 more elements
A compound having a formula 40 or a formula 42,
- wherein:
- A is hydroxyl, 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
- Ra, Rb and Rc, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, aryl and heteroaryl;
- R4 is selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, hydroxyl, alkoxy, aryloxy,
- R5 is selected from the group consisting of (i)-(iv) as follows:
- i) CH2CH(R6)CH2, where R6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy;
- ii) CH2C(R6R7)CH2, where R6 and R7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R6 and R7 are connected together to form a carbocyclic or heterocyclic ring;
- iii) CH2OCH2, CH2C(O)CH2, or CH2CH2;
- and
- iv) R5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring;
- and
- R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R8 and R9 are connected together to form a carbocyclic or heterocyclic ring.
11 more elements
A compound selected from a group consisting of compounds having the general formulas 29 or 43-47:
- wherein:
- A is hydroxyl, 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
- Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- R2 is hydrogen, alkyl, perfluoroalkyl, aryl and heteroaryl;
- R5 is selected from the group consisting of(i)-(iv) as follows:
- i) CH2CH(R6)CH2, where R6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy;
- ii) CH2C(R6R7)CH2, where R6 and R7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R6 and R7 are connected together to form a carbocyclic or heterocyclic ring;
- iii) CH2OCH2, CH2C(O)CH2, or CH2CH2;
- and
- iv) R5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring;
- and
- R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R8 and R9 connected together to form a carbocyclic or heterocyclic ring;
- and
- each of the three R groups in SiR3 is independently selected from a group consisting of alkyl, aryl and alkoxy.
12 more elements
A compound having the general formula 3:
- wherein
- R0 is methyl;
- and
- Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl.
1 more element
A compound having the general formula 29:
- wherein:
- A is hydroxyl, 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
- Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl.
1 more element
A compound having the general formula 44:
- wherein:
- A is hydroxyl, 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 and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- and
- R5 is selected from the group consisting of(i)-(iv) as follows:
- i) CH2CH(R6)CH2, where R6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy;
- ii) CH2C(R6R7)CH2, where R6 and R7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R6 and R7 are connected together to form a carbocyclic or heterocyclic ring;
- iii) CH2OCH2, CH2C(O)CH2, or CH2CH2;
- and
- iv) R5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring.
7 more elements
A compound having the general formula 46
- wherein:
- A is hydroxyl, 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
- Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- R2 is hydrogen, alkyl, perfluoroalkyl, aryl or heteroaryl;
- R5 is selected from the group consisting of (i)-(iv) as follows:
- i) CH2CH(R6)CH2, where R6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy;
- ii) CH2C(R6R7)CH2, where R6 and R7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R6 and R7 are connected together to form a carbocyclic or heterocyclic ring;
- iii) CH2OCH2, CH2C(O)CH2, or CH2CH2;
- and
- iv) R5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring;
- and
- R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R8 and R9 are connected together to form a carbocyclic or heterocyclic ring.
10 more elements
A compound of the general formula 25
- wherein:
- Ra and Rb, are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, aryl and heteroaryl;
- Q is selected from the group consisting of:
- —C(O)-A, —SO2-A, —PO(OR)-A, where A is hydroxyl, 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;
- and
- Y and Z 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, hydroxyl, 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.
4 more elements
Dependencies are inferred from the claim text.