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US 2016/0318862 A1Published application
Synthesis of delta 12-pgj3 and related compounds
AssigneeWilliam Marsh Rice University
InventorsKyriacos C. NICOLAOU, Philipp HERETSCH, Christopher R.H. HALE, Abdellatif El Marrouni EL GHZAOUI, Kiran Kumar PULUKURI, Ruocheng YU, Charles GROVE
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Abstract
In one aspect, the present invention provides novel derivatives of Δ12-PGJ3 and modular synthetic pathways to obtaining Δ12-PGJ3 and derivatives thereof. In some aspects, the present derivatives of Δ12-PGJ3 are useful as chemotherapeutic agents. The present disclosure also describes compositions of these derivatives as well as methods of use of the derivatives thereof.
Claims31
A compound of the formula:
- wherein:
- Y1 is O, NR1, or N—OR1;
- wherein:
- R1 is hydrogen, alkyl(C≦6), or substituted alkyl(C≦6);
- X1 is hydrogen, alkyl(C≦8), substituted alkyl(C≦8),
- or taken together with X2 as defined below;
- wherein:
- A1 is alkanediyl(C≦8), alkenediyl(C≦8), alkynediyl(C≦8), arenediyl(C≦12), heteroarenediyl(C≦12), or a substituted version of any of these groups;
- n is 0, 1, 2, 3, 4, 5, or 6;
- X3 is hydrogen, hydroxy, amino, cyano, or;
- alkyl(C≦12), alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), heteroaryl(C≦12), heterocycloalkyl(C≦12), alkoxy(C≦12), alkenyloxy(C≦12), alkynyloxy(C≦12), aryloxy(C≦12), heteroaryloxy(C≦12), heterocycloalkyloxy(C≦12), acyloxy(C≦12), alkylamino(C≦12), dialkylamino(C≦12), alkenylamino(C≦12), alkynylamino(C≦12), arylamino(C≦12), heteroarylamino(C≦12), heterocycloalkylamino(C≦12), amido(C≦12), or a substituted version of any of these groups;
- or —C(O)NR2R3, —C(O)R2;
- or —Y2—R4;
- wherein:
- R2 and R3 are each independently hydrogen, hydroxy, alkyl(C≦8), aryl(C≦8), alkoxy(C≦8), alkylsulfonyl(C≦8), arylsulfonyl(C≦8), or a substituted version of any of the last five groups;
- or R2 is -alkoxydiyl(C≦6)-S(O)2-aryl(C≦12) or a substituted version of this group;
- Y2 is alkanediyl(C≦12), substituted alkanediyl(C≦12);
- alkoxydiyl(C≦12), or substituted alkoxydiyl(C≦12);
- and R4 is hydrogen, —C(O)NR2R3, or —C(O)R2;
- wherein R2 and R3 are as defined above and
- X2 is
- or taken together with X1 as defined below;
- wherein:
- A2 is alkanediyl(C≦8), alkenediyl(C≦8), alkynediyl(C≦8) or a substituted version of any of these groups;
- or —CH2CH(OR4)—;
- wherein:
- R4 is alkyl(C≦12);
- alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), heteroaryl(C≦12), acyl(C≦12), or a substituted version of any of these groups;
- X4 is hydrogen, hydroxy, or
- alkyl(C≦12), alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), heteroaryl(C≦12), heterocycloalkyl(C≦12), aryloxy(C≦12), heteroaryloxy(C≦12), heterocycloalkoxy(C≦12), arylthio(C≦12), heteroarylthio(C≦12), heterocycloalkylthio(C≦12), arylsulfinyl(C≦12), heteroarylsulfinyl(C≦12), heterocycloalkylsulfinyl(C≦12), arylsulfonyl(C≦12), heteroarylsulfonyl(C≦12), heterocycloalkylsulfonyl(C≦12), or a substituted version of any of these groups;
- and
- o is 1, 2, 3, 4, 5, or 6;
- wherein:
- X1 and X2 are taken together as shown in formula (II):
- wherein:
- Y1 is O, NH, or N—OR1;
- wherein:
- R1 is hydrogen, alkyl(C≦6), or substituted alkyl(C≦6);
- A1 is alkanediyl(C≦8), alkenediyl(C≦8), alkynediyl(C≦8), arenediyl(C≦12), heteroarenediyl(C≦12), or a substituted version of any of these groups;
- z is 1, 2, 3, 4, 5, or 6;
- X5 is CR4R5, O, NH, NR6, or S;
- wherein:
- R4, R5, and R6 are each independently H, alkyl(C≦8), aryl(C≦8), aralkyl(C≦8);
- or a substituted version of any of the last three groups;
- and
- X6 is alkyl(C≦12);
- alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), heteroaryl(C≦12) or a substituted version of any of these groups;
- provided that the compound does not have the formula:
- or a pharmaceutically acceptable salt thereof.
46 more elements
-6. (canceled)
-95. (canceled)
(canceled)
-101. (canceled)
(canceled)
(canceled)
110-114. (canceled)
-118. (canceled)
-130. (canceled)
A method of preparing a compound comprised by reacting a base with a compound of the formula:
- wherein:
- Y2 is O, S, NH, or NA1;
- wherein:
- A1 is alkyl(C≦6), alkoxy(C≦6), or a substituted version of any of these groups;
- Y3 is alkyl(C≦18), alkenyl(C≦18), alkynyl(C≦18), aryl(C≦18), aralkyl(C≦18), heteroaryl(C≦18), heteroaralkyl(C≦18), heterocycloalkyl(C≦18), or a substituted version of any these groups;
- or —X1-A2-R1;
- wherein:
- X1 is alkanediyl(C≦8), alkenediyl(C≦8), alkynediyl(C≦8), arenediyl(C≦12), heteroarenediyl(C≦12), or a substituted version of any of these groups;
- A2 is a covalent bond, O, S, S(O), S(O)2, NH, or NR2;
- wherein R2 is alkyl(C≦6) or substituted alkyl(C≦6);
- and
- R1 is alkyl(C≦12), alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), aralkyl(C≦12), heteroaryl(C≦12), heteroaralkyl(C≦12), heterocycloalkyl(C≦12), acyl(C≦12), or a substituted version of any of these groups;
- and then adding a compound of the formula:
- wherein:
- Y4 is alkyl(C≦18), alkenyl(C≦18), alkynyl(C≦18), aryl(C≦18), aralkyl(C≦18), heteroaryl(C≦18), heteroaralkyl(C≦18), heterocycloalkyl(C≦18), or a substituted version of any these groups;
- or —X2-A3-R3;
- wherein:
- X2 is alkanediyl(C≦8), alkenediyl(C≦8), alkynediyl(C≦8), arenediyl(C≦12), heteroarenediyl(C≦12), or a substituted version of any of these groups;
- A3 is a covalent bond, O, S, S(O), S(O)2, NH, or NR4;
- wherein R4 is alkyl(C≦6) or substituted alkyl(C≦6);
- and
- R3 is alkyl(C≦12), alkenyl(C≦12), alkynyl(C≦12), aryl(C≦12), aralkyl(C≦12), heteroaryl(C≦12), heteroaralkyl(C≦12), heterocycloalkyl(C≦12), acyl(C≦12), or a substituted version of any of these groups;
- to form a compound of the formula:
- wherein Y2, Y3, and Y4 are as defined above.
21 more elements
-293. (canceled)
A method of preparing an enone of the formula:
- wherein:
- Y1 is alkyl(C≦18), alkenyl(C≦18), alkynyl(C≦18), aralkyl(C≦18), heteroaralkyl(C≦18), or a substituted version of any of these groups;
- and
- Y2 is O, S, and NR1,
- wherein R1 is hydrogen, alkyl(C≦6), or substituted alkyl(C≦6);
- comprising
- A) reacting a compound of the formula:
- with an acid and a compound of the formula:
- wherein:
- R2 is hydroxy, mercapto, or —NHR1 wherein R1 is as defined above;
- to form a compound of the formula:
- wherein:
- Y3 is —O—, —S—, or —NR1—, wherein R1 is as defined above;
- B) reacting the compound of formula LXIX with a base and a compound of formula X1—Y1, wherein X1 is halo or a group which enhances the ability of the hydroxyl group to be eliminated and Y1 is as defined above;
- to form a compound of the formula:
- wherein:
- Y1 and Y3 are as defined above;
- and
- C) reducing the compound of formula LXX with a reducing agent to form a compound of formula LXVI.
16 more elements
-434. (canceled)
Dependencies are inferred from the claim text.