Back to results
US 10,590,158 B2Granted
Total synthesis of shishijimicin A and analogs thereof
AssigneeWilliam Marsh Rice University
InventorsKyriacos C. Nicolaou, Ruofan Li, Zhaoyong Lu, Te-ik Sohn, James Woods, Emmanouil N. Pitsinos
Life of this patent
Estimating the term…
Abstract
In one aspect, the present disclosure provides shishijimicin analogs of the formula: wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, antibody drug conjugates of the compounds are also provided.
Claims19
A compound of the formula:
- wherein:
- R1 is -alkanediyl(C≤8)-(S)x-A3 or -substituted alkanediyl(C≤8)-(S)x-A3;
- wherein:
- A3 is hydrogen or alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤12), heteroaryl(C≤12), aralkyl(C≤12), acyl(C≤12), or a substituted version of any of these groups;
- and
- x is 1, 2, or 3;
- R2 is hydroxy, or alkoxy(C≤8), acyloxy(C≤8), or substituted version of either of these groups;
- R3 is NHC(O)R16, wherein:
- R16 is alkoxy(C≤8), alkenyloxy(C≤8), alkylamino(C≤8), dialkylamino(C≤8), or substituted version of any of these groups;
- R4 and R5 are each independently selected from hydrogen and halo;
- X1 is O, S, or NH;
- A1 is -alkanediyl(C≤12)-C(O)-A2 or -substituted alkanediyl(C≤12)-C(O)-A2, or
- wherein:
- X4 is —CH2— or —O—;
- R8 is hydrogen, alkyl(C≤8), cycloalkyl(C≤8), substituted alkyl(C≤8), or substituted cycloalkyl(C≤8);
- R9 is hydrogen, halo, hydroxy, mercapto, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), alkylthio(C≤8), substituted alkylthio(C≤8);
- R10 is hydroxy, oxo, or R10 is taken together with R11 and is —OCHA4O—;
- provided that when R10 is oxo then R10 and the carbon atom to which it is bound are joined by a double bond, and when R10 is taken together with R11 then R10 and the carbon atom to which it is bound are joined by a single bond;
- wherein A4 is aryl(C≤12) or substituted aryl(C≤12), or
- wherein:
- X5 is O, S, or NR18;
- wherein:
- R18 is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- Z1 is CH or N;
- and
- R17 is hydrogen, hydroxy, amino, hydrazino, carboxy, halo, or nitro;
- or alkyl(C≤12), alkoxy(C≤12), or a substituted version of either of these groups;
- R11 is hydrogen, hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8);
- R12 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), or
- —O-alkanediyl(C≤8)-alkylamino(C≤12),
- —OC(O)-alkanediyl(C≤8)-alkylamino(C≤12), or
- OC(O)NH-alkanediyl(C≤8)-alkylamino(C≤12), or a substituted version of any of these groups;
- or
- wherein:
- R14 is amino or hydroxy;
- or alkoxy(C≤12), alkylamino(C≤12), dialkyl-amino(C≤12), or a substituted version of any of these groups, or —NRaRb, wherein:
- Ra and Rb are each hydrogen, alkyl(C≤12), substituted alkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), —C(O)O-alkanediyl(C≤6)-Rc, —C(O)-alkanediyl(C≤6)-Rc, -alkanediyl(C≤6)-Rc, or a substituted version of either of these group;
- wherein:
- Rc is hydrogen, amino, carboxy, hydroxyl, acyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), dialkylamino(C≤8), alkylsulfonyl(C≤8), arylsulfonyl(C≤8), or a substituted version of either of these groups;
- R15 is hydrogen, hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8);
- R20 and R21 are hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), or substituted alkoxy(C≤8);
- A2 is hydrogen or
- wherein:
- X5 is O, S, or NR18;
- wherein:
- R18 is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), or substituted acyl(C≤8);
- n is 1, 2, 3, 4, or 5;
- Z2, Z3, and Z4 are each independently N or CR13;
- and
- R13 is hydrogen, amino, carboxy, hydroxy, hydrazino, halo, nitro, or mercapto;
- alkyl(C≤12), acyl(C≤12), alkoxy(C≤12), acyloxy(C≤12), or a substituted version of either of these groups;
- or
- A1 is
- wherein:
- Y1 is alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- X2 and X3 are each independently selected from —O—, —S—, or —NR19—, wherein:
- R19 is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6);
- R6 is aryl(C≤18), heteroaryl(C≤18), or a substituted version of either of these groups;
- R7 is alkyl(C≤12) or substituted alkyl(C≤12);
- provided that the compound is not:
- or a pharmaceutically acceptable salt thereof.
58 more elements
A method of preparing a compound of the formula:
- wherein:
- R1 is -alkanediyl(C≤8)-(S)x-A3 or -substituted alkanediyl(C≤8)-(S)x-A3;
- wherein:
- A3 is hydrogen or alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤12), heteroaryl(C≤12), aralkyl(C≤12), acyl(C≤12), or a substituted version of any of these groups;
- and
- x is 1, 2, or 3;
- R2 is hydroxy, or alkoxy(C≤8), acyloxy(C≤8), or substituted version of either of these groups, or a protected hydroxy group;
- R3 is NHC(O)R16, wherein:
- R16 is alkoxy(C≤8), alkenyloxy(C≤8), alkylamino(C≤8), dialkylamino(C≤8), or substituted version of any of these groups;
- R4 and R5 are each independently selected from hydrogen and halo;
- X1 is O, S, or NH, or X1 is a protected carbonyl wherein the protected carbonyl is a group of the formula —O(CH2)cO—, wherein c is 1, 2, 3, or 4;
- A1 is -alkanediyl(C≤12)-C(O)-A2 or -substituted alkanediyl(C≤12)-C(O)-A2;
- or
- A1 is:
- wherein:
- X4 is —CH2— or —O—;
- R8 is hydrogen, alkyl(C≤8), cycloalkyl(C≤8), substituted alkyl(C≤8), or substituted cycloalkyl(C≤8);
- R9 is hydrogen, halo, hydroxy, mercapto, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), alkylthio(C≤8), substituted alkylthio(C≤8), or a protected hydroxy group or a protected thiol group;
- R10 is hydroxy, oxo, or R10 is taken together with R11 and is —OCHA4O—;
- provided that when R10 is oxo then R10 and the carbon atom to which it is bound are joined by a double bond, and when R10 is taken together with R11 then R10 and the carbon atom to which it is bound are joined by a single bond;
- wherein A4 is aryl(C≤12) or substituted aryl(C≤12), or
- wherein:
- Z1 is CH or N;
- and
- R17 is hydrogen, hydroxy, amino, hydrazino, carboxy, halo, or nitro;
- or alkyl(C≤12), alkoxy(C≤12), or a substituted version of either of these groups;
- R11 is hydrogen, hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8), or a protected hydroxy group;
- R12 is hydrogen, hydroxy, alkoxy(C≤8), substituted alkoxy(C≤8), or a protected hydroxy group, or
- —O-alkanediyl(C≤8)-alkylamino(C≤12), —OC(O)-alkanediyl(C≤8)-alkylamino(C≤12), or —OC(O)NH-alkanediyl(C≤8)-alkylamino(C≤12), or a substituted version of any of these groups;
- or
- wherein:
- R14 is amino or hydroxy;
- or alkoxy(C≤12), alkylamino(C≤12), dialkyl-amino(C≤12), or a substituted version of any of these groups, or —NRaRb, wherein:
- Ra and Rb are each hydrogen, alkyl(C≤12), substituted alkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), —C(O)O-alkanediyl(C≤6)-Rc,
- —C(O)-alkanediyl(C≤6)-Rc, -alkanediyl(C≤6)-Rc, or a substituted version of either of these group;
- wherein:
- Rc is hydrogen, amino, carboxy, hydroxyl, acyl(C≤8), alkoxy(C≤8), alkylamino(C≤8), dialkylamino(C≤8), alkylsulfonyl(C≤8), arylsulfonyl(C≤8), or a substituted version of either of these groups, or
- a protected amino or hydroxy group;
- R15 is hydrogen, hydroxy, alkoxy(C≤8), or substituted alkoxy(C≤8), or a protected hydroxy group;
- R20 and R21 are hydrogen, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), or substituted alkoxy(C≤8);
- A2 is hydrogen or
- wherein:
- X5 is O, S, or NR18;
- wherein:
- R18 is hydrogen, alkyl(C≤8), substituted alkyl(C≤8), acyl(C≤8), or substituted acyl(C≤8), or;
- n is 1, 2, 3, 4, or 5;
- Z2, Z3, and Z4 are each independently N or CR13;
- and
- R13 is hydrogen, amino, carboxy, hydroxy, hydrazino, halo, or nitro;
- alkyl(C≤12), acyl(C≤12), alkoxy(C≤12), acyloxy(C≤12), or a substituted version of either of these groups, or a protected thiol, amino, or hydroxy group;
- or
- A1 is
- wherein:
- Y1 is alkanediyl(C≤8) or substituted alkanediyl(C≤8);
- X2 and X3 are each independently selected from —O—, —S—, or —NR19—, wherein:
- R19 is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6);
- R6 is aryl(C≤18), heteroaryl(C≤18), or a substituted version of either of these groups;
- R7 is alkyl(C≤12) or substituted alkyl(C≤12);
- comprising reacting a compound of the formula:
- wherein:
- X1, R1, R2, R3, R4, and R5 are as defined above;
- with a compound of the formula:
- wherein:
- X4, A2, R8, R9, R10, R11, and R12 are as defined above;
- and
- Y2 is hydrogen or an activating group;
- or
- with a compound of the formula:
- wherein:
- Y1, X2, X3, R6, and R7 are as defined above;
- and
- Y3 is a leaving group;
- wherein the method optionally further comprises reacting the product with a compound of the formula:
- Y4-alkanediyl(C≤12)-C(O)-A2 or Y4-substituted alkanediyl(C≤12)-C(O)-A2;
- wherein:
- Y4 is a leaving group;
- in the presence of a Lewis acid.
74 more elements
Dependencies are inferred from the claim text.