Back to results
US 7,067,552 B2Granted
Radiosensitizing taxanes and their pharmaceutical preparations
AssigneeFlorida State University
InventorsRobert A. Holton, Hossain Nadizadeh, Li-Xi Yang
Life of this patent
Estimating the term…
Abstract
Taxanes containing electron-affinic radiosensitizing functional groups, their pharmaceutical preparations, and methods of making and using this new class of highly potent radiosensitizers of tumor cells.
Claims17
A compound comprising a taxane containing at least 2 electron-affinic radiosensitizing functional groups.
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOOZ2, RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ4, RSG1 or RSG2;
- R7 is hydrogen, halogen, —OT7, —OCOZ7, —OCOOZ7, RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1 or RSG2;
- R10 is hydrogen, keto, —OT10, —OCOZ10, —OCOOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 is alkyl, heterosubstituted alkyl, alkenyl, heterosubstituted alkenyl, alkynyl, heterosubstituted alkynyl, phenyl, heteroaryl, or heterosubstituted heteroaryl;
- X4 is hydrogen, alkyl, heterosubstituted alkyl, alkenyl, heterosubstituted alkenyl, alkynyl, heterosubstituted alkynyl, phenyl, heteroaryl, or heterosubstituted heteroaryl;
- X5 is —X10, -—OX10, —SX11, or —NX8X11;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is alkyl, heterosubstituted alkyl, alkenyl, heterosubstituted alkenyl, alkynyl, heterosubstituted alkynyl, phenyl, heteroaryl, or heterosubstituted heteroaryl;
- X11 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z4, Z7, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1;
- provided that the compound contains at least one radiosensitizing group attached to the C2, C4, C7, C9, C10, C14, C3′ or C5′ position of the compound.
25 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ4, RSG1 or RSG2;
- R7 is hydrogen, halogen, —OT7, —OCOZ7, —OCOOZ7 RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1 or RSG2;
- R10, is hydrogen, keto, —OT10, —OCOZ10, —OCOOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or RSG1;
- X5 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z4, Z7, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOZ2, RSG1 or RSG2;
- R4 is RSG1 or RSG2;
- R7 is hydrogen, halogen, —OT7, —OCOZ7, —OCOOZ7, RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1 or RSG2;
- R10 is hydrogen, keto, —OT10, —OCOZ10, —OCOOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, or RSG1;
- X9 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z7, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOOZ2, RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ4, RSG1 or RSG2;
- R7 is RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1 or RSG2;
- R10 is hydrogen, keto, —OT10, —OCOZ10, —OCOOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T9 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or RSG1;
- X5 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z4, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOOZ2, RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ4, RSG1 or RSG2;
- R7 is hydrogen, keto, —OT7, —OCOZ7, —OCOOZ7, RSG1 or RSG2;
- R9 is RSG1 or RSG2;
- R10 is hydrogen, keto, —OT10, —OCOZ10, —OCOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T7 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or RSG1;
- X5 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z4, Z7 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOOZ2, RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ9 RSG1 or RSG2;
- R7 is hydrogen, keto, —OT7, —OCOZ7, —OCOOZ7, RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1 or RSG2;
- R10 is RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is hydrogen, hydroxy, protected hydroxy, RSG1 or RSG2;
- T2, T4, T7 and T9 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or RSG1;
- X5 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z4, Z7 and Z9 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A compound corresponding to the structure:
- wherein
- M comprises ammonium or is a metal;
- R1 is hydrogen or hydroxy;
- R2 is —OT2, —OCOZ2, —OCOOZ2, RSG1 or RSG2;
- R4 is —OT4, —OCOZ4, —OCOOZ4, RSG1 or RSG2;
- R7 is hydrogen, keto, —OT7, —OCOZ7—OCOOZ7, RSG1 or RSG2;
- R9 is hydrogen, keto, —OT9, —OCOZ9, —OCOOZ9, RSG1or RSG2;
- R10 is hydrogen, keto, —OT10, —OCOZ10, —OCOOZ10, RSG1 or RSG2;
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
- R13 is hydroxy, protected hydroxy, keto, MO- or
- R14 is RSG1 or RSG2;
- T2, T4, T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
- X1 is —OX6;
- X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or heterosubstituted heteroaryl;
- X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or RSG1;
- X5 is —X10, —OX10, —SX10, or —NX8X10;
- X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG1 or RSG2;
- X10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG1 or RSG2;
- Z2, Z4, Z7, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl or heterosubstituted heteroaryl;
- RSG1 is an electron-affinic moiety;
- RSG2 is —L—(RSG1)n;
- L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
- and
- n is an integer greater than or equal to 1.
22 more elements
A method of killing tumor cells in a warm-blooded animal, the method comprising:
- (a) administering to the warm-blooded animal a taxane containing an electron-affinic radiosensitizing functional group,
- (b) followed by, after a time interval sufficient to enhance radiosensitization of the tumor cells, irradiating the tumor cells with a dose of radiation effective to kill the tumor cells.
Dependencies are inferred from the claim text.