Analogs of dehydrophenylahistins and their therapeutic use
Compounds represented by the following structure (II) are disclosed: as are methods for making such compounds. Compositions and methods for treating various disease conditions including cancer and non-cancer diseases associated with vascular proliferation are also disclosed.
1. A method of treating myeloma, comprising administering to a subject with myeloma a compound having the structure of Formula II or its tautomers, or pharmaceutically acceptable salts thereof:
wherein
R 2 and R 3 are each separately selected from the group consisting of a hydrogen atom; a halogen atom; mono-substituted; poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, and alkoxy; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkoxy, aryl, heteroaryl, amino, and nitro;
R 4 and R 6 are each separately selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophenyl, carboxy, and cyano;
X 1 and X 2 are separately selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom substituted with a R 5 group;
R 5 is selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C 1 -C 12 alkyl, unsaturated C 2 -C 12 alkenyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups;
Y is selected from the group consisting of an oxygen atom, a sulfur atom, an oxidized sulfur atom;
n is 0, 1, 2, 3, or 4; and
Ar is a cyclic or polycyclic aryl or heteroaryl ring system comprising between one and three rings, wherein:
each ring in said system is separately a 5, 6, 7, or 8 membered ring;
each ring in said system separately comprises 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; and
each ring in said system is optionally substituted with one or more substituents selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophene, carboxy, and cyano; and an optionally substituted fused ring selected from the group consisting of dioxole, dithiole, oxathiole, dioxine, dithiine, and oxathiine.
2. The method of claim 1 , wherein R 4 is a mono-substituted; poly-substituted or unsubstituted, straight or branched chain variant of C 1 -C 12 alkyl or C 2 -C 12 alkenyl.
3. The method of claim 2 , wherein R 4 is selected from the group consisting of 3 methyl-1-butene-3-yl.
4. The method of claim 2 , wherein R 4 is tert-butyl.
5. The method of claim 1 , wherein X 1 and X 2 are oxygen.
6. The method of claim 1 , wherein Y is O.
7. The method of claim 1 , wherein n is 0.
8. The method of claim 1 , wherein Ar is selected from the group consisting of:
optionally substituted with one or more substituents selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophene, carboxy, and cyano; and an optionally substituted fused ring selected from the group consisting of dioxole, dithiole, oxathiole, dioxine, dithiine, and oxathiine.
9. The method of claim 1 , wherein the compound has the structure of formula I:
wherein
R 1 , R 4 , and R 6 , are each separately selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C 1 -C 24 alkyl, unsaturated C 2 -C 12 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, —CO—O—R 7 , cyano, alkylthio, and halogenated alkyl including polyhalogenated alkyl, wherein R 7 is selected from a hydrogen atom, a halogen atom, and saturated C 1 -C 24 alkyl, unsaturated C 2 -C 12 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups;
R 1 ′ and R 1 ″ are each independently selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, —CO—O—R 7 , cyano, alkylthio, and halogenated alkyl including polyhalogenated alkyl, wherein R 7 is selected from a hydrogen atom, a halogen atom, and saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups;
R, R 1 ′ and R 1 ″ are either covalently bound to one another or are not covalently bound to one another;
R 2 and R 3 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C 1 -C 12 alkyl, unsaturated C 2 -C 12 alkenyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups;
m is an integer equal to zero, one or two;
Z, for each separate m, if non-zero, and Z 1 , Z 2 , Z 3 and Z 4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double bonds, provided that the ring formed by Z m -Z 4 is an aryl or heteroaryl ring.
10. The method of claim 1 , where said administration is in combination with radiation treatment.
11. A method of treating myeloma, comprising administering to a subject with myeloma a compound or a tautomer, or pharmaceutically acceptable salt thereof selected from the following:
12. The method of claim 1 , wherein R 4 and R 6 are each separately selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophene, carboxy, and cyano; and
Ar is a cyclic or polycyclic aryl or heteroaryl ring system comprising between one and three rings, wherein:
each ring in said system is separately a 5, 6, 7, or 8 membered ring;
each ring in said system separately comprises 0, 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; and
each ring in said system is optionally substituted with one or more substituents selected from the group consisting of hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: aryloxycarbonyloxy cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophene, carboxy, and cyano; and an optionally substituted fused ring selected from the group consisting of dioxole, dithiole, oxathiole, dioxine, dithiine, and oxathiine.