CA2496203A1 - Analogs of indole-3-carbinol metabolites as chemotherapeutic and chemopreventive agents - Google Patents

Analogs of indole-3-carbinol metabolites as chemotherapeutic and chemopreventive agents

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CA2496203A1
CA2496203A1 CA 2496203 CA2496203A CA2496203A1 CA 2496203 A1 CA2496203 A1 CA 2496203A1 CA 2496203 CA2496203 CA 2496203 CA 2496203 A CA2496203 A CA 2496203A CA 2496203 A1 CA2496203 A1 CA 2496203A1
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alkyl
substituted
hydrogen
method
selected
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CA2496203C (en )
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Ling Jong
Wan-Ru Chao
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SRI International
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Sri International
Ling Jong
Wan-Ru Chao
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/08Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Novel compounds useful as chemotherapeutic and chemopreventive agents are provided. The compounds are analogs of indole-3-carbinol metabolites wherein the structures and substituents of the compounds are selected to enhance the compounds~ overall efficacy, particularly with respect to therapeutic activity, oral bioavailability, long-term safety, patient tolerability, and therapeutic window. The compounds are useful not only in treatment of cancer but also in prevention of cancer. One preferred class of the novel compounds have the structure of formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined herein. Pharmaceutical compositions are provided as well, as are methods of synthesis and use.

Claims (123)

CLAIMS:
1. A compound having the structure of formula (I) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are substituents independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl, with the provisos that: at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is other than hydrogen; and when R1, R2, R3, R4, R5, R6, R7, and R8 are selected from hydrogen, halo, alkyl, and alkoxy, then R11 and R12 are other than hydrogen and alkyl.
2. ~The compound of claim 1, wherein R1, R3, R4, R5, R7, R8, and R9 are hydrogen, such that the compound has the structure of formula (Ia) -63- ~~~

3. ~The compound of claim 2, wherein R2 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy, C5-C20 aryloxy, C2-C12 alkylcarbonyl, C6-C20 arylcarbonyl, C2-C12 acyloxy, C2-C12 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C12 alkylcarbonato, carboxy, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, amino, mono- and di-(C1-C12 alkyl)-substituted amino, C2-C12 alkylamido, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
4. ~The compound of claim 3, wherein R2 and R6 are independently selected from the group consisting of halo, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkoxycarbonyl, C2-C12 alkylcarbonato, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
5. ~The compound of claim 2, wherein R10 is C1-C12 alkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C1-C12 alkylsulfanyl, C2-C12 alkoxycarbonyl, or C2-C12 alkylcarbonato.
6. ~The compound of claim 2, wherein R11 and R12 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkoxycarbonyl, amino-substituted C1-C12 alkyl, (C1-C12 alkylamino)-substituted C1-C12 alkyl, and di-(C1-C12 alkyl)amino)-substituted C1-C12 alkyl.
7. ~The compound of claim 1, wherein at least one of R2, R6, and R10 is C2-C12 alkoxycarbonyl or C2-C12 alkylcarbonato.
8. ~The compound of claim 7, wherein at least one of R2, R6, and R10 is C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonato.
9. ~The compound of claim 2, wherein:
R2 and R6 are independently selected from hydrogen and C2-C6 alkoxycarbonyl;

-64-~

R10 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, alkoxycarbonyl, or C2-C6 alkylcarbonato; and R11 and R12 are independently selected from hydrogen and C1-C6 alkyl.
10. ~The compound of claim 9, wherein:
R2 and R6 are independently selected from hydrogen and ethoxycarbonyl;
R10 is hydrogen, methoxy, ethoxycarbonyl, ethylcarbonato, or perfluorinated C1-C6 alkyl; and R11 and R12 are hydrogen.
11. ~The compound of claim 10, wherein R2, R6, and R10 are ethoxycarbonyl.
12. ~The compound of claim 10, wherein R2 and R6 are ethoxycarbonyl and R10 is heptafluoro-(n-propyl).
13. ~The compound of claim 10, wherein R2 and R6 are ethoxycarbonyl and R10 is methoxy.
14. ~A compound having the structure of formula (II) wherein:
R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms, with the proviso that one but not both of R2 and R6 can be amino, mono-substituted amino, or di-substituted amino;
R11 and R12 are independently selected from the group consisting of hydrogen, Cl-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl;
R13 and R14 are defined as for R1, R2, R3, R4, R5, R6, R7, and R8, with the proviso that at least one of R13 and R14 is other than hydrogen; and X is O, S, arylene, heteroarylene, CR15R16or NR17 wherein R15 and R16 are hydrogen, C1-C6 alkyl, or together form =CR18R19 where R18 and R19 are hydrogen or C1-C6 alkyl, and R17 is as defined for R11 and R12.
15. The compound of claim 14, wherein R1, R3, R4, R5, R7, and R8 are hydrogen, and X is CR15R16, such that the compound has the structure of formula (IIa)
16. The compound of claim 15, wherein R2 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkoxy, C5-C20 aryloxy, C2-C12 alkylcarbonyl, C6-C20 arylcarbonyl, C2-C12 acyloxy, C2-C12 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C12 alkylcarbonato, carboxy, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, amino, mono- and di-(C1-C12 alkyl)-substituted amino, C2-C12 alkylamido, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
17. The compound of claim 16, wherein R2 and R6 are independently selected from the group consisting of halo, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkoxycarbonyl, C2-C12 alkylcarbonato, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
18. The compound of claim 17, wherein at least one of R2 and R6 is C2-C12 alkoxycarbonyl or C2-C12 alkylcarbonato.
19. The compound of claim 15, wherein R11 and R12 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkoxycarbonyl, amino-substituted C1-C12 alkyl, (C1-C12 alkylamino)-substituted C1-C12 alkyl, and di-(C1-C12 alkyl)amino-substituted C1-C12 alkyl.
20. The compound of claim 15, wherein R13 and R14 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C1-C12 alkoxy, and C2-C12 alkoxycarbonyl.
21. The compound of claim 15, wherein R15 and R16 are independently selected from hydrogen and C1-C12 alkyl, or together form =CR18R19 where R18 and R19 are hydrogen or C1-C6 alkyl.
22. The compound of claim 15, wherein:
R2 and R6 are independently selected from hydrogen and C2-C6 alkoxycarbonyl;
R11 and R12 are independently selected from hydrogen and C1-C6 alkyl;
R13 and R14 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkoxycarbonyl; and R15 and R16 are independently selected from hydrogen and C1-C6 alkyl, or together form =CH2.
23. The compound of claim 22, wherein:
R2 and R6 are independently selected from hydrogen and ethoxycarbonyl;
R11 and R12 are hydrogen;
R13 and R14 are independently selected from hydrogen, methyl, and ethoxycarbonyl; and R15 and R16 are hydrogen.
24. The compound of claim 23, wherein R2 and R6 are ethoxycarbonyl.
25. A compound having the structure of formula (III) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R20, and R21 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy,C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl,C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms;
R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl; and X is O, S, arylene, heteroarylene, CR15R16 or NR17 wherein R15 and R16 are hydrogen, C1-C6 alkyl, or together form =CR18R19 where R18 and R19 are hydrogen or C1-C6 alkyl, and R17 is as defined for R11 and R12.

-68-~
26. The compound of claim 25, wherein R1, R3, R4, R5, R7, and R8 are hydrogen, and X is CR15R16, such that the compound has the structure of formula (IIIa)
27. The compound of claim 26, wherein R2 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, C1-C12 alkyl, C2-C12 alkenyl; C1-C12 alkoxy, C5-C20 aryloxy, C2-C12 alkylcarbonyl, C6-C20 arylcarbonyl, C2-C12 acyloxy, C2-C12 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C12 alkylcarbonato, carboxy, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, amino, mono- and di-(C1-C12 alkyl)-substituted amino, C2-C12 alkylamido, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
28. The compound of claim 27, wherein R2 and R6 are independently selected from the group consisting of halo, C1-C12 alkyl, C1-C12 alkoxy; C2-C12 alkoxycarbonyl, C2-C12 alkylcarbonato, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
29. The compound of claim 28, wherein at least one of R2 and R6 is C2-C12 alkoxycarbonyl or C2-C12 alkylcarbonato.
30. The compound of claim 26, wherein R11 and R12 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkoxycarbonyl, amino-substituted C1-C12 alkyl, (C1-C12 alkylamino)-substituted C1-C12 alkyl, and di-(C1-C12 alkyl)amino-substituted C1-C12 alkyl.
31. The compound of claim 26, wherein R15 and R16 are independently selected from hydrogen and C1-C12 alkyl, or together form =CR18R19 where R18 and R19 are hydrogen or C1-C6 alkyl.
32. The compound of claim 26, wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C1-C12 alkoxy, and C2-C12 alkoxycarbonyl.
33. The compound of claim 26, wherein:

R2 and R6 are independently selected from hydrogen and C2-C6 alkoxycarbonyl;
R11 and R12 are independently selected from hydrogen and C1-C6 alkyl;
R15 and R16 are independently selected from hydrogen, C1-C6 alkyl, or together form =CH2;
and R20 and R21 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkoxycarbonyl.
34. The compound of claim 33, wherein:
R2 and R6 are independently selected from hydrogen and ethoxycarbonyl;
R11 and R12 are hydrogen;
R15 and R16 are hydrogen; and R20 and R21 are independently selected from hydrogen, methyl, and ethoxycarbonyl.
35. The compound of claim 34, wherein R2 and R6 are ethoxycarbonyl.
36. A compound having the structure of formula (IV) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R5A, R6A, R7A, R8A, R22 and R23 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms;
R11, R12, and R12A are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl; and X1 and X2 are independent selected from O, S, arylene, heteroarylene, CR15R16 and NR17 wherein R15 and R16 are hydrogen, C1-C6 alkyl, or together form =CR18R19 where R18 and R19 are hydrogen or C1-C6 alkyl, and R17 is as defined for R11 and R12, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R5A, R6A, R7A, R8A, R11 R22 and R23 is other than hydrogen.
37. The compound of claim 36, wherein R1, R3, R4, R5, R7, R8, R5A, R7A, and R8A are hydrogen, and X1 and X2 are CH2, such that the compound has the structure of formula (IVa) with the proviso that at least one of R2, R6, R6A, R11, R12, R12A, R22 and R23 is other than hydrogen.
38. The compound of claim 37, wherein R2, R6, R6A, R22, and R23 are independently selected from the group consisting of halo, C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkoxycarbonyl, C2-C12 alkylcarbonato, carbamoyl, mono-(C1-C12 alkyl)-substituted carbamoyl, di-(C1-C12 alkyl)-substituted carbamoyl, C1-C12 alkylsulfanyl, C1-C12 alkylsulfinyl, and C1-C12 alkylsulfonyl.
39. The compound of claim 38, wherein at least one of R2, R6, R6A, R22, and R23 is C2-C12 alkoxycarbonyl or C2-C12 alkylcarbonato.
40. The compound of claim 37, wherein R11, R12, and R12A are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkoxycarbonyl, amino-substituted C1-C12 alkyl, (C1-C12 alkylamino)-substituted C1-C12 alkyl, and di-(C1-C12 alkyl)amino-substituted C1-C12 alkyl.
41. The compound of claim 37, wherein:
R2, R6, R6A, R22, and R23 are independently selected from hydrogen and C2-C6 alkoxycarbonyl; and R11, R12, and R12A are independently selected from hydrogen and C1-C6 alkyl.
42. The compound of claim 41, wherein:
R2, R6, R6A, R22, and R23 are independently selected from hydrogen and ethoxycarbonyl;
R11, R12, and R12A are hydrogen;
43. The compound of claim 42, wherein at least one of R2, R6, R6A, R22, and R23 is ethoxycarbonyl.
44. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of formula (I) (I) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are substituents independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is other than hydrogen.
45. The composition of claim 44, wherein R1, R3, R4, R5, R7, R8, and R9 are hydrogen, such that the compound has the structure of formula (Ia)
46. The composition of claim 44, wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
47. The composition of claim 46, wherein the oral dosage form is a tablet.
48. The composition of claim 46, wherein the oral dosage form is a capsule.
49. The composition of claim 44, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration and the composition comprises a parenterally administrable formulation.
50. The composition of claim 45, wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
51. The composition of claim 50, wherein the oral dosage form is a tablet.
52. The composition of claim 50, wherein the oral dosage form is a capsule.
53. The composition of claim 45, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration and the composition comprises a parenterally administrable formulation.
54. A pharmaceutical composition comprising the compound of any one of claims 14, 15, 25, 26, 36, and 37 in combination with a pharmaceutically acceptable carrier.
55. The composition of claim 54, wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
56. The composition of claim 55, wherein the oral dosage form is a tablet.
57. The composition of claim 55, wherein the oral dosage form is a capsule.
58. The composition of claim 54, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration and the composition comprises a parenterally administrable formulation.
59. A method for preventing or treating cancer in a mammalian individual, comprising administering to the individual a therapeutically effective amount of a compound having the structure of formula (I) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are substituents independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is other than hydrogen.
60. The method of claim 59, wherein R1, R3, R4, R5, R7, R8, and R9 are hydrogen, such that the compound has the structure of formula (Ia)
61. The method of claim 59, wherein the cancer is an estrogen-dependent cancer.
62. The method of claim 61, wherein the cancer is of the breast, cervix, uterus, ovaries, or endometrium.
63. The method of claim 62, wherein the cancer is breast cancer.
64. The method of claim 62, wherein the cancer is ovarian cancer.
6s. The method of claim 61, wherein the cancer is metastasized.
66. The method of claim 61, wherein the cancer is a drug-resistant cancer.
67. The method of claim 66, wherein the cancer exhibits multiple drug resistance.
68. The method of claim 59, wherein the cancer is a non-estrogen-dependent cancer.
69. The method of claim 68, wherein the cancer is of the prostate, liver, lung, colon or pancreas.
70. The method of claim 68, wherein the cancer is metastasized.
71. The method of claim 68, wherein the cancer is a drug-resistant cancer.
72. The method of claim 71, wherein the cancer exhibits multiple drug resistance.
73. The method of claim 60, wherein the cancer is an estrogen-dependent cancer.
74. The method of claim 73, wherein the cancer is of the breast, cervix, uterus, ovaries, or endometrium.
75. The method of claim 74, wherein the cancer is breast cancer.
76. The method of claim 74, wherein the cancer is ovarian cancer.
77. The method of claim 73, wherein the cancer is metastasized.
78. The method of claim 73, wherein the cancer is a drug-resistant cancer.
79. The method of claim 78, wherein the cancer exhibits multiple drug resistance.
80. The method of claim 60, wherein the cancer is a non-estrogen-dependent cancer.
81. The method of claim 80, wherein the cancer is of the prostate, liver, lung, colon or pancreas.
82. The method of claim 80, wherein the cancer is metastasized.
83. The method of claim 80, wherein the cancer is a drug-resistant cancer.
84. The method of claim 83, wherein the cancer exhibits multiple drug resistance.
85. A method for preventing or treating cancer in a mammalian individual, comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 14, 15, 25, 26, 36, and 37.
86. The method of claim 85, wherein the cancer is an estrogen-dependent cancer.
87. The method of claim 86, wherein the cancer is of the breast, cervix, uterus, ovaries, or endometrium.
88. The method of claim 87, wherein the cancer is breast cancer.
89. The method of claim 87, wherein the cancer is ovarian cancer.
90. The method of claim 86, wherein the cancer is metastasized.
91. The method of claim 86, wherein the cancer is a drug-resistant cancer.
92. The method of claim 91, wherein the cancer exhibits multiple drug resistance.
93. The method of claim 85, wherein the cancer is a non-estrogen-dependent cancer.
94. The method of claim 93, wherein the cancer is of the prostate, liver, lung, colon or pancreas.
95. The method of claim 93, wherein the cancer is metastasized.
96. The method of claim 93, wherein the cancer is a drug-resistant cancer.
97. The method of claim 96, wherein the cancer exhibits multiple drug resistance.
98. A method for treating an individual predisposed to or suffering from an estrogen-related condition, disease or disorder other than an estrogen-dependent cancer, comprising administering to the individual a therapeutically effective amount of a compound having the structure of formula (I) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are substituents independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is other than hydrogen.
99. The method of claim 98, wherein R1, R3, R4, R5, R7, R8, and R9 are hydrogen, such that the compound has the structure of formula (Ia)
100. A method for treating an individual predisposed to or suffering from an estrogen-related condition, disease or disorder other than an estrogen-dependent cancer, comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 14, 15, 25, 26, 36, and 37.
101. A method for treating an individual predisposed to or suffering from a viral infection, comprising administering to the individual a therapeutically effective amount of a compound having the structure of formula (I) wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are substituents independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, halocarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24 alkyl)-substituted carbamoyl, di-(C1-C24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24 alkyl)-substituted amino, mono- and di-(C5-C20 aryl)-substituted amino, C2-C24 alkylamido, C5-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, and combinations thereof, and further wherein any two adjacent (ortho) substituents may be linked to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and R11 and R12 are independently selected from the group consisting of hydrogen, C1-C24 alkyl, C2-C24 alkoxycarbonyl, amino-substituted C1-C24 alkyl, (C1-C24 alkylamino)-substituted C1-C24 alkyl, and di-(C1-C24 alkyl)amino-substituted C1-C24 alkyl, with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is other than hydrogen.
102. The method of claim 101, wherein R1, R3, R4, R5, R7, R8, and R9 are hydrogen, such that the compound has the structure of formula (Ia)
103. A method for treating an individual predisposed to or suffering from a viral infection, comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 14, 15, 25, 26, 36, and 37.
104. The method of claim 101, wherein the viral infection is caused by a DNA
virus.
105. The method of claim 104, wherein the DNA virus is human papillomavirus.
106. The method of claim 101, wherein the viral infection is a retroviral infection.
107. The method of claim 102, wherein the viral infection is caused by a DNA
virus.
108. The method of claim 107, wherein the DNA virus is human papillomavirus.
109. The method of claim 102, wherein the viral infection is a retroviral infection.
110. The method of claim 103, wherein the viral infection is caused by a DNA
virus.
111. The method of claim 110, wherein the DNA virus is human papillomavirus.
112. The method of claim 110, wherein the viral infection is a retroviral infection.
113. A method for synthesizing a 6-substituted 5,7-dihydro-indolo[2,3-b]carbazole compound, comprising treating an N-protected 3,3'-diindolylmethane with an organolithium reagent in the presence of a reactant selected from the group consisting of an anhydride, an acyl chloride, an alkyl carbonate, an aryl carbonate, an alkyl chloroformate, and an aryl chloroformate.
114. The method of claim 113, wherein the organolithium reagent is lithium 2,2,6,6-tetramethylpiperidide or lithium diisopropylamide.
115. The method of claim 113, wherein the anhydride has the structure R-(CO)-O-(CO)-R, wherein R is alkyl or substituted alkyl.
116. The method of claim 115, wherein R is alkyl.
117. The method of claim 116, wherein R is methyl.
118. The method of claim 115, wherein R is substituted alkyl.
119. The method of claim 118, wherein R is fluorinated alkyl.
120. The method of claim 119, wherein R is perfluorinated lower alkyl.
121. The method of claim 113, wherein the reactant is an alkyl chloroformate, such that the 6-substituted 5,7-dihydro-indolo[2,3-b]carbazole is a 6-alkylcarbonato-5,7-dihydro-indolo[2,3-b]carbazole.
122. The method of claim 113, wherein the reactant is an alkyl chloroformate and the reaction is carried out in the presence of acid, such that the 6-substituted 5,7-dihydro-indolo[2,3-b]carbazole is a 6-hydroxy-5,7-dihydro-indolo[2,3-b]carbazole.
123. The method of claim 122, further comprising contacting the 6-hydroxy-5,7-dihydro-indolo[2,3-b]carbazole with an alkylating reagent to provide a 6-alkoxy-5,7-dihydro-indolo[2,3-b]carbazole.
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