Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom's Macroglobulinemia
Disclosed are methods of treating Waldenstrom's Macroglobulinemia comprising administering to the animal, a therapeutically effective amount of a heterocyclic compound of Formula I.
1. A method of treating resistant Waldenstrom's Macroglobulinemia comprising administering to an animal a compound having the structure of Formula I, or a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 1 , R 3 , and R 4 are separately selected from the group consisting of a hydrogen, a halogen, a mono-substituted, a poly-substituted or an unsubstituted moiety of the following residues: saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl or C 2 -C 24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, cycloalkylacyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, thio, sulfoxide, sulfone, sulfonate esters, thiocyano, boronic acids and esters, and halogenated alkyl including polyhalogenated alkyl;
wherein m is equal to 1 or 2;
wherein n is equal to 1 or 2;
wherein each of E 1 , E 2 , E 3 and E 4 is a substituted or unsubstituted heteroatom; and
wherein E 5 is selected from the group consisting of OH, O, OR 10 , S, SR 11 , SO 2 R 11 , NH, NH 2 , NOH, NHOH, NR 12 , and NHOR 13 .
2. The method of claim 1 , wherein R 10-13 are selected from the group consisting of hydrogen and a substituted or unsubstituted moiety of any of the following: C 1-24 alkyl, aryl, and heteroaryl.
3. The method of claim 1 , wherein the animal is a mammal.
4. The method of claim 1 , wherein the animal is a human.
5. The method of claim 1 , wherein the animal is a rodent.
6. The method of claim 1 , further comprising co-administering a chemotherapeutic agent.
7. The method of claim 6 , wherein the chemotherapeutic agent is selected from the group consisting of Adriamycin, Doxorubicin, 5-Fluorouracil, Cytosine arabinoside (“Ara-C”), Cyclophosphamide, Thiotepa, Busulfan, Cytoxan, Taxol, Taxotere, Methotrexate, Cisplatin, Melphalan, Vinblastine, Bleomycin, Etoposide, Ifosfamide, Mitomycin C, Mitoxantrone, Vincreistine, Vinorelbine, Carboplatin, Teniposide, Daunomycin, Caminomycin, Aminopterin, Dactinomycin, Mitomycins, Esperamicins, Melphalan, tamoxifen and onapristone.
8. The method of claim 6 , wherein the chemotherapeutic agent is a proteasome inhibitor.
9. The method of claim 8 , wherein the proteasome inhibitor is bortezomib.
10. The method of claim 8 , wherein the proteasome inhibitor is carfilzomib.
11. The method of claim 6 , wherein the chemotherapeutic agent is a histone deacetylase inhibitor.
12. The method of claim 11 , wherein the compound having the structure of Formula I and the histone deacetylase inhibitor work in a synergistic manner to treat Waldenstrom's Macroglobulinemia.
13. The method of claim 11 , wherein the histone deacetylase inhibitor is selected from the group consisting of MS-275, APHA compound 8, Apicidin, (−)-Depudecin, sodium butyrate, Scriptaid, Sirtinol, Trichostatin A, Valproic acid (VPA) and Vorinostat (suberoylanilide hydroxamic acid (SAHA)).
14. The method of claim 6 , wherein the chemotherapeutic agent is a vascular disrupting agent.
15. The method of claim 14 , wherein the vascular disrupting agent is NPI-2358.
16. The method of claim 14 , wherein the vascular disrupting agent is combratostatin CA4P.
17. A method of treating resistant Waldenstrom's Macroglobulinemia comprising administering to an animal a compound having the structure of Formula I-15, or a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 8 is hydrogen, fluorine, chlorine, bromine or iodine.
18. The method of claim 17 , wherein the compound is:
19. The method of claim 17 , wherein the animal is a mammal.
20. The method of claim 17 , wherein the animal is a human.
21. The method of claim 17 , wherein the animal is a rodent.
22. The method of claim 17 , further comprising co-administering a chemotherapeutic agent.
23. The method of claim 22 , wherein the chemotherapeutic agent is selected from the group consisting of Adriamycin, Doxorubicin, 5-Fluorouracil, Cytosine arabinoside (“Ara-C”), Cyclophosphamide, Thiotepa, Busulfan, Cytoxin, Taxol, Toxotere, Methotrexate, Cisplatin, Melphalan, Vinblastine, Bleomycin, Etoposide, Ifosfamide, Mitomycin C, Mitoxantrone, Vincreistine, Vinorelbine, Carboplatin, Teniposide, Daunomycin, Caminomycin, Aminopterin, Dactinomycin, Mitomycins, Esperamicins, Melphalan, tamoxifen and onapristone.
24. The method of claim 22 , wherein the chemotherapeutic agent is a proteasome inhibitor.
25. The method of claim 24 , wherein the proteasome inhibitor is bortezomib.
26. The method of claim 24 , wherein the proteasome inhibitor is carfilzomib.
27. The method of claim 22 , wherein the chemotherapeutic agent is a histone deacetylase inhibitor.
28. The method of claim 27 , wherein the compound having the structure of Formula I and the histone deacetylase inhibitor work in a synergistic manner to treat Waldenstrom's Macroglobulinemia.
29. The method of claim 27 , wherein the histone deacetylase inhibitor is selected from the group consisting of MS-275, APHA compound 8, Apicidin, (−)-Depudecin, sodium butyrate, Scriptaid, Sirtinol, Trichostatin A, Valproic acid (VPA) and Vorinostat (suberoylanilide hydroxamic acid (SAHA)).
30. The method of claim 22 , wherein the chemotherapeutic agent is a vascular disrupting agent.
31. The method of claim 30 , wherein the vascular disrupting agent is NPI-2358.
32. The method of claim 30 , wherein the vascular disrupting agent is combratostatin CA4P.
33. A method of inhibiting the growth of a resistant Waldenstrom's Macroglobulinemia cell comprising contacting the cell with a compound having the structure of Formula I, or a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 1 , R 3 , and R 4 are separately selected from the group consisting of a hydrogen, a halogen, a mono-substituted, a poly-substituted or an unsubstituted moiety of the following residues: saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl or C 2 -C 24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, cycloalkylacyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, thio, sulfoxide, sulfone, sulfonate esters, thiocyano, boronic acids and esters, and halogenated alkyl including polyhalogenated alkyl;
wherein m is equal to 1 or 2;
wherein n is equal to 1 or 2;
wherein each of E 1 , E 2 , E 3 and E 4 is a substituted or unsubstituted heteroatom; and
wherein E 5 is selected from the group consisting of OH, O, OR 10 , S, SR 11 , SO 2 R 11 , NH, NH 2 , NOH, NHOH, NR 12 , and NHOR 13 .
34. A method of inhibiting the growth of a resistant Waldenstrom's Macroglobulinemia cell comprising contacting the cell with a compound having the structure of Formula I-15, or a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 8 is hydrogen, fluorine, chlorine, bromine or iodine.
35. The method of claim 34 , wherein the compound is:
36. A method of inducing apoptosis of a resistant Waldenstrom's Macroglobulinemia cell comprising contacting the cell with a compound having the structure of Formula I, and a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 1 , R 3 , and R 4 are separately selected from the group consisting of a hydrogen, a halogen, a mono-substituted, a poly-substituted or an unsubstituted moiety of the following residues: saturated C 1 -C 24 alkyl, unsaturated C 2 -C 24 alkenyl or C 2 -C 24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, cycloalkylacyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, thio, sulfoxide, sulfone, sulfonate esters, thiocyano, boronic acids and esters, and halogenated alkyl including polyhalogenated alkyl;
wherein m is equal to 1 or 2;
wherein n is equal to 1 or 2;
wherein each of E 1 , E 2 , E 3 and E 4 is a substituted or unsubstituted heteroatom; and
wherein E 5 is selected from the group consisting of OH, O, OR 10 , S, SR 11 , SO 2 R 11 , NH, NH 2 , NOH, NHOH, NR 12 , and NHOR 13 .
37. A method of inducing apoptosis of a resistant Waldenstrom's Macroglobulinemia cell comprising contacting the cell with a compound having the structure of Formula I-15 and a pharmaceutically acceptable salt or pro-drug ester thereof:
wherein R 8 is hydrogen, fluorine, chlorine, bromine or iodine.
38. The method of claim 37 , wherein the compound is: