US2015374656A1PendingUtilityA1
Compositions and methods of use of phorbol esters
Individually held — no corporate assignee on recordPriority: Jan 31, 2007Filed: Sep 3, 2015Published: Dec 31, 2015
Est. expiryJan 31, 2027(~0.5 yrs left)· nominal 20-yr term from priority
Inventors:Richard L. Chang
A61K 31/23C07C 69/013C07C 69/33A61K 31/60A61K 31/606C07C 2603/40A61K 45/06A61K 31/225C07C 69/22A61P 35/02A61P 35/00A61K 31/55A61K 31/573A61P 31/18A61K 31/618C07C 2103/40A61K 31/222A01N 63/00A01N 43/46Y02A50/30
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Claims
Abstract
Methods and compositions containing a phorbol ester or a derivative of a phorbol ester are provided for the treatment of cytopathic diseases. Cytopathic diseases may be caused by a variety means such as viral infections like HIV and AIDS, or the development of neoplasms in a mammalian subject. The methods and compositions of the invention are effective for inhibiting de novo HIV infection, upregulating viral expression from latent provirus, inhibiting HIV-induced cytopathic effects, down regulating the HIV receptor, increasing Th1 cytokine expression, decreasing Th2 cytokine expression, increasing ERK phosphorylation, inducing apoptosis in malignant cells, inducing remission, maintaining remission, as chemotherapeutic agents, as well as for decreasing symptoms of cytopathic diseases and opportunistic infections that may accompany such diseases. Additional compositions and methods are provided which employ a phorbol ester or derivative compound in combination with at least one additional agent such as those used in HAART protocols, therapeutic agents used to treat opportunistic infections due to HIV, or chemotherapeutic agents to yield more effective treatment tools against cytopathic diseases in mammalian subjects.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for preventing or treating HIV infection or disease in a mammalian subject comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, and R 3 is selected from hydrogen,
and substituted derivatives thereof.
2 . The method of claim 1 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
3 . The method of claim 1 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
4 . The method of claim 1 , wherein the phorbol ester is 12-O-tetradecanoyl-phorbol-13-acetate.
5 . The method of claim 1 , further comprising administering at least one secondary anti-retroviral or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent HIV in said subject.
6 . The method of claim 5 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
7 . The method of claim 5 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2.
8 . The method of claim 1 , wherein said effective amount comprises between about 10 and 1500 μg of said phorbol ester or derivative compound of Formula I every other day.
9 . The method of claim 1 , wherein said effective amount comprises between about 150 to 500 μg of said phorbol ester or derivative compound of Formula I every other day.
10 . The method of claim 1 , wherein said effective amount of said phorbol ester compound or derivative compound of Formula I is administered once per day.
11 . A method for preventing or treating one or more symptoms or conditions of HIV infection or AIDS in a mammalian subject comprising administering an effective amount of phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, and R 3 is selected from hydrogen,
and substituted derivatives thereof.
12 . The method of claim 11 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
13 . The method of claim 11 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
14 . The method of claim 11 , wherein the phorbol ester is 12-O-tetradecanoylphobol-13-acetate.
15 . The method of claim 11 , further comprising administering at least one secondary anti-retroviral or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat symptoms or conditions of AIDS in said subject.
16 . The method of claim 11 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
17 . The method of claim 11 , wherein the at least one secondary anti-retroviral or other adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2.
18 . The method of claim 11 , wherein the one or more symptoms or conditions of AIDS are oral lesions, fatigue, skin thrush, fever, lack of appetite, diarrhea, apthous ulcers, malabsorption, thrombocytopenia, weight loss, anemia, and lymph node enlargement, mycobacterium avium complex, salmonellosis, syphilis, neuroshyphilis, turberculosis, bacillary angiomatosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, pelvic inflammatory disease, Burkitt's lymphoma, cryptococcal meningitis, histoplasmosis, Kaposi's sarcoma, lymphoma, systemic non-Hodgkin's lymphoma, primary CNS lymphoma, cryptosporidiosis, isosporiasis, microsporidiosis, pneumocystis carinii pneumonia, toxoplasmosis, cytomegalovirus, hepatitis, herpes simplex, herpes zoster, human papiloma virus, molluscum contagiosum, oral hairy leukoplakia, and progressive multifocal leukoencephalopathy.
19 . A method for controlling HIV infection in a mammalian subject to reduce or prevent AIDS comprising administering to said subject an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof, to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof and R 3 is selected from hydrogen,
and substituted derivatives thereof.
20 . The method of claim 19 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
21 . The method of claim 19 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
22 . The method of claim 19 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
23 . A composition for preventing or alleviating HIV in a mammalian subject comprising an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, and R 3 is selected from hydrogen,
and substituted derivatives thereof.
24 . The composition of claim 23 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
25 . The composition of claim 23 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
26 . The composition of claim 23 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
27 . The composition of claim 23 , further comprising at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation with said phorbol ester or derivative compound of Formula I.
28 . The composition of claim 23 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2.
29 . A method for activating latent reservoirs of HIV comprising administering an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, and R 3 is selected from hydrogen,
and substituted derivatives thereof.
30 . The method of claim 29 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
31 . The method of claim 29 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
32 . The method of claim 29 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
33 . The method of claim 29 , further comprising administering a secondary anti-retroviral or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or related or derivative compound of Formula I.
34 . The method of claim 33 , wherein the secondary anti-retroviral or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
35 . The method of claim 33 , wherein the secondary anti-retroviral or adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2.
36 . The method of claim 29 , wherein said effective amount comprises between about 10 and 1500 μg of said phorbol ester or derivative compound of Formula I every other day.
37 . The method of claim 29 , wherein said effective amount comprises between about 150 to 500 μg of said phorbol ester or derivative compound of Formula I every other day.
38 . The method of claim 29 , wherein said effective amount of said phorbol ester compound or derivative compound of Formula I is administered once per day.
39 . A method of increasing the expression of Th1 cytokines comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, and R 3 is selected from hydrogen,
and substituted derivatives thereof.
40 . The method of claim 39 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
41 . The method of claim 39 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
42 . The method of claim 39 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
43 . The method of claim 39 , further comprising administering a secondary or other adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to upregulate Th1 cytokines.
44 . The method of claim 43 , wherein the secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
45 . The method of claim 43 , wherein the secondary or adjunctive therapeutic agent is selected from the group consisting of: protease inhibitors, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, combination drugs, entry and fusion inhibitors, acyclovir, adefovir dipivoxil, aldesleukin, amphotericin b, azithromycin, calcium hydroxylapatite, clarithromycin, doxorubicin, dronabinol, entecavir, epoetin alfa, etoposide, fluconazole, ganciclovir, immunoglobulins, interferon alfa-2, isoniazid, itraconazole, megestrol, paclitaxel, peginterferon alfa-2, pentamidine, poly-1-lactic acid, ribavirin, rifabutin, rifampin, somatropin, testosterone, trimetrexate, valganciclovir; integrase inhibitors, microbicides, and IL-2.
46 . The method of claim 39 , wherein said effective amount comprises between about 10 and 1500 μg of said phorbol ester or derivative compound of Formula I every other day.
47 . The method of claim 39 , wherein said effective amount comprises between about 150 to 500 μg of said phorbol ester or derivative compound of Formula I every other day.
48 . The method of claim 40 , wherein said effective amount of said phorbol ester compound or derivative compound of Formula I is administered once per day.
49 . A method of treating or preventing neoplasms in a mammalian subject comprising administering an effective amount of a phorbol ester or derivative of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, R 3 is selected from hydrogen,
and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent neoplasms in said subject.
50 . The method of claim 49 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
51 . The method of claim 49 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
52 . The method of claim 49 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
53 . The method of claim 49 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
54 . The method of claim 49 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
55 . The method of claim 49 , wherein two secondary or adjunctive therapeutic agents are administered to said subject.
56 . The method of claim 55 , wherein the two secondary or adjunctive therapeutic agents are dexamethasone and choline magnesium trisalicylate.
57 . The method of claim 49 , wherein said effective amount comprises between about 10 and 1500 μg of said phorbol ester or derivative compound of Formula I every day.
58 . The method of claim 49 , wherein said effective amount comprises between about 150 to 500 μg of said phorbol ester or derivative compound of Formula I every day.
59 . The method of claim 49 wherein the neoplasm is caused by a hematological malignancy/bone marrow disorder.
60 . The method of claim 59 , wherein the hematological malignancy/bone marrow disorder is leukemia.
61 . The method of claim 60 , wherein the leukemia is acute myeloid leukemia.
62 . The method of claim 49 , wherein the neoplasm is a solid tumor.
63 . The method of claim 49 , wherein the neoplasm is a relapsing neoplasm.
64 . The method of claim 49 , wherein the neoplasm is refractory.
65 . A method for preventing or treating one or more symptoms or conditions of neoplastic disease in a mammalian subject comprising administering an effective amount of phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, R 3 is hydrogen,
and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent symptoms of neoplastic disease in said subject.
66 . The method of claim 65 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
67 . The method of claim 65 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
68 . The method of claim 65 , wherein the phorbol ester is 12-O-tetradecanoylphobol-13-acetate.
69 . The method of claim 68 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
70 . The method of claim 68 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
71 . The method of claim 68 , wherein the one or more symptoms or conditions of neoplastic disease are anemia, chronic fatigue, excessive or easy bleeding, easy bruising, shortness of breath, petechiae, recurrent fever, swollen gums, slow healing of cuts, bone and joint discomfort, recurrent infections, weight loss, itching, night sweats, lymph node swelling, fever, abdominal pain and discomfort, disturbances in vision, coughing, loss of appetite, pain in the chest, difficulty swallowing, swelling, a need to urinate frequently, difficulty starting urination, difficulty holding back urine, weak or interrupted flow of urine, painful or burning urination, difficulty in having an erection, painful ejaculation, blood in urine or semen, frequent pain or stiffness, or weakness.
72 . A method for inducing remission in a mammalian subject suffering from neoplastic disease comprising administering to said subject an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof, to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof; R 3 is hydrogen,
and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester of derivative compound of Formula I to induce remission in said subject.
73 . The method of claim 72 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to induce remission in said subject.
74 . The method of claim 72 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
75 . The method of claim 72 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
76 . The method of claim 72 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
77 . The method of claim 72 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
78 . A method for inducing apoptosis in a neoplasm in a mammalian subject suffering from neoplastic disease comprising administering to said subject an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof, to said subject
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, R 3 is hydrogen,
and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester of derivative compound of Formula I to induce apoptosis in a neoplasm in said subject.
79 . The method of claim 78 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation or coordinate treatment regimen with said phorbol ester or derivative compound of Formula I to treat or prevent malignancy in said subject.
80 . The method of claim 78 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
81 . The method of claim 78 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
82 . The method of claim 78 , wherein the at least one secondary or adjunctive therapeutic agent is administered to said subject in a coordinate administration protocol, simultaneously with, prior to, or after, administration of said phorbol ester to said subject.
83 . The method of claim 82 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
84 . A composition for preventing or treating neoplastic disease in a mammalian subject comprising an effective amount of a phorbol ester or derivative compound of Formula I, or a pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof
wherein R 1 and R 2 are selected from the group consisting of hydrogen,
and substituted derivatives thereof, R 3 is hydrogen,
and substituted derivatives thereof; and at least one secondary or adjunctive therapeutic agent that is effective in a combinatorial formulation with said phorbol ester or derivative compound of Formula I to treat or prevent a neoplasm in said subject.
85 . The composition of claim 84 , wherein R 1 or R 2 is
the remaining R 1 or R 2 is
and R 3 is hydrogen.
86 . The composition of claim 84 , wherein the phorbol ester is phorbol 13-butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-deoxyphorbol 13-isobutyrate-20-acetate, 12-deoxyphorbol 13-phenylacetate, 12-deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-acetate.
87 . The composition of claim 84 , wherein the phorbol ester is 12-O-tetradecanoylphorbol-13-acetate.
88 . The composition of claim 84 , wherein the at least one secondary or adjunctive therapeutic agent is selected from the group consisting of: doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin, cyclophosphamide, gemtuzumab ozogamicin, idarubicin, mercaptopurine, mitoxantrone, thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine, methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
89 . The composition of claim 84 , wherein the composition contains at least two secondary or adjunctive therapeutic agents.
90 . The composition of claim 89 , wherein the at least two secondary or adjunctive therapeutic agents are dexamethasone and choline magnesium trisalicylate.Join the waitlist — get patent alerts
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