Method of Treating Cancer and Other Conditions or Disease States Using L-Cytosine Nucleoside Analogs

• US 20090286754A1
• Filed: 11/22/2006
• Published: 11/19/2009
• Est. Priority Date: 12/02/2005
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Cheng, Yung-Chi
• Granted Patent: US 7,951,788 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis

Abstract

The present invention relates to the use of the compound according to formula (I) Where S is (A) or (B); X is H or F; R¹ is H, an acyl group, a C₁-C₂₀ alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a (C) or (D) group; Where Nu is a radical of a biologically active compound such as an anticancer, antihyperproliferative or antiviral compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably H or a C₁-C₂ alkyl group; k is 0-12, preferably, 0-2; R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group; and pharmaceutically acceptable salts, solvates or polymorphs thereof for the treatment of tumors, cancer and hyperproliferative diseases, among other conditions or disease states.

Claims

1. A pharmaceutical composition comprising an effective amount of at least one compound according to the structure:

Where S is

X is H or F;

R¹ is H, an acyl group, a C_1-20 alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as an anticancer or antiviral compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety;

Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably H or a C₁-C₁₂ alkyl group;

k is 0-12, preferably, 0-2;

R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;

and pharmaceutically acceptable salts, solvates or polymorphs thereof, optionally in combination with an effective amount of an additional anti-cancer agent, and optionally, a pharmaceutically acceptable carrier, additive or excipient.

2. The composition according to claim 1 wherein said anti-cancer compound is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

3. The composition according to claim 1 wherein said anti-cancer compound is selected from the group consisting of Aldesleukin;

Alemtuzumab;

alitretinoin;

allopurinol;

altretamine;

amifostine;

anastrozole;

arsenic trioxide;

Asparaginase;

BCG Live;

bexarotene capsules;

bexarotene gel;

bleomycin;

busulfan intravenous;

busulfan oral;

calusterone;

capecitabine;

carboplatin;

carmustine;

carmustine with Polifeprosan 20 Implant;

celecoxib;

chlorambucil;

cisplatin;

cladribine;

cyclophosphamide;

cytarabine;

cytarabine liposomal;

dacarbazine;

dactinomycin;

actinomycin D;

Darbepoetin alfa;

daunorubicin liposomal;

daunorubicin, daunomycin;

Denileukin diftitox, dexrazoxane;

docetaxel;

doxorubicin;

doxorubicin liposomal;

Dromostanolone propionate;

Elliott'"'"'s B Solution;

epirubicin;

Epoetin alfa estramustine;

etoposide phosphate;

etoposide (VP-16);

exemestane;

Filgrastim;

floxuridine (intraarterial);

fludarabine;

fluorouracil (5-FU);

fulvestrant;

gemtuzumab ozogamicin;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

meclorethamine (nitrogen mustard);

megestrol acetate;

melphalan (L-PAM);

mercaptopurine (6-MP);

mesna;

methotrexate;

methoxsalen;

mitomycin C;

mitotane;

mitoxantrone;

nandrolone phenpropionate;

Nofetumomab;

LOddC;

Oprelvekin;

oxaliplatin;

paclitaxel;

pamidronate;

pegademase;

Pegaspargase;

Pegfilgrastim;

pentostatin;

pipobroman;

plicamycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

talbuvidine (LDT);

talc;

tamoxifen;

temozolomide;

teniposide (VM-26);

testolactone;

thioguanine (6-TG);

thiotepa;

topotecan;

toremifene;

Tositumomab;

Trastuzumab;

tretinoin (ATRA);

Uracil Mustard;

valrubicin;

valtorcitabine (monoval LDC);

vinblastine;

vinorelbine;

zoledronate; and

mixtures thereof.

4. The composition according to claim 1 wherein R¹ is H, a C₂-C₁₈ acyl group or a phosphate group and R² is H.

5. The composition according to claim 1 wherein R¹ is H and R² is H.

6. A method of treating a tumor or cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound according to the structure:

Where S is

X is H or F;

R¹ is H, an acyl group, a C_1-20 alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as an anticancer or antiviral compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety;

Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably H or a C₁-C₁₂ alkyl group;

k is 0-12, preferably, 0-2;

R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;

and pharmaceutically acceptable salts, solvates or polymorphs thereof., optionally in combination with an effective amount of at least one additional anti-cancer agent.

7. The method according to claim 6 wherein said tumor is benign.

8. The method according to claim 7 wherein said tumor is cancerous.

9. The method according to any of claim 6 wherein said cancer is selected from the group consisting of stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, multiple myeloma, leukemia, melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing'"'"'s sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms'"'"' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer and lymphoma cancer.

10. The method according to claim 6 wherein said cancer is leukemia.

11. The method according to claim 6 wherein said cancer is colon cancer.

12. The method according to claim 6 wherein said cancer is bladder.

13. The method according to claim 6 wherein said cancer is prostate.

14. The method according to claim 6 wherein said cancer is breast.

15. The method according to claim 6 wherein said cancer is lung cancer.

16. The method according to claim 6 wherein said cancer is nasopharyngeal cancer.

17. The method according to claim 6 wherein said cancer is ovarian cancer.

18. The method according to claim 6 wherein said cancer is lymphoma.

19. The method according to claim 6 wherein said cancer is hepatocellular.

20. The method according to claim 6 wherein said cancer is melanoma.

21. The method according to claim 6 wherein said compound is coadministered with an effective amount of at least one additional anti-cancer compound.

22. The method according to claim 21 wherein said anti-cancer compound anti-cancer compound is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

23. The method according to claim 21 wherein said anti-cancer compound is selected from the group consisting of Aldesleukin;

Alemtuzumab;

alitretinoin;

allopurinol;

altretamine;

amifostine;

anastrozole;

arsenic trioxide;

Asparaginase;

BCG Live;

bexarotene capsules;

bexarotene gel;

bleomycin;

busulfan intravenous;

busulfan oral;

calusterone;

capecitabine;

carboplatin;

carmustine;

carmustine with Polifeprosan 20 Implant;

celecoxib;

chlorambucil;

cisplatin;

cladribine;

cyclophosphamide;

cytarabine;

cytarabine liposomal;

dacarbazine;

dactinomycin;

actinomycin D;

Darbepoetin alfa;

daunorubicin liposomal;

daunorubicin, daunomycin;

Denileukin diftitox, dexrazoxane;

docetaxel;

doxorubicin;

doxorubicin liposomal;

Dromostanolone propionate;

Elliott'"'"'s B Solution;

epirubicin;

Epoetin alfa estramustine;

etoposide phosphate;

etoposide (VP-16);

exemestane;

Filgrastim;

floxuridine (intraarterial);

fludarabine;

fluorouracil (5-FU);

fulvestrant;

gemtuzumab ozogamicin;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

meclorethamine (nitrogen mustard);

megestrol acetate;

melphalan (L-PAM);

mercaptopurine (6-MP);

mesna;

methotrexate;

methoxsalen;

mitomycin C;

mitotane;

mitoxantrone;

nandrolone phenpropionate;

Nofetumomab;

LOddC;

Oprelvekin;

oxaliplatin;

paclitaxel;

pamidronate;

pegademase;

Pegaspargase;

Pegfilgrastim;

pentostatin;

pipobroman;

plicamycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

talbuvidine (LDT);

talc;

tamoxifen;

temozolomide;

teniposide (VM-26);

testolactone;

thioguanine (6-TG);

thiotepa;

topotecan;

toremifene;

Tositumomab;

Trastuzumab;

tretinoin (ATRA);

Uracil Mustard;

valrubicin;

valtorcitabine (monoval LDC);

vinblastine;

vinorelbine;

zoledronate; and

mixtures thereof.

24. The method to claim 6 wherein R¹ is H, a C₂-C₁₈ acyl group or a phosphate group and R² is H.

25. The method according to claim 6 wherein said compound is 3TC, FTC, LFD4C or mixtures thereof.

26. A method of treating psoriasis, genital warts or a hyperproliferative disease in a patient in need thereof comprising administering to said patient an effective amount of a compound according to the structure:

Where S is

X is H or F;

R¹ is H, an acyl group, a C₁-C₂₀ alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety;

Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably H or a C₁-C₁₂ alkyl group;

k is 0-12, preferably, 0-2;

R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;

and pharmaceutically acceptable salts, solvates or polymorphs thereof.

27. A method according to claim 26 wherein R¹ is H, a C₂-C₁₈ acyl group or a phosphate group and R² is H.

28. The method according to claim 26 wherein said compound is 3TC, FTC, LFD4C or mixtures thereof.

29. The method according to claim 26 wherein said hyperproliferative disease is hyperkeratosis, ichthyosis, keratoderma or lichen planus.

35. The method according to claim 26 wherein said compound is co-administered with an anti-hyperproliferative agent.

30. A method of treating HCV or a chronic inflammatory disease comprising administering to a patient in need of treatment an effective amount of a compound according to the structure:

Where S is

X is H or F;

R¹ is H, an acyl group, a C_1-20 alkyl or ether group, a phosphate, diphosphate, triphosphate or a phosphodiester group, a

Where Nu is a radical of a biologically active compound such as an anticancer or antiviral compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety;

Each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably H or a C₁-C₁₂ alkyl group;

k is 0-12, preferably, 0-2;

R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;

and pharmaceutically acceptable salts, solvates or polymorphs thereof.

31. The method according to claim 30 wherein said chronic inflammatory disease is rheumatoid arthritis or osteoarthritis.

32. A compound according to the structure:

Where S is

X is H or F;

R¹ is a

Where Nu is a radical of a biologically active compound such that an amino group or hydroxyl group from said biologically active agent forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety;

each R⁸ is independently H, or a C₁-C₂₀ alkyl or ether group, preferably a C₁-C₁₂ alkyl group;

k is 0-12, preferably, 0-2;

R² is H, an acyl group or a C₁-C₂₀ alkyl or ether group;

and pharmaceutically acceptable salts, solvates or polymorphs thereof.

33. The compound according to claim 32 wherein Nu is a radical of an anticancer agent selected from the group consisting of Aldesleukin;

Alemtuzumab;

alitretinoin;

allopurinol;

altretamine;

amifostine;

anastrozole;

arsenic trioxide;

Asparaginase;

BCG Live;

bexarotene capsules;

bexarotene gel;

bleomycin;

busulfan intravenous;

busulfan oral;

calusterone;

capecitabine;

carboplatin;

carmustine;

carmustine with Polifeprosan 20 Implant;

celecoxib;

chlorambucil;

cisplatin;

cladribine;

cyclophosphamide;

cytarabine;

cytarabine liposomal;

dacarbazine;

dactinomycin;

actinomycin D;

Darbepoetin alfa;

daunorubicin liposomal;

daunorubicin, daunomycin;

Denileukin diftitox, dexrazoxane;

docetaxel;

doxorubicin;

doxorubicin liposomal;

Dromostanolone propionate;

Elliott'"'"'s B Solution;

epirubicin;

Epoetin alfa estramustine;

etoposide phosphate;

etoposide (VP-16);

exemestane;

Filgrastim;

floxuridine (intraarterial);

fludarabine;

fluorouracil (5-FU);

fulvestrant;

gemtuzumab ozogamicin;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

meclorethamine (nitrogen mustard);

megestrol acetate;

melphalan (L-PAM);

mercaptopurine (6-MP);

mesna;

methotrexate;

methoxsalen;

mitomycin C;

mitotane;

mitoxantrone;

nandrolone phenpropionate;

Nofetumomab;

LOddC;

Oprelvekin;

oxaliplatin;

paclitaxel;

pamidronate;

pegademase;

Pegaspargase;

Pegfilgrastim;

pentostatin;

pipobroman;

plicamycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

talbuvidine (LDT);

talc;

tamoxifen;

temozolomide;

teniposide (VM-26);

testolactone;

thioguanine (6-TG);

thiotepa;

topotecan;

toremifene;

Tositumomab;

Trastuzumab;

tretinoin (ATRA);

Uracil Mustard;

valrubicin;

valtorcitabine (monoval LDC);

vinblastine;

vinorelbine;

zoledronate; and

mixtures thereof.

34. The compound according to claim 32 wherein Nu is a radical of an anti-viral agent.

36-55. -55. (canceled)