Method of treating cancer and other conditions or disease states using L-cytosine nucleoside analogs

• US 7,951,788 B2
• Filed: 11/22/2006
• Issued: 05/31/2011
• Est. Priority Date: 12/02/2005
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Cheng, Yung-chi
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US11/992,044
• Publication Number:
  US 20090286754A1
• Time in Patent Office: 1,651 Days
• Field of Search: None
• 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 method of treating cancer in a patient or subject in need thereof comprising administering to said patient an effective amount of at least one compound according to the structure:

2. The method according to claim 1 wherein said patient or subject is human and R¹ and R² are each independently H, a C₂-C₁₈ acyl group or a phosphate group.

3. The method according to claim 2 wherein R¹ and R² are each independently H or a C₂-C₁₈ acyl group.

4. The method according to claim 2 wherein R¹ and R² are each H.

5. The method according to claim 1 wherein said cancer is a canderous tumor.

6. The method according to claim 5 wherein said cancer is selected from the group consisting of colon, rectal, pancreatic and melanoma.

7. The method according to claim 1 wherein said cancer is pancreatic cancer or leukemia.

8. The method according to claim 5 wherein said cancer is pancreatic or colon.

9. The method according to claim 5 wherein said cancer is bladder.

10. The method according to claim 5 wherein said cancer is prostate.

11. The method according to claim 5 wherein said cancer is breast.

12. The method according to claim 5 wherein said cancer is lung.

13. The method according to claim 5 wherein said cancer is nasopharyngeal.

14. The method according to claim 5 wherein said cancer is ovarian.

15. The method according to claim 5 wherein said cancer is lymphoma.

16. The method according to claim 5 wherein said cancer is melanoma.

17. The method according to claim 5 wherein said cancer is pancreatic.

19. The method according to claim 1 wherein said patient or subject is a human and R¹ and R² are each independently H, a C₂-C₁₈ acyl group or a phosphate group.

20. The method according to claim 19 wherein R¹ and R² are each independently H or a C₂-C₁₈ acyl group.

21. The method according to claim 19 wherein R¹ and R² are each H.

22. The method according to claim 20 wherein said cancer is a cancerous tumor.

25. The method according to claim 20 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

26. The method according to claim 21 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

27. The method according to claim 22 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

29. The method according to claim 19 wherein said additional anti-cancer compound is selected from the group consisting of Aldesleukin;

Alemtuzumab;

alltretinoin;

allopurinol;

altretamine;

amifostine;

anastrozole;

arsenic trioxide;

Asparaginase;

BCG Live;

bexarotene capsules;

bexarotene gel;

bleomycin;

busulfin intravenous;

busulfan oral;

calusterone;

capecitabine;

carboplatin;

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;

gemcitabine, gemtuzumab ozogamicin;

gleevec;

goserelin acetate;

hydroxyurea;

Ibriturnomab 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-MLP);

mesna;

methotrexate;

methoxsalen;

mitomycin C;

mitotane;

mitoxantrone;

nandrolone phenpropionate;

Nofetumomab;

LOddC;

Oprelvekin;

oxaliplatin;

paclitaxel;

pamidronate;

pegademase;

Pegaspargase;

Pegifigrastim;

pentostatin;

pipobroman;

plicarnycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

surafenib;

talbuvidine (LDT);

talc;

tamoxifen;

tarceva;

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.

30. The method according to claim 20 wherein said additional 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;

gemcitabine, gemtuzumab, ozogamicin;

gleevec;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

mechlorethamine (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;

surafenib;

talbuvidine (LDT);

talc;

tamoxifen;

taarceva;

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.

31. The method according to claim 21 wherein said additional 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;

gemcitabine, gemtuzumab ozogamicin;

gleevac;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

mechlorethamine (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;

surafenib;

talbuvidine (LDT);

talc;

tamoxifen;

tarceva;

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.

32. The method according to claim 22 wherein said additional 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;

gemcitabine, gemtuzumab ozogamicin;

gleevac;

goserelin acetate;

hydroxyurea;

Ibritumomab Tiuxetan;

idarubicin;

ifosfamide;

imatinib mesylate;

Interferon alfa-2a;

Interferon alfa-2b;

irinotecan;

letrozole;

leucovorin;

levamisole;

lomustine (CCNU);

mechlorethamine (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;

surafenib;

talbuvidine (LDT);

talc;

tamoxifen;

tarceva;

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.

18. A method of treating cancer in a patient or subject in need thereof comprising administering to said patient an effective amount of at least one compound according to the structure:

23. The method according to claim 18 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

24. The method according to claim 18 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent or a microtubule inhibitor.

28. The method according to claim 18 wherein said additional 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;

Denileuldn 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;

gemcitabine, gemtuzumab ozogamicin;

gleevec;

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;

plicarmycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

surafenib;

talbuvidine (LDT);

talc;

tamoxifen;

tarceva;

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.

33. The method according to claim 18 wherein said cancer is a cancerous tumor.

34. The method according to claim 33 wherein said cancer is selected from the group consisting of colon, rectal, pancreatic and melanoma.

35. The method according to claim 33 wherein said cancer is pancreatic.

36. The method according to claim 18 wherein said cancer is leukemia.

37. The method according to claim 33 wherein said cancer is colon.

38. The method according to claim 33 wherein said cancer is bladder.

39. The method according to claim 33 wherein said cancer is prostate.

40. The method according to claim 33 wherein said cancer is breast.

41. The method according to claim 33 wherein said cancer is lung or pancreatic.

42. The method according to claim 33 wherein said cancer is nasopharyngeal.

43. The method according to claim 33 wherein said cancer is ovarian.

44. The method according to claim 33 wherein said cancer is lymphoma.

45. The method according to claim 33 wherein said cancer is melanoma.

46. The method according to claim 33 wherein said additional anticancer agent is fluorouracil, oxaliplatin, gemcitabine or mixtures thereof.