Claims for Patent: 10,536,415

Summary for Patent: 10,536,415

Title:	2\'-Fluoro-6\'-methylene carbocyclic nucleosides and methods of treating viral infections
Abstract:	The present invention relates to 2\'-Fluoro-6\'-methylene carbocyclic nucleosides, pharmaceutical compositions containing these nucleosides and their use in the treatment or prophylaxis of a number of viral infections and secondary disease states and conditions thereof, especially including Hepatitis B virus (HBV) and secondary disease states and conditions thereof (cirrhosis and liver cancer), Heptatitis C virus (HCV), Herpes Simplex virus I and II (HSV-1 and HSV-2), cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and Epstein Barr virus (EBV) and secondary cancers which occur thereof (lymphoma, nasopharyngeal cancer, including drug resistant (especially including lamivudine and/or adefovir resistant) and other mutant forms of these viruses, especially HBV.
Inventor(s):	Chu; Chung K. (Stratham, GA), Wang; Jianing (San Diego, CA)
Assignee:	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC. (Atlanta, GA)
Application Number:	15/609,080
Patent Claims:	1. A nucleoside compound according to the structure: ##STR00033## Where B is ##STR00034## Wherein R.sup.1 and R.sup.1a are each independently, H, an acyl group, a C.sub.1-C.sub.20 alkyl or ether group, an amino acid residue (D or L), a phosphate, diphosphate, triphosphate, phosphodiester or phosphoramidate group or together R.sup.1 and R.sup.1a form a carbodiester or phosphodiester group with the oxygen atoms to which they are bonded; R.sup.2 is H, an acyl group, a C.sub.1-C.sub.20 alkyl or ether group or an amino acid residue (D or L); or a pharmaceutically acceptable salt, or enantiomer thereof. 2. The compound according to claim 1, wherein R.sup.1a is H. 3. The compound according to claim 1 wherein R.sup.1 and R.sup.2 are each independently H or a C.sub.2-C.sub.20 acyl group. 4. The compound according to claim 2 wherein R.sup.1 and R.sup.2 are each independently H or a C.sub.2-C.sub.20 acyl group. 5. The compound according to claim 1 wherein R.sup.2 is H or a C.sub.2-C.sub.20 acyl group. 6. The compound according to claim 2 wherein R.sup.2 is 1H or a C.sub.2-C.sub.20 acyl group. 7. The compound according claim 1 wherein R.sup.1, R.sup.1a and R.sup.2 are each H. 8. The compound according to claim 1 which is represented by the chemical structure: ##STR00035## Where B is ##STR00036## 9. The compound according to claim 8 wherein R.sup.1 is H, an acyl group, a phosphate, phosphodiester or phosphoramidate group, and R.sup.1 and R.sup.2 are each independently H or a C.sub.2-C.sub.20 acyl group. 10. The compound according to claim 8 wherein R.sup.1 is an acyl group, a phosphate, phosphodiester or phosphoramidate group, R.sup.1a is H and R.sup.2 is H or a C.sub.2-C.sub.20 acyl group. 11. The compound according to claim 8 wherein R.sup.1 together with the nucleoside to which it is attached forms a group according to the structure: ##STR00037## where each R.sup.5 and R.sup.6 is independently selected from H, a C.sub.1 to C.sub.20 linear, branched or cyclic alkyl group, alkoxyalkyl, aryloxyalkyl, aryl, alkoxy or alkoxycarbonyloxy group, each of which groups may be optionally substituted, with the proviso that at least one R.sup.5 group is other than H, or the two R.sup.5 groups together form a five- or six-membered heterocyclic group; B' is a group according to the structure 0 or ##STR00038## Where i is 0, 1, 2 or 3; R.sup.7 is a C.sub.1 to C.sub.20 linear, branched or cyclic alkyl, acyl, alkoxyalkyl, aryloxyalkyl or aryl group, each of which groups may be optionally substituted; R.sup.8 is sidechain of an amino acid: and Each R'' is independently a C.sub.1 to C.sub.20 linear, branched or cyclic alkyl or a phenyl or heteroaryl group, each of which groups may be optionally substituted. 12. The compound according to claim 8 wherein R.sup.1, together with the nucleoside to which it is attached is a group according to the structure: ##STR00039## Where R.sup.6 is a C.sub.1-C.sub.20 alkyl or an optionally substituted phenyl group; B' is a group according to the structure ##STR00040## Where R.sup.8 is a C.sub.1-C.sub.3 linear or branch-chained alkyl group; and R'' is a C.sub.1-C.sub.20 linear, cyclic or branch-chained alkyl group or an optionally substituted phenyl group. 13. The compound according to claim 8 wherein R.sup.2 and R.sup.1a are each independently H or a C.sub.2-C.sub.20 acyl group; R.sup.1, together with the nucleoside to which it is attached is a group according to the structure: ##STR00041## Where R.sub.6 is an optionally substituted phenyl group; and B' is a group according to the structure ##STR00042## Where R.sup.8 is methyl; and R'' is a C.sub.1-C.sub.4 linear or branch-chained alkyl group. 14. A compound according to claim 8 wherein R.sup.2 and R.sup.1a are each independently H or a C.sub.2-C.sub.20 acyl group; and R.sup.1 is a ##STR00043## group; Where R.sub.p1 is an optionally substituted C.sub.1-C.sub.20 alkyl group; and R.sup.P is H, nitro, cyano, methoxy, or a C.sub.1-C.sub.3 alkyl group optionally substituted with from 1-3 halogen substituents. 15. The compound according to claim 14 wherein R.sup.1 is ##STR00044## Where R.sup.P is H or C.sub.1-C.sub.3 alkyl group and R.sub.p1 is methyl, ethyl, isopropyl or isobutyl. 16. The compound according to claim 15 wherein R.sup.p is H and R.sub.p1 is methyl or isopropyl. 17. The compound according to claim 15 wherein R.sup.1 is a ##STR00045## group, Where R.sup.P is H or C.sub.1-C.sub.3 alkyl group. 18. The compound according to claim 14 wherein R.sup.p is H. 19. The compound according to claim 14 wherein R.sub.p1 is a C.sub.1-C.sub.4 alkyl group. 20. The compound ##STR00046## 21. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. 22. A pharmaceutical composition comprising an effective amount of a compound according to claim 8, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. 23. A pharmaceutical composition comprising an effective amount of a compound according to claim 20, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. 24. The pharmaceutical composition according to claim 22 comprising an effective amount of an additional antiviral agent. 25. The composition according to claim 24 wherein said additional antiviral agent is acyclovir, famciclovir, ganciclovir, valaciclovir, vidaribine, ribavirin, zoster-immune globulin (ZIG), lamivudine, adefovir dipivoxil, entecavir, telbivudine, clevudine, tenofovir or a mixture thereof. 26. The composition according to claim 24 wherein said additional antiviral agent is selected from the group consisting of Hepsera (adefovir dipivoxil), lamivudine, entecavir, telbivudine, tenofovir, emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir, racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1), NM 283, VX-950 (telaprevir), SCH 50304, TMC435, VX-500, BX-813, SCH503034, R1626, ITMN-191 (R7227), R7128, PF-868554, TT033, CGH-759, GI 5005, MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190, ACH-1095, GSK625433, TG4040 (MVA-HCV), A-831, F351, NS5A, NS4B, ANA598, A-689, GNI-104, IDX102, ADX184, GL59728, GL60667, PSI-7851, TLR9 Agonist, PHX1766, SP-30 and mixtures thereof. 27. The composition according to claim 24 wherein said additional antiviral agent is selected from the group consisting of Hepsera (adefovir dipivoxil), lamivudine, entecavir, telbivudine, tenofovir, emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir, racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1) and mixtures thereof. 28. A composition according to claim 22 further in combination with at least one anticancer agent. 29. The composition according to claim 28 wherein said anticancer agent 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); 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. 30. A method of treating a viral infection caused by Hepatitis B virus (HBV) in a patient in need of therapy comprising administering to said patient an effective amount of a composition according to claim 22. 31. The method according to claim 30 wherein said HBV is a drug resistant or multiple drug resistant strain of HBV. 32. A method of reducing the likelihood of a viral infection caused by Hepatitis B virus (HBV) in a patient at risk for a viral infection comprising administering to said patient an effective amount of a composition according to claim 22.

Details for Patent 10,536,415

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-11-16
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	06/21/1989		2029-11-16
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2029-11-16
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2029-11-16