Claims for Patent: 8,877,731

Summary for Patent: 8,877,731

Title:	Azido nucleosides and nucleotide analogs
Abstract:	Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof. Examples of viral infections include a respiratory syncytial viral (RSV) and influenza infection.
Inventor(s):	Beigelman; Leonid (San Mateo, CA), Deval; Jerome (Pacifica, CA), Smith; David Bernard (San Mateo, CA), Wang; Guangyi (Carlsbad, CA), Rajwanshi; Vivek Kumar (Cupertino, CA)
Assignee:	Alios Biopharma, Inc. (South San Francisco, CA)
Application Number:	13/236,486
Patent Claims:	1. A method of ameliorating or treating a viral infection selected from a human respiratory syncytial virus (RSV) viral infection and an influenza A virus viral infection comprising administering a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject suffering from the viral infection, wherein the compound of Formula (II) has the structure: ##STR00190## wherein: B.sup.1a is selected from the group consisting of an optionally substituted heterocyclic base and an optionally substituted heterocyclic base with a protected amino group; R.sup.1a is selected from the group consisting of hydrogen, an optionally substituted acyl, ##STR00191## n.sup.a is 0, 1, or 2; R.sup.2a and R.sup.3a are independently selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl and an optionally substituted C.sub.1-6 haloalkyl; R.sup.4a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6 alkyl, --OR.sup.18a and --OC(.dbd.O)R.sup.19a; R.sup.5a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6 alkyl, --OR.sup.20a and --OC(.dbd.O)R.sup.21a; R.sup.6a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6 alkyl, --OR.sup.22a and --OC(.dbd.O)R.sup.23a; or R.sup.5a and R.sup.6a are both oxygen atoms and linked together by a carbonyl group; R.sup.7a is selected from the group consisting of hydrogen, halogen, optionally substituted C.sub.1-6 alkyl, --OR.sup.24a and --OC(.dbd.O)R.sup.25a; R.sup.8a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl and an optionally substituted C.sub.1-6 haloalkyl; R.sup.9a and R.sup.12a are independently absent or hydrogen; R.sup.10a is absent or hydrogen; each R.sup.11a is independently absent or hydrogen; R.sup.13a is absent or hydrogen; R.sup.14a is selected from the group consisting of an --O-optionally substituted aryl, an --O-optionally substituted heteroaryl and an --O-optionally substituted heterocyclyl, and R.sup.15a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or R.sup.14a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R.sup.15a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or R.sup.14a is O.sup.-, hydroxy or an --O-optionally substituted C.sub.1-6 alkyl, and R.sup.15a and R.sup.5a together are O; R.sup.16a is selected from the group consisting of an --O-optionally substituted aryl, an --O-optionally substituted heteroaryl and an --O-optionally substituted heterocyclyl, and R.sup.17a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or R.sup.16a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R.sup.17a is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or R.sup.16a is O.sup.-, hydroxy or an --O-optionally substituted C.sub.1-6 alkyl, and R.sup.17a and R.sup.5a together are O; R.sup.18a, R.sup.20a, R.sup.22a and R.sup.24 are independently hydrogen or an optionally substituted C.sub.1-6 alkyl; and R.sup.19a, R.sup.21a, R.sup.23a and R.sup.25a are independently selected from the group consisting of an optionally substituted C.sub.1-6 alkyl and an optionally substituted C.sub.3-6 cycloalkyl. 2. The method of claim 1, wherein R.sup.2a and R.sup.3a are hydrogen. 3. The method of claim 1, wherein at least one of R.sup.2a and R.sup.3a is hydrogen; and the other of R.sup.2a and R.sup.3a is an optionally substituted C.sub.1-6 alkyl or an optionally substituted C.sub.1-6 haloalkyl. 4. The method of claim 1, wherein R.sup.1a is hydrogen or an optionally substituted acyl. 5. The method of claim 1, wherein R.sup.1a is selected from the group consisting of ##STR00192## 6. The method of claim 5, wherein R.sup.1a is ##STR00193## and R.sup.14a is an optionally substituted aryl, an optionally substituted N-linked .alpha.-amino acid or an optionally substituted N-linked .alpha.-amino acid ester derivative. 7. The method of claims 6, wherein R.sup.15a is an optionally substituted N-linked .alpha.-amino acid or an optionally substituted N-linked .alpha.-amino acid ester derivative. 8. The method of claim 5, wherein R.sup.1a is ##STR00194## and R.sup.14a and R.sup.15a each independently have the structure: ##STR00195## wherein R.sup.26a is hydrogen or an optionally substituted C.sub.1-4-alkyl; R.sup.27a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6 haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.6 aryl, an optionally substituted C.sub.10 aryl, and an optionally substituted aryl(C.sub.1-6 alkyl); and R.sup.28a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6-alkyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-6 alkyl), and an optionally substituted haloalkyl, or R.sup.26a and R.sup.27a are taken together to form an optionally substituted C.sub.3-6 cycloalkyl. 9. The method of claim 8, wherein R.sup.26a is hydrogen; R.sup.27a is hydrogen or methyl; and R.sup.28a is methyl or benzyl. 10. The method of claim 5, wherein R.sup.1a is ##STR00196## and R.sup.14a is O.sup.-, hydroxy or an --O-optionally substituted C.sub.1-6 alkyl, and R.sup.15a and R.sup.5a together are O. 11. The method of claim 5, wherein R.sup.1a is ##STR00197## and R.sup.16a is an --O-optionally substituted aryl, an optionally substituted N-linked .alpha.-amino acid or an optionally substituted N-linked .alpha.-amino acid ester derivative. 12. The method of claim 11, wherein R.sup.17a is an optionally substituted N-linked .alpha.-amino acid or an optionally substituted N-linked .alpha.-amino acid ester derivative. 13. The method of claim 5, wherein R.sup.1a is ##STR00198## and R.sup.16a and R.sup.17a each independently have the structure: ##STR00199## wherein: R.sup.29a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.1-6 haloalkyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted C.sub.6 aryl, an optionally substituted C.sub.10 aryl and an optionally substituted aryl(C.sub.1-6 alkyl); R.sup.30a is hydrogen or an optionally substituted C.sub.1-4-alkyl; and R.sup.31a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6-alkyl, an optionally substituted C.sub.3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C.sub.1-6 alkyl) and an optionally substituted C.sub.1-6haloalkyl, or R.sup.29a and R.sup.30a are taken together to form an optionally substituted C.sub.3-6 cycloalkyl. 14. The method of claim 13, wherein R.sup.29a is hydrogen; R.sup.30a is hydrogen or methyl; and R.sup.31a is methyl or benzyl. 15. The method of claim 1, wherein R.sup.1a is ##STR00200## and R.sup.16a is O.sup.-, hydroxy or an --O-optionally substituted C.sub.1-6 alkyl; and R.sup.17a and R.sup.5a together are O. 16. The method of claim 1, wherein B.sup.1a is selected from the group consisting of: ##STR00201## wherein: R.sup.A2a is selected from the group consisting of hydrogen, halogen and NHR.sup.J2a, wherein R.sup.J2a is selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.K2a and --C(.dbd.O)OR.sup.L2a; R.sup.B2a is halogen or NHR.sup.W2a, wherein R.sup.W2a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl, an optionally substituted C.sub.3-8 cycloalkyl, --C(.dbd.O)R.sup.M2a and --C(.dbd.O)OR.sup.N2a; R.sup.C2a is hydrogen or NHR.sup.O2a, wherein R.sup.O2a is selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.P2a and --C(.dbd.O)OR.sup.Q2a; R.sup.D2a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl and an optionally substituted C.sub.2-6 alkynyl; R.sup.E2a is selected from the group consisting of hydrogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.3-8 cycloalkyl, --C(.dbd.O)R.sup.R2a and --C(.dbd.O)OR.sup.S2a; R.sup.F2a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl and an optionally substituted C.sub.2-6 alkynyl; Y.sup.2a is N or CR.sup.I2a, wherein R.sup.I2a is selected from the group consisting of hydrogen, halogen, an optionally substituted C.sub.1-6-alkyl, an optionally substituted C.sub.2-6-alkenyl and an optionally substituted C.sub.2-6-alkynyl; R.sup.G2a is an optionally substituted C.sub.1-6 alkyl; R.sup.H2a is hydrogen or NHR.sup.T2a, wherein R.sup.T2a is independently selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.u2a and --C(.dbd.O)OR.sup.V2a, R.sup.Y2a is hydrogen or NHR.sup.Z2a, wherein R.sup.Z2a is selected from the group consisting of hydrogen, --C(.dbd.O)R.sup.AA2a and --C(.dbd.O)OR.sup.BB2a; R.sup.K2a, R.sup.L2a, R.sup.M2a, R.sup.N2a, R.sup.P2a, R.sup.Q2a, R.sup.R2a, R.sup.S2a, R.sup.U2a, R.sup.V2a, R.sup.AA2a and R.sup.BB2a are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6 cycloalkynyl, C.sub.6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C.sub.1-6 alkyl), heteroaryl(C.sub.1-6 alkyl) and heteroalicyclyl(C.sub.1-6 alkyl). 17. The method of claim 16, wherein B.sup.1a is selected from the group consisting of ##STR00202## 18. The method of claim 1, wherein R.sup.7a is --OR.sup.24a or an optionally substituted C.sub.1-6 alkyl; and R.sup.8a is hydrogen. 19. The method of claim 1, wherein R.sup.7a is hydrogen or a halogen; and R.sup.8a is hydrogen. 20. The method of claim 1, wherein R.sup.5a is --OR.sup.20a. 21. The method of claim 1, wherein R.sup.6a is --OR.sup.22a, hydrogen or a halogen. 22. The method of claim 1, wherein R.sup.5a and R.sup.6a are both oxygen atoms and linked together by a carbonyl group. 23. The method of claim 1, wherein the compound is selected from the group consisting of: ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## or a pharmaceutically acceptable salt of any of the foregoing. 24. The method of claim 1, wherein the compound is selected from the group consisting of: ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## or a pharmaceutically acceptable salt of any of the foregoing. 25. A method of inhibiting replication of a virus selected from human respiratory syncytial virus (RSV) and influenza A virus comprising contacting a cell infected with the virus with an effective amount of the compound recited in claim 1, or a pharmaceutically acceptable salt thereof. 26. A method of ameliorating or treating a viral infection selected from human respiratory syncytial virus viral influenza A virus viral infection comprising contacting a cell infected with the virus with an effective amount of the compound recited in claim 1, or a pharmaceutically acceptable salt thereof. 27. A method of ameliorating or treating a human respiratory syncytial virus viral infection comprising administering a therapeutically effective amount of the compound recited in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a second anti-RSV agent to a subject suffering from the viral infection. 28. The method of claim 27, wherein the second anti-RSV agent is selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, 1-cyclopropyl-3-[[1-(4-hydroxybutyl) benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one, (4,4''-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,- 5)triazin-2-ylaminol}-biphenyl-2,2''-disulfonic-acid), -1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e][1,4]di-azepin-3-yl)-urea, 5,5'-bis[1-(((5-amino-1H-tetrazolyl)imino)-methyl)]-2,2',4''-methylidynet- risphenol, ##STR00216## .alpha.-Neuraminic acid, N-acetyl-2-O-[3-(docosyloxy)-2-[(docosyloxy)methyl]-2-methylpropyl]-4,7,8- ,9-tetrakis(hydrogen sulfate), sodium salt and N-cyclopropyl-6-[4-[(2-phenylbenzoyl)amino]benzoyl]-4,5-dihydrothieno[3,2- -d][1]benzazepine-2-carboxamide. 29. A method of treating or ameliorating a human respiratory syncytial virus viral infection comprising contacting a cell infected with the virus with an effective amount of the compound recited in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a second anti-RSV agent. 30. The method of claim 29, wherein the second anti-RSV agent is selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, 1-cyclopropyl -3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-o- ne, (4,4''-bis-{4,6-bis- [3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}- -biphenyl-2,2''-disulfonic-acid), (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]di-a- zepin-3-yl)-urea, 5,5'-bis[1-(((5-amino-1H-tetrazolyl)imino)-methyl)]-2,2',4''-methylidynet- risphenol, ##STR00217## .alpha.-Neuraminic acid, N-acetyl-2-O-[3-(docosyloxy)-2-[(docosyloxy)methyl]-2-methylpropyl]-, 4,7,8,9-tetrakis(hydrogen sulfate), sodium salt and N-clopropyl-6-[4-[(2-phenylbenzoyl)amino]benzoyl]-4,5-dihydrothieno[3,2-d- ][1]benzazepine-2-carboxamide.

Details for Patent 8,877,731

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	06/19/1998		2030-09-22
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2030-09-22
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2030-09-22
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	06/13/2008		2030-09-22