Claims for Patent: 9,949,994

Summary for Patent: 9,949,994

Title:	Methods for treating Filoviridae virus infections
Abstract:	Provided are compounds, methods, and pharmaceutical compositions for treating Filoviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula IV: ##STR00001## The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
Inventor(s):	Chun; Byoung Kwon (Pleasanton, CA), Clarke; Michael O\'Neil Hanrahan (Redwood City, CA), Doerffler; Edward (Foster City, CA), Hui; Hon Chung (Foster City, CA), Jordan; Robert (Foster City, CA), Mackman; Richard L. (Millbrae, CA), Parrish; Jay P. (El Dorado Hills, CA), Ray; Adrian S. (Burlingame, CA), Siegel; Dustin (San Carlos, CA)
Assignee:	GILEAD SCIENCES, INC. (Foster City, CA)
Application Number:	15/246,240
Patent Claims:	1. A method of treating a Filoviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula IV: ##STR00150## or a pharmaceutically acceptable salt thereof; wherein, R.sup.7 is selected from the group consisting of a) H, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11, --S(O)(OR.sup.11), --S(O).sub.2(OR.sup.11), or --SO.sub.2NR.sup.11R.sup.12; ##STR00151## c) a group selected from: ##STR00152## wherein: R.sup.c is selected from the group of phenyl, 1-naphthyl, 2-naphthyl, ##STR00153## R.sup.d is selected from the group of H and CH.sub.3; R.sup.e1 and R.sup.e2 are each independently selected from the group of H, (C.sub.1-C.sub.6)alkyl and benzyl; R.sup.f is selected from the group of H, (C.sub.1-C.sub.8)alkyl, benzyl, (C.sub.3-C.sub.6)cycloalkyl, and --CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl; R.sup.g is selected from the group of (C.sub.1-C.sub.8)alkyl, --O--(C.sub.1-C.sub.8)alkyl, benzyl, --O-benzyl, --CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl, --O--CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl, and CF.sub.3; and n' is an integer selected from the group of 1, 2, 3, and 4; and d) a group of the formula: ##STR00154## wherein: Q is selected from the group of O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), and N--NR.sub.2; Z.sup.1 and Z.sup.2, when taken together, are -Q.sup.1(C(R.sup.Y).sub.2).sub.3Q.sup.1-; wherein each Q.sup.1 is independently selected from the group of O, S, and NR; and each R.sup.y is independently selected from the group of H, F, Cl, Br, I, OH, R, --C(=Q.sup.2)R, --C(=Q.sup.2)OR, --C(=Q.sup.2)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3, --SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR), --OC(=Q.sup.1)R, --OC(=Q.sup.2)OR, --OC(=Q.sup.2)(N(R).sub.2), --SC(=Q.sup.2)R, --SC(=Q.sup.2)OR, --SC(=Q.sup.2)(N(R).sub.2), --N(R)C(=Q.sup.2)R, --N(R)C(=Q.sup.2)OR, --N(R)C(=Q.sup.2)N(R).sub.2, --SO.sub.2NR.sub.2, --CN, --N.sub.3, --NO.sub.2, --OR, and Z.sup.3; or when taken together, two R.sup.y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each Q.sup.2 is independently, O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or N--NR.sub.2; or Z.sup.1 and Z.sup.2 are each, independently, a group of the Formula Ia: ##STR00155## wherein: each Q.sup.3 is independently selected from the group of a bond, O, CR.sub.2, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), N--NR.sub.2, S, S--S, S(O), and S(O).sub.2; M2 is an integer selected from the group of 0, 1 and 2; each R.sup.x is independently R.sup.y or the formula: ##STR00156## wherein: each M1a, M1c, and M1d is an integer independently selected from the group of 0 and 1; M12c is an integer selected from the group of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12; Z.sup.3 is Z.sup.4 or Z.sup.5; Z.sup.4 is R, --C(Q.sup.2)R.sup.y, --C(Q.sup.2)Z.sup.5, --SO.sub.2R.sup.y, or --SO.sub.2Z.sup.5; and Z.sup.5 is a carbocycle or a heterocycle wherein Z.sup.5 is independently substituted with 0 to 3 R.sup.y groups; each R.sup.11 or R.sup.12 is independently H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.4-C.sub.8)carbocyclylalkyl, (C.sub.6-C.sub.20)optionally substituted aryl, optionally substituted heteroaryl, --C(.dbd.O)(C.sub.1-C.sub.8)alkyl, --S(O).sub.n(C.sub.1-C.sub.8)alkyl or (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and R.sup.12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with --O--, --S--or --NR.sup.a--; each R.sup.a is independently selected from the group of H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl, (C.sub.4-C.sub.8)carbocyclylalkyl, --C(.dbd.O)R, --C(.dbd.O)OR, --C(.dbd.O)NR.sub.2, --C(.dbd.O)SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR), and --SO.sub.2NR.sub.2; wherein each R is independently selected from the group of H, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, (C.sub.6-C.sub.20)aryl, (C.sub.6-C.sub.20)substituted aryl, (C.sub.2-C.sub.20)heterocyclyl, (C.sub.2-C.sub.20)substituted heterocyclyl, (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl and substituted (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl; each n is an integer independently selected from the group of 0, 1, and 2; and wherein each (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl or (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl of each R.sup.11 or R.sup.12 is, independently, optionally substituted with one or more substituents selected from the group of halo, hydroxy, CN, N.sub.3, N(R.sup.a).sub.2 and OR.sup.a; and wherein one or more of the non-terminal carbon atoms of each said (C.sub.1-C.sub.8)alkyl may be optionally replaced with --O--, --S--or --NR.sup.a--. 2. The method of claim 1 wherein R.sup.7 is H. 3. The method of claim 1 wherein R.sup.7 is ##STR00157## wherein R.sup.f is selected from the group of H, C.sub.1-C.sub.8 alkyl, benzyl, C.sub.3-C.sub.6 cycloalkyl, and --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl; and R.sup.g is selected from the group of C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl, --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, --O--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3. 4. The method of claim 1 wherein R.sup.7 is ##STR00158## 5. The method of claim 1 wherein the compound of Formula IV is: ##STR00159## ##STR00160## or a pharmaceutically acceptable salt thereof. 6. The method of claim 1 wherein the compound of Formula IV is: ##STR00161## or a pharmaceutically acceptable salt thereof. 7. The method of claim 1 further comprising administering a therapeutically effective amount of at least one other therapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a .beta.2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating Filoviridae virus infections; or mixtures thereof. 8. The method of claim 7 wherein the at least one other therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam.RTM.), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydr- oxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h- ]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 inhibitors), or rVSV-EBOV or mixtures thereof. 9. The method of claim 1 wherein the Filoviridae infection is caused by a Filoviridae virus. 10. The method of claim 1 wherein the Filoviridae infection is caused by an ebolavirus. 11. The method of claim 1 wherein the Filoviridae infection is caused by Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, or Zaire ebolavirus. 12. The method of claim 1 wherein the Filoviridae infection is caused by a Marburg virus. 13. A compound: ##STR00162## ##STR00163## ##STR00164## or a pharmaceutically acceptable salt thereof. 14. A method of treating a Filoviridae infection in a human in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound ##STR00165## or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient; the method further comprising administering a therapeutically effective amount of at least one other therapeutic agent selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam.RTM.), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydr- oxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h- ]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV and mixtures thereof. 15. The method of claim 14 wherein the at least one other therapeutic agent is ZMapp.

Details for Patent 9,949,994

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		2034-10-29
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2034-10-29