Methods for treating
Provided are compounds, methods, and pharmaceutical compositions for treating Filoviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula IV: The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
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:
or a pharmaceutically acceptable salt thereof;
wherein,
R 7 is selected from the group consisting of
a) H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ;
c) a group selected from:
wherein:
R c is selected from the group of phenyl, 1-naphthyl, 2-naphthyl,
R d is selected from the group of H and CH 3 ;
R e1 and R e2 are each independently selected from the group of H, (C 1 -C 6 )alkyl and benzyl;
R f is selected from the group of H, (C 1 -C 8 )alkyl, benzyl, (C 3 -C 6 )cycloalkyl, and —CH 2 —(C 3 -C 6 )cycloalkyl;
R g is selected from the group of (C 1 -C 8 )alkyl, —O—(C 1 -C 8 )alkyl, benzyl, —O-benzyl, —CH 2 —(C 3 -C 6 )cycloalkyl, —O—CH 2 —(C 3 -C 6 )cycloalkyl, and CF 3 ; and
n′ is an integer selected from the group of 1, 2, 3, and 4; and
d) a group of the formula:
wherein:
Q is selected from the group of O, S, NR, + N(O)(R), N(OR), + N(O)(OR), and N—NR 2 ;
Z 1 and Z 2 , when taken together, are -Q 1 (C(R Y ) 2 ) 3 Q 1 -;
wherein
each Q 1 is independently selected from the group of O, S, and NR; and
each R y is independently selected from the group of H, F, Cl, Br, I, OH, R, —C(=Q 2 )R, —C(=Q 2 )OR, —C(=Q 2 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(=Q 1 )R, —OC(=Q 2 )OR, —OC(=Q 2 )(N(R) 2 ), —SC(=Q 2 )R, —SC(=Q 2 )OR, —SC(=Q 2 )(N(R) 2 ), —N(R)C(=Q 2 )R, —N(R)C(=Q 2 )OR, —N(R)C(=Q 2 )N(R) 2 , —SO 2 NR 2 , —CN, —N 3 , —NO 2 , —OR, and Z 3 ; or when taken together, two R y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;
each Q 2 is independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ; or
Z 1 and Z 2 are each, independently, a group of the Formula Ia:
wherein:
each Q 3 is independently selected from the group of a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), and S(O) 2 ;
M2 is an integer selected from the group of 0, 1 and 2;
each R x is independently R y or the formula:
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 3 is Z 4 or Z 5 ;
Z 4 is R, —C(Q 2 )R y , —C(Q 2 )Z 5 , —SO 2 R y , or —SO 2 Z 5 ; and
Z 5 is a carbocycle or a heterocycle wherein Z 5 is independently substituted with 0 to 3 R y groups;
each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 )optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl; or R 11 and R 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 a —;
each R a is independently selected from the group of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR 2 , —C(═O)SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), and —SO 2 NR 2 ; wherein
each R is independently selected from the group of H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, (C 6 -C 20 )aryl, (C 6 -C 20 )substituted aryl, (C 2 -C 20 )heterocyclyl, (C 2 -C 20 )substituted heterocyclyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl and substituted (C 6 -C 20 )aryl(C 1 -C 8 )alkyl;
each n is an integer independently selected from the group of 0, 1, and 2; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl of each R 11 or R 12 is, independently, optionally substituted with one or more substituents selected from the group of halo, hydroxy, CN, N 3 , N(R a ) 2 and OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S—or —NR a —.
2. The method of claim 1 wherein R 7 is H.
3. The method of claim 1 wherein R 7 is
wherein
R f is selected from the group of H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl; and
R g is selected from the group of C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, —O—CH 2 —C 3 -C 6 cycloalkyl, and CF 3 .
4. The method of claim 1 wherein R 7 is
5. The method of claim 1 wherein the compound of Formula IV is:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the compound of Formula IV is:
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 β2-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®), 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-(hydroxymethyl)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:
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
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®), 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-(hydroxymethyl)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.