Methods for treating Filoviridae virus infections

Patent metadata

Field	Value
Publication number	US-9949994-B2
Application number	US-201615246240-A
Country	US
Kind code	B2
Filing date	Aug 24, 2016
Priority date	Oct 29, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

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.

First claim

What is claimed is:

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 dip

Assignees

• Gilead Sciences Inc

Inventors

• Chun Byoung Kwon
• Clarke Michael O'Neil Hanrahan
• Doerffler Edward
• Hui Hon Chung
• Jordan Robert
• Mackman Richard L
• Parrish Jay P
• Ray Adrian S
• Siegel Dustin

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title