US2023027727A1PendingUtilityA1
Methods for treating arenaviridae and coronaviridae virus infections
Est. expirySep 16, 2035(~9.1 yrs left)· nominal 20-yr term from priority
Inventors:Michael O`Neil Hanrahan ClarkeJoy Yang FengRobert JordanRichard L. MackmanAdrian S. RayDustin Siegel
A61K 31/706A61K 31/7056A61P 43/00A61K 45/06A61K 2300/00A61K 31/53A61P 31/14A61K 31/675A61K 31/4965A61K 31/683A61K 31/664A61P 31/12A61K 31/4184
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Claims
Abstract
Provided are methods for treating Arenaviridae and Coronaviridae virus infections by administering nucleosides and prodrugs thereof, of Formula I. wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Lassa virus and Junin virus infections.
Claims
exact text as granted — not AI-modified1 . A method for treating an Arenaviridae infection comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or ester, thereof,
wherein:
each R 1 is H or halogen;
each R 2 , R 3 , R 4 and R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl;
or any two R 2 , R 3 , R 4 and R 5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;
R 6 is OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , —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 ), —SO 2 NR 11 R 12 halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (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, or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl;
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 ), and —SO 2 NR 11 R 12 ,
wherein:
R c is selected from phenyl, 1-naphthyl, 2-naphthyl,
R d is H or CH 3 ;
R e1 and R e2 are each independently H, (C 1 -C 6 )alkyl or benzyl;
R f is selected from 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 (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 selected from 1, 2, 3, and 4; and
d) a group of formula:
wherein:
Q is O, S, NR, + N(O − )(R), N(OR), + N(O − )(OR), or 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 O, S, or NR; and
each R y is independently 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 —OR, r-Z 2 ; 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 Formula Ia:
wherein:
each Q 3 is independently a bond, O, CR 2 , NR, + N(O − )(R), N(OR), + N(O − )(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
M2 is 0, 1 or 2;
each R x is independently R y or a formula:
wherein:
each M1a, M1c, and M1d is independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 1 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (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, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, OR 11 or SR 11 ;
each R 9 and R 10 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —
CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 1 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11 or SR 11 ;
each R 11 and 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 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), or —SO 2 NR 2 ;
wherein
each R is independently 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 or substituted (C 6 -C 20 )aryl(C 1 -C 8 )alkyl;
each n is independently 0, 1, or 2; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl of each R 2 , R 3 , R 5 , R 6 , R 11 and R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or 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 —; and
wherein each (C 6 -C 20 )aryl(C 1 -C 8 )alkyl of each R 6 , R 11 , and R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; 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
the compound is a compound of Formula IV:
or a pharmaceutically acceptable salt or ester, thereof.
3 . The method of claim 1 wherein R 7 is H.
4 . The method of claim 1 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 ), and —SO 2 NR 11 R 12
b)
wherein:
R c is selected from phenyl, 1-naphthyl, 2-naphthyl,
R d is H or CH 3 ;
R e1 and R e2 are each independently H or C 1 -C 6 alkyl;
R f is selected from 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 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 selected from 1, 2, 3, and 4.
5 . The method of claim 1 wherein R 7 is
wherein Z 1 and Z 2 are each, independently, a group of structure:
6 . The method of claim 1 wherein R 7 is
wherein Z 1 and Z 2 are each, independently, a group of structure:
7 . The method of claim 1 wherein R 7 is
wherein each Q 3b is, independently, O or N(R).
8 . The method of claim 7 wherein each Q 3b is O and each R x is independently:
wherein M12c is 1, 2 or 3 and each Q 3 is independently a bond, O, CR 2 , or S.
9 . The method of claim 1 wherein R 7 is
10 . The method of claim 1 wherein R 7 is
11 . The method of claim 1 wherein R 7 is
12 . The method of claim 11 wherein R f is C 1 -C 8 alkyl.
13 . The method of claim 1 wherein R 7 is
14 . The method of claim 1 wherein R 7 is
15 . The method of claim 14 wherein R f is C 1 -C 8 alkyl.
16 . The method of claim 14 wherein R f is C 1 -C 6 alkyl.
17 . The method of claim 1 wherein R 7 is:
18 . The method of claim 17 wherein R g is C 1 -C 8 alkyl.
19 . The method of claim 18 wherein R g is C 1 -C 6 alkyl.
20 . The method of claim 1 wherein R 7 is selected from the group consisting of:
21 . The method of claim 1 wherein R 7 is
22 . The method of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
23 . The method of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
24 . The method of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
25 . The method of claim 24 wherein the compound is:
or a pharmaceutically acceptable salt or ester thereof.
26 . The method of claim 1 further comprising administering a pharmaceutically acceptable carrier or excipient.
27 . 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 Arenaviridae virus infections; or mixtures thereof.
28 . The method of claim 27 wherein the at least one other therapeutic agent is selected from the group consisting of ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof.
29 . The method of claim 1 wherein the Arenaviridae infection is caused by an Arenaviridae virus.
30 . The method of claim 1 wherein the Arenaviridae infection is caused by a Lassa virus.
31 . The method of claim 1 wherein the Arenaviridae infection is caused by a Junin virus.
32 . The method of claim 1 wherein the Arenaviridae infection is caused by a Lassa virus strain selected from the group consisting of Josiah, NL, z148, Macenta, AV, and CSF.
33 . The method of claim 1 wherein an Arenaviridae polymerase is inhibited.
34 .- 39 . (canceled)
40 . A method for treating a Cornaaviridae infection 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) —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 ), and —SO 2 NR 11 R 12 ,
wherein
each R 11 and 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, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or 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 is optionally be-replaced with —O—, —S— or —NR a —;
each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, 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), or —SO 2 NR 2 ;
wherein each R is independently 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, arylalkyl or substituted arylalkyl; and
wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 11 and R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl is optionally replaced with —O—, —S— or —NR a —,
wherein:
R c is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
R d is H or CH 3 ;
R e1 and R e2 are each independently H, C 1 -C 6 alkyl or benzyl; and
R f is selected from the group consisting of H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 -C 3 -C 6 cycloalkyl;
d) a group of the formula:
wherein
Q is O, S, NR, + N(O − )(R), N(OR), + N(O − )(OR), or 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 O, S, or NR; and
each R y is independently 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 2 )R, —OC(=Q 2 )OR, —OC(=Q 2 )(N(R) 2 ), —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 —OR; 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 a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O − )(OR), N—NR 2 , S—S, S(O), or S(O) 2 ;
M2 is 0, 1 or 2;
each R x is independently R y or the formula:
wherein:
each M1a, M1c, and M1d is independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
41 . (canceled)
42 . The method of claim 40 wherein R 7 is selected from the group consisting of
a) —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 ), and —SO 2 NR 11 R 12 ,
wherein:
R c is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
R d is H or CH 3 ;
R e1 and R e2 are each independently H or C 1 -C 6 alkyl; and
R f is selected from the group consisting of H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 -C 3 -C 6 cycloalkyl.
43 . (canceled)
44 . The method of claim 40 wherein R 7 is
wherein Z 1 and Z 2 are each, independently, a group of structure:
45 . The method of claim 40 , wherein R 7 is
wherein each Q 3b is, independently, O or N(R).
46 . The method of claim 45 wherein each Q 3b is O and each R x is independently:
wherein M12c is 1, 2 or 3 and each Q 3 is independently a bond, O or CR 2 .
47 . The method of claim 4 Q wherein R 7 is
48 . The method of claim 40 , wherein R 7 is
49 . (canceled)
50 . (canceled)
51 . The method of claim 39 wherein R 7 is
52 . The method of claim 40 wherein R 7 is
53 . The method of claim 52 wherein R f is C 1 -C 8 alkyl.
54 . The method of claim 52 wherein R f is C 1 -C 6 alkyl.
55 .- 58 . (canceled)
59 . The method of claim 40 wherein the compound of Formula IV is:
or a pharmaceutically acceptable salt thereof.
60 . The method of claim 40 wherein the compound of Formula IV is:
or a pharmaceutically acceptable salt thereof.
61 . The method of claim 40 wherein the compound of Formula IV is:
or a pharmaceutically acceptable salt thereof.
62 . The method of claim 40 wherein the compound of Formula IV is:
or a pharmaceutically acceptable salt thereof.
63 . The method of claim 40 further comprising a pharmaceutically acceptable carrier or excipient.
64 . The method of claim 40 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 a Coronaviridae virus infections; or mixtures thereof.
65 . The method of claim 40 , wherein the Coronaviridae infection is caused by a Coronaviridae virus.
66 . The method of claim 40 , wherein the Coronaviridae infection is caused by a Coronaviridae virus selected from SARS, MERS, 229E, NL63, OC43, and HKU1.
67 .- 74 . (canceled)Join the waitlist — get patent alerts
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