IP Library › Granted Patent US 10,874,683

Granted Patent B2

US 10,874,683 · App. 16/083,177 · Granted Dec 29, 2020

N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Inventors: George R. Painter (Atlanta, GA); David B. Guthrie (Avondale Estates, GA); Gregory R. Bluemling (Decatur, GA); Michael R. Natchus (Alpharetta, GA)

Assignee: Emory University

A61K31/7068 A61P31/14 C07H19/067 C07H19/10 A61K9/008 Y02A50/391

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Quick Facts

Patent No.: US 10,874,683
App. No.: 16/083,177
Granted: Dec 29, 2020
Kind: B2

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Abstract

This disclosure relates to certain N4-hydroxycytidine derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of a Zika virus infection.

Claims (185)

1. A method of treating a Zika virus infection comprising administering an effective amount of a compound of Formula I, to a subject in need thereof, wherein the compound of Formula I is:

or salt thereof, wherein

Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;

V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;

W is CH 2 , NH, S or O;

X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;

Y is N or CR″;

Z is N or CR″;

each R″ is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 1 is hydrogen, monophosphate, diphosphate, triphosphate,

alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;

Y 1 is O or S;

Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;

Y 3 is OH or BH 3 − M + ;

R 2 is hydrogen, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;

R 3 is hydrogen, hydroxy, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ;

R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;

R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;

R 6 is hydrogen, hydroxy, alkoxy, alkyl, ethynyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ;

each R 7 is independently selected from absent, hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;

R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;

R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;

R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;

R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;

R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;

R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;

R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;

R 13′ is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13′ is optionally substituted with one or more, the same or different, R 20 ;

R 14′ is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14′ is optionally substituted with one or more, the same or different, R 20 ;

R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 20 is optionally substituted with one or more, the same or different, R 21 ;

R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; and

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

2. The method of claim 1 , wherein the compound is administered through the lungs.

3. The method of claim 1 , wherein the compound is a compound of the structure:

4. The method of claim 1 , wherein the compound is a compound of Formula IB:

or a salt thereof, wherein

V is absent, O, NH, NR 15 , S, CH 2 , or CHR 15 ;

X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;

Y is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 1 is hydrogen, monophosphate, diphosphate, triphosphate,

Y 1 is O or S;

Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;

Y 3 is OH or BH 3 − M + ;

R 15 is hydrogen, Lipid, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

5. The method of claim 1 , wherein the compound is a compound of the structure:

or a salt thereof.

6. The method of claim 1 , wherein the compound is a compound of the structure:

or a salt thereof.

7. The method of claim 1 , wherein the compound is a compound of the structure:

of a salt thereof.

8. The method of claim 1 , further comprising administering an additional antiviral compound selected from NITD008, BCX4430, or a combination thereof.

9. The method of claim 1 , wherein Q-R 7 is OH.

10. The method of claim 1 , wherein R 1 is

R 8 is hydrogen, hydroxy, or benzyloxy, and

R 9 is (C 6 -C 22 )alkyl.

11. The method of claim 1 , wherein the compound is selected from:

1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-((nonanoyloxy)amino)pyrimidin-2-one;

1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-((((heptyloxy)carbonyl)oxy)amino)pyrimidin-2-one; and

isopropyl(((3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)alaninate.

12. The method of claim 1 , wherein the compound is a compound of Formula IC,

or a salt thereof, wherein

X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;

Y is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 1 is hydrogen, monophosphate, diphosphate, triphosphate,

Y 1 is O or S;

Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;

Y 3 is OH or BH 3 − M + ;

R 15 is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

13. The method of claim 1 , wherein the compound is a compound of Formula ID,

or a salt thereof, wherein

W is CH 2 , NH, S or O;

X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;

Y is N or CR″;

Z is N or CR″;

each R 11 is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 1 is hydrogen, monophosphate, diphosphate, triphosphate,

Y 1 is O or S;

Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;

Y 3 is OH or BH 3 − M + ;

R 15′ is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;

R 15 and R 15′ can form a ring that is optionally substituted with one or more, the same or different, R 20 ;

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

14. The method of claim 1 , wherein the compound is a compound of Formula IE,

or salt thereof, wherein

Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;

V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;

W is CH 2 , NH, S or O;

X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;

Y is N or CR″;

Z is N or CR″;

each R 11 is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 15 and R 15′ can form a ring that is optionally substituted with one or more, the same or different, R 20 ;

If Q=—O(C═O)V— and V═NR 7 then the R 7 s can together form a ring that is optionally substituted with one or more, the same or different, R 20 ;

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

15. The method of claim 1 , wherein the compound is a compound of Formula II,

or salt thereof, wherein

Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;

V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;

W is CH 2 , NH, S or O;

X is CH 2 or O;

Y is N or CR″;

Z is N or CR″;

each R 11 is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;

R 1 is monophosphate, diphosphate, triphosphate,

Y 1 is O or S;

Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;

Y 3 is OH or BH 3 − M + ;

If Q=—O(C═O)V— and V═NR 7 then the R 7 s can together form a ring that is optionally substituted with one or more, the same or different, R 20 ;

Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

16. The method of claim 1 , further comprising administering an additional antiviral compound.

Assignments (3)

CONFIRMATORY LICENSE Recorded Oct 5, 2020

From: EMORY UNIVERSITY

To: DEFENSE THREAT REDUCTION AGENCY, US DOD

Reel/Frame 053970/0621 →

CONFIRMATORY LICENSE Recorded May 19, 2020

From: EMORY UNIVERSITY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 052700/0220 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2019

From: PAINTER, GEORGE R.; GUTHRIE, DAVID BRIAN; BLUEMLING, GREGORY R.; NATCHUS, MICHAEL GEORGE

To: EMORY UNIVERSITY

Reel/Frame 048528/0870 →

Continuity (2)

Provisional Application 62306163 · Mar 10, 2016

Related Publication 20190083520A1 · Mar 21, 2019

Cited By (2)

US 12,329,770 US 12,551,497