Antiviral Agents and Nucleoside Analogs for Treatment of Zika Virus

Patent metadata

Field	Value
Publication number	US-2024216414-A1
Application number	US-202418603143-A
Country	US
Kind code	A1
Filing date	Mar 12, 2024
Priority date	Mar 23, 2016
Publication date	Jul 4, 2024
Grant date	—

Abstract

The present invention is directed to compounds, compositions and methods for treating or preventing Zika virus. The compounds include pyrimidine and purine nucleosides and prodrugs thereof, including certain N 4 -hydroxycytidine nucleoside derivatives, sulfasalazine, and various entry inhibitors.

First claim

1 . A method for treating Zika comprising administering to a patient in need of thereof an effective amount of a compound having one of the following formulas:

wherein:
X 1 is H, C 1 -C 6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, COR 1 , or COOR 1 ;
X 2 is hydrogen, C 1 -C 6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OH, COR 1 , OCOR 1 , COOR 1 or OCOOR 1 ;
each X 3 and X 4 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, alkylaryl, halogen (F, Cl, Br, I), NH 2 , OH, SH, CN, or NO 2 ;
Y 1 and Y 2 are, independently, N, or C—X 3 ,
R 1 is independently CH 2 —O(CO)—X 5 ; CH 2 —O(CO)O—X 5 , C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, C 3-10 cycloalkyl, C 3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, C 3-10 cycloalkyl, or C 3-10 cycloalkyl alkyl;
X 5 is independently, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1-6 alkyl, alkoxy, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-6 alkyl, or C 1-6 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, or C 3-10 cycloalkyl,
Sugar is of Formula (II):

wherein:
W is CL 2 or CL 2 CL 2 , wherein L independently is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl can each optionally contain one or more heteroatoms;
D is H, —C(O)R 1 , —C(O)OR 1 , —C(O)N(R 1 ) 2 , —C(O)SR 1 , —C(O)S(O)R 1 , —C(O)SO 2 R 1 , —SOR 1 , —SO 2 R 1 —SO 2 OR 1 , —S(O) 2 R 1 , —S(O) 2 N(R 1 ) 2 , a diphosphate ester, a triphosphate ester, a phosphonate, a lipid, or stabilized phosphate prodrug;
R 1 is, independently, —CH 2 —O(CO)—X 5 ; —CH 2 —O(CO)O—X 5 , C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, alkoxy, di(C 1 -C 6 alkyl)-amino, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-6 alkyl, or C 1-6 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, or C 3-10 cycloalkyl;
X 5 is independently, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, alkoxy, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-6 alkyl, or C 1-6 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, or C 3-10 cycloalkyl;
A is O, S, CH 2 , CHF, CF 2 , C═CH 2 , C═CHF, or C═CF 2 ;
R 4′ is selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , N 3 , C(O)OH, CH 2 OH, C(O)NH 2 , C(S)NH 2 , C(O)OR, R, OR, SR, SSR, NHR, and NR 2 ;
R 7′ , R 5 , R 5′ , R 6 , R 6′ , and R 7′ are independently selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , N 3 , C(O)OH, CN, CH 2 OH, C(O)NH 2 , C(S)NH 2 , C(O)OR, R, OR, SR, SSR, NHR, and NR 2 ; with the proviso that there are not two NH 2 , OH, and/or SH moieties on the same carbon atom;
R 5′ and R 6′ can come together to form a ring

and
R is independently a C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 3 -C 6 cycloalkyl, aryl, alkylaryl, or arylalkyl.

2 . The method of claim 1 , wherein the compounds are of Formula A.

3 . The method of claim 1 , wherein the compounds are of Formula B.

4 . The method of claim 1 , wherein A is O.

5 . The method of claim 1 , wherein R 4′ and R 7′ are both H.

6 . The method of claim 1 , wherein R 6 or R 6′ is OH.

7 . The method of claim 1 , wherein X 2 is —OH, OCOR 1 , or OCOOR 1 .

8 . The method of claim 1 , wherein R 5 and R 5′ , are methyl and OH.

9 . The method of claim 1 , wherein R 5 and R 5′ , are methyl and F.

10 . The method of claim 1 , wherein R 5 and R 5′ are both halogens.

11 . The method of claim 1 , wherein the compound or salt thereof is administered in combination with a second anti-Zika agent.

12 . The method of claim 11 , wherein the second anti-Zika agent is galidesivir (BCX4430), an entry inhibitor, a reverse transcriptase inhibitor, a protease inhibitor, or an immune-based therapeutic agent.

Assignees

• Univ Emory

Inventors

• Schinazi Raymond F
• Amblard Franck
• Cox Bryan D
• Bassit Leda
• Zhou Longhu
• Gavegnano Christina

Classifications

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• A61K31/655

  Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/4706 Primary

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61P31/14

  for RNA viruses · CPC title