Combined modalities for nucleosides and/or NADPH oxidase (NOX) inhibitors as myeloid-specific antiviral agents

Patent metadata

Field	Value
Publication number	US-12239655-B2
Application number	US-201816958572-A
Country	US
Kind code	B2
Filing date	Dec 27, 2018
Priority date	Dec 27, 2017
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

Nucleoside compounds, which in some embodiments include an alkynyl substituent at the 4′-position, compositions and methods for treating or preventing HIV and other viral infections, particularly where the virus is present in macrophages, microglia, and primary myeloid cells, and eliminating and/or treating infection in patients infected by these viruses, are disclosed.

First claim

We claim:

1. A method of treating HIV, comprising administering one or more compounds of Formula (A) or Formula (B) to a patient in need of treatment thereof, wherein Formula (A) and Formula (B) are shown below:

or a pharmaceutically acceptable salt thereof, wherein:
Y is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl,
R is selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclic, alkylaryl, arylalkyl, hydroxyl, nitro, cyano, cyanoalkyl, azido, azidoalkyl, formyl, hydrazino, OR′, SR′, COOR′, COR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′,
wherein each R′ is independently H, a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
R 1 is and R 1A are, independently, H, CH 3 , CH 2 F, CHF 2 , or CF 3 , wherein, when R 1 is Me, the carbon to which it is attached may be wholly or partially R or S or any mixture thereof, or R 1 and R 1A can combine to form a C 3-7 cycloalkyl ring;
R 2 is substituted or unsubstituted C 2-8 alkynyl;
R 4 is P(O)R 6 R 7 , wherein, when chirality exists at the phosphorous center of R 4 , it may be wholly or partially Rp or Sp or any mixture thereof,
R 5 is O, CH 2 , S, Se, CHF, CF 2 , or C═CH 2 ,
R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, CN or N 3 when R 5 is O, and
R 3 is selected from the group consisting of H, CN, substituted or unsubstituted (C 1-8 )alkyl, substituted or unsubstituted (C 2-8 )alkenyl, substituted or unsubstituted (C 2-8 )alkynyl, O—(C 1-8 ) alkyl and N 3 when R 5 is CH 2 , CHF, CF 2 , or C═CH 2 ,
R 8 and R 8′ are independently selected from the group consisting of H, C(O)(C 1-8 )alkyl, C(O)(C 1-8 )branched alkyl, C(O)NH(C 1-8 )alkyl, C(O)NH(C 1-8 )branched alkyl, C(O)aryl C(O)(C 1-8 ) alkyl-aryl, C(O)NH(C 1-8 )alkyl-aryl C(O)O(C 1-8 )alkyl, C(O)O(C 1-8 )branched alkyl, and C(O)O(C 1-8 )alkyl-aryl, or OR 8 as it appears in Formulas A is an ester derived from an alpha amino acid,
R 6 and R 7 are independently selected from the group consisting of:
(a) OR 15 where R 15 is aryl, wherein aryl is optionally substituted with zero to three substituents independently selected from the group consisting of (CH 2 ) 0-6 CO 2 R 16 and (CH 2 ) 0-6 CON(R 16 ) 2 ;
where R 16 is independently H, substituted or unsubstituted C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl-C 1-6 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 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;

(b) the ester of a D- or L-amino acid where R 17 is restricted to those occurring in natural L-amino acids, and
R 18 is H, C 1-20 alkyl, the carbon chain derived from a fatty alcohol or C 1-20 alkyl optionally substituted with a C 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl-C 1-6 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 1-6 alkyl, alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or cycloalkyl;
Base is selected from the group consisting of:

X 1 is CH, C—(C 1-6 )alkyl, C—(C 2-6 )alkenyl, C—(C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, C—(C 1-6 )hydroxyalkyl, C—OR 22 , C—N(R 22 ) 2 , C-halo, C—CN or N,
R 22 is independently H, (C 1-10 )alkyl, (C 1-10 )haloalkyl or (C 3-7 )cycloalkyl,
R 9 is OH, NH 2 , halo, O(C 1-10 )alkyl, O(C 3-7 )cycloalkyl, NH(C 1-10 )alkyl, N((C 1-10 )alkyl) 2 , NH(C 3-7 )cycloalkyl, NH(CO)(C 1-20 )alkyl, NH(CO)O(C 1-20 )alkyl, NHOH, NHO(CO)(C 1-20 )alkyl, or NHO(CO)NH(C 1-20 )alkyl,
R 10 is H, F or CH 3 and
X 2 is H, F, Cl, Br, I, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, C—(C 3-7 )cycloalkyl, C—(C 1-6 ) haloalkyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )hydroxyalkyl, OR 22 , N(R 22 ) 2 , NHC(O)OR 22 , NHC(O)N(R 22 ) 2 , NHC(O)R 22 , CN or NH 2 ;

or Base is

wherein:
each R′, R″, and R″′ are independently selected from the group consisting of H, OH, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, C 3-6 cycloalkyl, Br-vinyl, —O—C 1-6 alkyl, O—C 2-6 alkenyl, O—C 2-6 alkynyl, O-aryl, O-aralkyl, —O-acyl, O—C 3-6 cycloalkyl, NH 2 , NHC 1-6 alkyl, N-di-C 1-6 -alkyl, NH-acyl, N-aryl, N-aralkyl, NHC 3-6 cycloalkyl, F, Cl, Br, I, CN, COOH, CONH 2 , CO 2 C 1-6 alkyl, CONHC 1-6 alkyl, CON-di-C 1-6 alkyl, OH, CF 3 , CH 2 OH, (CH 2 ) m OH, (CH 2 ) m NH 2 , (CH 2 ) m CO 2 H, (CH 2 ) m CN, (CH 2 ) m NO 2 , and (CH 2 ) m CONH 2 ;
m is 0 or 1;
X 2 is H, straight chained, branched or cyclic optionally substituted alkyl, CH 3 , CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , CH 2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR 1B B, COO-alkyl, COO-aryl, CO—Oalkoxyalkyl, CONH 2 , CONHR 1B , CON(R 1B ) 2 , chloro, bromo, fluoro, iodo, CN, N 3 , OH, OR 1B , NH 2 , NHR 1B , NR 1B 2 ,
each X 3 is independently a straight chained, branched or cyclic optionally substituted alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted C 2-6 alkenyl, C 2-6 haloalkenyl, Br-vinyl, optionally substituted alkynyl, C 2-6 haloalkynyl, N 3 , CN, —C(O)OH, —C(O)OR 1B , —C(O)O(C 1-6 alkyl), —C(O)NH 2 , —C(O)NHR 1B , —C(O)NH(C 1-6 alkyl), —C(O)N(R 1B ) 2 , —C(O)N(C 1-6 alkyl) 2 , OH, OR 1B , —O(acyl), —O(C 1-6 acyl), —O(alkyl), —O(C 1-6 alkyl), —O(C 2-6 alkenyl), —O(C 2-6 alkynyl), —O(aralkyl), —O(cycloalkyl), chloro, bromo, fluoro, iodo, NH 2 , —NH(C 1-6 alkyl), —NHR 1B , —NR 1B 2 , —NH(acyl), —N(C 1-6 alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), or —N(acyl) 2 ;
each Y 2 is independently O, S, Se, NH, or NR 1B ;
each Y 3 is independently H, F, Cl, Br, or I; and
each R 1B is independently hydrogen, acyl, alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl;
wherein, in each occurrence, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, are optionally substituted with from 1-3 substituents selected from the group consisting of halogen, hydroxyl, nitrile, amino, alkylamino, arylamino, alkoxy, thioalkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, deuterated analogs thereof, and pharmaceutically-acce

Assignees

• Schinazi Raymond F
• Amblard Franck
• Gavegnano Christina
• Cox Bryan
• Mengshetti Seema
• Univ Emory

Inventors

• Schinazi Raymond F
• Amblard Franck
• Gavegnano Christina
• Cox Bryan
• Mengshetti Seema

Classifications

• C07H19/16

  Purine radicals · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D279/20

  with hydrogen atoms directly attached to the ring nitrogen atom · CPC title