Combined modalities for nucleosides and/or NADPH oxidase (NOX) inhibitors as myeloid-specific antiviral agents
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.
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-acceptable salts thereof.
2. The method of claim 1 , wherein the compounds have the formula:
and deuterated analogs thereof.
3. The method of claim 2 , wherein R 2 is ethynyl.
4. The method of claim 1 , wherein R 4 is a phosphoramidate prodrug.
5. The method of claim 1 , wherein R 15 is phenyl or pyridinyl.
6. The method of claim 1 , wherein the compounds are deuterated at one or more positions on the base, R 1 , R 2 , R 3 , R 4 , R or Y.
7. The method of claim 1 , wherein R 8 and R 8′ are H.
8. The method of claim 1 , wherein Y is H.
9. The method of claim 1 , wherein Y is Me.
10. The method of claim 1 , wherein one or both of R 8 and R 8′ are H.
11. The method of claim 1 , wherein the compound has one of the following formulas:
12. The method of claim 1 , wherein the compound has the formula:
deuterated analogs thereof, or a pharmaceutically-acceptable salt thereof.
13. The method of claim 1 , wherein the compounds can be present in the β-D or β-L configuration.
14. The method of claim 1 , wherein the compound is administered in combination with a pharmaceutically-acceptable carrier or excipient.
15. The method of claim 14 , wherein the compound is administered in the form of a transdermal composition or a nanoparticulate composition.
16. The method of claim 14 , wherein the compound is administered in combination with a second antiviral agent.
17. The method of claim 16 , wherein the second antiviral agent is selected from the group consisting of EFdA, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors, Fusion Inhibitors, Entry Inhibitors, CCR5 co-receptor antagonists, HIV integrase strand transfer inhibitors, JAK inhibitors, immunomodulators, dasatinib, MAPK inhibitors, mTOR inhibitors, β-catenin inhibitors, interferon inhibitors, interferon, HDAC inhibitors, PKC agonists, TLR4 agonists, reactivation agents, and combinations thereof.
18. The method of claim 17 , wherein the JAK inhibitor is selected from the list consisting of tofacitinib, baricitinib, and ruxolitinib.
19. The method of claim 1 , further comprising administering a NOX inhibitor.
20. The method of claim 19 , wherein the NOX inhibitor is selected from the group consisting of AEBSF, Apocyanin, DPI, GK-136901 (4-methyl-5-pyridin-2-ylmethyl-2-o-tolyl-1,2-dihydro-5H-pyrazolo[4.3-c]pyridine-3,6-dione), ML171 (2-acetylphenothazine), Plumbagin, S17834 ([6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl) 1 -H benzo(pyran-4-one]), VAS2870 (1,3-benzoxazol-2-yl-3-benzyl-3H-[1, 2, 3,]triazolo]4,5-d]pyrimidin-7-yl sulfide), VAS3947 (7-(2-Oxazolylthio)-3-(phenylmethyl)-3H-1, 2, 3-triazolo[4,5-d]pyrimidine), GKT-831 (Setanaxib), an amido thiadiazole derivative, a bi-aromatic or tri-aromatic compound, a methoxyflavone derivative, a peptide, a piperazine derivative, a pyrazole derivative, a pyrazoline dione derivative, a pyrazolo pyridine derivative, a quinazoline or quinoline derivative, a tetrahydroindole derivative, a tetrahydroisoquinoline derivative, Scopoletin, or a 2,5-disubstituted benzoxazole or benzothiazole derivative.
21. The method of claim 20 , wherein the peptide is NOX2ds-tat (NOX2 docketing sequence-tat) or PR-39 (Proline-Arginine-39).
22. The method of claim 20 , wherein the NOX inhibitor is selected from the group consisting of Ebselen, Neopterin, APBA, Diapocynin, deuterated analogs thereof, and pharmaceutically-acceptable salts thereof.