Nucleotide analogs
AssigneeGilead Sciences, Inc.
InventorsNorbert Bischofberger, Robert J. Jones, Murty Arimilli, Kuei-Ying Lin, Michael Louie, Lawrence R. McGee, Ernest J. Prisbe
Life of this patent
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Abstract
Nucleotide analogs characterized by the presence of an amidate linked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or ester bond that is hydrolyzed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for their synthesis and use are described.
Claims29
A compound of the formula IIb ##STR23## wherein n is an integer having a value from 1 to 5 and if n>1, each --C(R.sup.3)(R.sup.2)-- may be the same or different;
- n1 is an integer;
- R.sup.1 is H or C.sub.1 -C.sub.9 alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen, C.sub.3 -C.sub.6 aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen or C.sub.3 -C.sub.9 aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen;
- R.sup.2 is independently H or C.sub.1 -C.sub.9 alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen, C.sub.3 -C.sub.6 aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen or C.sub.3 -C.sub.9 aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR.sup.4 and halogen;
- R.sup.3 is independently C(O)--OR.sup.4, amino, C.sub.1 -C.sub.3 alkylamino, C.sub.1 -C.sub.3 alkyldiamino, C.sub.1 -C.sub.6 alkenylamino, hydroxy, thiol, C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 alkthiol, (CH.sub.2).sub.n COOR.sup.4, alkoxyphenyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.6 -C.sub.12 aryl which is substituted or unsubstituted with OH, halogen, SH, NH.sub.2, phenyl, hydroxyphenyl or alkoxyphenyl;
- R.sup.4 is H provided that n1 is greater than 1, or is C.sub.3 -C.sub.9 alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen, C.sub.3 -C.sub.6 aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen, C.sub.3 -C.sub.9 aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen;
- Z is --CHR.sup.7 --R.sup.11 --(CH.sub.2).sub.m1 --C#(R.sup.8)((CH.sup.2).sub.m2 (R.sup.9))--(CH.sub.2).sub.m3 --R.sup.10 --(CH.sub.2).sub.m4 --, --O--C.sub.6 H.sub.4 --CH.sub.2 --, --CHR.sup.7 --O--CHR.sup.7 --O--CHR.sup.7, --CHR.sup.7 --(CHR.sup.13).sub.m1 --CHR.sup.14 --R.sup.10 --, ##STR24## R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.8 is H or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, azidomethyl or azidoethyl;
- R.sup.9 is halogen (F, Cl, Br or I), H or OH;
- R.sup.10 is O, CH.sub.2 or a chemical bond;
- R.sup.11 is O, S, CH.sub.2, CHF, CF.sub.2 ;
- O is --C(R.sup.12).sub.2 --CH.sub.2 --, --C(R.sup.12)--O--, --CR.sup.12 .dbd.CR.sup.12, or --C.tbd.C--, wherein each R.sup.12 is independently H, or halogen;
- R.sup.13 is H, halogen, OH, CH.sub.3, CH.sub.2 OH, or C.sub.3 -C.sub.12 acyloxymethyl;
- R.sup.14 is independently H, halogen, OH, CH.sub.3, CH.sub.2 OH, C.sub.3 -C.sub.12 acyloxymethyl, or C.sub.2-C.sub.12 acyloxy;
- R.sup.25 is CH.sub.2, CHF or O;
- R.sup.26 is CH or S, provided that when R.sup.25 is CH, R.sup.26 is not S;
- R.sup.27 is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkoxy or when, R.sup.26 is S, R.sup.27 is absent;
- R.sup.27a is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.28 is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
- R.sup.29 is O, S, CH.sub.2, CHF, CF.sub.2 ;
- R.sup.32 is O;
- n2 is an integer having a value from 0 to 6;
- m1 is an integer having a value from 0 to 4;
- m2 is an integer having a value from 0 to 4;
- m3 is an integer having a value from 0 to 4;
- m4 is an integer having a value from 0 to 4;
- the carbon atom designated C# is in the R, S or RS configuration;
- and
- B is a base.
A compound of the formula Ib ##STR25## wherein L.sup.1 is an amino acid or polypeptide residue bonded to the phosphorus atom of the compound by an amidate bond and any carboxyl group that is linked by less than about 5 atoms to the amidate N is esterified or amidated;
- X.sup.1 is O or S;
- the carbon atom designated # is in the R, S or RS configuration;
- and
- B is a base.
A compound of the formula Id ##STR27## wherein L.sup.1 and L.sup.2 are independently an amino acid or polypeptide residue bonded to the phosphorus atom of the nucleotide analog amidate by an amidate bond, or an oxyester, thioester, a substituted or unsubstituted amine, or hydroxy, provided that one or both of L.sup.1 and L.sup.2 is an amino acid or polypeptide residue and any carboxyl group that is linked by less than about 5 atoms to the amidate N is esterified or amidated:
- Z is --CHR.sup.7 --R.sup.11 --(CH.sub.2).sub.m1 --C#(R.sup.8)((CH.sup.2).sub.m2 (R.sup.9))--(CH.sub.2).sub.m3 --R.sup.10 --(CH.sub.2).sub.m4 --, --O--C.sub.6 H.sub.4 --CH.sub.2 --, --CHR.sup.7 --O--CHR.sup.7 --O--CHR.sup.7 --CHR.sup.7 --(CHR.sup.13).sub.m1 --CHR.sup.14 R.sup.10 --, ##STR28## R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;
- R.sup.8 is H or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, azidomethyl or azidoethyl;
- R.sup.9 is halogen (F, Cl, Br or I), H or OH;
- R.sup.10 is O, CH.sub.2 or a chemical bond;
- R.sup.11 is O, S, CH.sub.2, CHF, CF.sub.2 ;
- O is --C(R.sup.12).sub.2 --CH.sub.2 --, --C(R.sup.12).sub.2 --O--, --CR.sup.12 .dbd.CR.sup.12, or --C.tbd.C--, wherein each R.sup.12 is independently H, or halogen;
- R.sup.13 is H, halogen, OH, CH.sub.3, CH.sub.2 OH, or C.sub.3 -C.sub.12 acyloxymethyl;
- R.sup.14 is independently H, halogen, OH, CH.sub.3, CH.sub.2 OH, C.sub.3 -C.sub.12 acyloxymethyl, or C.sub.2 -C.sub.12 acyloxy;
- R.sup.25 is CH.sub.2, CHF or O;
- R.sup.26 is CH or S, provided that when R.sup.25 is CH, R.sup.26 is not S;
- R.sup.27 is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or when, R.sup.26 is S, R.sup.27 is absent;
- R.sup.27a is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy;
- R.sup.28 is H, OH, halogen, N.sub.3, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
- R.sup.29 is O, S, CH.sub.2, CHF, CF.sub.2 ;
- R.sup.32 is O;
- n2 is an integer having a value from 0 to 6;
- m1 is an integer having a value from 0 to 4;
- m2 is an integer having a value from 0 to 4;
- m3 is an integer having a value from 0 to 4;
- m4 is an integer having a value from 0 to 4;
- the carbon atom designated C# is in the R, S or RS configuration;
- and
- B is a base.
Dependencies are inferred from the claim text.