Nucleotide analogs

A compound of the formula Ib

• 50
• and stereoisomers and salts of such compounds wherein
• X1 is O or S;
• L1 is an amino acid, a polypeptide residue, a substituted or unsubstituted amine, an oxyester or a thio ester;
• and
• the carbon atom designated # has linked substituents that are in the R, S or RS configuration, provided that L1 is not a C1—C4 alkyl ester or, when when B is cytosin—1—yl, then L1is not OCH2C(O)NR5a2, OCH2C(O)OR5a, OCH2OC(O)R5a, OCH(R5a)OC(O)R5a(R, S or RS stereochemistry), OCH2C(R5a)2CH2OH, OCH2OR5a, OR5a, NHR5aor NR5a2 wherein R5ais C1-C20 alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy and halogen, and provided that when X1 is O and B is adenine, cytosine, guanine, thymine, uracil, 2,6- diamino purine, hypoxanthine, or Z2;
• wherein Z2 is
• 51
• Q is independently chosen from H, Cl, NHRX, NRX2, NHC(O)RX, N(C(O)RX)2, OH or NCHN(RX)2, then L1 is not ORY, NH2, NHRX, or N(RX)2 where RY represents a physiologically hydrolyzable ester group selected from the group consisting of CH2C(O)N(RX)2, CH2C(O)ORX, CH2OC(O)RX, CH(RX)OC(O)RX, CH2C(RX)2CH2OH, or CH2ORX;
• RY may also be RX provided that RY and RX are not simultaneously alkyl;
• RX represents C1-C20 alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen.

A compound of the formula (OR31)2P(O)—Z1—B or (OR)(OR31)P(O)—Z1—B, wherein;

• B is a heterocyclic base;
• Z1 is selected from the group consisting of —CH2—O—CH2—CH2—, —CH2 —C#H(CH2OH)CH2—, —CH2—O#H(CH3)—CH2—, —CH2—O—C#H(CH2F)—CH2—, H2—O—C#H(CH═CH2)—CH2— and CH2—O—C#H(CH2N3)—CH2—;
• R is H,
• C3-C24 1-acyloxy-1-alkyl,
• C6-C24 1-acyloxy-1-aryl-1-alkyl,
• C3-C24 1-acyloxy-2-alkoxy-1-alkyl,
• C3-C24 1-acyloxy-2-halo-1-alkyl,
• C1-C20 alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),
• C3-C20 aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, nitro, OH, O, N and halogen, or
• C4-C20 aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, nitro, OH, O, N and halogen;
• R31 is 2,3-dihydro-6-hydroxyindene;
• sesamol;
• catechol monoester;
• —CH2—C(O)—N(R7)2 wherein each R7 is hydrogen or C1-4 alkyl and is the same or different;
• CH2—S(O)(R7);
• CH2—S(O)2(R7);
• OH2CH(OC(O)CH2R7)—CH2(OC(O)CH2R7);
• cholesteryl;
• a monosaccharide;
• a disaccharide;
• an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;
• glycerol;
• an α-D-β-diglyceride;
• trimethoxybenzyl;
• triethoxybenzyl;
• 2-alkyl pyridinyl (C1-4 alkyl);
• 62
• C3-C6 aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C1-C12 alkoxy, cyano, nitro, OH, C1-C12 haloalkyl, C1C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
• or C1-C4 alkylene—C3C6 aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, Cl—C12 alkoxy, cyano, nitro, OH, C1-C12 haloalkyl, C1-C12 alkyl, C2C2 alkenyl or C2-C12 alkynyl, provided that when Z1 is CH2—OCH2—CH2— and B is adenin-9-yl, both R31 are not 4-nitrobenzyl or 4-trifluoromethyl—benzyl, and provided that when Z1 is —CH2-O—CH2—CH2—, CH2-O—C#H(CH2OH)—CH2—, —CH2—O—C#H(CH3)—CH2—, CH2—O—C#H(CH2F)—CH2— or —CH2O—C#H(CH═CH2)CH2— and B is adenine, cytosine, guanine, thymine, uracil, 2,6-diamino purine, hypoxanthine, or Z2;
• wherein Z2 is
• 63
• Q is independently chosen from H, Cl, NHRX, NRX2, NHC(O)RX, N(C(O)RX)2, OH or NCHN(RX)2, then L1 is not ORY, NH2, NHRX, or N(RX)2 where RY represents a physiologically hydrolyzable ester group selected from the group consisting of CH2C(O)N(RX)2, CH2C(O)ORX, CH2OC(O)RX, CH(RX)OC(O)RX, CH2C(RX)2CH2OH, or CH2ORX;
• RY may also be RX provided that RY and RXare not simultaneously alkyl;
• RXrepresents C1C20 alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen.

A compound of the formula (L1)2P(O)—Z—B1 or

• 64
• wherein
• substituents linked to the carbon atom designated # are in the R, S or RS configuration;
• L1 is independently an amino acid, a polypeptide, an oxyester, a thioester or a substituted or unsubstituted amine;
• B1 is a protected heterocyclic base;
• and
• Z—B1 is
• 65
• wherein
• R27 is H, OH, halogen, N3, C1-C4 alkyl, C1-C4 alkoxy or when, R26 is S, R27 is absent;
• R28 is H, OH, halogen, N3, C1-C4 alkyl or C1-C4 alkoxy;
• R29 is O, S, CH2, CHF or CF2;
• R33 is H, OH, TBSO, halogen, cyano, CH2N3, C1-C4 alkyl, C1-C4 alkoxy, CH2OH or azido;
• and
• R34 is H, CH2CN or CF3, with the proviso that, for structure XXX, when R25 is O or CH2 and R29 CH2 or 0, L1 is not H or C1-C6 alkyl, provided that for compounds of structure
• 66
• when B1 is
• 67
• wherein Q is independently chosen from H, Cl, NHRX, NRX2, NHC(O)RX, N(C(O)RX)2, OH or NCHN(RX)2, then L1 is not ORY, NH2, NHRX, or N(RX)2 where RY represents a physiologically hydrolyzable ester group selected from the group consisting of CH2C(O)N(RX)2, CH2C(O)ORX, CH2OC(O)RX, CH(RX)OC(O)RX, CH2C(RX)2CH2OH, or CH2ORX;
• RY may also be RXprovided that RY and RXare not simultaneously alkyl;
• RXrepresents C1-C20 alkyv, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen;
• provided that when R25 is O, R29 is CH2, R26 is CH, R27 is OH, R28 is H or F, and B is adenine, thymine, guanine, cytosine or protected adenine, protected guanine or protected cytosine, both L1 are not H, methyl or phenyl.

A compound of the formula (OR35)(OR35)P(O)—Z—B, wherein;

• B is a heterocyclic base;
• R35 is independently R or R31, wherein R is independently
• H,
• C3C24 1-acyloxy-1-alkyl,
• C6C24 1-acyloxy-1-aryl-1-alkyl,
• C3C24 1-acyloxy- 2-alkoxy-1-alkyl,
• C3C24 1-acyloxy- 2-halo-1-alkyl,
• C1-C20 aikyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),
• C3-C20 aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,
• C4-C20 aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,
• C3-C6 aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C1-C12 alkoxy, cyano, nitro, hydroxy, C1-C12 haloalkyl, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, or
• C1-C4 alkylene-C3-C6 aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C1-C12 alkoxy, cyano, nitro, hydroxy, C1-C12 haloalkyl, C1-C12 alkyl, C2-C2 alkenyl or C2-C12 alkynyl;
• R31 is 2,3-dihydro-6-hydroxyindene;
• sesamol;
• catechol monoester;
• —CH2(O)—N(R7)2 wherein each R7 the same or different;
• —CH2—S(O)(R7);
• CH2—S(O)2(R7);
• OCH2CH(OC(O)CH2R7)—CH2(OC(O)CH2R7);
• cholesteryl;
• a monosaccharide;
• a disaccharide;
• an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;
• glycerol;
• an α-D-β-diglyceride;
• trimethoxybenzyl;
• triethoxybenzyl;
• 2-alkyl pyridinyl (C1-4 alkyl);
• 70
• C3-C6 aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C1-C12 alkoxy, cyano, nitro, OH, C1-C12 haloalkyl, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
• or
• C1-C4 alkylene C3-C6 aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C1-C12 alkoxy, cyano, nitro, OH, C1-C12 haloalkyl, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
• Z—B is selected from the group consisting of
• 71
• wherein
• substituents linked to the carbon atom designated # are in the R, S or RS configuration,
• R25 is CH2, CHF or O;
• R26 is CH or S, provided that when R25 is CH, R26 is not S;
• R27 is H, OH, halogen, N3, C14 alkyl, C1-C4 alkoxy or when, R26 is S, R27 is absent;
• R28 is H, OH, halogen, N3, C1C4 alkyl or C1-C4 alkoxy;
• R29 is 0, 5, CH2, CHF or CF2;
• R33 is H, OH, TBSO, halogen, cyano, CH2N3, C1-C4 alkyl, C14 alkoxy, CH2OH or azido;
• and
• R34 is H, CH2CN or CF3, with the proviso that, for structure XXX, when R25 is O or CH2 and R29 CH2 or O, R35 is not H or Cj6 alkyl;
• and
• provided that when R25 is CH2, R29 is CH2, R26 is CH, R27 is H, R28 is H, and B is adenine, R35 are not both H or C3H7;
• and
• provided that when R25 is O, R29 is CH2, R26 is S, R28 is H, and B is cytosine or protected cytosine, R35 are not both H or ethyl;
• and
• provided that when R25 is CH2, R29 is O, R26 is CH, R27 is H, R28 is H, and B is adenine, guanine, hypoxanthine, cytosine, uracil or thymine, R35 are not both H or C3H7;
• and
• provided that when R25 is O, R29 is CH2, R26 is CH, R27 is N3, R28 is H, and B is thyrnine, R35 is not H or phenyl;
• and
• provided that when R25 is CH2, R29 is O, R26 is CH, R27 is H, R28 is H, and B is thyrnine, R35 is not H or C16 alkyl;
• and
• provided that when R25 is O, R29 is CH2, R26 is CH, R27 is OH, R28 is H or F, and B is adenine, thymine, guanine, cytosine or protected adenine, protected guanine or protected cytosine, both R35 are not H, methyl or phenyl;
• and
• provided that when R25 is O, R29 is O, R26 is CH, R27 is H, OH or C1C4 F alkyl, R28 is H, OH or C1-C4 alkyl, and B is xanthine, substituted xanthine, guanine, substituted guanine, purine, substituted purine, cytosine, substituted cytosine, thymine, uracil, substituted uracil, adenine or substituted adenine, R35 is not H or C1-C6 alkyl.

A compound of the formula (R31O)2P(O)—CH2OH or (R31O)2P(OSi(CH3)3) wherein

• R31 is trimethoxybenzyl;
• triethoxybenzyl;
• 2-alkyl pyridinyl (C1-4 alkyl);
• 73
• wherein R7 is hydrogen or C1-4 alkyl;
• or C3-C6 aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C1-C12 alkoxy, cyano, nitro, Cl12 haloalkyl, C1-C12 alkyl or C2-12 alkynyl, provided that for compound (R31O)2P(O)H2—OH, R31 is not phenyl.

A method to synthesize a compound of structure (R31O)2P(O)—CH2—OH comprising silylating a compound of structure (R31O)2P(O)H with about 1 equivalent of bis(trimethylsilyl)trifluoroacetamide, drying the resulting compound and reacting the resulting compound with paraformaidehyde containing catalytic amounts of a lewis acid, wherein R31 is trimethoxybenzyl;

• triethoxybenzyl;
• 2-alkyl pyridinyl (C1-4 alkyl);
• 74
• wherein R7 is hydrogen or C1-4 alkyl;
• C3C6 aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C1C12 alkoxy, cyano, nitro, C1-C12 haloalkyl, C1-C12 alkyl or C2-12 alkynyl.

A method to synthesize a compound of structure

• 75
• by reacting a compound of structure
• 76
• with iodine and (R31O)2P(O)—CH2OH at high temperature, wherein B2 is a heterocyclic base or a protected heterocyclic base;
• R31 is trimethoxybenzyl;
• triethoxybenzyl;
• 2-alkyl pyridinyl (C1-4 alkyl);
• 77
• wherein R7 is hydrogen or C1-4 alkyl;
• C3C6 aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C1-C12 alkoxy, cyano, nitro, C1-C12 haloalkyl, C1-C12 alkyl or C2-12 alkynyl;
• and R44 is iodine or fluorine.

A compound having the formula

• 78
• and stereoisomers and salts of such compounds wherein
• B is a purine or pyrimidine base;
• R35 is R or R31;
• R is 2-alkoxyphenyl, 3-alkoxyphenyl, 4-alkoxyphenyl (C1-C12 alkyl), 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 4-haloalkylphenyl (1-5 halogens, C1C12 alkyl), carboalkoxyphenyl (C1-4 alkyl), 2-haloalkylbenzyl, 3-haloalkylbenzyl, 4-haloalkylbenzyl (1 to 5 halogen atoms, C1-C12 alkyl), alkylsalicylphenyl (C1-C4 alkyl), alkoxy ethyl (C1-C6 alkyl), aryloxy ethyl (C6-C9 aryl optionally substituted by OH, NH2, halo, C1-4 alkyl or C1-4 alkyl substituted by OH or by 1 to 3 halo atoms), 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyi, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-trichloromethylphenyl, 4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4arboethoxyphenyl (—C6H4—C(O)—OC2H5), 2,3-dicarboethoxyphenyl, 2,4-dicarboethoxyphenyl, 2,5-dicarboethoxyphenyl, 2,6-dicarboethoxyphenyl, 3,4-dicarboethoxyphenyl, 3,5-dicarboethoxyphenyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl (C5H4N), 2-nitrophenyl, 3-nitrophenyl 4-nitrophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicylphenyl, 3-ethylsalicylphenyl, 4ethylsalicylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 1,8-dihydroxy-naphthyl (—O—C10H6—OH or —O—C10H6—), 2,2′-dihydroxybiphenyl (—O—C6H4—C6H4—), methoxy ethyl (CH2CH2H3), phenoxymethyl, phenoxy ethyl, —C6H4-CH2—N(CH3)2 or N-ethylmorpholino —(CH2)2—N[(CH2)2(CH2)2]O);
• R31 is 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, —CH2-C(O)—N(R7)2 wherein each R7 is the same or different, CH2—S(O)(R7), CH2—S(O )2(R7), O CH2 CH(OC(O)CH2R7)H2(OC(O)CH2R7), cholesteryl, enolpyruvate, glycerol, an α-D-p—diglyceride, trimethoxybenzyl, triethoxybenzyl or 2-alkyl pyridinyl (C1-4 alkyl);
• R7 is H or C1-C4 alkyl;
• and
• the carbon atom designated # has linked substituents that are in the R, S or RS configuration.