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US 7,067,641 B2Granted
Phosphinoamidite carboxylates and analogs thereof in the synthesis of oligonucleotides having reduced internucleotide charge
AssigneeLievre Cornu LLC
InventorDouglas J. Dellinger
Life of this patent
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Abstract
Nucleoside phosphinoamidite carboxylates and analogs are provided that have the structure of formula (III) wherein A is hydrogen, hydroxyl, lower alkoxy, lower alkoxy-substituted lower alkoxy, halogen, SH, NH2, azide or DL wherein D is O, S or NH and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl; B is a nucleobase; and one of R11 and R12 is a blocking group and the other is (IV) or (VI) in which W, X, Y, Z, R1 and n are as defined herein.
Claims26
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, halogen, lower alkoxy, lower alkoxy-substituted lower alkoxy, SH, NH2, azide or DL wherein D is O, S or NH and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (IV)
- in which
- R1 is hydrogen, a protecting group removable by an elimination reaction, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;
- n is zero or 1;
- W is NR2R3 or DL wherein R2 and R3 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, or R2 and R3 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle, D is O, S or NH, and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;
- X is O, S, NH, or NR7 wherein R7 is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;
- Y is —(Y′)m—(CR8R9)— wherein m is zero or 1, Y′ is hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene, wherein R8 and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl and with the proviso that P is directly attached to at least one carbon atom;
- and
- Z is O, S, NH or NR10 wherein R10 is as defined for R7;
- wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.
11 more elements
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, or protected hydroxyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (IV)
- in which
- R1 is hydrogen, a protecting group removable by an elimination reaction, or an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl;
- W is NR2R3 or DL wherein R2 and R3 are unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, or R2 and R3 are linked to form a substituted or unsubstituted, five- or six-membered nitrogen-containing heterocycle, D is O, S or NH, and L is a heteroatom-protecting group removable by an elimination reaction;
- n is zero or 1;
- X is O or S;
- Y is —(Y′)m—(CR8R9)— wherein m is zero or 1, Y′ is an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkylene, arylene, aralkylene, alkarylene, cycloalkylene, cycloalkylalkylene, cycloalkylarylene, alkenylene, cycloalkenylene, alkynylene and aralkynylene, wherein R8 and R9 are independently selected from hydrogen and unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, and with the proviso that P is directly attached to at least one carbon atom;
- and
- Z is O or S;
- wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.
11 more elements
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, or protected hydroxyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (IV)
- wherein:
- R1 is hydrogen, lower alkyl, or a hydroxyl-protecting group removable by an elimination reaction;
- R2 and R3 are lower alkyl, or R2 and R3 are linked to form a piperidino, piperazino or morpholino ring;
- n is zero or 1;
- and
- Y is —(Y′)m—(CH2)— wherein m is zero or 1 and Y′ is lower alkylene.
8 more elements
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, halogen, lower alkoxy, lower alkoxy-substituted lower alkoxy, SH, NH2, azide or DL wherein D is O, S, or N, and L is a heteroatom-protecting group, unsubstituted hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or substituted heteroatom-containing hydrocarbyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (VI)
- in which
- R1 is hydrogen, a protecting group removable by an elimination reaction, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;
- n is zero or 1;
- X is O, S, NH, or NR7 wherein R7 is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl;
- Y is —(Y′)m—(CR8R9)— wherein m is zero or 1, Y′ is hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene, wherein R8 and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl and substituted heteroatom-containing hydrocarbyl, and with the priviso that P is attached to at least one carbon atom;
- and
- each Z is independently O, S, NH or NR10 wherein R10 is as defined for R7;
- wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.
10 more elements
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, or protected hydroxyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (VI)
- in which
- R1 is hydrogen, a protecting group removable by an elimination reaction, or an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl;
- n is zero or 1;
- X is O or S;
- Y is —(Y′)m—(CR8R9)— wherein m is zero or 1, Y′ is an unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moiety selected from the group consisting of alkylene, arylene, aralkylene, alkarylene, cycloalkylene, cycloalkylalkylene, cycloalkylarylene, alkenylene, cycloalkenylene, alkynylene and aralkynylene, wherein R8 and R9 are independently selected from hydrogen and unsubstituted, substituted, heteroatom-containing or substituted heteroatom-containing moieties selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, cycloalkylalkyl, cycloalkylaryl, alkenyl, cycloalkenyl, alkynyl and aralkynyl, and with the proviso that P is directly attached to at least one carbon atom;
- and
- each Z is independently O or S;
- wherein said substituted moieties refer to molecules wherein one or more atoms of hydrogen have been replaced with a lower hydrocarbyl moiety or functional group selected from hydroxyl, alkoxy, thio, amino, and halo.
10 more elements
A compound having the formula (III)
- wherein:
- A is hydrogen, hydroxyl, or protected hydroxyl;
- B is a nucleobase;
- and
- one of R11 and R12 is a blocking group and the other has the formula (VII)
- wherein:
- R1 is hydrogen, lower alkyl, or a hydroxyl-protecting group;
- n is zero or 1;
- and
- Y is —(Y′)m—(CH2)— wherein m is zero or 1 and Y′ is lower alkylene.
7 more elements
Dependencies are inferred from the claim text.