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US 6,051,699 AGranted
Process for the synthesis of oligomeric compounds
AssigneeIsis Pharmaceuticals, Inc.
InventorVasulinga T. Ravikumar
Life of this patent
Estimating the term…
Abstract
Synthetic processes are provided wherein oligomeric compounds are prepared having phosphodiester, phosphorothioate, and phosphorodithioate covalent linkages. Also provided are synthetic intermediates useful in the processes.
Claims62
A method for the preparation of an oligomeric compound comprising a moiety having the Formula IX:
- ##STR17## wherein:
- Z is CN, halogen, NO.sub.2, alkaryl, sulfoxyl, sulfonyl, thio, substituted sulfoxyl, substituted sulfonyl, or substituted thio, wherein the substituents are selected from the group consisting of alkyl, aryl, or alkaryl;
- and
- X.sub.1 is O or S;
- comprising the steps of:
- (a) providing a compound having the Formula II:
- ##STR18## wherein:
- each R.sub.1, is, independently, H, --OH, --F, or --O--X.sub.3 --D;
- X.sub.3 is alkyl having from 1 to 10 carbons;
- D is H, amino, protected amino, alkyl substituted amino, imidazole, or (--O--X.sub.3).sub.p, where p is 1 to about 10;
- each X.sub.2 is O or S;
- R.sub.3 and R.sub.3a are each hydrogen, a hydroxyl protecting group, or a linker connected to a solid support;
- each B, independently, is a naturally occurring or non-naturally occurring nucleobase or a protected naturally occurring or non-naturally occurring nucleobase;
- n is O to about 50;
- Q is a phosphorus protecting group;
- R.sub.5 is --N (R.sub.6).sub.2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
- R.sub.6 is straight or branched chain alkyl having from 1 to 10 carbons;
- (b) reacting the compound of Formula II with a compound having the Formula III:
- ##STR19## wherein R.sub.3a is hydrogen;
- m is 0 to about 50;
- and
- R.sub.2 is a hydroxyl protecting group, or a linker connected to a solid support, provided that R.sub.2 and R.sub.3 are not both simultaneously a linker connected to a solid support;
- to form the oligomeric compound.
20 more elements
A compound having the Formula VII:
- A--X.sub.1 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --Z VII
- wherein:
- X.sub.1 is O or S;
- A is (R.sub.7)(R.sub.8)P--;
- R.sub.8 is R.sub.5, or has the Formula X:
- ##STR21## wherein:
- each R.sub.1, is, independently, H, --OH, --F, --O--X.sub.3 --D;
- X.sub.3 is alkyl having from 1 to 10 carbons;
- D is H, amino, protected amino, alkyl substituted amino, imidazole, or (--O--X.sub.3).sub.p, where p is 1 to about 10;
- each X.sub.2 is O or S;
- R.sub.5 is --N(R.sub.6).sub.2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
- each Q is a phosphorus protecting group;
- m is 0 to about 50;
- each B, independently, is a naturally occurring or non-naturally occurring nucleobase or a protected naturally occurring or non-naturally occurring nucleobase;
- and
- R.sub.7 is R.sub.5, or has the Formula VIII:
- ##STR22## wherein:
- R.sub.3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support;
- and
- n is 0 to about 50;
- with the proviso that the sum of m and n do not exceed 50;
- and
- Z is CN, halogen, NO.sub.2, alkaryl, sulfoxyl, sulfonyl, thio, substituted sulfoxyl, substituted sulfonyl, or substituted thio, wherein the substituents are selected from the group consisting of alkyl, aryl, or alkaryl.
20 more elements
A compound having the Formula:
- wherein:
- each R.sub.1, is, independently, H, --OH, --F, or --O--X.sub.3 --D;
- D is H, amino, protected amino, alkyl substituted amino, imidazole, or (--O--X.sub.3).sub.p, where p is 1 to about 10;
- R.sub.2 is a hydroxyl protecting group, or a linker connected to a solid support;
- R.sub.3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support, provided that R.sub.2 and R.sub.3 are not both simultaneously a linker connected to a solid support;
- X.sub.1 is O or S;
- each X.sub.2 is O or S;
- each X.sub.3 is alkyl having from 1 to 10 carbons;
- each Q is a phosphorus protecting aroup;
- m and n are each independently an integer from 0 to about 50, provided that the sum of m and n does not exceed 50;
- each B, independently, is a naturally occurring or non-naturally occurring nucleobase or a protected naturally occurring or non-naturally occurring nucleobase;
- and
- Z is CN, halogen, NO.sub.2, alkaryl, sulfoxyl, sulfonyl, thio, substituted sulfoxyl, substituted sulfonyl, or substituted thio, wherein the substituents are selected from the group consisting of alkyl, aryl, or alkaryl.
10 more elements
An oligomeric compound comprising a moiety having the Formula IX:
- ##STR24## wherein:
- Z is CN, halogen, NO.sub.2, alkaryl, sulfoxyl, sulfonyl, thio, substituted sulfoxyl, substituted sulfonyl, or substituted thio, wherein the substituents are selected from the group consisting of alkyl, aryl, or alkaryl;
- and
- X.sub.1 is O or S;
- prepared by the steps of:
- (a) providing a compound having the Formula II:
- ##STR25## wherein:
- each R.sub.1, is, independently, H, --OH, --F, or --O--X.sub.3 --D;
- X.sub.3 is alkyl having from 1 to 10 carbons;
- D is H, amino, protected amino, alkyl substituted amino, imidazole, or (--O--X.sub.3).sub.p, where p is 1 to about 10;
- each X.sub.2 is O or S;
- R.sub.3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support;
- each B, independently, is a naturally occurring or non-naturally occurring nucleobase or a protected naturally occurring or non-naturally occurring nucleobase;
- n is 0 to about 50;
- each Q is a phosphorus protecting group;
- R.sub.5 is --N(R.sub.6).sub.2, or a heterocycloalkyl or heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
- R.sub.6 is straight or branched chain alkyl having from 1 to 10 carbons;
- (b) reacting the compound of Formula II with a compound having the Formula III:
- ##STR26## wherein R.sub.3a is hydrogen;
- and R.sub.2 is a hydroxyl protecting group, or a linker connected to a solid support;
- (c) oxidizing the product of step (b) to form a further compound having the Formula III, wherein R.sub.3a is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support.
18 more elements
A compound of Formula:
- X.sub.5 --X.sub.1 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --CN
- wherein:
- X.sub.1 is O or S;
- X.sub.5 is H or (J).sub.2 P--;
- and J is halogen.
2 more elements
Dependencies are inferred from the claim text.