Patent ID: 6326478
Filing Date: 2001-12-04
Classification: C07H,Y02P

Abstract:
A method for the preparation of an oligomeric compound comprising a moiety having the Formula I: ##STR36##wherein:A is a diradical derived from a monocyclic or bicyclic aromatic ring system;R.sub.11 and R.sub.12 are each independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, alkaryl, and aralkyl;or R.sub.11 and R.sub.12 together with the carbon atoms to which they are attached form an optionally substituted aliphatic or aromatic ring having from 4 to 6 ring atoms;X.sub.4 is selected from the group consisting of alkaryl, aralkyl, sulfonyl, thio, substituted sulfonyl, and substituted thio, wherein said substituent is alkyl, aryl, or alkaryl;or X.sub.4 is a group of formula --C(.dbd.O)--R.sub.40 where R.sub.40 is selected from the group consisting of lower alkyl, aryl, aralkyl, and heteroaryl wherein said lower alkyl, aryl, aralkyl or heteroaryl groups can be optionally substituted with one or more aryl, aralkyl, or acetyl groups;or X.sub.4 is a group of formula --(--CH.sub.2 --CH.sub.2 --).sub.d Si(R.sub.9).sub.3 where d is 0 or 1;each R.sub.9 is, independently, alkyl having 1 to about 10 carbon atoms, or aryl having 6 to about 10 carbon atoms;X.sub.1 and X.sub.5 are each independently O or S; comprising:(a) providing a compound having the Formula II: ##STR37##wherein:each R.sub.1 is H, OH, F, or a group of formula Z--R.sub.22 --(R.sub.23).sub.v --,Z is O, S, NH, or N--R.sub.22 --(R.sub.23).sub.v ;R.sub.22 is C.sub.1 -C.sub.20 alkylene, C.sub.2 -C.sub.20 alkenylene, or C.sub.2 -C.sub.20 alkynylene;R.sub.23 is selected from the group consisting of hydrogen, amino, halogen, hydroxyl, thio, keto, carboxyl, nitrilo, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, N-phthalimido, imidazolyl, azido, hydrazino, hydroxylamino, isocyanato, sulfonyl, sulfidyl, silyl, aryl, and a radical or diradical derived from a heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;or R.sub.23 is a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;v is from 0 to about 10;or R.sub.1 has one of the formulas: ##STR38##wherein:y1 is 0 or 1;y2 is 0 to 10;y3 is 1 to 10;provided that said formulas do not form a peroxide;E is N(R.sub.41) (R.sub.42) or N.dbd.C(R.sub.41) (R.sub.42);each R.sub.41 and each R.sub.42 is independently selected from the group consisting of H, C.sub.1 -C.sub.10 alkyl, and a nitrogen protecting group, or R.sub.41 and R.sub.42 taken together form a nitrogen protecting group; or R.sub.41 and R.sub.42 taken together with the N or C atom to which they are attached form a ring structure that can include at least one heteroatom selected from N and O;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;M is an optionally protected internucleoside linkage;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 nitrogen, sulfur, and oxygen; andR.sub.6 is straight or branched chain alkyl having from 1 to 10 carbons; and(b) reacting the compound of Formula II with a compound having Formula III: ##STR39##wherein m is 0 to about 50;R.sub.3a is hydrogen;R.sub.2 is selected from the group consisting of a hydrogen, hydroxyl protecting group, and 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.