Process for the synthesis of oligomeric compounds
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
출원번호
US-0021277
(1998-02-10)
발명자
/ 주소
Capaldi Daniel C.
Ravikumar Vasulinga T.
출원인 / 주소
Isis Pharmeuticals, Inc.
대리인 / 주소
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
인용정보
피인용 횟수 :
30인용 특허 :
20
초록
Synthetic processes are provided wherein oligomeric compounds are prepared having phosphodiester, phosphorothioate, and phosphorodithioate covalent linkages. Also provided are synthetic intermediates useful in such processes.
대표청구항▼
[ What is claimed is:] [1.] A method for the preparation of an oligomeric compound having a moiety of Formula I: [ STR 38 ] wherein: X.sub.4 is Z or H;Z is CN, halogen, alkaryl, substituted sulfoxyl, substituted sulfonyl, or a substituted thio group, wherein said substituent is alkyl, aryl, or alkar
[ What is claimed is:] [1.] A method for the preparation of an oligomeric compound having a moiety of Formula I: [ STR 38 ] wherein: X.sub.4 is Z or H;Z is CN, halogen, alkaryl, substituted sulfoxyl, substituted sulfonyl, or a substituted thio group, wherein said substituent is alkyl, aryl, or alkaryl; andX.sub.1 is O or S; prising the steps of:(a) providing a compound having the Formula II: [ STR 39 ] wherein: each R.sub.1, is, independently, H, --OH, --F, or --O--X.sub.3 --D;X.sub.3 is alkylenyl having from 1 to 10 carbons;D is H, amino, protected amino, alkyl substituted amino, imidazolyl, or (--O--X.sub.3).sub.p H where p is 1 to about 10;each X.sub.2 is O or S;R.sub.3 is selected from the group consisting of hydrogen, a hydroxyl protecting group, and a linker connected to a solid support;each B, independently, is selected from the group consisting of a naturally occurring nucleobase, a non-naturally occurring nucleobase, a protected naturally occurring nucleobase, and a protected non-naturally occurring nucleobase;n is 0 to about 50;each Q is --X.sub.1 H or [ STR 40 ] R.sub.5 is selected from the group consisting of --N(R.sub.6).sub.2, a heterocycloalkyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen, and a 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: [ STR 41 ] wherein R.sub.3a is hydrogen; 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; form the oligomeric compound. [20.] A compound hating Formula VII: [ STR 47 ] wherein: X.sub.4 is Z or H;Z is CN, halogen, alkaryl, substituted sulfoxyl, substituted sulfonyl, or a substituted thio group, wherein said substituent is alkyl, aryl or alkaryl;X.sub.1 is O or S;A is (R.sub.7) (R.sub.8) P--; andR.sub.8 is P.sub.5, or has the Formula VIII: [ STR 48 ] wherein: each R.sub.1 is, independently, H, --OH, --F, or --O--X.sub.3 --D;X.sub.3 is alkylenyl having from 1 to 10 carbons;D is H, amino, protected amino, alkyl substituted amino, imidazolyl, or (--O--X.sub.3).sub.p H, where p is 1 to about 10;each X.sub.2 is O or S;R.sub.5 is selected from the group consisting of --N(R.sub.6).sub.2, a heterocycloalkyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen and a heterocycloalkenyl ring containing from 4 to 7 atoms, and having up to 3 heteroatoms selected from nitrogen, sulfur, and oxygen;each Q is --X.sub.1 H or [ STR 49 ] m is 0 to about 50; each B, independently, is selected from the group consisting of a naturally occurring nucleobase, a non-naturally occurring nucleobase, a protected naturally occurring nucleobase and a non-naturally occurring nucleobase; andR.sub.7 is R.sub.5, or has the Formula IX: [ STR 50 ] wherein: R.sub.3 is hydrogen, a hydroxyl protecting group, or a linker connected to a solid support; andn is 0 to about 50; with the proviso that the sum of m and n does not exceed 50 and with the proviso that both R.sub.7 and R.sub.8 cannot be R.sub.5 simultaneously. [41.] A compound having Formula XI: 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, imidazolyl, or (--O--X.sub.3).sub.p H, 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 alkylenyl having from 1 to 10 carbons;each Q is --X.sub.1 H or [ STR 52 ] 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 selected from the group consisting of a naturally occurring nucleobase, a non-naturally occurring nucleobase, a protected naturally occurring nucleobase and a non-naturally occurring nucleobase;X.sub.4 is Z or H; andZ is CN, halogen, alkaryl, substituted sulfoxyl, substituted sulfonyl, or a substituted thio group, wherein said substituent is alkyl, aryl, or alkaryl.
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