IP Library › Patent Application 13085256

Patent Application

App. No. 13/085,256

5-POSITION MODIFIED PYRIMIDINES AND THEIR USE

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Patent No.: US None
App. No.: 13/085,256

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Abstract

The present disclosure relates to the field of nucleic acid chemistry, specifically to 5-position modified uridines as well as phosphoramidite and triphosphate derivatives thereof. The present disclosure also relates to methods of making and using the same.

Claims (79)

1 . A compound selected from the compounds having the following structure or a salt thereof:

wherein

R is selected from the group consisting of −(CH 2 ) n —R X1 ;

R X1 is selected from the group consisting of

wherein

R X4 is selected from the group consisting of a branched or linear lower alkyl (C1-C20); halogen (F, Cl, Br, I); nitrile (CN); boronic acid (BO 2 H 2 ); carboxylic acid (COOH); carboxylic acid ester (COOR X2 ); primary amide (CONH 2 ); secondary amide (CONHR X2 ); tertiary amide (CONR X2 R X3 ); sulfonamide (SO 2 NH 2 ); N-alkylsulfonamide (SONHR X2 );

wherein

R X3 are independently selected from the group consisting of a branched or linear lower alkyl (C1-C20); phenyl (C 6 H 5 ); an R X4 substituted phenyl ring (R X4 C 6 H 4 ), wherein R X4 is defined above; a carboxylic acid (COOH); a carboxylic acid ester (COOR X5 ), wherein R X5 is a branched or linear lower alkyl (C1-C20); and cycloalkyl, wherein R X2 =R X3 =(CH 2 )n;

wherein n=0-10;

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido;

wherein

R′ is selected from the group consisting of —OAc; —OBz and —OSiMe 2 tBu;

wherein

R″ is selected from the group consisting of H, DMT and triphosphate (−P(O)(OH)—O—P(O)(OH)—O—P(O)(OH) 2 ) or a salt thereof; and

wherein

can be replaced with carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside.

2 . A compound according to claim 1 having the following structure:

3 . A compound according to claim 1 having the following structure or a salt thereof:

4 . A compound having the following structure:

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido; and

wherein

5 . A compound of claim 4 , wherein the oligonucleotide is selected from a ribonucleic acid or a deoxyribonucleic acid.

6 . A compound of claim 5 , wherein said oligonucleotide further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position.

7 . A compound of claim 6 , wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′OEt), 2′-O-propyl (2-Pr) and 2′-O—CH 2 CH 2 OCH 3 .

8 . A compound of claim 1 incorporated as part of an aptamer.

9 . A compound of claim 8 , wherein the aptamer is selected from a ribonucleic acid or a deoxyribonucleic acid.

10 . A compound of claim 9 , wherein said aptamer further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position.

11 . A compound of claim 10 , wherein said chemical Modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr) and 2′-O—CH 2 CH 2 OCH 3 .

12 . An oligonucleotide comprising at least one modified nucleotide having the following structure:

R is selected from the group consisting of —(CH 2 ) n —R X1 ;

R X1 is selected from the group consisting of:

wherein

R X2 and R X3 are independently selected from the group consisting of a branched or linear lower alkyl (C1-C20); phenyl (C 6 H 5 ); an R X4 substituted phenyl ring (R X4 C 6 H 4 ), wherein R X4 is defined above; a carboxylic acid (COOH); a carboxylic acid ester (COOR X5 ), wherein R X5 is a branched or linear lower alkyl (C1-C20); and cycloalkyl, wherein R X2 =RX3=(CH 2 )n;

wherein n=0-10;

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido; and

wherein

13 . An oligonucleotide of claim 12 , wherein the oligonucleotide is selected from a ribonucleic acid or a deoxyribonucleic acid.

14 . An oligonucleotide of claim 13 , wherein said oligonucleotide further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected froth a ribose position, a deoxyribose position, a phosphate position, and a base position.

15 . An oligonucleotide of claim 14 , wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap.

16 . An oligonucleotide comprising at least one modified nucleotide independently selected from the following structures:

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido; and

wherein

17 . An oligonucleotide of claim 16 , wherein the oligonucleotide is selected from a ribonucleic acid or a deoxyribonucleic acid.

18 . An oligonucleotide of claim 17 , wherein said oligonucleotide further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position.

19 . An oligonucleotide of claim 18 , wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′—OMe), 2′-O-ethyl (2′—OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap.

20 . An aptamer comprising at least one modified nucleotide having the following structure:

R is selected from the group consisting of —(CH 2 ) n —R X1 ;

R X1 is selected from the group consisting of

wherein

R X4 is selected from the group consisting of a branched or linear lower alkyl (C1-C20); halogen (F, Cl, Br, I); nitrile (CN); boronic acid (B0 2 H 2 ); carboxylic acid (COOH); carboxylic acid ester (COOR X2 ); primary amide (CONH 2 ); secondary amide (CONHR X2 ); tertiary amide (CONR X2 R X3 ) sulfonamide (SO 2 NH 2 ); N-alkylsulfonamide (SONHR X2 );

wherein

wherein n=0-10;

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido; and

wherein

21 . An aptamer of claim 20 , wherein the aptamer is selected from a ribonucleic acid or a deoxyribonucleic acid.

22 . An aptamer of claim 21 , wherein said aptamer further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position.

23 . An aptamer of claim 22 , wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-O Me), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap.

24 . An aptamer comprising at least one modified nucleotide independently selected from the following structures:

wherein

X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3 and -azido; and

wherein

27 . The aptamer of claim 24 wherein the oligonucleotide is selected from a ribonucleic acid or a deoxyribonucleic acid.

28 . The aptamer of claim 25 , wherein said oligonucleotide further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position.

29 . An aptamer of claim 26 , wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap.

49 - 50 . (canceled)

51 . A compound of claim 4 incorporated as part of an aptamer.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 24, 2011

From: ROHLOFF, JOHN; JANJIC, NEBOJSA; CARTER, JEFFREY D.; FOWLER, CATHERINE

To: SOMALOGIC, INC.

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