Heteroatomic oligonucleoside linkages
First Claim
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1. A compound having structure:
- ##STR7## wherein;
L1 --L2 --L3 --L4 is CR1a R1b --CR2a R2b --CR3a R3b --Z4, CR1a R1a --CR2a R2b --Z3 --Z4, CR1a R1b --Z2 --CR3a R3b --Z4, Z1 --CR2a R2b --CR3a R3b --Z4, CR1a R1b --Z2 --Z3 --Z4, Z1 --CR2a R2b --Z3 --Z4 or Z1 --Z2 --CR3a R3b --Z4 ;
Z1, Z2, Z3 and Z4 are, independently, O, NR4, S, SO, SO2, Se, P(═
Y1)Y2 or Si(R6)2 ;
R1a, R1b, R2a, R2b, R3a and R3b are, independently, H, R5, O--R5, S--R5, NR4 R5 ;
or, independently, together R1a and R1b, or R2a and R2b, or R3a and R3b are ═
O;
X is H, OH, O--R5, S--R5, NR4 --R5, R5, F, Cl, Br, CN, CF3, OCF3, OCN, SOCH3, SO2 CH3, ONO2, NO2, N3, aminoalkylamino, polyalkylamino or substituted silyl;
Y1 is O, S, Se, or NR4 ;
Y2 is OH, OR5, SH, SR5, SeH, R5, BH3 or NR4 R5 ;
R4, R5 and R6 are, independently, one of;
an electron pair of a multiple bond;
H;
straight or branched chain alkyl or substituted alkyl;
straight or branched chain alkenyl or substituted alkenyl;
straight or branched chain alkynyl or substituted alkynyl;
14 C-containing lower alkyl, lower alkenyl or lower alkynyl;
substituted or unsubstituted alkaryl or aralkyl;
14 C-containing alkaryl or aralkyl;
aryl;
alicyclic;
a reporter molecule; and
where said substituents are OH, ═
O, CO2 H, O-alkyl, SH, S-alkyl, NH-alkyl, N-(alkyl)2, alkyl, F, Cl, Br, CN, CF3, OCF3, OCN, SOCH3, SO2 CH3, ONO2, NO2, N3, NH2, aryl, aralkyl, sulfide, or silyl;
Q is O or CH2 ;
n is an integer greater than 0;
Bx is a variable heterocyclic base moiety; and
said alkyl groups have 1 to 12 carbon atoms, said alkenyl and alkynyl groups have 2 to 12 carbon atoms, said alkaryl and aralkyl groups have 7 to 14 carbon atoms, and said aryl groups have 6 to 14 carbon atoms.
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Abstract
Oligonucleotide-mimicking macromolecules that have improved nuclease resistance are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligonucleotides with four atom linking groups provide unique compounds that are useful in regulating RNA expression and in therapeutics. Methods of synthesis and use also are disclosed.
480 Citations
29 Claims
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1. A compound having structure:
- ##STR7## wherein;
L1 --L2 --L3 --L4 is CR1a R1b --CR2a R2b --CR3a R3b --Z4, CR1a R1a --CR2a R2b --Z3 --Z4, CR1a R1b --Z2 --CR3a R3b --Z4, Z1 --CR2a R2b --CR3a R3b --Z4, CR1a R1b --Z2 --Z3 --Z4, Z1 --CR2a R2b --Z3 --Z4 or Z1 --Z2 --CR3a R3b --Z4 ;Z1, Z2, Z3 and Z4 are, independently, O, NR4, S, SO, SO2, Se, P(═
Y1)Y2 or Si(R6)2 ;R1a, R1b, R2a, R2b, R3a and R3b are, independently, H, R5, O--R5, S--R5, NR4 R5 ;
or, independently, together R1a and R1b, or R2a and R2b, or R3a and R3b are ═
O;X is H, OH, O--R5, S--R5, NR4 --R5, R5, F, Cl, Br, CN, CF3, OCF3, OCN, SOCH3, SO2 CH3, ONO2, NO2, N3, aminoalkylamino, polyalkylamino or substituted silyl; Y1 is O, S, Se, or NR4 ; Y2 is OH, OR5, SH, SR5, SeH, R5, BH3 or NR4 R5 ; R4, R5 and R6 are, independently, one of;
an electron pair of a multiple bond;
H;
straight or branched chain alkyl or substituted alkyl;
straight or branched chain alkenyl or substituted alkenyl;
straight or branched chain alkynyl or substituted alkynyl;
14 C-containing lower alkyl, lower alkenyl or lower alkynyl;
substituted or unsubstituted alkaryl or aralkyl;
14 C-containing alkaryl or aralkyl;
aryl;
alicyclic;
a reporter molecule; and
where said substituents are OH, ═
O, CO2 H, O-alkyl, SH, S-alkyl, NH-alkyl, N-(alkyl)2, alkyl, F, Cl, Br, CN, CF3, OCF3, OCN, SOCH3, SO2 CH3, ONO2, NO2, N3, NH2, aryl, aralkyl, sulfide, or silyl;Q is O or CH2 ; n is an integer greater than 0; Bx is a variable heterocyclic base moiety; and said alkyl groups have 1 to 12 carbon atoms, said alkenyl and alkynyl groups have 2 to 12 carbon atoms, said alkaryl and aralkyl groups have 7 to 14 carbon atoms, and said aryl groups have 6 to 14 carbon atoms. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
- ##STR7## wherein;
Specification
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Current AssigneeISIS Pharmaceuticals Incorporated
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Original AssigneeISIS Pharmaceuticals Incorporated
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InventorsTeng, Kelly, Cook, Phillip Dan, Sanghvi, Yogesh S.
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Primary Examiner(s)Elliott, George C.
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Assistant Examiner(s)LARSON, THOMAS GEORGE
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Application NumberUS08/392,675Time in Patent Office964 DaysField of Search536/23.1, 536/24.1, 536/24.5, 536/25.6, 536/22.1, 536/24.3, 536/24.31, 536/24.32, 536/25.3, 514/44, 435/6, 435/91.31US Class Current536/23.1CPC Class CodesA61K 31/70 Carbohydrates; Sugars; Deri...A61K 47/59 obtained otherwise than by ...C07D 405/04 directly linked by a ring-m...C07D 405/14 containing three or more he...C07F 7/1804 Compounds having Si-O-C lin...C07H 19/04 Heterocyclic radicals conta...C07H 19/06 Pyrimidine radicalsC07H 19/10 with the saccharide radical...C07H 19/16 Purine radicalsC07H 21/00 Compounds containing two or...
