Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1998-10-08
2000-07-11
Riley, Jezia
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
435 6, 536 221, 536 231, 536 2531, 536 2533, 536 2534, 536 254, 536 2541, 536 256, 514 1, 514 44, C07H 2100, C07H 1900, C07H 2102, C07H 2104
Patent
active
060874902
DESCRIPTION:
BRIEF SUMMARY
This invention relates to chemical compounds which are dinucleotide analogues, to their preparation and to oligonucleotide analogues incorporating at least one unit derived therefrom.
For several years there has been interest in structural analogues of natural oligonucleotides because of their utility as antisense inhibitors of protein expression in biological systems and as pharmaceuticals in the treatment of viruses such as influenza, herpes and HIV, and in the treatment of cancer. Amongst the analogues of recent interest are those in which the groups linking the sugar moieties of oligonucleotides are modified by the replacement of the 3' and 5' oxy linkages by other linking groups.
WO 91/15499 describes oligonucleotides which are said to be of general formula ##STR3## where B is a nucleic acid base; A is --O-- or --CH.sub.2 --; X and Z are each --O--, --S--, --NH-- or --CH.sub.2 -- where X and Z may be the same or different; V and W are .dbd.O, .dbd.S, .dbd.Se, --NH.sub.2, alkoxy, --OH or --SH, where V and W may be the same or different in a monomer unit; L is --H or a partner of a bonding pair; C is --OR where R is an alkyl, alkenyl or alkynyl group optionally substituted by one or more halogen, cyano, carboxy, hydroxy, nitro and/or mercapto radicals; and n is any integer.
WO 91/15499 does not disclose any oligonucleotides of the above formula in which one of X and Z is --NH-- and the other is --CH.sub.2, one of V and W is .dbd.O and the other is alkoxy, and does not suggest how such compounds might be prepared. The preparation of such oligonucleotides has remained a problem. It has now been found that such oligonucleotides can be prepared from novel dinucleotide analogues. The novel dinucleotide analogues, and oligonucleotides containing units derived therefrom, have good stability towards nuclease hydrolysis and good hybridization properties, facilitating their use as antisense inhibitors of gene expression and as pharmaceuticals for the treatment of diseases such as cancer and viruses such as influenza, herpes and HIV.
Accordingly, the present invention provides compounds which are dinucleotide analogues of formula ##STR4## and salts thereof, where B.sup.1 and B.sup.2 are each independently a monovalent nucleoside base radical, --OY.sup.2, ##STR5## where R.sup.9 is hydrogen, halogen, hydroxy, --OY.sup.5 or R.sup.13, R.sup.10 is hydrogen, halogen or R.sup.14, R.sup.11 is hydroxy, R.sup.15 or --OR.sup.15 where R.sup.15 is a C.sub.1 to C.sub.10 aliphatic group, a C.sub.3 to C.sub.8 cycloaliphatic group, a C.sub.6 to C.sub.10 aromatic group or a C.sub.7 to C.sub.13 araliphatic group, and R.sup.12 is hydrogen, R.sup.12.sub.a or --COR.sup.12.sub.a where R.sup.12.sub.a is a C.sub.1 to C.sub.10 aliphatic group, a C.sub.3 to C.sub.8 cycloaliphatic group, a C.sub.6 to C.sub.10 aromatic group or a C.sub.7 to C.sub.13 araliphatic group, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 are each indpendently a hydroxy-protecting group, and R.sup.7, R.sup.8, R.sup.13 and R.sup.14 are each independently a C.sub.1 to C.sub.10 aliphatic group, a C.sub.3 to C.sub.8 cycloaliphatic group, a C.sub.6 to C.sub.10 aromatic group or a C.sub.7 to C.sub.13 araliphatic group.
The hydroxy-protecting groups Y.sup.1 to Y.sup.5 may be any groups capable of protecting a hydroxyl group against undesired reaction. Such groups are well known. Generally, Y.sup.1 to Y.sup.5 are protecting groups previously specified for use in nucleotide chemistry. Preferably, Y.sup.1 is R.sup.16, --COR.sup.16 or --SO.sub.2 R.sup.16, Y.sup.2 is R.sup.17, --COR.sup.17 or --SO.sub.2 R.sup.17, Y.sup.3 is R.sup.18, --COR.sup.18 or --SO.sub.2 R.sup.18, Y.sup.4 is R.sup.19, --COR.sup.19 or --SO.sub.2 R.sup.19 and Y.sup.5 is R.sup.20, --COR.sup.20 or --SO.sub.2 R.sup.20, or one or more of Y.sup.1 to Y.sup.5 is tri(C.sub.1 -C.sub.15 hydrocarbyl)silyl, where R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are each independently a C.sub.1 to C.sub.10 aliphatic group, a C.sub.3 to C.sub.8 cycloaliphatic group, a C.sub.6 to C.sub.10 aromatic group or a C.sub.7 to
REFERENCES:
patent: 5789562 (1998-08-01), Seela et al.
Rammler D.H. et al., Biochemistry, vol. 6, No. 6, pp. 1828-1837 (1967). *
Baxter Anthony David
Baylis Eric Keith
Collingwood Stephen Paul
Fairhurst Robin Alec
Taylor Roger John
Borovian Joseph J.
Novartis AG
Riley Jezia
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