Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-04-14
1999-09-14
Marschel, Ardin H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 245, 514 1, 514 44, C07H 1900, C07H 2102, C07H 2104, A01N 4304
Patent
active
059524782
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds which are intermediates for dinucleotide analogues and oligonucleotide analogues, the preparation of these compounds, and their use in preparing dinucleotide analogues and their use as pharmaceuticals.
For several years there has been interest in structural analogues of natural oligonucleotides because of their utility as anti-sense probes for inhibiting gene 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 92/20822 describes oligonucleotide analogues comprising subunits at least some of which have the general structure ##STR2## wherein B.sub.x is a variable base moiety; Q is O, CH.sub.2, CHF or CF.sub.2 ; X is H, OH, C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl, or aralkyl, F, Cl, Br, CN, CF.sub.3, OCF.sub.3, OCN, O--, S--, or N-alkyl, O--, S--, or N-alkenyl, SOCH.sub.3, SO.sub.2 CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a group for improving the pharmacokinetic properties of an oligonucleotide or a group for improving the pharmacodynarnic properties of an oligonucleotide;
L.sub.1 and L.sub.4 are, independently, CH.sub.2, C.dbd.O, C.dbd.S, C--NH.sub.2, C--NHR.sub.3, C--OH, C--SH, C--O--R.sub.1 or C--S--R.sub.1 and L.sub.2 and L.sub.3 are, independently, CR.sub.1 R.sub.2, C.dbd.CR.sub.1 R.sub.2, C.dbd.NR.sub.3 P(O)R.sub.4, P(S)R.sub.4, C.dbd.O, C.dbd.S, O, S, SO, SO.sub.2, NR.sub.3 or SiR.sub.5 R.sub.6 or L.sub.2 and L.sub.3 together form part of an alkene, alkyne, aromatic ring, carbocycle or heterocycle, or L.sub.1, L.sub.2, L.sub.3 and L.sub.4 together comprise a --CH.dbd.N--NH--CH.sub.2 -- or CH.sub.2 --O--N.dbd.CH-- moiety;
R.sub.1 and R.sub.2 are independently H, OH, SH, NH.sub.2, C.sub.1 to C.sub.10 alkyl, substituted alkyl, alkenyl, alkaryl or aralkyl, alkoxy, thioalkoxy, alkylamino, aralkylamino, substituted alkylamino, heterocycloalkyl, heterocycloalkylamino, aminoalkylamino, polyalkylamino, halo, formyl, keto, benzoxy, carboxamido, thiocarboxamido, ester, thioester, carboxamidine, carbamyl, ureido, guanidino, an RNA cleaving group, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide;
R.sub.3 is H, OH, NH.sub.2, lower alkyl, substituted lower alkyl, alkoxy, lower alkenyl, aralkyl, alkylamino, aralkylamino, substituted alkylamino, heterocycloalkyl, heterocycloalkylamino, aminoalkylamino, polyalkylamino, a RNA cleaving group, a group for improving the pharmacokinetic properties of an oligonucleotide or a group for improving the pharmacodynarnic properties of an oligonucleotide;
R.sub.4 is OH, SH, NH.sub.2, O-alkyl, S-alkyl, NH-alkyl, O-alkylheterocyclo, S-alkylheterocyclo, N-alkylheterocyclo or a nitrogen-containing heterocycle; and
R.sub.5 and R.sub.6 are, independently, C.sub.1 to C.sub.6 alkyl or alkoxy; provided that if L.sub.1 is C.dbd.O or C.dbd.S then L.sub.2 is not NR.sub.3 or if L.sub.4 is C.dbd.O or C.dbd.S then L.sub.3 is not NR.sub.3 ; that if one of L.sub.2 or L.sub.3 is C.dbd.O or C.dbd.S then the other of L.sub.2 or L.sub.3 is not NR.sub.3 ; that if L.sub.2 is P(O)R.sub.4 and R.sub.4 is OH and X is OH and B.sub.x is uracil or adenine, then L.sub.3 is not O; and that if L.sub.1, L.sub.2 and L.sub.4 are CH.sub.2 and X is H or OH and Q is O then L.sub.3 is not S, SO or SO.sub.2.
WO 91/15499 describes oligonucleotides of 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
Baxter Anthony David
Collingwood Stephen Paul
Taylor Roger John
Marschel Ardin H.
McCormack Myra H.
Novartis Finance Corporation
Riley Jezia
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