Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates

• US 5,393,878 A
• Filed: 03/17/1994
• Issued: 02/28/1995
• Est. Priority Date: 10/17/1991
• Status: Expired due to Fees

• Current Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Leumann, Christian
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): PRATS, FRANCISCO CHANDLER
• Application Number:
  US08/214,737
• Time in Patent Office: 348 Days
• Field of Search: 536/28.2, 536/28.3, 536/28.4, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/28.55, 544/298, 544/309, 544/314, 544/317, 514/274, 514/269
• US Class Current: 536/28.2
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds of the formula I in the form of the racemates or enantiomers thereof, ##STR1## in which R₁ and R₂ independently of one another are hydrogen or a protective group, and B is a purine or pyrimidine radical or an analogue thereof, can be used as antiviral active ingredients or for the preparation of biologically active oligonucleotides.

Claims

1. A compound of the formula I in the form of a racemate or enantiomer thereof, ##STR51## in which R_l and R₂ independently of one another are hydrogen or a protective group, and B is a pyrimidine.

2. A compound of the formula I according to claim 1, in which R₁ and R₂ are in each case hydrogen.

3. A compound of the formula I according to claim 1, in which R₁ and R₂ independently of one another are linear or branched C₁ -C₈ alkyl, C₇ -C₁₂ aralkyl, triphenylsilyl alkyldiphenylsilyl, dialkylphenylsilyl and trialkylsilyl, having 1 to 20 C atoms in the alkyl groups, C₂ -C₁₂ acyl, R₃ -SO₂ --, in which R₃ is C₁ -C₁₂ alkyl, C₅ cycloalkyl or C₆ cycloalkyl, phenyl, benzyl, C₁ -C₁₂ alkylphenyl, C₁ -C₁₂ alkylbenzyl, or halophenyl or halobenzyl, or R₁ and R₂ are C₁ -C₁₂ alkoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, methyl- or methoxy- or chlorophenyloxycarbonyl or -benzyloxycarbonyl.

4. A compound of the formula I according to claim 3, in which R₁ and R₂ independently of one another are linear or branched C₁ -C₄ alkyl, C₇ -C₁₂ aralkyl, trialkylsilyl having 1 to 12 C atoms in the alkyl groups, C₂ -C₈ acyl, R₃ --SO₂ --, in which R₃ is C₁ -C₆ alkyl, phenyl, benzyl, C₁ -C₄ alkylphenyl, C₁ -C₄ alkylbenzyl, or halophenyl or halobenzyl, or R₁ and R₂ are C₁ -C₈ alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl.

5. A compound of the formula I according to claim 1, in which R₁ and R₂ are identical protective groups.

6. A compound of the formula I according to claim 1, in which R₁ and R₂ are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromobenzyl, diphenylmethyl, di(methylphenyl)methyl, di(dimethylphenyl)methyl, di(methoxyphenyl)methyl, di(dimethoxyphenyl)methyl, trityl, tri(methylphenyl)methyl, tri(dimethylphenyl)methyl, tri(methoxyphenyl)methyl, tri(dimethoxyphenyl)methyl, trimethylsilyl, triethylsilyl, tri-n-propylsilyl, i-propyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, n-octyldimethylsilyl, (1,1,2,2-tetramethylethyl)dimethylsilyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl, bromobenzoyl, methylphenylsulfonyl, ethylphenylsulfonyl, propylphenylsulfonyl, butylphenylsulfonyl, phenylphenylsulfonyl, benzylphenylsulfonyl, p-bromophenyl sulfonyl, p-methoxyphenyl)sulfonyl, p-methylphenylsulfonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, methytphenyloxycarbonyl, methoxyphenyloxycarbonyl, chlorophenyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzyloxycarbonyl and chlorobenzyloxycarbonyl.

7. A compound of the formula I according to claim 1, in which B in formula I as pyrimidine is a uracil, thymine or cytosine radical of the formulae III, IIIa and IIIb, ##STR52## in which R₁₁ is H or C₁ -C₄ alkyl, and R₁₂ and R₁₃ independently of one another are H, OH, SH, NH₂, NHNH₂, NHOH, NHOalkyl having 1 to 12 C atoms, F, Cl, Br, alkyl or hydroxyalkyl or aminoalkyl or alkoxy or alkylthio, having 1 to 12 C atoms, the hydroxyl and amino groups being unsubstituted or substituted by a protective group, or R₁₂ and R₁₃ are phenyl, benzyl, primary amino having 1 to 20 C atoms or secondary amino having 2 to 30 C atoms, and the hydrogen atoms of the NH₂ group in formula IIIb are unsubstituted or substituted by C₁ -C₆ alkyl, benzoyl or benzyl, as well as the dihydro derivatives of the radicals of the formulae III, IIIa and IIIb.

8. A compound of the formula I according to claim 7, in which R₁₂ is H, C₁ -C₆ alkyl or C₁ -C₆ hydroxyalkyl, F, Cl, Br, NH₂, benzoylamino, mono-di-C₁ -C₆ alkylamino.

9. A compound of the formula I according to claim 7 in which R₁₃ is H, C₁ -C₆ alkyl or C₁ -C₆ alkoxy or C₁ -C₆ hydroxyalkyl, F, Cl, Br, NH₂, benzoylamino, mono- or di-C₁ -C₆ alkylamino.

10. A compound of the formula I according to claim 8, in which R₁₂ is H, F, Cl, Br, NH₂, NHCH₃, N(CH₃)₂ or C₁ -C₄ alkyl.

11. A compound of the formula I according to claim 9, in which R₁₃ is H, C₁ -C₄ alkyl, NH₂, NHCH₃ or (CH₃)₂ N.

12. A compound of the formula I according to claim 1, in which B is uracil, thymine, cytosine, 5-fluorocracil, 5-chlorouracil, 5-bromouracil, dihydrouracil, pseudouracil, 1-methylpseudouracil, 5-methyluracil, 3-methylcytosine or 5-methylcytosine.

13. A compound of the formula I according to claim 1, which is the α

- or β

-anomer of the formula IV, ##STR53##

14. A compound of the formula I according to claim, 13, which is the β

-anomer of the formula IVa, ##STR54##