Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates

• US 5,319,080 A
• Filed: 10/13/1992
• Issued: 06/07/1994
• 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:
  US07/959,851
• Time in Patent Office: 602 Days
• Field of Search: 536/27.14, 536/28.2, 536/27.1, 536/27.13, 536/27.21, 536/28.1, 514/45, 514/49, 514/261, 514/265, 514/269, 544/242, 544/245, 544/264, 544/265, 544/268, 544/269, 544/297
• US Class Current: 536/27.1
• 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 R₁ and R₂ independently of one another are hydrogen or a protective group for hydroxyl and B is a purine.

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

3. A compound 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 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 according to claim 1, in which R₁ and R₂ are identical protective groups.

6. A compound according to claim 1, in which R₁ and R₂ are identical or different protecting groups selected from the group consisting of 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-bromophenylsulfonyl, p-methoxyphenylsulfonyl, p-methylphenylsulfonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butyoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, methylphenyloxycarbonyl, methoxyphenyloxycarbonyl, chlorophenyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzyloycarbonyl and chlorobenzyloxycarbonyl.

7. A compound according to claim 1, in which B, as a purine radical, is a radical of the formulae II, IIa, IIb, IIc, IId or IIe ##STR52## in which R₄ is H, Cl, Br or OH, and R₅, R₆ and R₇ 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 are phenyl, benzyl, secondary amino having 1 to 20 C atoms or tertiary amino having 2 to 30 C atoms, and R₁₁ is H or C₁ -C₄ alkyl.

8. A compound according to claim 7, in which the protective group for hydroxyl and amino groups is C₁ -C₈ acyl.

9. A compound according to claim 7, in which the secondary amino has 1 to 12 C atoms and the tertiary amino has 2 to 12 C atoms.

10. A compound according to claim 7, in which the secondary amino and tertiary amino are radicals of the formula R₈ R₉ N in which R₈ is H or independently has the meaning of R₉, and R₉ is C₁ -C₂₀ alkyl, C₁ -C₂₀ aminoalkyl, C₁ -C₂₀ hydroxyalkyl;

carboxyalkyl or carbalkoxyalkyl, the carbalkoxy group having 2 to 8 C atoms and the alkyl group having 1 to 6, C atoms;

C₂ -C₂₀ alkenyl;

phenyl, mono- or di(C₁ -C₄ alkyl- or C₁ -C₄ alkoxy)phenyl, benzyl, mono- or di(C₁ -C₄ alkyl- or C₁ -C₄ alkoxy)benzyl;

or 1,2-, 1,3- or 1,4-imidazolyl-C₁ -C₆ alkyl, or R₈ and R₉ together are tetra- or pentamethylene, 3-oxa-1,5-pentylene, --CH₂ --NR₁₀ --CH₂ CH₂ -- or --CH₂ CH₂ --NR₁₀ --CH₂ CH₂ --, in which R₁₀ is H or C₁ -C₄ alkyl, the amino group in the aminoalkyl being unsubstituted or substituted by one or two C₁ -C₄ alkyl or C₁ -C₄ hydroxyalkyl groups and the hydroxl group in the hydroxyalkyl is free or etherified with C₁ -C₄ alkyl.

11. A compound according to claim 9, in which the secondary amino and tertiary amino are methyl-, ethyl-, dimethyl-, diethyl-, allyl-, mono- or di-(hydroxyeth-2-yl)-, phenyl- and benzyl-, acetyl- and benzoyl-amino.

12. A compound according to claim 7, in which R₄ in formulae II, IIb, IIc, IId and IIe is hydrogen.

13. A compound according to claim 7, in which R₇ in formula IId is hydrogen.

14. A compound according to claim 7, in which R₅ and R₆ in formulae II, IIa, IIb, IIc, IId and IIe independently of one another are H, F, Cl, Br, OH, SH, NH₂, NHOH, NHNH₂, methylamino, dimethylamino, benzoylamino, methoxy, ethoxy and methylthio.

15. A compound according to claim 1, in which B is a purine radical selected from the group consisting of adenine, N-methyladenine, N-benzoyladenine, 2-methyladenine, 2-methylthioadenine, 2-aminoadenine, 3-carbaadenine, 7-carbaadenine, 1-carbaadenine, 6-hydroxypurine, 2-amino-6-chloropurine, 2-amino-6-methylthiopurine, 2-amino-6-hydroxypurine, 3-carba-6-chloropurine, guanine and 2-methylguanine.

16. A compound according to claim 1, which is an α

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

17. A compound according to claim 16, which is the β

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

18. A compound according to claim 10 wherein R₉ is carbalkoxyalkyl, the carbalkoxy group having 2 to 8 C atoms and the alkyl group having 1 to 4 C atoms.