Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates

• US 5,700,920 A
• Filed: 06/06/1995
• Issued: 12/23/1997
• Est. Priority Date: 07/01/1992
• Status: Expired due to Fees

• Current Assignee: Novartis Corporation (Novartis Ag)
• Original Assignee: Novartis Corporation (Novartis Ag)
• Inventors: Eschenmoser, Albert, Altmann, Karl-Heinz, Imwinkelried, Rene
• Primary Examiner(s): Marschel, Ardin H.
• Assistant Examiner(s): Riley, Jezia
• Application Number:
  US08/471,212
• Time in Patent Office: 931 Days
• Field of Search: 536/22.1, 536/23.1, 536/25.3, 514/44, 435/6
• US Class Current: 536/22.1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07C 215/44 bound to carbon atoms of the same ring or condensed ring system
• CPC Class Codes: C07C 275/50 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 239/50 Three nitrogen atoms
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds of the formulae I and Ia and their racemates ##STR1## in which A is --CH₂ -- or --CH₂ CH₂ --, R₁ is hydrogen or a protective group, R₂ is hydrogen or a protective group or a radical forming a phosphorus-containing nucleotide bridge 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. An oligonucleotide of the formula V

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, 30, 31, 32, 33, 34, 35, 36, 37)

2. An oligonucleotide of the formula V according to claim 1, wherein the bridge group Y is --P(O)O.sup.⊕

, --P(O)S.sup.⊖

--, --P(S)S.sup.⊖

--, --P(O)R₁₆ --, --P(O)NR₁₇ R₁₈ --, or --CH₂ --, in which R₁₆ is H or C₁ -C₆ alkyl, and R₁₇ and R₁₈ independently of one he another have the meaning of R₁₆.

3. An oligonucleotide of the formula V according to claim 2, wherein the bridge group Y is --P(O)O.sup.⊕

--.

4. An oligonucleotide of the formula V according to claim 1, wherein y is a number from 0 to 100.

5. An oligonucleotide of the formula V according to claim 4, wherein y is a number from 0 to 50.

6. An oligonucleotide of the formula V according to claim 5, wherein y is a number from 0 to 20.

7. An oligonucleotide of the formula V according to claim 1, wherein the radicals of the formulae VI and/or VIa are bonded between radicals of natural or synthetic nucleosides.

8. An oligonucleotide of the formula V according to claim 7, wherein 2 to 5 identical or different radicals of the formulae VI and/or VIa follow one another.

9. An oligonucleotide of the formula V according to claim 1, wherein 4 to 30 nucleoside units and 1 to 12 radicals of the formulae VI and/or VIa are present in all.

10. An oligonucleotide of the formula V according to claim 1, in which B as a purine radical or an analogue thereof is a radical of the formula II, IIa, IIb, IIc, IId or IIe ##STR48## in which R₄ is H, Cl, Br or OH or O(C₁ -C₁₂ alkyl), and R₅, R₆ and R₇ independently of one another are H, OH, SH, NH₂, NHNH₂, NHOH, NHOalkyl having 1 to 12 C atoms, --N═

CH--N(C₁ -C₁₂ alkyl)₂, F, Cl, Br, alkyl or hydroxyalkyl or aminoalkyl or alkoxy or alkylthio having 1 to 12 C atoms, where the hydroxyl and amino groups are unsubstituted or substituted by a protective group, phenyl, benzyl, primary amino having 1 to 20 C atoms or secondary amino having 2 to 30 C atoms, and R₁₁ is H or C₁ -C₄ alkyl.

11. An oligonucleotide of the formula V according to claim 10, in which the protective group for hydroxyl and amino groups is C₁ -C₈ acyl.

12. An oligonucleotide of the formula V according to claim 10, in which the primary amino comprises 1 to 12 C atoms and the secondary amino 2 to 12 C atoms.

13. An oligonucleotide of the formula V according to claim 10, in which the primary amino and secondary 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, -aminoalkyl or -hydroxy-alkyl;

carboxyalkyl or carbalkoxyalkyl, where the carbalkoxy group comprises 2 to 8 C atoms and the alkyl group 1 to 6, preferably 1 to 4 C atoms;

C₂ -C₂₀ alkenyl;

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

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

14. An oligonucleotide of the formula V according to claim 13, in which the primary amino and secondary amino are methyl-, ethyl-, dimethyl-, diethyl-, allyl-, mono- or di(hydroxyeth-2-yl)-, phenyl- and benzyl-, acetyl- or benzoylamino.

15. An oligonucleotide of the formula V according to claim 10, in which R₄ in the formulae II, IIb, IIc, IId and IIe is hydrogen.

16. An oligonucleotide of the formula V according to claim 10, in which R₇ in formula IId is hydrogen.

17. An oligonucleotide of the formula V according to claim 10, in which R₅ and R₆ in the 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 or methylthio.

18. An oligonucleotide of the formula V according to claim 10, in which B is a purine radical or a radical of a purine analogue from the series consisting of adenine, N-methyl-adenine, 2-methylthioadenine, 2-aminoadenine, 6-hydroxypurine, 2-amino-6-chloropurine, 2-amino-6-methylthiopurine, guanine and N-isobutyrylguanine.

19. An oligonucleotide of the formula V according to claim 1, in which B as an analogous pyrimidine radical is a uracil, thymine or cytosine radical of the formulae III, IIIa and IIIb ##STR49## 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, where the hydroxyl and amino groups are unsubstituted or substituted by a protective group, 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, and the dihydro derivatives of the radicals of the formulae III, IIIa and IIIb.

20. An oligonucleotide of the formula V according to claim 19, in which R₁₂ is H, C₁ -C₆ alkyl or -hydroxyalkyl, F, Cl, Br, NH₂, benzoylamino, mono- or di-C₁ -C₆ allkyl-amino.

21. An oligonucleotide of the formula V according to claim 19, in which R₁₃ is H, C₁ -C₆ alkyl or -alkoxy or -hydroxyalkyl, F, Cl, Br, NH₂, benzoylamino, mono- or di-C₁ -C₆ alkylamino.

22. An oligonucleotide of the formula V according to claim 20, in which R₁₂ is H, F, Cl, Br, NH₂, NHCH₃, N(CH₃)₂ or C₁ -C₄ alkyl.

23. An oligonucleotide of the formula V according to claim 22, in which R₁₃ is H, C₁ -C₄ alkyl, NH₂, NHCH₃ or (CH₃)₂ N.

24. An oligonucleotide of the formula V according to claim 19, in which B as a radical of a pyrimidine analogue is derived from uracil, thymine, cytosine, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, dihydrouracil or 5-methylcytosine.

25. An oligonucleotide of the formula V according to claim 1, in which y is a number from 2 to 50, Y is the group --P(O)O.sup.⊕

--, U, V and W are each identical or different radicals of a natural or synthetic nucleoside and at least one of the radicals U, V or W is of the formula VI or VIa, A is --CH₂ -- and B is the radical of a natural nucleoside base.

26. An oligonucleotide of the formula V according to claim 25, in which the radicals of a natural nucleoside are those of adenosine, cytidine, guanosine, uridine, thyroidine, 2'"'"'-deoxyadenine, 2'"'"'-deoxycytidine and 2'"'"'-deoxyguanosine.

27. An oligonucleotide of the formula V according to claim 25, in which the radicals B as natural nucleoside bases are adenine, cytosine, guanine, thymine, uracil, 2-aminoadenine or 5-methylcytosine.

28. An oligonucleotide of the formula V according to claim 25, wherein the radicals of the formulae VI and/or VIa are bonded between radicals of natural or synthetic nucleosides.

29. An oligonucleotide of the formula V according to claim 20, wherein 2 to 5 identical or different radicals of the formulae VI and/or VIa follow one another.

30. An oligonucleotide of the formula V according to claim 25, wherein y is a number from 2 to 20 and 1 to 12 radicals of the formulae VI and/or VIa are present.

31. The use of an oligonucleotide of the formula V according to claim 1 as a diagnostic for the detection of viral infections or genetically related diseases.

32. An oligonucleotide of the formula V according to claim 1 for use in a therapeutic process for the treatment of diseases in mammals including humans by means of interaction with nucleotide sequences in the body.

33. A pharmaceutical preparation comprising an effective amount of an oligonucleotide of the formula V according to claim 1 on its own or together with other active ingredients, a pharmaceutical carrier, and, if appropriate, excipients.

34. An oligonucleotide of the formula V according to claim 1, wherein the radicals of the formula VI or VI are bonded in the end position.

35. An oligonucleotide of the formula V according to claim 1, wherein the radicals of the formula VI or VI are bonded in the sequence.

36. An oligonucleotide of the formula V according to claim 25, wherein the radicals of the formula VI or VI are bonded in the end position.

37. An oligonucleotide of the formula V according to claim 25, wherein the radicals of the formula VI or VI are bonded in the sequence.