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

• US 5,610,300 A
• Filed: 06/06/1995
• Issued: 03/11/1997
• Est. Priority Date: 07/01/1992
• Status: Expired due to Fees

• Current Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Altmann, Karl-Heinz, Eschenmoser, Albert, Imwinkelried, Ren e
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US08/469,045
• Time in Patent Office: 644 Days
• Field of Search: 544/229, 544/243, 544/244, 544/311, 544/312, 544/313, 544/314, 544/317, 514/269, 514/274, 514/258, 514/261, 514/81, 514/63, 514/262
• US Class Current: 544/244
• 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. A compound of the formula I or Ia or their racemates ##STR47## in which A is --CH₂ -- or --CH₂ CH₂ --, R₁ is hydrogen or a protective group, R₂ is hydrogen a protective group for alcohols or a radical forming a phosphorous-containing nucleotide bridge group of the formula:

##STR48## in which Y_a is hydrogen, C₁ -C₁₂ alkyl, C₆ -C₁₂ aryl, C₇ -C₂₀ alkaryl, --OR_b, --SR_b, --NH₂, primary amino, secondary amino, O^- M⁺ or S^- M⁺ ;

X_a is oxygen or sulfur;

R_a is hydrogen, M⁺, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl or C₆ -C₁₂ aryl, or the group R_a O-- is N-heteroaryl-N-yl having 5 ring members and 1 to 3 N atoms;

Rb is hydrogen, C₁ -C₁₂ alkyl or C₆ -C₁₂ -aryl; and

M⁺ is Na⁺, K⁺, Li⁺, NH₄⁺ or primary, secondary, tertiary or quaternary ammonium;

where alkyl, aryl, aralkyl and alkaryl in Y_a, R_a and R_b are unsubstituted or substituted by alkoxy, alkylthio, halogen, --CN, --NO₂, phenyl, nitrophenyl or halophenyl; and

B is pyrimidine radical having formula II or IIe;

##STR49## in which R₄ is H, Cl, Br or OH or --O--alkyl having 1 to 12 C atoms, and R₅, R₆ and R₇ independently of one another are H, OH, SH, NH₂, NHNH₂, NHOH, NHO alkyl 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, the hydroxyl and amino groups being 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.

2. A compound according to claim 1, wherein R₁ and R₂ are each hydrogen.

3. A compound according to claim 1, wherein A is --CH₂ --.

4. A compound according to claim 1, wherein R₁ and R₂ are independently of one another linear or branched C₁ -C₈ alkyl, C₇ -C₁₈ aralkyl, triphenylsilyl, alkyldiphenylsilyl, dialkylphenylsilyl or trialkylsilyl having 1 to 20 C atoms in the alkyl groups, --(C₁ -C₈ alkyl)₂ Si--O--Si(C₁ -C₈ alkyl)₂ --, C₂ -C₁₂ acyl, R₃ --SO₂ --, in which R₃ is C₁ -C₁₂ alkyl, C₅ -- or C₆ cycloalkyl, phenyl, benzyl, C₁ -C₁₂ alkylphenyl, C₁ -C₁₂ alkylbenzyl, or are C₁ -C₁₂ alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylphenoxycarbonyl or methylbenzyloxycarbonyl which is unsubstituted or substituted by F, Cl, Br, C₁ -C₄ alkoxy, tri(C₁ -C₄ alkyl)silyl or C₁ -C₄ alkylsulfonyl, or 9-fluorenylmethoxycarbonyl.

5. A compound according to claim 4, wherein R₁ and R₂ independently of one another are linear or branched C₁ -C₄ alkyl, C₇ -C₁₈ aralkyl, trialkylsilyl having 1 to 12 C atoms in the alkyl groups, --(CH₃)₂ Si--O--Si(CH₃)₂ --, --(i--C₃ H₇)₂ Si--O--Si(iC₃ H₇)₂ --, C₂ -C₈ acryl, R₃ --SO₂ --, in which R₃ is C₁ -C₆ alkyl, phenyl, benzyl, C₁ -C₄ alkylphenyl, C₁ -C₄ alkylbenzyl, halophenyl or halobenzyl, or are C₁ -C₈ alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl.

6. A compound according to claim 4, wherein R₁ and R₂ independently of one another are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl;

benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, dimethoxybenzyl, bromobenzyl;

diphenylmethyl, di(methylphenyl)methyl, di(dimethylphenyl)methyl, di(methoxyphenyl)methyl, di(methoxyphenyl)(phenyl)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, --(CH₃)₂ Si--O--Si(CH₃)₂ --, --(i--C₃ H₇)₂ Si--O--Si(iC₃ H₇)₂ --;

acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, benzoyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl or bromobenzoyl;

methyl-, ethyl-, propyl-, butyl-, phenyl-, benzyl-, p-bromo-, p-methoxy- or p-methylphenylsulfonyl;

methoxy-, ethoxy-, n- or i-propoxy- or n-, i- or t-butoxycarbonyl, or phenoxycarbonyl, benzyloxycarbonyl, methyl- or methoxy- or chlorophenoxycarbonyl or -benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl.

7. A compound according to claim 1, wherein R₁ and R₂ are the same protective groups.

8. A compound according to claim 1, in which the protective group for hydroxyl and amino groups is C₁ -C₈ acyl.

9. A compound according to claim 1, in which the primary amino contains 1 to 12 C atoms and the secondary amino 2 to 12 C atoms.

10. A compound according to claim 1, 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 -hydroxyalkyl;

carboxyalkyl or carbalkoxyalkyl, where the carbalkoxy group contains 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 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, 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.

11. A compound according to claim 10, in which the primary amino and secondary amino are methyl-, ethyl-, dimethyl-, diethyl-, allyl-, mono- or di(hydroxyeth-2-yl)-, phenyl-, benzyl-, acetyl-, isobutyryl- and benzoylamino.

12. A compound according to claim 1, in which R₄ in the formulae II, IIb, IIc, IId and IIe is hydrogen.

13. A compound according to claim 1, in which R₇ in formula IId is hydrogen.

14. A compound according to claim 1, in which R₅ and R₆ in the formulae II 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 or a radical of a purine analogue from the series consisting of adenine, N-methyladenine, N-benzoyladenine, 2-methylthioadenine, 2-aminoadenine, 2-hydroxypurine, 2-amino-6-chloropurine, 2-amino-6-methylthiopurine, guanine and N-isobutyrylguanine.

16. A compound according to claim 1, wherein X_a is O, R_a is β

-cyanoethyl, and Y_a is di(i-propyl)amino.