Supports for oligomer synthesis

• US 7,202,264 B2
• Filed: 11/15/2004
• Issued: 04/10/2007
• Est. Priority Date: 01/31/2003
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Manoharan, Muthiah, Guzaev, Andrei P., Wang, Zhiwei, Ravikumar, Vasulinga, Kumar, Raju Krishna
• Primary Examiner(s): McKane; Joseph K.
• Assistant Examiner(s): BARKER, MICHAEL P
• Application Number:
  US10/989,197
• Publication Number:
  US 20050208588A1
• Time in Patent Office: 876 Days
• Field of Search: 548/431, 548/435, 514/411
• US Class Current: 514/411
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/18 Bridged systems
• CPC Class Codes: C07D 493/18 Bridged systems

Abstract

Universal linkers, their facile processes of manufacture and methods of using the same are provided.

Claims

1. A compound of formula (II):

2. A compound of claim 1, wherein for formula (II) when one of A, Q, or W is SM or L-SM, the other two of A, Q or W are not SM or L-SM.

3. A compound of claim 1, wherein Q and W are each hydrogen and G₁ is O.

4. A compound of claim 1, wherein one of Q and W is hydrogen and the other is hydrogen or a blocking group, and G₁, Y₁ and Y₂ are each O.

5. A compound of claim 4, wherein the blocking group is selected from 4,4′

-dimethoxytrityl, monomethoxytrityl, 9-phenylxanthen-9-yl, 9-(p-methoxyphenyl)xanthen-9-yl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p,p-dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, mesyl, tosyl, 4,4′

,4″

-tris-(benzyloxy)trityl 4,4′

,4″

-tris-(4,5-dichlorophthalimido)trityl, 4,4′

,4′

-tris(levulinyloxy)trityl, 3(imidazolylmethyl)-4,4′

-dimethoxytrityl, 4-decyloxytrityl, 4-hexadecyloxytrityl, 9-(4-octadecyloxyphenyl)xanthene-9-yl, 1,1-bis-(4-methoxyphenyl)-1-pyrenylmethyl, p-phenylazophenyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,4-dinitrophenylethoxycarbonyl, 4-(methylthiomethoxy)butyryl, 2-(methylthiomethoxymethyl)-benzoyl, 2-isopropylthiomethoxymethyl)benzoyl, 2-(2,4-dinitrobenzenesulphenyloxymethyl)benzoyl, levulinyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, or acetoacetyl.

6. A compound of claim 1, wherein one of Q and W is (C═

O)—

(CH₂)_n—

(C═

O)O⁻

, wherein n is an integer from 1–

20, and the other is a blocking group.

7. A compound of claim 6, wherein n is 2.

8. A compound of claim 1, wherein one of Q and W is hydrogen, blocking group, a protected or unprotected nucleosidyl moiety or a protected or unprotected oligonucleotide moiety and the other is selected from L, SM or L-SM.

9. A compound of claim 8, wherein the blocking group is selected from 4,4′

-dimethoxytrityl, monomethoxytrityl, 9-phenylxanthen-9-yl, 9 methoxyphenyl)xanthen-9-yl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorotrityl, diphenylmethyl, p,p-dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, mesyl, tosyl, 4,4′

,4″

-tris-(benzyloxy)trityl, 4,4′

,4″

-tris(4,5-dichlorophthalimido)trityl, 4,4′

,4″

-tris(levulinyloxy)trityl, 3-(imidazolylmethyl)-4,4′

-dimethoxytrityl, 4-decyloxytrityl, 4-hexadecyloxytrityl 9-(4-octadecyloxyphenyl)xanthene-9-yl, 1,1-bis-(4-methoxyphenyl)-1′

-pyrenylmethyl, p-phenylazophenyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,4-dinitrophenylethoxycarbonyl, 4-(methylthiomethoxy)butyryl, 2-(methylthiomethoxymethyl)benzoyl, 2-(isopropylthiomethoxymethyl)benzoyl, 2-(2,4-dinitrobenzenesulphenyloxymethyl)benzoyl, levulinyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, or acetoacetyl.

10. A compound of claim 8, wherein n is 2.

11. A compound of claim 8, wherein said support medium is selected from a controlled pore glass, oxalyl-controlled pore glass, silica-containing particles, polymers of polystyrene, copolymers of polystyrene, and divinylbenzene, copolymers of dimethylacrylamide and N,N-bisacryloylethylenediamine, a soluble support medium, or PEPS.

12. A compound of claim 8, wherein Q is hydrogen, a blocking group, a protected or unprotected nucleosidyl moiety, or a protected or unprotected oligonucleotidyl moiety.

13. A compound of claim 1, wherein A is selected from a substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, or a substituted or unsubstituted heterocyclic.

14. A compound of claim 13, wherein A is substituted or unsubstituted aromatic.

15. A compound of claim 14, wherein A is substituted or unsubstituted phenyl.

16. A compound of claim 1, wherein one of Q and W is hydrogen, blocking group, a protected or unprotected nucleosidyl moiety or a protected or unprotected oligonucleotidyl moiety and the other is selected from L, SM or L-SM.

17. A compound of claim 16, wherein the blocking group is selected from 4,4′

-dimethoxytrityl, monomethoxytrityl, 9-phenylxanthen-9-yl, 9-(p-methoxyphenyl)xanthen-9-yl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p,p-dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, mesyl, tosyl, 4,4′

,4″

-tis (benzyloxy)trityl, 4,4′

,4″

-tris-(4,5-dichlorophthalimido)trityl, 4,4′

,4″

-tris(levulinyloxy)trityl, 3-(imidazolylmethyl)-4,4′

-dimethoxytrityl, 4-decyloxytrityl, 4-hexadecyloxytrityl, 9-(4-octadecyloxyphenyl)xanthene-9-yl, 1,1-bis-(4methoxyphenyl)-1′

-pyrenylmethyl, p-phenylazophenyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,4-dinitrophenylethoxycarbonyl, 4-(methylthiomethoxy)butyryl, 2-(methylthiomethoxymethyl)-benzoyl, 2-(isopropylthiomethoxymethyl)benzoyl, 2-(2,4-dinitrobenzenesulphenyloxymethyl)benzoyl, levulinyl, triethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, or acetoacetyl.

18. A compound of claim 16, wherein n is 2.

19. A compound of claim 16, wherein SM is selected from a controlled pore glass, oxalyl-controlled pore glass, silica-containing particles, polymers of polystene, copolymers of polystyrene, and divinylbenzene, copolymers of dimethylacrylamide and N,N-bisacryloylethylenediamine, a soluble support medium, or PEPS.

20. A compound of claim 1 having the formula:

21. A compound of claim 20 wherein:

W is SM or L-SM;

Q is hydrogen, a blocking group, a protected or unprotected nucleosidyl moiety, a protected or unprotected nucleosidyl moiety attached through a phospholinker, or a protected or unprotected oligonucleotidyl moiety; and

A is a substituted or unsubstituted aromatic group.

22. A compound of claim 21 wherein Q is hydrogen.

23. A compound of claim 21 wherein A is phenyl.

24. A compound of claim 21 wherein Q is hydrogen, a protected or unprotected nucleosidyl moiety, a protected or unprotected nucleosidyl moiety attached through a phospholinker, or a protected or unprotected oligonucleotidyl moiety, and A is phenyl.

25. A process of making a compound of formula (II):

26. A process for functionalizing a support medium with a first monomeric subunit, the process comprising:

providing a support-bound compound of formula (II);

27. The process of claim 26, wherein the first monomeric subunit is an activated phosphoramidite nucleoside.

28. The process of claim 26, further comprising reacting said monomer-functionalized support medium with a capping agent;

and optionally treating said monomer-functionalized support medium with an oxidizing agent.

29. The process of claim 28, further comprising:

(a) deblocking said further protected hydroxyl group to give a reactive hydroxyl;

(b) treating said reactive hydroxyl with an additional monomeric subunit bearing a further protected hydroxyl to produce an extended compound;

(c) reacting the extended compound with a capping reagent;

(d) optionally contacting the product of step (b) with an oxidizing or sulfurizing agent;

optionally repeating steps (a)–

(d) one or more times to form an oligomeric compound.

30. The process of claim 29, wherein said treating of said reactive hydroxyl group with a further monomeric subunit is performed in the presence of an activating agent.

31. The process of claim 26, wherein said support medium is controlled pore glass, oxalyl-controlled pore glass, silica-containing particles, polymers of polystyrene, copolymers of polystyrene, copolymers of styrene and divinylbenzene, copolymers of dimethylacrylamide and N,N′

-bisacryloylethylenediamine, soluble support medium or PEPS.

32. The process of claim 26, wherein said support medium is controlled pore glass, polymers of polystyrene or copolymers of polystyrene.

33. The process of claim 26, wherein said blocking group is 4,4′

-dimethoxytrityl, monomethoxytrityl, 9-phenylxanthen-9-yl, 9-(p-methoxyphenyl) xanthen-9-yl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-chlorophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p,p-dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-phenylbenzoyl, mesyl, tosyl, 4,4′

,4″

-tris-(benzyloxy)trityl, 4,4′

,4″

-tris-(4,5-dichlorophthalimido)trityl 4,4′

,4″

-tris(levulinyloxy)tityl, 3-(imidazolylmethyl)-4,4′

-dimethoxytrityl, 4-decyloxytrityl, 4-hexadecyloxytrityl, 9-(4-octadecyloxyphenyl)xanthene-9-yl, 1,1-bis-(4-methoxyphenyl)-1-pyrenyl methyl, p-phenylazophenyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,4-dinitrophenylethoxy carbonyl, 4-(methylthiomethoxy)butyryl, 2-(methylthiomethoxymethyl)-benzoyl, 2-(isopropylthiomethoxymethyl)benzoyl, 2-(2,4dinitrobenzenesulphenyloxymethyl)benzoyl, or levulinyl groups.

34. The process of claim 29, wherein said oligomeric compound is an oligonucleotide, modified oligonucleotide, oligonucleotide analog, oligonucleotide, oligonucleotide mimetic, hemimer, gapmer or chimera.