Pyrrolidine-containing monomers and oligomers

• US 5,519,134 A
• Filed: 01/11/1994
• Issued: 05/21/1996
• Est. Priority Date: 01/11/1994
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Hebert, Normand, Acevedo, Oscar L.
• Primary Examiner(s): McKane, Joseph K.
• Application Number:
  US08/180,134
• Time in Patent Office: 861 Days
• Field of Search: 548/412, 548/413, 548/530, 548/531, 548/542, 548/546, 548/314.7, 548/518, 548/519, 548/523, 548/524, 548/364.1, 548/465, 548/466, 548/467, 548/361.1, 548/361.5 , 548/362.1, 548/362.5, 548/440, 548/441, 548/443, 548/444, 548/446, 544/242, 544/243, 544/298, 544/335, 544/102, 544/104, 544/35
• US Class Current: 544/243
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/337 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 9/572 Five-membered rings

Abstract

Novel pyrrolidine monomers bearing various functional groups are used to prepare oligomeric structures. The pyrrolidine monomers can be joined via standard phosphate linkages including phosphodiester and phosphorothioate linkages. Useful functional groups include nucleobases as well as polar groups, hydrophobic groups, ionic groups, aromatic groups and/or groups that participate in hydrogen-bonding.

Claims

1. A compound having structure I:

##STR3## wherein;

X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support;

Y is H or a hydroxyl protecting group;

Z is L_1a, L_1b -G₁, L₂, L₂ -G₂, NR₃ R₄, a nitrogen-containing heterocycle, a phosphate group, a polyether group, a polyethylene glycol group;

L_1a is alkyl having 1 to about 20 carbon atoms, alkenyl having 2 to about 20 carbon atoms, or alkynyl having 2 to about 20 carbon atoms;

L_1b is alkylene having 1 to about 20 carbon atoms, alkenylene having 2 to about 20 carbon atoms, or alkynylene having 2 to about 20 carbon atoms;

L₂ is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;

G₁ is halogen, OR₁, SR₂, NR₃ R₄, C(═

NH)NR₃ R₄, NHC(═

NH)NR₃ R₄, CH═

O, C(═

O)OR₅, CH(NR₃ R₄)(C(═

O)OR₅), C(═

O)NR₃ R₄, a metal coordination group, or a phosphate group;

G₂ is halogen, OH, SH, SCH₃, or NR₃ R₄ ;

R₁ is H, alkyl having 1 to about 6 carbon atoms, or a hydroxyl protecting group;

R₂ is H, alkyl having 1 to about 6 carbon atoms, or a thiol protecting group;

R₃ and R₄ are, independently, H, alkyl having 1 to about 6 carbon atoms, or an amine protecting group;

R₅ is H, alkyl having 1 to about 6 carbon atoms, or an acid protecting group;

Q is L_1b, G₃, L_1b -G₃ or G₃ -L_1b -G₃ ;

G₃ is C(═

O), C(═

S), C(O)--O, C(O)--NH, C(S)--O, C(S)--NH or S(O)₂ ;

n is 0 or 1;

wherein if X is H, n is 1, and Q is SO₂, then Z is not aryl;

wherein if n is 0 and Z is L_1a, then X is not H; and

wherein if n is 1 and Q is L_1b, then Z is not L_1a.

2. The compound of claim 1 wherein Y is a hydroxyl protecting group.

3. The compound of claim 2 wherein Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl.

4. The compound of claim 1 wherein X is H, an activated phosphite group, or a solid support.

5. The compound of claim 4 wherein X is a phosphoramidite.

6. The compound of claim 1 wherein n is 1 and Q is carbonyl, carboxy, acetyl or succinyl.

7. The compound of claim 1 wherein Z is a nitrogen-containing heterocycle.

8. The compound of claim 7 wherein said heterocycle is imidazole, pyrrole, or carbazole.

9. The compound of claim 8 wherein Z is imidazole.

10. The compound of claim 1 wherein Z is a purine or a pyrimidine.

11. The compound of claim 10 wherein Z is adenine, guanine, cytosine, uridine, or thymine.

12. The compound of claim 11 wherein Q is acetyl.

13. The compound of claim 1 wherein Z is alkyl having 1 to about 20 carbon atoms.

14. A compound having structure I:

##STR4## wherein;

X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support;

Y is H or a hydroxyl protecting group;

Z is aryl having 6 to about 14 carbon atoms or aralkyl having 7 to about 15 carbon atoms;

L_1b is alkylene having 1 to about 20 carbon atoms, alkenylene having 2 to about 20 carbon atoms, or alkynylene having 2 to about 20 carbon atoms;

Q is L_1b, G₃, L_1b -G₃ or G₃ -L_1b -G₃ ;

G₃ is C(═

O), C(═

S), C(O)--O, C(O)--NH, C(S)--O, C(S)--NH or S(O)₂ ; and

n is 0 or 1;

wherein if X is H, n is 1, and Q is SO₂, then Z is not aryl.

15. The compound of claim 14 wherein Z is fluorenylmethyl, phenyl, or benzyl.

16. A compound having structure I:

##STR5## wherein;

X is H, a phosphate group, an activated phosphate group, an activated phosphite group, or a solid support;

Y is H or a hydroxyl protecting group;

Z is polyethylene glycol or glutamyl;

L_1b is alkylene having 1 to about 20 carbon atoms, alkenylene having 2 to about 20 carbon atoms, or alkynylene having 2 to about 20 carbon atoms;

Q is L_1b, G₃, L_1b -G₃ or G₃ -L_1b -G₃ ;

G₃ is C(═

O), C(═

S), C(O)--O, C(O)--NH, C(S)--O, C(S)--NH or S(O)₂ ;

n is 0 or 1.