4-desmethyl nucleoside analogs and oligomers thereof

• US 6,320,040 B1
• Filed: 10/07/1999
• Issued: 11/20/2001
• Est. Priority Date: 07/27/1990
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Teng, Kelly, Cook, Phillip Dan
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US09/414,146
• Time in Patent Office: 775 Days
• Field of Search: 536/22.1, 536/23.1, 536/24.3, 536/24.5, 536/25.3, 536/25.32, 536/26.6, 536/27.1, 536/27.21, 536/27.6, 536/27.81, 536/28.1, 536/28.4, 536/28.5, 536/28.53, 536/28.54, 435/6, 435/375, 514/44
• US Class Current: 536/25.3
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 49/0006 Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• 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 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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

Abstract

Tetrahydrofuranyl compounds are provided that are functionalized to include pendant conjugate groups, and which are useful in diagnosis assays and as research reagents. Novel intermediates for the synthesis of the compounds are also provided.

Claims

1. A method for forming a compound having structure:

comprising the steps of;

providing a first compound having structure;

contacting said first compound with a second compound comprising a member of formula;

 

said contacting being for a time and under reaction conditions effective to form a linkage between said first and said second compounds;

wherein;

R_L is a group of formula;

2. A method for forming a compound having structure:

comprising the steps of;

providing a first compound having structure;

contacting said first compound with a second compound having a member of formula;

 

said contacting being for a time and under reaction conditions effective to form a linkage between said first and said second compounds;

wherein;

L is a group of formula;

3. A method for forming a compound having structure:

providing a first compound having structure;

contacting said first compound with a second compound comprising a member having formula;

 

said contacting being for a time and under reaction conditions effective to form a linkage between said first and said second compounds;

wherein;

R_C is O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-alkaryl, O-aralkyl, a polyglycol, an aromatic or nonaromatic ring system, a polyamine, a polyether, a steroid molecule, a reporter molecule, an aromatic lipophilic molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, a lipid soluble vitamin, a carbohydrate, a terpene molecule, a phospholipid, an intercalator, a cell receptor binding molecule, a crosslinking agent, or a porphyrin;

n is an integer greater than 0;

B_X is a nucleobase;

X is H, OH, O-alkyl, O-alkoxylalkyl, O-alkylamino, or F;

Q is O, S, CH₂, CHF or CF₂;

L₁ is CR_1aR_1b or Z₁;

L₂ is CR_2aR_2b or Z₂;

L₃ is CR_3aR_3b or Z₃;

L₄ is Z₄;

R_E is trifluoromethylsulfonyl, methylsulfonyl, halogens, O-trichloroacetimidate, acyloxy, dialkyl phosphite, 2,4,6-trichlorophenyl, p-toluenesulfonyl, 4-dimethylaminoazobenzenesulfonyl or 5-dimethylaminonaphthalenesulfonyl;

R_F is L₁—

L₂—

L₃Z₄;

Z₁, Z₂, Z₃ and Z₄ are, independently, O, NR₄, S, SO, SO₂, Se, P(═

Y₁)Y₂ or Si(R₆)₂;

R_1a, R_1b, R_2a, R_2b, R_3a and R_3b are, independently, H, R₅, O—

R₅, S—

R₅, NR₄R₅;

independently, together R_1a and R_1b, or R_2a and R_2b, or R_3a and R_3b are ═

O;

Y₁ is O, S, Se, or NR₄;

Y₂ is OH, OR₅, SH, SR₅, SeH, R₅, BH₃ or NR₄R₅; and

R₄, R₅ and R₆ are, independently, one of;

an electron pair of a multiple bond;

H;

straight or branched chain alkyl or substituted alkyl;

straight or branched chain alkenyl or substituted alkenyl;

straight or branched chain alkynyl or substituted alkynyl;

¹⁴C-containing lower alkyl, lower alkenyl or lower alkynyl;

substituted or unsubstituted alkaryl or aralkyl;

¹⁴C-containing alkaryl or aralkyl;

aryl;

alicyclic;

a reporter molecule; and

where said substituents are OH, ═

O, CO₂H, 0-alkyl, SH, S-alkyl, NH-alkyl, N-(alkyl)₂, alkyl, F, Cl, Br, CN, CF₃, OCF₃, OCN, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, aryl, aralkyl, sulfide, or silyl.

4. A method for forming a compound having structure:

comprising the steps of;

providing a first compound having, structure;

contacting said first compound with a second compound comprising a member having formula;

 

said contacting being for a time and under reaction conditions effective to form a linkage between said first and said second compounds;

wherein;

J is a leaving group;

n is an integer greater than 0;

B_X is a nucleobase;

X is H, OH, O-alkyl, O-alkoxylalkyl, O-alkylamino, or F;

Q is O, S, CH₂, CHF or CF₂;

L₁ is CR_1aR_1b or Z₁;

L₂ is CR_2aR_2b or Z₂;

L₃ is CR_3aR_3b or Z₃;

L₄ is Z₄;

R_E is trifluoromethylsulfonyl, methylsulfonyl, halogens, O-trichloroacetimidate, acyloxy, dialkyl phosphite, 2,4,6-trichlorophenyl, p-toluenesulfonyl, 4-dimethylaminoazobenzenesulfonyl or 5-dimethylaminonaphthalenesulfonyl;

R_F is L₁—

L₂—

L₃Z₄;

Z₁, Z₂, Z₃ and Z₄ are, independently, O, NR₄, S, SO, SO₂, Se, P(═

Y₁)Y₂ or Si(R₆)₂;

R_1a, R_1b, R_2a, R_2b, R_3a and R_3b are, independently, H, R₅, O—

R₅, S—

R₅, NR₄R₅;

independently, together R_1a and R_1b, or R_2a and R_2b, or R_3a and R_3b are ═

O;

Y₁ is O, S, Se, or NR₄;

Y₂ is OH, OR₅, SH, SR₅, SeH, R₅, BH₃ or NR₄R₅; and

R₄, R₅ and R₆ are, independently, one of;

an electron pair of a multiple bond;

H;

straight or branched chain alkyl or substituted alkyl;

straight or branched chain alkenyl or substituted alkenyl;

straight or branched chain alkynyl or substituted alkynyl;

¹⁴C-containing lower alkyl, lower alkenyl or lower alkynyl;

substituted or unsubstituted alkaryl or aralkyl;

¹⁴C-containing alkaryl or aralkyl;

aryl;

alicyclic;

a reporter molecule; and

where said substituents are OH, ═

O, CO₂H, O-alkyl, SH, S-alkyl, NH-alkyl, N-(alkyl)₂, alkyl, F, Cl, Br, CN, CF₃, OCF₃, OCN, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, aryl, aralkyl, sulfide, or silyl.