Pyrimidine nucleosides

• US 6,369,040 B1
• Filed: 08/27/1999
• Issued: 04/09/2002
• Est. Priority Date: 01/11/1990
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Acevedo, Oscar L., Dunkel, Martin G., Cook, Phillip Dan
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US09/384,826
• Time in Patent Office: 956 Days
• Field of Search: 536/25.3, 536/25.31, 536/25.32, 536/25.33, 536/25.34, 536/25.6, 536/26.7, 536/26.8, 536/27.6, 536/27.8, 536/27.81, 536/28.5, 536/28.53, 536/28.54, 514/44, 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/51, 514/52
• US Class Current: 514/49
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/333 Modified A
• CPC Class Codes: C12N 2310/336 Modified G
• CPC Class Codes: C12N 2310/3511 : intercalating or cleaving agent
• CPC Class Codes: C12N 2310/3521 : Methyl
• CPC Class Codes: C12N 2310/3523 : Allyl
• CPC Class Codes: C12N 2310/3527 : Other alkyl chain
• CPC Class Codes: C12N 2310/3531 : Hydrogen
• CPC Class Codes: C12N 2310/3533 : Halogen
• CPC Class Codes: C12N 2740/16322 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 9/0069 : acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Y 113/11012 : Linoleate 13S-lipoxygenase (1.13.11.12)
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Novel 2- and 4-substituted pyrimidine nucleosides and oligonucleosides are provided, as are methods and intermediates useful in preparing same.

Claims

1. A pharmaceutical composition comprising a compound having the following formula:

wherein;

R₅ is H or CH₃;

one of R₂ and R₄ is ═

O, ═

NH, or ═

NH₂⁺; and

the other of R₂ and R₄ is Q, ═

C(R_A)—

Q, C(R_A)(R_B)—

C(R_C)(R_D)—

Q, C(R_A)═

C(R_C)—

Q or C≡

C—

Q;

each R_A, R_B, R_C and R_D is, independently [are] H, SH, OH, NH₂, or C₁-C₂₀ alkyl, or one of (R_A) and (R_B) or (R_C) and (R_D) is combined to give ═

O and each of the other of (R_A) and (R_B) or (R_C) and (R_D) is, independently H, SH, OH, NH₂, or C₁-C₂₀ alkyl;

Q is halogen, hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ alkylamine, C₁-C₂₀ alkyl-N-phthalimide, C₁-C₂₀ alkylimidazole, C₁-C₂₀ alkylbis-imidazole, NH₂, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, hydroxyl, thiol, keto, carboxyl, nitrates, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, a polyether, or a depurination enhancing group;

T₃ and T₅ independently are H, phosphate, an activated phosphate, a hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages;

X₁ and X₂ independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, polyamines, polyamides, or polyethers;

or

T₃ and one of X₁ or X₂, together, form a hydroxyl protecting group; and

provided that when T₅ is a hydroxyl protecting group or together T₃ and one of X₁ or X₂ is a hydroxyl protecting group, then R₂ is not CH₃; and

that when T₃ and T₅ are OH or O-benzoyl, then R₂ is not CH₂OC₆H₅; and

that when R₄ is Q, then Q is not hydrogen, hydroxyl, thiol, amino or hydrogen.

2. A process of treating an organism having a disease characterized by the undesired production of a protein, comprising contacting the organism with a compound having the formula:

wherein;

R₅ is H or CH₃;

one of R₂ and R₄ is ═

O, ═

NH, or ═

NH₂⁺; and

the other of R₂ and R₄ is Q, ═

C(R_A)—

Q, C(R_A)(R_B)—

C(R_C)(R_D)—

Q, C(R_A)═

C(R_C)—

Q or C≡

C—

Q;

each R_A, R_B, R_C and R_D is, independently H, SH, OH, NH₂, or C₁-C₂₀ alkyl, or one of (R_A) and (R_B) or (R_C) and (R_D) is combined to give ═

O and each of the other of (R_A) and (R_B) or (R_C) and (R_D) is, independently H, SH, OH, NH₂, or C₁-C₂₀ alkyl;

Q is halogen, hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ alkylamine, C₁-C₂₀ alkyl-N-phthalimide, C₁-C₂₀ alkylimidazole, C₁-C₂₀ alkylbis-imidazole, NH₂, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, hydroxyl, thiol, keto, carboxyl, nitrates, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, a polyether, or a depurination enhancing group;

T₃ and T₅ independently are H, phosphate, an activated phosphate, a hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages;

X₁ and X₂ independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alky, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, polyamines, polyamides, or polyethers;

or

T₃ and one of X₁ or X₂, together, form a hydroxyl protecting group; and

provided that when T₅ is a hydroxyl protecting group or together T₃ and one of X₁ or X₂ is a hydroxyl protecting group, then R₂ is not CH₃; and

that when T₃ and T₅ are OH or O-benzoyl, then R₂ is not CH₂OC₆H₅; and

that when R₄ is Q, then Q is not hydrogen, hydroxyl, thiol, amino or hydrogen.

4. The method of claim 2 wherein said organism is a human.

5. The method of claim 2 wherein said disease is a herpes virus.

6. The method of claim 2 wherein said disease is a papilloma virus.

3. A method of modulating the production or activity of a protein in an organism comprising contacting the organism with a compound having the following formula:

wherein;

R₅ is H or CH₃;

one of R₂ and R₄ is ═

O, ═

NH, or ═

NH₂⁺; and

the other of R₂ and R₄ is Q, ═

C(R_A)—

Q, C(R_A)(R_B)—

C(R_C)(R_D)—

Q, C(R_A)═

C(R_C)—

Q or C≡

C—

Q;

each R_A, R_B, R_C and R_D is, independently H, SH, OH, NH₂, or C₁-C₂₀ alkyl, or one of (R_A) and (R_B) or (R_C) and (R_D) is combined to give ═

O and each of the other of (R_A) and (R_B) or (R_C) and (R_D) is, independently H, SH, OH, NH₂, or C₁-C₂₀ alkyl;

Q is halogen, hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ alkylamine, C₁-C₂₀ alkyl-N-phthalimide, C₁-C₂₀ alkylimidazole, C₁-C₂₀ alkylbis-imidazole, NH₂, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, hydroxyl, thiol, keto, carboxyl, nitrates, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, O-(hydroxyl protecting group), a leaving group, a heterocycle, a polyamine, a polyamide, a polyether, or a depurination enhancing group;

T₃ and T₅ independently are H, phosphate, an activated phosphate, a hydroxyl protecting group, a nucleoside, a nucleotide, an oligonucleotide comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages, or an oligonucleoside comprising up to 50 nucleosides joined together by 3′

-5′

internucleoside linkages;

X₁ and X₂ independently are hydrogen, halogen, hydroxyl, O-(hydroxyl protecting group), thiol, carboxyl, nitrate, nitro, nitroso, nitrile, trifluoromethyl, fluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocyclic, alicyclic, carbocyclic, polyamines, polyamides, or polyethers;

or

T₃ and one of X₁ or X₂, together, form a hydroxyl protecting group; and

provided that when T₅ is a hydroxyl protecting group or together T₃ and one of X₁ or X₂ is a hydroxyl protecting group, then R₂ is not CH₃; and

that when T₃ and T₅ are OH or O-benzoyl, then R₂ is not CH₂OC₆H₅; and

that when R₄ is Q, then Q is not hydrogen, hydroxyl, thiol, amino or hydrogen.

7. The method of claim 3 wherein said organism is a human.