Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same

• US 5,130,302 A
• Filed: 12/20/1989
• Issued: 07/14/1992
• Est. Priority Date: 12/20/1989
• Status: Expired due to Fees

• Current Assignee: Boron Biologicals Incorporated, Duke University, University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: Boron Biologicals Incorporated
• Inventors: Sood, Anup, Spielvogel, Bernard F., Hall, Iris H., Ramsay Shaw, Barbara
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): WILSON, JAMES O
• Application Number:
  US07/453,311
• Time in Patent Office: 937 Days
• Field of Search: 536/23, 536/27, 536/28, 536/29, 536/51, 536/4.1, 536/122, 536/18.1, 536/17.1, 514/45, 514/46, 514/49, 514/50, 514/51, 514/64, 424/1.1, 604/20
• US Class Current: 514/45
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 5/02 Boron compounds
• 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

Abstract

A novel class of pharmaceutically active boronated nucleosides are provided. The nucleosides are boronated at a ring nitrogen of the purine or pyrimidine or analogues thereof. Also provided are phosphate esters of these nucleosides and oligomers thereof. Methods of making and using the boronated nucleosides are also disclosed.

Claims

1. A boronated nucleoside comprising a nucleoside which is N-boronated on the nucleoside base with a boron-containing substituent selected from the group consisting of --BH₂ CN, --BH₃, and --BH₂ COOR, wherein R is C1 to C18 alkyl.

2. A boronated nucleotide comprising a 5'"'"' phosphate ester of a nucleoside according to claim 1.

3. A boronated oligonucleotide comprising a chain of ribonucleotides or deoxyribonucleotides, at least one nucleotide or said oligonucleotide comprising a nucleotide according to claim 2.

4. A boronated nucleoside according to claim 1 wherein the boron-containing substituent is --BH₂ CN.

5. A boronated nucleoside according to claim 1 wherein the base of said nucleoside is selected from the group consisting of adenine, cytosine, guanine, and inosine.

6. A boronated nucleoside according to claim 1 selected from the group consisting of:

guanosine-N7-cyanoborane;

inosine-N7-cyanoborane;

adenosine-N1-cyanoborane;

cytidine-N3-cyanoborane;

guanosine-N7-borane;

inosine-N7-borane;

adenosine-N1-borane;

cytidine-N3-borane;

guanosine-N7-carbomethoxyborane;

inosine-N7-carboethoxyborane;

adenosine-N1-carbopropoxyborane;

cytidine-N3-carbobutoxyborane;

2'"'"'-deoxyguanosine-N7-cyanoborane;

2'"'"'-deoxyinosine-N7-cyanoborane;

2'"'"'-deoxyadenosine-N1-cyanoborane;

2'"'"'-deoxycytidine-N3-cyanoborane;

2'"'"'-deoxyguanosine-N7-borane;

2'"'"'-deoxyinosine-N7-borane;

2'"'"'-deoxyadenosine-N1-borane;

2'"'"'-deoxycytidine-N3-borane;

2'"'"'-deoxyguanosine-N7-carbomethoxyborane;

2'"'"'-deoxyinosine-N7-carboethoxyborane;

2'"'"'-deoxyadenosine-N1-carbopropoxyborane;

2'"'"'-deoxycytidine-N3-carbobutoxyborane;

11. A boronated oligonucleotide comprising a chain of 2 to 50 ribonucleotides or deoxyribonucleotides, at least one nucleotide of said oligonucleotide comprising a nucleotide according to claim 2.

12. A boronated oligonucleotide comprising a chain of 2 to 30 ribonucleotides or deoxyribonucleotides, at least one nucleotide of said oligonucleotide comprising a nucleotide according to claim 2.

13. A boronated oligonucleotide comprising a chain of 2 to 18 ribonucleotides or deoxyribonucleotides, at least one nucleotide of said oligonucleotide comprising a nucleotide according to claim 2.

15. A method according to claim 13, wherein the boronated nucleoside is selected from the group conssiting of 2'"'"'-deoxyguanosine-N7-cyanoborane, 2'"'"'-deoxyinosine-N7-cyanoborane, 2'"'"'-deoxyadenosine-N1-cyanoborane, and 2-'"'"'-deoxycytidine-N3-cyanoborane.

7. '"'"' . 3'"'"'-dideoxyguanosine-N7-cyanoborane;

2'"'"',3'"'"'-dideoxyinosine-N7-cyanoborane;

2'"'"',3'"'"'-dideoxyadenosine-N1-cyanoborane;

2'"'"',3'"'"'-dideoxycytidine-N3-cyanoborane;

2'"'"',3'"'"'-dideoxyguanosine-N7-borane;

2'"'"',3'"'"'-dideoxyinosine-N7-borane;

2'"'"',3'"'"'-dideoxyadenosine-N1-borane;

2'"'"',3'"'"'-dideoxycytidine-N3-borane;

2'"'"',3'"'"'-dideoxyguanosine-N7-carbomethoxyborane;

2'"'"',3'"'"'-dideoxyinosine-N7-carboethoxyborane;

2'"'"',3'"'"'-dideoxyadenosine-N1-carbopropoxyborane;

2'"'"',3'"'"'-dideoxycytidine-N3-carbobutoxyborane.

8. A boronated nucleoside selected from the group consisting of 2'"'"'-deoxyguanosine-N7-cyanoborane, 2'"'"'-deoxyinosine-N7-cyanoborane, 2'"'"'-deoxyadenosine-N1-cyanoborane, 2'"'"'-deoxycytidine-N3-cyanoborane, and 2'"'"',3'"'"'-dideoxycytidine-N3-cyanoborane.

10. A pharmaceutical formulation according to claim 8 wherein the boronated nucleoside is selected from one or more of the group consisting of 2'"'"'-deoxyinosine-N7-cyanoborane, 2'"'"'-deoxyadenosine-N7-cyanoborane, 2'"'"'-deoxycytidine-N1-cyanoborane, and 2'"'"'-deoxycytidine-N3-cyanoborane.

9. A pharmaceutical formulation comprising an effective anti-inflammatory or anti-tumor amount of a boronated nucleoside in a pharmaceutically acceptable carrier, said boronated nucleoside comprising a nucleoside which is N-boronated on the nucleoside base with a boron-containing substituent selected from the group consisting of --BH₂ CN, --BH₃, and --BH₂ COOR, wherein R is C1 to C18 alkyl.

14. A method for treating a mammal suffering from inflammation comprising administering to said mammal an effective anti-inflammatory amount of a boronated nucleoside comprising a nucleoside which is N-boronated on the nucleoside base with a boron-containing substituent selected from the group consisting of --BH₂ CN, --BH₃, and --BH₂ COOR, wherein R is C1 to C18 alkyl.