2-Substituted arabinofuranosyl nucleosides and nucleotides

• US 4,230,698 A
• Filed: 05/12/1978
• Issued: 10/28/1980
• Est. Priority Date: 05/12/1978
• Status: Expired due to Term

• Current Assignee: Research Corporation
• Original Assignee: Research Corporation
• Inventors: Cheng, Yung-Chi, Bloch, Alexander, Bobek, Miroslav V.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Hazel, Blondel
• Application Number:
  US05/905,529
• Time in Patent Office: 900 Days
• Field of Search: 536/23, 536/24, 536/27, 536/28, 536/29, 424/180
• US Class Current: 514/49
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 9/04 Cyclic acetals

Abstract

Novel arabinofuranosyl nucleosides and nucleotides having 2'"'"'-azido, 2'"'"'-amino, or 2'"'"'-hydrocarbylamino substituents, which have antitumor, antiviral, and antimicrobial properties, are prepared by condensation of a pyrimidine, purine, or 1,3-oxazine base with an acylated 2-azido-2-deoxyarabinofuranosyl halide, followed by deblocking and catalytic hydrogenation, where appropriate, to convert the 2'"'"'-azido group to a 2'"'"'-amino group and, if desired, alkylation or the like to convert the 2'"'"'-amino group to a 2'"'"'-hydrocarbylamino group.

Claims

1. A compound selected from the group consisting of arabinofuranosyl nucleosides of the formula ##STR12## wherein Z is a pyrimidinyl-1 or purinyl-9 moiety, X is selected from the group consisting of amino, azido, and hydrocarbylamino of 1 to 7 carbon atoms, and each of R and R¹ is selected from the group consisting of hydrogen, acetyl, propionyl, butyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, undecanoyl, lauroyl, benzoyl, phenylacetyl, phenylpropionyl, o-, m-, and p-methylbenzoyl, β

-cyclopentylpropionyl, and dihydrocinnamoyl, and acid addition salts thereof.

4. The compound of claim 1 wherein X is amino or azido.

5. The compound of claim 1 wherein X is amido, R is hydrogen or benzoyl, and R¹ is hydrogen or acetyl.

6. The compound of claim 1 wherein X is amino or azido, each of R and R¹ is hydrogen, and the acid addition salts are pharmaceutically acceptable acid addition salts.

7. The compound of any of claims 4, 5, or 6 wherein Z is a pyrimidinyl-1 moiety from a pyrimidine base of the formula ##STR15## wherein R⁴ is amino, hydroxy, thio, hydroxylamino, alkylamino, arylamino, or aralkylamino, and R⁵ is fluoro, bromo, chloro, hydrogen, iodo, mercapto, nitro, nitrilo, thiocyanato, alkyl, alkenyl, or alkynyl.

8. The compound of any of claims 4, 5, or 6 wherein Z is a purinyl-9 moiety from a purine base of the formula ##STR16## wherein R⁶ is amino, hydrogen, hydroxylamino, thio, chloro, alkylamino, arylamino, or aralkylamino, and R⁷ is hydrogen, oxo, chloro, fluoro, amino, nitro, thio, or hydroxyalkyl.

9. The compound of any of claims 4, 5, or 6 wherein Z is selected from the group consisting of uracilyl-1, thyminyl-1, 5-fluorouracilyl-1, adeninyl-9, guaninyl-9, and 6-chloropurinyl-9.

2. A compound selected from the group consisting of 1-(2-amino-2-deoxy-β

-D-arabinofuranosyl)cytosine of the formula;

##STR13## and pharmaceutically acceptable acid addition salts thereof.

3. A compound selected from the group consisting of 1-(2-azido-2-deoxy-β

-D-arabinofuranosyl)cytosine of the formula;

##STR14## and pharmaceutically acceptable acid addition salts thereof.

10. A composition in dosage unit form comprising an arabinofuranosyl nucleoside of the formula ##STR17## wherein Z is a pyrimidinyl-1 or purinyl-9 moiety, X is selected from the group consisting of amino, azido, and hydrocarbylamino of 1 to 7 carbon atoms, and each of R and R¹ is selected from the group consisting of hydrogen, acetyl, propionyl, butyryl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, undecanoyl, lauroyl, benzoyl, phenylacetyl, phenylpropionyl, o-, m-, and p-methylbenzoyl, β

-cyclopentylpropionyl, and dihydrocinnamoyl, said nucleoside being either in the free base form or in the form of a pharmaceutically acceptable acid addition salt, and a sterile, compatible, pharmaceutical carrier for said nucleoside.

11. The composition of claim 10 wherein the arabinofuranosyl nucleoside is a compound selected from the group consisting of 1-(2-amino-2-deoxy-β

-D-arabinofuranosyl) cytosine of the formula;

##STR18## and pharmaceutically acceptable acid addition salts thereof.

12. The composition of claim 10 wherein the arabinofuranosyl nucleoside is a compound selected from the group consisting of 1-(2-azido-2-deoxy-β

-D-arabinofuranosyl) cytosine of the formula;

##STR19## and pharmaceutically acceptable acid addition salts thereof.