Cytidine nucleotide derivatives

• US 4,086,417 A
• Filed: 10/15/1975
• Issued: 04/25/1978
• Est. Priority Date: 10/15/1974
• Status: Expired due to Term

• Current Assignee: Asahi Kasei Kogyo Kabushiki Kaisha (Asahi Kasei Corporation)
• Original Assignee: Asahi Kasei Kogyo Kabushiki Kaisha (Asahi Kasei Corporation)
• Inventors: Sakurai, Yoshio, Akiyama, Minoru, Tsukagoshi, Shigeru, Ishida, Torao
• Primary Examiner(s): Brown, Johnnie R.
• Application Number:
  US05/622,794
• Time in Patent Office: 923 Days
• Field of Search: 260/211.5 R, 536/29, 536/23
• US Class Current: 536/26.21
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

A nucleotide derivative represented by the general formula: ##STR1## wherein R represents an acyl group having 14 - 22 carbon atoms and having an aliphatic acyl moiety; X represents a hydrogen atom, a halogen atom, an alkyl group having 1 - 4 carbon atoms, or a trifluoromethyl group; and at least one, but not all, of Y₁, Y₂, and Y₃ represents a phosphate, a pyrophosphate, a triphosphate, or a salt thereof, the balance of Y₁, Y₂ and Y₃ representing a hydroxyl group; or in case of ribosyl, Y₁ and Y₃, or Y₂ and Y₃ represent, at the same time, the aforesaid phosphate, pyrophosphate, triphosphate or salt thereof and the remaining group of Y₁, Y₂ or Y₃ represents a hydroxyl group; or in case of arabinosyl, Y₁ and Y₂, or Y₂ and Y₃ represent, at the same time, the aforesaid phosphate, pyrophosphate, triphosphate or salt therof and the remaining group of Y₁, Y₂ or Y₃ represents a hydroxyl group. The nontoxic salts of these phosphates are useful as an antileukemialagent for mice which is soluble in water and has high stability.

Claims

1. A nucleotide derivative represented by the general formula ##STR6## wherein R represents an acyl group having 14 to 22 carbon atoms and having an aliphatic acyl moiety;

X represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or a trifluoromethyl group; and

one of Y₁ and Y₃, or both Y₁ and Y₃, or both Y₂ and Y₃ in case of ribosyl; and

one of Y₁ and Y₃, or both Y₁ and Y₂ or both Y₂ and Y₃ in case of arabinosyl, represent a phosphate, a pyrophosphate, a triphosphate, or a salt thereof, the balance of Y₁, Y₂ and Y₃ representing a hydroxyl group, wherein said salt is a pharmaceutically acceptable salt.

2. The nucleotide derivative as claimed in claim 1, wherein said pharmaceutically acceptable salt is a pharmaceutically acceptable alkaline or alkaline earth metal salt, pharmaceutically acceptable ammonium salt or a pharmaceutically acceptable amine salt.

3. The nucleotide derivative as claimed in claim 2, wherein said pharmaceutically acceptable alkaline or alkaline earth metal salt is a sodium salt, a potassium salt, a calcium salt or an aluminum salt;

said pharmaceutically acceptable ammonium salt is an ammonium salt; and

said pharmaceutically acceptable amine salt is a trialkylamine, procaine, dibenzylamine, N-benzyl-β

-phenethylamine, N,N'"'"'-dibenzylethylene diamine, dehydrobiethylamine, an N-lower alkyl piperidine, arginine, lysine or choline.

4. The nucleotide derivative as claimed in claim 1, wherein said furanosyl is arabinofuranosyl.

5. The nucleotide derivative as claimed in claim 4, wherein X is a hydrogen atom.

6. The nucleotide derivative as claimed in claim 5, wherein said acyl group (R) is a straight chain fatty acid acyl group having 14 to 22 carbon atoms.

7. The nucleotide derivative as claimed in claim 6, wherein said acyl group is a myristoyl group, a pentadecanoyl group, a palmitoyl group, a margaroyl group, a stearoyl group, a nonadecanoyl group, an arachidoyl group, a heneicosanoyl group or a behenoyl group.

8. The nucleotide derivative as claimed in claim 7, wherein said acyl group is a stearoyl group.

9. The nucleotide derivative as claimed in claim 7, wherein at least one of Y₁ and Y₃ is a phosphate or a pharmaceutically acceptable salt thereof.

10. The nucleotide derivative as claimed in claim 7, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-phosphate, an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-3'"'"',5'"'"'-diphosphate or a pharmaceutically acceptable salt thereof.

11. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-phosphate or a pharmaceutically acceptable salt thereof.

12. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-3'"'"',5'"'"'-diphosphate or a pharmaceutically acceptable salt thereof.

13. The nucleotide derivative as claimed in claim 1, wherein said acyl group (R) is a myristoyl group, a pentadecanoyl group, a palmitoyl group, a margaroyl group, a stearoyl group, a nonadecanoyl group, an arachidoyl group, a heneicosanoyl group, or a behenoyl group, and said furabosyl is ribofuranosyl.

14. The nucleotide derivative as claimed in claim 1, wherein one of Y₁ and Y₂, or both Y₁ and Y₃, or both Y₂ and Y₃ in case of ribosyl;

and Y₁, or both Y₁ and Y₂ or both Y₂ and Y₃ in case of arabinosyl, represent a phosphate, a pyrophosphate, a triphosphate, or a salt thereof, the balance of Y₁, Y₂ and Y₃ representing a hydroxyl group, wherein said salt is a pharmaceutically acceptable salt.

15. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-3'"'"',5'"'"'-diphosphate or a sodium salt thereof.

16. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-2'"'"',3'"'"'-diphosphate or a pharmaceutically acceptable salt thereof.

17. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-2'"'"',3'"'"'-diphosphate or a sodium salt thereof.

18. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofurabosylcytosine-2'"'"'-phosphate or a pharmaceutically acceptable salt thereof.

19. The nucleotide derivative as claimed in claim 1, whrerin said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-2'"'"'-phosphate or a sodium salt thereof.

20. The nucleotide derivative as claimed in claim 1, whrerin said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-pyrophosphate or a pharmaceutically acceptable salt thereof.

21. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-pyrophosphate or a sodium salt.

22. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-triphosphate or a pharmaceutically acceptable salt thereof.

23. The nucleotide derivative as claimed in claim 1, wherein said derivative is an N⁴ -acyl-1-β

-D-arabinofuranosylcytosine-5'"'"'-triphosphate or a sodium salt thereof.

24. The nucleotide derivative as claimed in claim 1, wherein X is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and a trifluoromethyl group.

25. The nucleotide derivative as claimed in claim 1, wherein one of Y₁ and Y₃ or both Y₁ and Y₃, or both Y₂ and Y₃ in case of ribosyl;

and one of Y₁ and Y₃, or both Y₁ and Y₂ or both Y₂ and Y₃ in case of arabinosyl, represent a phosphate, a pyrophosphate, a triphosphate, or a salt thereof, the balance of Y₁, Y₂ and Y₃ representing a hydroxyl group, wherein said salt is a pharmaceutically acceptable salt.