Biologically active ATP analogs

• US 5,620,676 A
• Filed: 03/31/1995
• Issued: 04/15/1997
• Est. Priority Date: 03/08/1994
• Status: Expired due to Term

• Current Assignee: Health and Human Services The Government of The United Sates of America As Represented By
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Fischer, Bilha, Maillard, Michel, Jacobson, Kenneth A.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US08/414,438
• Time in Patent Office: 746 Days
• Field of Search: 424/1.73, 424/1.11, 424/1.65, 424/1.81, 424/1.85, 514/263, 514/260, 536/28.55, 536/28.54
• US Class Current: 424/1.73
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention provides certain novel adenosine triphosphate (ATP) analogs, pharmaceutical compositions, and methods of using such analogs in the treatment of septic shock and other disease conditions. Examples of the ATP analogs include the mono-, di- and triphosphates of adenosines with various selected substituents at the 2, 6, 8, and 9-positions, such as alkyl, alkylphenyl, phenylalkyl, S-alkyl, S-alkenyl, S-alkylcyano, S-phenyl, S-alkylphenyl, S-alkylamino, S-alkylthioalkyl, S-alkylthiocyanato, S-alkylaminophenyl, S-alkylnitrophenyl, hydroxy, bromo, fluoro, chloro, and aminoalkylamino. The present invention also provides pharmaceutical compositions of and methods of using certain xanthine and uracil derivatives for the above disease conditions. Examples of the xanthine derivatives include xanthines having alkyl or alkyltriphosphate substituents at the 1, 3, and 7-positions. Examples of the uracil derivatives include 5-fluoro- and 5-bromo uracil triphosphates. Also provided are assays for assessing the binding of the ATP analogs.

Claims

1. A compound of the formula ##STR7## wherein one of R^1a and R^1b is hydrogen, and the other of R^1a and R^1b is (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or (C₅ -C₁₀) aryl (C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthio(C₁ -C₇)alkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkylamino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, amino, amido, and hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate; and

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino (C₁ -C₇)alkyl amino, and hydrogen;

or a pharmaceutically acceptable salt thereof;

provided that when R³ is hydroxyl, then at least one of R² and R⁵ is not hydrogen; and

further provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.

2. The compound of claim 1, wherein R^1a and R^1b are individually hydrogen or methyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₃)alkylaminophenyl, and S-(C₁ -C₃)alkylnitrophenyl;

R³ is hydroxyl;

R⁴ is monophosphate or diphosphate; and

R⁵ is hydrogen.

3. The compound of claim 1, wherein R³ is hydroxyl;

R⁴ is monophosphate; and

R^1a, R^1b and R⁵ are each hydrogen.

4. The compound of claim 3, wherein R² is selected from the group consisting of S-5-hexenyl, S-2-(4-nitrophenyl)ethyl, S-6-cyanohexyl, S-ethylaminophenyl, S-ethylthioethyl, S-2-pentyl, S-2-hexyl, S-2-heptyl, S-2-octyl, S-2-decyl, and S-2-undecyl.

5. The compound of claim 1, wherein R^1a is hydrogen;

R^1b is methyl;

R³ is hydroxyl;

R⁴ is monophosphate; and

R⁵ is hydrogen.

6. The compound of claim 5, wherein R² is S-5-hexenyl or S-ethylaminophenyl.

7. The compound of claim 1, wherein R³ is hydroxyl;

R⁴ is diphosphate; and

R^1a, R^1b, and R⁵ are each hydrogen.

8. The compound of claim 7, wherein R² is S-5-hexenyl.

9. The compound of claim 1, wherein R^1a is hydrogen, R^1b is methyl;

R³ is hydroxyl;

R⁴ is diphosphate; and

R⁵ is hydrogen.

10. The compound of claim 9, wherein R² is selected from the group consisting of 2-(5-hexenyl)thio, 2-(2-(p-nitrophenyl)ethyl)thio, 2-(6-cyanohexyl)thio, and 2-aminophenylethylthio.

11. The compound of claim 1, wherein R^1a is hydrogen, R^1b is phenylethyl;

R³ is hydroxyl;

R⁴ is triphosphate; and

R⁵ is hydrogen.

20. The compound of claim 1, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I .

12. N⁶ -phenylethyl-ATP.

13. A compound of the formula ##STR8## wherein one of R⁶ and R⁷ is a C₁ -C₃ alkyltriphosphate and the other of R⁶ and R⁷ is a (C₁ -C₃)alkyl;

and a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein R⁶ is ethyltriphosphate and R⁷ is methyl.

15. The compound of claim 13, wherein R⁶ is methyl and R⁷ is ethyltriphosphate.

21. The compound of claim 13, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I.

23. An assay for assessing the binding between an ATP analog and a sample, comprising contacting a compound of claim 21 with a sample under conditions sufficient to effect binding between said compound and a component of said sample, and measuring the degree of said binding.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound selected from the group consisting of ##STR9## is hydrogen and the other of R^1a and R^1b is (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or phenyl(C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthioalkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkyl amino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, hydrogen, and hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate;

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

one of R⁶ and R⁷ is a (C₁ -C₃)alkyltriphosphate and the other of R⁶ and R⁷ is a (C₁ -C₃)alkyl; and

R⁸ is selected from the group consisting of bromo, fluoro, chloro, and hydrogen; and

a pharmaceutically acceptable salt thereof;

provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.

17. The pharmaceutical composition of claim 16, wherein said compound is selected from the group consisting of formula (I) and formula (II);

one of R^1a and R_1b is hydrogen and the other of R^1a and R^1b is methyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇) alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₃)alkylaminophenyl, and S-(C₁ -C₃)alkylnitrophenyl;

R³ is hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate; and

R⁵ is hydrogen or amino(C₁ -C₇)alkyl amine; and

one of R⁶ and R⁷ is a (C₁ -C₃)alkyltriphosphate and the other of R⁶ and R⁷ is a (C₁ -C₃)alkyl; and

a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 16, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I.

18. A method for the selective activation of P_2X or P_2Y receptors, or sub-classes thereof, comprising contacting said receptor with an effective quantity of at least one agonist, wherein said agonist is selected from the group consisting of 2-(C₁ -C₁₁)alkylthio derivatives of adenosyl monophosphates or diphosphates, 2-(C₁ -C₁₁)alkylthio derivatives of adenosyl triphosphates having N⁶ -(C₁ -C₇)alkyl, 8-(6-aminohexylamino)ATP, 2'"'"', 3'"'"'-isopropylidene ATP, N⁶ -methylATP, 2'"'"'-deoxyATP, and 3'"'"'-benzylamino-3'"'"'-deoxyATP, and a pharmaceutically acceptable salt thereof.

19. A method for the treatment of septic shock or brain seizures in individuals in need of such treatment and for the improvement of memory and learning capabilities comprising contacting an effective quantity of a compound or combination of compounds to P_2X or P_2Y receptors, or sub-classes thereof, wherein said compound or combination of compounds is selected from the group consisting of ##STR10## wherein R^1a and R^1b are the same or different and are hydrogen, (C₁ -C₁₁)alkyl, or (C₁ -C₇)alkylphenyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)-cycloalkyl, S-(C₃ -C₇)alkylphenyl, S-(Ci-C₇) alkylamino, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthio, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkyl amino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, hydrogen, and hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate;

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

R⁶ and R⁷ are different and selected from the group consisting of (C₁ -C₃)alkyltriphosphate and (C₁ C₃)alkyl; and

R⁸ is selected from the group consisting of bromo, fluoro, chloro, and hydrogen;

provided that when R³ is hydroxyl, then at least one of R^1a, R^1b, R², R⁵ is not hydrogen; and

further provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.

22. An assay for assessing the binding between an ATP analog and a sample, comprising contacting a compound of the formula ##STR11## with a sample under conditions sufficient to effect binding between said compound and a component of said sample, and measuring the degree of said binding;

wherein one of R^1a and R^1b is hydrogen, and the other of R^1a and R^1b is (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or (C₅ -C₁₀)aryl (C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthio(C₁ -C₇)alkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkylamino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, amino, amido, and hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate; and

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

wherein said compound is radiolabelled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I;

or a pharmaceutically acceptable salt thereof;

provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.

25. A compound of the formula ##STR12## wherein R^1a and R^1b are the same or different and are hydrogen, (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or (C₅ -C₁₀)aryl(C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthio (C₁ -C₇)alkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkylamino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, amino, amido, and hydroxyl;

R⁴ is monophosphate, diphosphate, or triphosphate; and

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

or a pharmaceutically acceptable salt thereof;

provided that when R³ is hydroxyl, then at least one of R² and R⁵ is not hydrogen; and

further provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 25.

32. The compound of claim 25, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I.

33. The compound of claim 25, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I.

34. The compound of claim 25, wherein said compound is radiolabeled with ³ H, ¹⁴ C, ³² P, ³³ P, or ¹²⁵ I.

26. A compound of the formula ##STR13## wherein R^1a and R^1b are same or different and are hydrogen, (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or (C₅ -C₁₀)aryl(C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₇)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthio (C₁ -C₇)alkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkylamino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, amino, amido, and hydroxyl;

R⁴ is monophosphate or diphosphate; and

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

or a pharmaceutically acceptable salt thereof;

provided that when R³ is hydroxyl, then R⁵ is not hydrogen.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 26.

29. A compound of the formula ##STR14## wherein R⁶ and R⁷ are selected from the group consisting of (C₁ -C³)alkyltriphosphates;

and a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 29.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound selected from the group consisting of ##STR15## wherein R^1a and R^1b are same or different and are hydrogen, (C₁ -C₇)alkyl, (C₁ -C₇)alkylphenyl, or phenyl (C₁ -C₇)alkyl;

R² is selected from the group consisting of S-(C₁ -C₁₁)alkyl, S-(C₁ -C₇)alkenyl, S-(C₁ -C₇)alkylcyano, S-(C₃ -C₇)cycloalkyl, S-phenyl, S-(C₁ -C₃)alkylphenyl, S-(C₁ -C₇)alkylamino, S-(C₁ -C₇)alkylthioalkyl, S-(C₁ -C₇)alkylthiocyanato, S-(C₁ -C₃)alkylaminophenyl, S-(C₁ -C₃)alkylnitrophenyl, and hydrogen;

R³ is selected from the group consisting of (C₁ -C₇)alkyl, (C₁ -C₇)alkyl amino, (C₅ -C₁₀)aryl, (C₅ -C₁₀)arylamino, hydrogen, and hydroxyl;

R⁴ is monophosphate, diphosphate; and

triphosphate;

R⁵ is selected from the group consisting of bromo, fluoro, chloro, amino(C₁ -C₇)alkyl amino, and hydrogen;

one of R⁶ and R⁷ is a (C₁ -C₃)alkyltriphosphate and the other of R⁶ and R⁷ is a (C₁ -C₃)alkyl;

or a pharmaceutically acceptable salt thereof;

provided that when R³ is hydroxyl, then at least one of R² and R⁵ is not hydrogen; and

further provided that when R⁴ is triphosphate, R³ is hydroxyl and R⁵ is hydrogen.