Chemical compounds

• US 20030120071A1
• Filed: 08/12/2002
• Published: 06/26/2003
• Est. Priority Date: 03/13/1995
• Status: Active Grant

• Current Assignee: Christopher Mcguigan, Jan Balzarini
• Original Assignee: Christopher Mcguigan, Jan Balzarini
• Inventors: Balzarini, Jan, McGuigan, Christopher
• Granted Patent: US 7,018,989 B2
• Time in Patent Office: Days
• US Class Current: 544/243
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Aryl substituted phosphoryl derivatives of the formula

In which Ar is phenyl, naphthyl, or pyridyl, Y is O or S, X¹ is O, NR³, S, CR³R⁴, CR³W¹ or CW¹W², X² and X⁶ are a bond or X⁶ is CH₂ and X² is O, NR³, S, CR³R⁴, CR³W¹ or CW¹W², R³ and R⁴ are H, alkyl or phenyl, groups, W¹ and W² are heteroatoms, X³ is alkylene, X⁴ is oxygen or CH₂, X⁵ is a bond or CH₂, Z is O, NR⁵, S, alkyl or phenyl, R⁵ is H, alkyl or phenyl, J is H, alkyl, phenyl, or a heterocyclic or polycyclic group, Q is O, NR⁶, S, CR⁶R⁷, CR⁶W³ or CW³W⁴, R⁶ and R⁷ are H, alkyl or phenyl, and W³ and W⁴ are hetero atoms, T¹ and T² are H or CH₂R⁸, R⁸ is H, OH or F, or T¹ and T² together are —CH═CH— or —C(R⁹)(R¹⁰)C(R¹¹)(R¹²)—, R⁹ is H, halogeno, CN, NH₂, CO-alkyl, or alkyl, R¹⁰, R¹¹, and R¹² are H, N₃, halogen, CN, NH₂, CO-alkyl, or alkyl, and B is a purine or pyrimidine base, have antiviral activity, as for example against HIV. Particularly preferred are thymine and adenine derivatives of amino acid phenoxyphosphoroamidates. A typical embodiment is 2′,3′-dideoxy-2′,3′-didehydrothymidine 5′-(phenyl methoxy alaninyl) phosphoroamidate which can be prepared from phenyl methoxy alaninyl phosphorochloridate and 2′,3′-dideoxy-2′,3′-didehydrothymidine.

Claims

1. A compound of the formula (1)

2. A compound according to claim 1 wherein

Y is oxygen;

X¹ is NH;

X³ is CHR¹;

X⁴ is oxygen; and

Z is oxygen.

5. A compound according to any one of claims 1 to 4 wherein

X² is oxygen;

X⁶ is CH₂;

Q is oxygen;

X⁵ is absent; and

T¹ and T² together comprise the group;

6. A compound according to claim 5 wherein B is thymine.

7. A compound according to claim 6 wherein Ar, R¹ and J are defined as follows:

8. A compound according to any one of claims 1 to 4 wherein

X² is oxygen;

X⁶ is CH₂;

Q is oxygen;

X⁵ is absent; and

T¹ and T² together comprise the group;

9. A compound according to claim 8 wherein B is adenine or thymine.

10. A compound according to any one of claims 1 to 4 wherein

X²-X⁶ is absent

Q is oxygen;

X⁵ is CH₂;

T¹ and T² are independently selected from hydrogen and CH₂R⁸ wherein R⁸ is selected from H, OH and F.

11. A compound according to claim 9 wherein B is adenine.

12. A compound according to any one of claims 1 to 11 for use in a method of treatment, prophylaxis or diagnosis.

13. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment or prophylaxis of a viral infection.

14. Use of a compound according to claim 13 wherein the viral infection comprises HIV.

15. A process for the preparation of a compound according to any one of claims 1 to 11 comprising reaction of a compound of formula (11)

16. A method of prophylaxis or treatment of viral infection comprising administration to a patient in need of such treatment an effective dose of a compound according to any one of claims 1 to 11.

17. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for use in the inhibition of a reverse transcriptase by a nucleoside-resistance independent or nucleoside 5′

-triphosphate independent mode of action.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 in combination with a pharmaceutically acceptable excipient.

3. A compound of formula (10)

4. A compound according to claim 3 wherein

Y is oxygen;

X¹ is NH;

X³ is CHR¹; and

X⁴ is oxygen