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Details for Patent: 6,653,296

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Details for Patent: 6,653,296

Title: Antiretroviral enantiomeric nucleotide analogs
Abstract:Resolved enantiomers of the formula (IA) and (IB) ##STR1## wherein B is a purine or pyrimidine base or aza and/or deaza analogs thereof are useful in antiviral pharmaceutical compositions to treat retroviral infections.
Inventor(s): Holy; Antonin (Horni Pocernice, CZ), Dvorakova; Hana (Prague, CZ), De Clercq; Erik Desire Alice (Lovenjoel, BE), Balzarini; Jan Marie Rene (Heverlee, BE)
Assignee: Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic (CZ) N/A (BE) Rega Stichting v.z.w. (N/A)
Filing Date:Feb 02, 1995
Application Number:08/379,551
Claims:1. A compound of the formula: ##STR14##

including salts of such compounds, wherein said compound of Formula IA is substantially free of its enantiomer and wherein B is (a) an unsubstituted purine moiety, (b) a substituted purine moiety substituted independently at the 2 and/or 6 and/or 8 position by amino, halogen, hydroxy, alkoxy, alkylamino, dialkylamino, aralkylamino, pyrrolidino, morpholino, piperidino, benzoylamino, azido, mercapto or alkylthio, or (c) the 8-aza analog thereof, and wherein B is other than guanine or 2-amino-6-halopurine; R is H; and aryl in aralkylamino is a 6-10C aromatic group.

2. The compound of claim 1 of formula IA wherein B is adenine, 2,6-diaminopurine, 2-aminopurine, 8-bromoadenine, 6-mercaptopurine, 6-thioguanine, 2-methylthioadenine, 8-azaadenine, 8-azaguanine, or 8-aza-2,6-diaminopurine.

3. The compound of claim 2 wherein B is adenine, 8-azaguanine or 2,6-diaminopurine.

4. A compound of claim 3 wherein B is 2,6-diaminopurine.

5. A method to prepare a compound of the formula: ##STR15##

substantially free of its enantiomer wherein B is as defined in claim 1, which method comprises hydrolyzing a compound of the formula ##STR16##

which is substantially free of its enantiomer to remove R groups wherein R is independently alkyl(1-6C), aryl or aralkyl by treating with a halotrialkylsilane in a polar aprotic solvent medium.

6. The method of claim 5 wherein both R are 2-propyl.

7. The method of claim 5 wherein the compound of Formula VIIA is prepared by a process which comprises deprotecting a compound of the formula: ##STR17##

substantially free of its enantiomer wherein B' is a protected form of B as defined herein by treating said compound of Formula VIA with at least one deprotecting reagent.

8. The method of claim 7 wherein said compound of Formula VIA is prepared by a process which comprises reacting a compound of the formula: ##STR18##

substantially free of its enantiomer wherein B' is a protected form of B as herein defined with a compound of the formula

wherein LvO is a leaving group, and each R independently is alkyl(1-6C), under conditions wherein said compounds of Formulas VA and IV react to form a compound of Formula VIA.

9. The method of claim 8 wherein LvO is a p-toluenesulfonyloxy (TsO) group.

10. The method of claim 5 wherein the compound of Formula VIIA is prepared by alkylating purine or pyrimidine moiety B as defined in claim 1 in the presence of alkali metal hydride or carbonate with an (R)- or (S)-2-O-dialkylphosphonylmethyl compound of the formula: ##STR19##

substantially free of its enantiomer wherein LvO is a leaving group and R is independently alkyl(1-6C), aryl or aralkyl.

11. The method of claim 10 where said alkali carbonate is cesium carbonate.

12. The method of claim 10 wherein LvO is a p-toluenesulfonyloxy (TsO) group.

13. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine.

14. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-diethylaminopurine.

15. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-butylaminopurine.

16. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-(2-butyl)aminopurine.

17. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-cyclopropylaminopurine.

18. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-cyclopentylaminopurine.

19. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-cyclohexylaminopurine.

20. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-pyrrolidinopurine.

21. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-piperidinopurine.

22. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-morpholinopurine.

23. 9-(R)-(2-Phosphonomethoxypropyl)-2-amino-6-benzylaminopurine.

24. 9-(R)-(2-Phosphonomethoxypropyl)-8-azaguanine.

25. 8-(R)-(2-Phosphonomethoxypropyl)-8-azaguanine.

26. 7-(R)-(2-Phosphonomethoxypropyl)-8-azaguanine.

27. 9-(R)-(2-Phosphonomethoxypropyl)-8-aza-2,6-diaminopurine.

28. 8-(R)-(2-Phosphonomethoxypropyl)-8-aza-2,6-diaminopurine.

29. 9-(R)-(2-Phosphonomethoxypropyl)-6-mercaptopurine.

30. 9-(R)-(2-Phosphonomethoxypropyl)-N1,N6-ethenoadenine.

31. A compound selected from the group consisting of 9-(R)-(2-phosphonomethoxypropyl)-2,6-diaminopurine and the 8-aza analog thereof.

32. The compound of claim 2 wherein B is a adenine.

33. The compound of claim 1 wherein B is purine substituted at the 6 position with amino, hydroxy, alkoxy, alkylamino, dialkylamino, aralkylamino, azido, mercapto or alkylthio.

34. The compound of claim 33 wherein the 6 position is substituted with amino or azido.

35. The compound of claim 33 or 34 wherein the 2 position is substituted with amino.

36. The compound of claim 1 wherein is B 8-azapurine substituted at the 6 position by amino, halogen, hydroxy, alkoxy, alkylamino, dialkylamino, aralkylamino, benzoylamino, azido, mercapto or alkylthio.

37. The compound of claim 1 wherein alkyl is methyl or ethyl.

38. The compound of claim 1 wherein B is adenine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or xanthine or the 8-aza analogs thereof.

39. The compound of claim 1 wherein B is substituted with amino, alkoxy, alkylamino, dialkylamino, aralkylamino, benzoylamino, azido, mercapto or alkylthio, and wherein alkyl independently is C3, C4, C5 or C6 alkyl.

40. The compound of claim 39 wherein alkyl is 2-propyl, n-pentyl or neopentyl.
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