Antiretroviral enantiomeric nucleotide analogs

• US 6,653,296 B1
• Filed: 02/02/1995
• Issued: 11/25/2003
• Est. Priority Date: 08/05/1992
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
• Inventors: Dvorakova, Hana, Balzarini, Jan Marie Rene, De Clercq, Erik Desire Alice, Holy, Antonin
• Primary Examiner(s): BERNHARDT, EMILY A
• Assistant Examiner(s): Styles, C
• Application Number:
  US08/379,551
• Time in Patent Office: 3,218 Days
• Field of Search: 544/244, 544/118, 514/81, 558/179, 558/183, 558/186, 558/188-189
• US Class Current: 514/81
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 309/12 only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/6521 Six-membered rings
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

Resolved enantiomers of the formula (IA) and (IB)

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.

Claims

1. A compound of the formula:

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:

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

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:

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:

substantially free of its enantiomer wherein B′

is a protected form of B as herein defined with a compound of the formula

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:

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.

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.

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.