Antiviral compounds

• US 6,005,107 A
• Filed: 06/04/1997
• Issued: 12/21/1999
• Est. Priority Date: 12/23/1992
• Status: Expired due to Fees

• Current Assignee: Biochem Pharma, Incorporated (Shire plc)
• Original Assignee: Biochem Pharma, Incorporated (Shire plc)
• Inventors: Kong, Laval Chan Chun, Brown, William L., Nguyen-Ba, Nghe, Dionne, Gervais, Quimpere, Miguel
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/868,782
• Time in Patent Office: 930 Days
• Field of Search: 544/243, 544/244
• US Class Current: 544/243
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Nucleotide analogues having the general formula (I) and pharmaceutically acceptable derivatives: ##STR1## wherein n is 0 or an integer; X is O or S, CH₂, CH-halogen, CH--N₃, or C═CH₂ ;

Q and U are independently selected from: O, S, and CH(R_a) wherein R_a is hydrogen, OH, halogen, N₃, NH₂, SH, carboxyl, C_1-6 alkyl or R_a is CH₂ (R_b) wherein R_b is hydrogen, OH, SH, NH₂, C_1-6 alkyl or carboxyl; or both Q and U are CH when Q and U are linked by a double bond;

Z is selected from: O, a C_1-6 alkoxy, a C_1-6 thioalkyl, a C_1-6 aminoalkyl, (CH₂)_m wherein m is 0 or an integer, and N(R_c)₂ wherein both R_c are independently hydrogen or a C_1-6 alkyl; and

R2 is a purine or pyrimidine base or an analogue or derivative thereof. Members of this series of analogues possess anti-viral activity.

Claims

1. A process for producing a compound of formula (If):

##STR178## wherein n is 0-4;

X and Y are each independently O or S;

Z is (CH₂)_m ;

m is 1-6; and

R₂ is a purine or pyrimidine nucleotide base

wherein said purine or pyrimidine nucleotide base is optionally substituted by oxo, thioxo, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, --S-aryl, C_1-6 alkyl, C_2-6 -alkenyl, C_2-6 -alkenyl substituted with halogen or azido, C_2-6 -alkynyl, C_1-10 acyloxy, thiocarboxy, thiocarbamoyl, ureido, amidino, aryloxy, alkoxy, --S-alkyl, azido, aryl, --NR₃ R₄, or --N═

CHNR₃ R₄ ; and

R₃ and R4 are each independently hydrogen, hydroxyl, amino, C_1-6 -alkyl, C_2-6 -alkenyl, C_2-6 -alkynyl, C_1-10 acyl, aryl or carboxyl;

said process comprising;

a) coupling an intermediate of formula (IIc) ##STR179## wherein n, Y, and X are as defined above,

R_v is a hydroxy protecting group, and

W is a hydroxy group or a displaceable group, wherein said displaceable group is displaced during coupling,

with R₂ '"'"', wherein R₂ '"'"' is a substituted or unsubstituted purine or pyrimidine nucleotide base as defined for group R₂, optionally further hydroxylated or aminated,

to yield a phosphonate ester of a compound of formula (If); and

b) converting said ester to obtain a phosphonic acid of formula (If).

2. A process according to claim 1, wherein said displaceable group W is tosylate or halogen.

3. A process according to claim 1 wherein, when W is a hydroxy group, said coupling step is carried out under Mitsunobu reaction conditions.

4. A process according to claim 1, wherein when n is greater than 0, said intermediate of formula (IIc) is made by coupling an intermediate of formula (VII) with a linear alkane derivative of formula (V):

##STR180## wherein X and Y are each independently O or S;

W'"'"' is a hydroxy protecting group, a displaceable group, or an ester that may be modified to a displaceable group;

R_v is a hydroxy protecting group;

OR_W is a leaving group; and

R_W is a C_1-6 alkyl,

and optionally W'"'"' is converted to W.

5. A process according to claim 1, wherein when n is greater than 0, said intermediate of formula (Hc) is made by coupling an intermediate of formula (VIII) with a linear alkane derivative of formula (V):

##STR181## wherein X and Y are each independently O or S;

W'"'"' is a hydroxy protecting group, a displaceable group, or an ester that may be modified to a displaceable group;

R_v is a hydroxy protecting group;

OR_W is a leaving group; and

R_W is a C_1-6 alkyl,

and optionally W'"'"' is converted to W.

6. A process according to claim 1, wherein R_v is:

a C_1-6 -alkyl or aryl.

7. The process according to claim 1, wherein W is selected from the group consisting of:

tosylate and halogen, and, when the coupling step is carried out under Mitsunobu reaction conditions, W is hydroxy.

8. A process according to claim 4, wherein R_v is a C_1-6 alkyl or aryl.

9. A process according to claim 5, wherein R_v is a C_1-6 alkyl or aryl.

10. A process according to claim 4, wherein W'"'"' is silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy or halogen.

11. A process according to claim 5, wherein W'"'"' is silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy or halogen.

12. A process according to claim 1, wherein n is 0-4.

13. A process according to claim 1, wherein n is 0-1.

14. A process according to claim 1, wherein n is 1-4.

15. A process according to claim 14, wherein R_v is C_1-6 alkyl or aryl.

16. A process according to claim 15, wherein R_v is methyl, ethyl, isopropyl, or benzyl.

17. A process according to claim 16, wherein W is tosylate, halogen or hydroxy.

18. The process according to claim 1, wherein m is 1-4.

19. A process according to claim 1, wherein at least one of X and Y is S and said process further comprises oxidizing at least one of X and Y to form SO or SO₂.

20. A process according to claim 1, wherein R₂ is cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, or 2,6-diaminopurine.

21. A process according to claim 1, wherein R₂ is a purine nucleotide base, attached to group Z at the N₉ position of the base.

22. A process according to claim 1, wherein R₂ is a pyrimidine nucleotide base attached to the group Z at the N₁ or N₃ position of the base.

23. A process according to claim 1, wherein R₂ is a purine or pyrimidine nucleotide base.

24. A process according to claim 1, wherein X is O.

25. A process according to claim 1, wherein X is S.

26. A process according to claim 24, wherein Y is S.

27. A process according to claim 24, wherein Y is O.

28. A process according to claim 1, wherein m is 1-6.

29. A process according to claim 1, wherein Z is (CH₂)_m.

30. A process according to claim 1, wherein R₂ is of formulae A, B, C, F, M, or T:

##STR182## wherein;

X is oxygen or sulfur;

Y is oxygen or sulfur;

R₃ and R4 are each independently hydrogen, hydroxyl, amino, C_1-6 alkyl, C_2-6 -alkenyl, C_2-6 -alkynyl, C_1-6 alkoxy, C_1-10 acyl, aryl or carboxyl;

R5 and R6 are each independently hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, --S-aryl, C_1-6 alkyl, C_2-6 -alkenyl,

C_2-6 -alkenyl substituted by halogen or azido, C_2-6 -alkynyl, C_1-10 acyloxy, thiocarboxy, thiocarbamoyl, ureido, amidino, or aryloxy; and

R₇, R₈ and R₉ are each independently hydrogen, hydroxy, alkoxy, thiol, --S-alkyl, amino, halogen, azido, cyano, carboxy, alkoxycarbonyl, carbamoyl, C_1-6 alkyl, C_2-6 -alkenyl, C_2-6 -alynyl, C_1-10 acyloxy, aryl, aryloxy, thiocarboxy, thiocarbamoyl, ureido, amidino, or aryloxy.

31. A process according to claim 30, wherein R₂ is A, F or M.

32. A process according to claim 30, wherein W is tosylate, halogen, t-butyldiphenylsilyloxy or hydroxy.

33. A process according to claim 30, wherein R_v is a C_1-6 alkyl or aryl.

34. A process according to claim 30, wherein W'"'"' is silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy or halogen.