Antiviral compounds

• US 5,955,610 A
• Filed: 06/04/1997
• Issued: 09/21/1999
• 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:
  US08/868,706
• Time in Patent Office: 839 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 (Ib):

##STR179## wherein X and Y are each independently O or S;

Z is (CH₂)_m ;

m is 1;

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═

CH--NR₃ 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 (IIa)

wherein ##STR180## 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 R₂, optionally further hydroxylated or aminated,

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

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

2. The process according to claim 1, wherein said displaceable group W is selected from:

tosylate and halogen groups.

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. The process according to claim 1 wherein X and Y are independently O or S, said intermediate (IIa) is made by coupling an intermediate of formula (III):

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

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

m is 1; and

OR_w is a leaving group wherein R_w is a C_1-6 alkyl;

with a phosphorus containing agent.

5. The process according to claim 4, wherein said phosphorus-containing reagent is PCl₃ with P(OR_v)₃ wherein R_v is a hydroxy protecting group, and the reaction is carried out under Arbuzov conditions in the presence of zinc chloride.

6. The process according to claim 4, wherein said intermediate of formula (III) is made by the coupling of an intermediate of formula (VI) with a linear alkane derivative of formula (V):

##STR182## wherein X and Y are independently O or S;

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

m is 1; and

OR_w is a leaving group wherein R_w is a C_1-6 alkyl.

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

a C_1-6 alkyl, and aryl.

8. The process according to claim 4, wherein W'"'"' is selected from the group consisting of:

silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy, and halogen.

9. A process according to claim 5, wherein said intermediate of formula (III) is made by coupling an intermediate of formula (VI) with a linear alkane derivative of formula (V):

##STR183## wherein X and Y are independently O or S;

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

OR_w is a leaving group;

m is 1; and

R_w is a C_1-6 alkyl.

10. A process according to claim 6, wherein said intermediate of formula (III) is made by coupling an intermediate of formula (VI) with a linear alkane derivative of formula (V):

##STR184## wherein X and Y are independently O or S;

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

OR_w is a leaving group;

m is 1; and

R_w is a C_1-6 alkyl.

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

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

13. A process according to claim 9, wherein W'"'"' is silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy, or halogen.

14. A process according to claim 7, wherein R_v is C_1-6 alkyl or benzyl.

15. A process according to claim 9, wherein R_v is C_1-6 alkyl or benzyl.

16. A process according to claim 1, wherein W is tosylate, halogen, t-butyldiphenylsilyloxy or hydroxy.

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

18. A process according to claim 1, wherein R₂ '"'"' is a purine nucleotide base which is hydroxylated or aminated in the N₉ position.

19. A process according to claim 1, wherein R₂ '"'"' is a pyrimidine nucleotide base which is hydroxylated or aminated in the N₁ or N₃ position.

20. A process according to claim 1, wherein R₂ is formulae A-W:

##STR185## 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_1-6 -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 -alkynyl, C_1-10 acyloxy, aryl, aryloxy, thiocarboxy, thiocarbamoyl, ureido, amidino, or aryloxy.

21. A process according to claim 20, wherein R₂ is of formula A, F, or M.

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

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

24. 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.

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

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

27. A process according to claim 1, wherein Y is S.

28. A process according to claim 1, wherein Y is O.

29. A process according to claim 20, wherein W in formula IIa is tosylate, halogen, t-butyldiphenylsilyloxy or hydroxy.