Antiviral compounds

• US 6,127,540 A
• Filed: 10/04/1999
• Issued: 10/03/2000
• 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: Dionne, Gervais, Kong, Laval Chan Chun, Brown, William L., Nguyen-Ba, Nghe, Quimpere, Miguel
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K
• Application Number:
  US09/411,979
• Time in Patent Office: 365 Days
• Field of Search: 544/243, 544/244, 544/264, 544/276, 544/265, 544/277, 544/267, 544/254
• US Class Current: 544/244
• 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 (I):

##STR179## wherein n is 0;

X is O or S;

Q and U are, in each case independently, CH₂, CHOH, CH-halogen, CH--N₃, CH--CH₂ (R_b) wherein R_b is hydrogen, OH, SH, NH₂, C_1-6 alkyl or carboxyl;

or both Q and U are each CH linked by a double bond;

Z is (CH₂)_m wherein m is 1; and

R₂ is a purine or pyrimidine nucleotide base or an analogue thereof wherein the based is modified by replacing a ring C atom by an N atom, replacing a ring N atom by a C atom, removing a C atom or a combination of the above modifications;

said purine or pyrimidine nucleotide base or analogue thereof also optionally being 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, thiocarbamoyl, ureido, amidino, aryloxy, alkoxy, S-alkyl, azido, aryl, NR₃ R₄ where 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 the step of;

a) coupling an intermediate of formula (IIe);

##STR180## wherein n, m and X are as defined above;

R_15'"'"' and R_16'"'"' are, in each case independently, H or W'"'"' or CH-W'"'"';

W and W'"'"' are each independently a hydroxy protecting group or a displaceable group which is displaced during the coupling; and

R_v is a hydroxy protecting group;

with a purine or pyrimidine base or analogue thereof as defined for R₂ above, optionally modified, to yield an ester of formula (I), and

b) optionally, converting said ester to obtain a phosphonate derivative of formula (I).

2. The process according to claim 1, wherein when X is S, it may be oxidized to SO or SO₂.

3. The process according to claim 2, wherein R2 is selected from the group consisting of:

##STR181## wherein;

x is oxygen or sulfur;

y is oxygen or sulfur;

R₃ and R₄ are independently selected from the group consisting of hydrogen, hydroxyl, amino, C_1-6 alkyl or C_1-6 alkenyl, C_1-6 alkynyl, C_1-10 acyl, aryl or carboxyl;

R₅, R₆, R₁₁, and R₁₂ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, C_1-6 alkyl, C_1-6 alkenyl substituted or unsubstituted with halogen or azido, C_1-6 alkynyl, C_1-10 acyloxy, thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, or aryloxy; and

##STR182## wherein;

R₇, R₈, R₉, and R₁₀ are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, substituted amino, halogen, azido, cyano, carboxy, alkoxycarbonyl, carbamoyl, C_1-6 alkyl, C_1-6 alkenyl, or C_1-6 alkynyl, C_1-10 acyloxy, aryl, aryloxy, thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, and aryloxy.

4. The process according to claim 2, wherein U is CH₂.

5. The nucleotide analogue according to claim 2, wherein Q is CH₂, or CHOH.

6. The process according to claim 3, wherein R2 is selected from A), F), and M).

7. The process according to claim 3, wherein R2 is selected from:

cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, and 2,6-diaminopurine.

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

tosylate and halogen groups.

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

10. The process according to claim 1, wherein R_v is C_1-6 alkyl or aryl.

11. The process according to claim 1, wherein W'"'"' is silyloxy, acyloxy, aracyloxy, mesyloxy, tosyloxy, or halogen.

12. A process according to claim 1, wherein said intermediate of formula (IIe) is made by coupling an intermediate of formula (IVa):

##STR183## wherein W'"'"' and W" are independently a hydroxy protecting group or a displaceable group which is displaced during the coupling; and

R_15'"'"' and R_16'"'"' are independently H or W'"'"' or both form a double bond;

with a phosphorus-containing agent.

13. The process according to claim 10, wherein said intermediate of formula (IVa) is made by sequentially protecting the hydroxy groups of a compound of formula (IX):

##STR184## wherein R₁₅ '"'"' and R₁₆ '"'"' are independently H or W'"'"' or both form a double bond.

14. The process according to claim 10, wherein said phosphorus-containing reagent is PCl₃ with P(OR_v)₃ wherein R_v is a hydroxy protecting group, and the coupling is carried out under Arbuzov conditions with or without the presence of a Lewis acid.

15. The process according to claim 12, wherein said phosphorus-containing reagent is O═

P(OR_v)₂^- M.sup.⊕

, wherein R_v is a hydroxy protecting group and M is a metal, and the coupling is carried out under Michaelis-Becker conditions.

16. The process according to claim 14, wherein said Lewis acid, when present, is TiCl₄.

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

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

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

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