Process for preparing antiviral 2-phosponate nucleotide analogs

• US 6,194,576 B1
• Filed: 10/04/1999
• Issued: 02/27/2001
• 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: Brown, William L., Dionne, Gervais, Quimpere, Miguel, Kong, Laval Chan Chun, Nguyen-Ba, Nghe
• Primary Examiner(s): MCKENZIE, THOMAS C
• Application Number:
  US09/411,980
• Time in Patent Office: 512 Days
• Field of Search: 544/244, 544/243, 544/232, 544/214, 544/195, 546/24, 546/23, 548/112, 548/113
• US Class Current: 544/195
• 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:

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):

wherein

n is 0 or an integer,

X is O, S, CH₂, CH-halogen, CH—

N₃ or C═

CH₂;

Q is CH₂;

U is O or S;

Z is selected from;

—

O—

, —

O—

C_1-6 alkylene, —

S—

C_1-6 alkylene, —

NH—

C_1-6 alkylene, —

(CH₂)_m—

wherein m is from 0 to 6, and —

NH—

C_1-6 wherein R_c is hydrogen or a C_1-6 alkyl; and

R₂ is a purine or pyrimidine nucleotide base or an analogue,

wherein R₂ is selected from the group consisting of;

 

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_2-6 alkenyl, C_2-6 alkynyl, C_1-10 carboxylic-acid-acyl, aryl or carboxyl;

R₅, R₆, R₁₁, and R₁₂ are each independently of the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, —

S-aryl, C_1-6 alkyl, C_2-6 alkenyl substituted or unsubstituted with halogen or azido, C_2-6 alkynyl, C_1-10 carboxylic-acid-acyloxy, —

S—

COOH, —

S-carbamoyl, carbamate, ureido, amidino, or aryloxy; and

 

wherein;

R₇, R₈, R₉, and R₁₀ are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, —

S-alkyl, amino, substituted amino, halogen, azido, cyano, carboxy, alkoxycarbonyl, carbamoyl, C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, C_1-10 carboxylic-acid-acyloxy, aryl, aryloxy, —

S—

COOH, —

S-carbamoyl, carbamate, ureido, amidino, and aryloxy,

said process comprising;

a) coupling an intermediate of formula (IIf);

 

wherein n, m and X are as defined above;

Y is O or S;

R_v is a hydroxy protecting group; and

W is a displaceable group or a hydroxy group;

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

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

2. The process according to claim 1, wherein when either one of X or U 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:

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_2-6 alkenyl, C_2-6 alkynyl, C_1-10 carboxylic-acid-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, —

S-aryl′

, C_1-6 alkyl, C_2-6 alkenyl substituted or unsubstituted with halogen or azido, C_2-6 alkynyl, C_1-10 carboxylic-acid-acyloxy, —

S—

COOH, —

S-carbamoyl, carbamate, ureido, amidino, or aryloxy; and

wherein;

R₇, R₈, R₉, and R₁₀ are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, —

S-alkyl, amino, substituted amino, halogen, azido, cyano, carboxy, alkoxycarbonyl, carbamoyl, C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, C_1-10 carboxylic-acid-acyloxy, aryl, aryloxy, —

S—

COOH, —

S-carbamoyl, carbamate, ureido, amidino, and aryloxy.

4. The process according to claim 2, wherein n is 0 or an integer from 1 to 4.

5. The process according to claim 2, wherein Z is (CH₂)_m or a C_1-6 alkoxy.

6. The process according to claim 2, wherein X is O, S, CH₂, CH-halogen, or OH—

N₃.

7. The process according to claim 2, wherein n is 0 or 1.

8. The process according to claim 2, wherein X is O or S.

9. The process according to claim 2, wherein Z is (CH₂)_m wherein m is 0 or 1.

10. The process according to claim 3, wherein R2 is selected from A), or M).

11. 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.

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

tosylate and halogen groups.

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

14. The process according to claim 1, wherein said intermediate of formula (IIf) is made by coupling an intermediate of formula (IVb):

wherein W′ and

W″

are each independently a hydroxy protecting group, a displaceable group, or an ester radical, —

C(O)—

OR, that can be modified to a displaceable group with a trialkyl phosphite or phosphonate salt.

15. The process according to claim 14, 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 Michaelis-Arbuzov conditions with or without the presence of a Lewis acid.

16. The process according to claim 14, wherein said phosphorus-containing reagent is O═

P(OR_v)₂ M^⊕

′

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

17. The process according to claim 15, wherein said Lewis acid, when present, is TiCl₄.

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

19. The process according to claim 14, wherein W′

is silyloxy, carboxylic-acid-acyloxy, ar-carboxylic-acid-acyloxy, mesyloxy, tosyloxy, or halogen.

20. The process according to claim 16, wherein R_v is C_1-6 alkyl or aryl.