PROTECTED NUCLEOTIDE ANALOGS

• US 20090176732A1
• Filed: 12/19/2008
• Published: 07/09/2009
• Est. Priority Date: 12/21/2007
• Status: Abandoned Application

• Current Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Original Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Inventors: Beigelman, Leonid, Blatt, Lawrence, Lonnberg, Harri
• Application Number:
  US12/340,408
• Publication Number:
  US 20090176732A1
• Time in Patent Office: Days
• US Class Current: 514/51
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Disclosed herein are nucleotide analogs with one or more protecting groups, methods of synthesizing nucleotide analogs with one or more protecting groups and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with the nucleotide analogs with one or more protecting groups.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt, prodrug or prodrug ester:

wherein;

is a double or single bond;

A is selected from the group consisting of C, O and S;

B¹ is an optionally substituted heterocyclic base or a derivative thereof;

D is C═

CH₂ or O;

each R¹ is independently absent, hydrogen or

provided that at least one R¹ is

R² is selected from the group consisting of hydrogen, azido, —

CN, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy;

R³ is absent or selected from the group consisting of hydrogen, halogen, hydroxy and an optionally substituted C_1-4 alkyl;

R⁴ is absent or selected from the group consisting of hydrogen, halogen, azido, amino and hydroxy;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, —

CN, —

NC, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy;

R⁶ is absent or selected from the group consisting of hydrogen, halogen, hydroxy, —

CN, —

NC, an optionally substituted C_1-4 alkyl, an optionally substituted haloalkyl and an optionally substituted hydroxyalkyl, or when the bond to R⁵ indicated by is a double bond, then R⁵ a C_1-4 alkenyl and R⁶ is absent;

R⁷ and R⁸ are each independently —

C≡

N or an optionally substituted substituent selected from the group consisting of C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl;

R⁹ is hydrogen or an optionally substituted C_1-4-alkyl; and

m is 1 or 2.

2. The compound of claim 1, wherein R⁷ is —

C≡

N and R⁸ is an optionally substituted C_1-6 alkoxycarbonyl.

3. The compound of claim 1, wherein R⁷ is —

C≡

N and R⁸ is an optionally substituted C_1-6 organylaminocarbonyl.

4. The compound of claim 1, wherein both R⁷ and R⁸ are an optionally substituted C_1-6 organylcarbonyl.

5. The compound of claim 1, wherein both R⁷ and R⁸ are an optionally substituted C_1-6 alkoxycarbonyl.

6. The compound of claim 1, wherein R⁹ is an optionally substituted C_1-4-alkyl.

7. The compound of claim 1, wherein

is selected from the group consisting of:

8. The compound of claim 7, wherein

9. The compound of claim 1, wherein both R¹ groups are the same.

10. The compound of claim 1, wherein B¹ is selected from the group consisting of:

wherein;

R^A is hydrogen or halogen;

R^B is hydrogen, an optionally substituted C_1-4 alkyl, or an optionally substituted C_3-8 cycloalkyl;

R^C is hydrogen or amino;

R^D is hydrogen or halogen;

R^E is hydrogen or an optionally substituted C_1-4alkyl; and

Y is N or CR^F, wherein R^F hydrogen, halogen or an optionally substituted C_1-4-alkyl.

11. The compound of claim 10, wherein B¹ is selected from the group consisting of:

12. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

13. The compound of claim 1, wherein the compound of Formula (I) is:

15. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

16. A method of ameliorating or treating a viral infection comprising administering to a subject suffering from the viral infection a therapeutically effective amount of a compound of claim 1.

14. A compound of Formula (II) or a pharmaceutically acceptable salt, prodrug or prodrug ester:

wherein;

B² is an optionally substituted heterocyclic base or a derivative thereof;

D² is O or —

CH₂—

;

each R¹⁰ and R¹¹ are each independently absent, hydrogen or

provided that at least one of R¹⁰ and R¹¹ are

R¹² is hydrogen or —

(CH₂)—

OH;

R¹³ and R¹⁴ are each independently —

C≡

N or an optionally substituted substituent selected from the group consisting of C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl;

R¹⁵ is hydrogen or an optionally substituted C_1-4-alkyl; and

n is 1 or 2.

17. A method comprising reacting a first reactant, wherein the first reactant comprises a nucleoside with a phosphoamidite attached to the 5′

-carbon or a protected nucleoside derivative with a phosphoamidite attached to the 5′

-carbon, with a second reactant that comprises a compound of Formula (G) having the structure

to form a compound having the structure

wherein at least one R²⁴ has the formula

wherein R^7a, R^8a, R²⁵ and R²⁶ are each independently —

C≡

N or an optionally substituted substituent selected from the group consisting of C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl;

R^9a and R²⁷ are each independently hydrogen or an optionally substituted C_1-4-alkyl;

p is 1 or 2;

r is 1 or 2;

NS² is a nucleoside or a protected nucleoside derivative; and

the other R²⁴ is a biolabile group.

18. A method comprising, oxidizing the phosphorus in a compound having the structure

wherein at least one R²⁴ has the formula

wherein R²⁵ and R²⁶ are each independently —

C≡

N or an optionally substituted substituent selected from the group consisting of C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl;

R²⁷ is hydrogen or an optionally substituted C_1-4-alkyl;

r is 1 or 2;

NS² is a nucleoside or a protected nucleoside derivative; and

the other R²⁴ is a biolabile group, to phosphorus (V).

19. A method comprising reacting a first reactant, wherein the first reactant comprises a phosphite, with a second reactant that comprises a compound of Formula (G) having the structure

and a third reactant comprising a nucleoside or a protected nucleoside derivative;

to form a compound having the structure

wherein at least one R²⁸ has the formula

wherein R^7a, R^8a, R³⁰ and R³¹ are each independently —

C≡

N or an optionally substituted substituent selected from the group consisting of C_1-8 organylcarbonyl, C_1-8 alkoxycarbonyl and C_1-8 organylaminocarbonyl;

R^9a and R³² are each independently hydrogen or an optionally substituted C_1-4-alkyl;

p is 1 or 2;

s is 1 or 2;

NS² is a nucleoside or a protected nucleoside derivative; and

the other R²⁸ is a biolabile group.

20. A compound selected from the group consisting of: