Urea nucleosides as therapeutic and diagnostic agents

• US 6,914,138 B2
• Filed: 08/09/2002
• Issued: 07/05/2005
• Est. Priority Date: 03/27/1996
• Status: Expired due to Fees

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Eaton, Bruce, Kirschenheuter, Gary
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Lewis, Patrick T.
• Application Number:
  US10/216,553
• Publication Number:
  US 20030069414A1
• Time in Patent Office: 1,061 Days
• Field of Search: 536/27.1, 536/27.11, 536/27.3, 536/27.8, 536/27.81, 536/28.1, 536/28.5
• US Class Current: 536/27.1
• CPC Class Codes: C07H 11/02 Nitrates; Nitrites
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Modified nucleosides and methods of making and using the nucleosides are disclosed. The compounds can be prepared by reacting nucleoside starting materials that contain a suitable leaving group at one or more of the carbon atoms in the purine or pyrimidine ring, with a vinylstannane, carbon monoxide, and a palladium catalyst to provide 1-ene-3-one intermediates. These intermediates are then reacted with suitably functionalized primary or secondary amines via a Michael reaction. When the intermediate is a 5-position modified pyrimidine ring, and the amine contains a second hydrogen, it can do a second Michael reaction with the ene-one or the ene-imine in the pyrimidine ring. Appropriate modification of the amine reactant can yield products with various bioactivities. The nucleosides can be used therapeutically as anti-cancer, anti-bacterial or anti-viral drugs. The nucleosides can also be used for diagnostic applications, for example, by incorporating a radiolabel or fluorescent label into the molecule. The nucleosides can be used to prepare oligonucleotides for use in various applications, either alone or in combination with other modified nucleosides and/or naturally occurring nucleosides.

Claims

1. A compound of the formula:

wherein;

X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, —

NR¹⁰₂, and —

C(O)C(R⁸)₂CH(R⁸)NR¹R², and wherein at least one of X is —

C(O)C(R⁸)₂CH(R⁸)NR¹R²;

R¹ and R² are independently selected from the group consisting of H, C₁-C₁₈ alkyl, alkenyl or alkynyl, phenyl, aralkyl, alkaryl, an alkanoic acid, an ester or amide derivative of an alkanoic acid, a peptide fragment, an HIV aspartyl protease inhibitor, a group that is cleaved intracellularly, and a group that increases the hydrophilicity, hydrophobicity, or hydrogen bonding capacity of the compound;

R³, R⁴ and R⁵ are independently selected from the group consisting of H, —

OH, protected oxy-, —

NH₂, F, —

N₃, —

CN, —

NC, —

OAc, —

SAc, —

OBz, and —

OSiR⁷₃, wherein R⁷ is C₁-C₄ alkyl or phenyl;

R⁶ is selected from the group consisting of —

OH, protected oxy-, phosphate, diphosphate, triphosphate, phosphate esters, phosphoramidites, phosphorothionates, and phosphorodithionates;

R⁸ is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, and —

C(O)—

R⁹, where R⁹ selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and alkoxy;

R¹⁰ is independently selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and R⁹C(O);

the protected oxy-groups of R⁴ and R⁵ taken together can represent an isopropylidene group of the formula (—

OC(CH₃)₂O—

) or an orthoformate group of the formula (—

OCH(OR⁷)O—

); and

the protected oxy-groups of R⁵ and R⁶ taken together can represent a 3′

,-5′

-tetraalkyldisiloxane group (—

OSi(alkyl)₂OSi(alkyl)₂O—

).

2. The compound of claim 1, further comprising a radiolabel or a fluorescent label.

3. The compound of claim 1 wherein R¹ or R² is an HIV aspartyl protease inhibitor and R⁵ is —

N₃.

4. The compound of claim 3 wherein the protease inhibitor is selected from the group consisting of —

CH₂CH₂C(OH)(Ph)CH₂CH₂, —

CH₂CH₂C(OH)(4-ClPh)CH₂CH₂—

, —

CH₂CH₂C(OH)(4-FPh)CH₂CH₂—

5. The compound of claim 1 wherein R² and R³ are H or CH₃.

6. The compound of claim 1 wherein R⁴ and R⁵ together are OC(CH₃)₂O.

7. The compound of claim 1 wherein R⁶ is OH.

8. The compound of claim 1 wherein R¹ is CH(alkyl or aralkyl)CO₂Et.

9. The compound of claim 1 wherein R¹ is alkyl-(4-imidazole).

10. The compound of claim 1 wherein R⁴ and R⁵ together are —

OSi(iPr)₂OSi(iPr)₂O—

.