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1. WO2013013009 - 2',3'-DIDEOXY-2'-α-FLUORO-2'-β-C-METHYLNUCLEOSIDES AND PRODRUGS THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

WHAT IS CLAIMED IS:

1. A compound of formula (I):


(I)

or a pharmaceutically acceptable prodrug, salt, solvate, a stereoisomic, tautomeric or polymorphic form, a metabolite thereof, wherein:

R1 is selected from H, monophosphate, diphosphate, triphosphate or their stable phosphate prodrugs, acyl (R2CO-), R2OC(0)-, and R2NHC(0)-, RaRbNC(0)-;

R is selected from alkyl, alkenyl, alkynyl, aryl, benzyl, cycloalkyl, heterocyclyl, and heteroaryl;

Ra and Rb are independently selected from alkyl, alkenyl, alkynyl, aryl, benzyl, cycloalkyl, heterocyclyl, and heteroaryl, or alternatively, Ra and Rbtogether with the nitrogen atom (N) to which they are attached, form a 4- to 7-membered ring;

X is selected from H, NH2, and halogen (I, Br, CI, F); and

X6 is selected from H, -OH, -OMe, -OEt, -SMe, alkyloxy, aryloxy,

cycloalkyloxy, alkylthio, arylthio, cycloalkylthio, alkylamino, dialkylamino, arylamino, diarylamino, arylalkylamino, cycloalkylamino, and cyclopropylamino, wherein dialkyl portion of the dialkylamino group optionally forms a ring along with the nitrogen atom of the amino groupwherein any of the amino and hydroxyl groups are optionally protected.

2. A compound of claim 1 or its pharmaceutically acceptable prodrug or salt thereof, selected from compounds of formulae:


wherein R is defined as in claim 1.

3. The compound of claim 1 or 2, or its pharmaceutically acceptable prodrug or salt thereof, wherein R1 is H, a monophosphate, diphosphate, or

triphosphate.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from stable phosphate prodrug compounds of formulae:


wherein:

X2 and X6 are defined as in claim 1 ;

R3 and R4 are independently selected from alkyl, cycloalkyl, aryl, benzyl, and substituents characterized by formulae:


wherein: R is defined as in claim 1;

Ar is unsubstituted or substituted aryl or heteroaryl;

R5 and R6 are independently selected from alkyl, alkenyl, alkynyl, aryl, benzyl, cycloalkyl, heterocyclyl, heteroaryl, or alternatively, R5 and R6 together form a 4- to 7-membered ring along with the nitrogen atom (N) to which they are attached;

wheren R5R6N can be aminoacid residue and aminoalcohol derivative of formulae:

wherein:

R is defined as in claim 1 ; and

R7, R8, R9, R10 and Rn are each independently selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, each substituted or

unsubstituted, wherein R 7 and R 8 together or R 10 and R 11 together, along with the carbon atoms to which they are attached, can optionally independently form a 3- to 7-membered ring.

5. The compound of claim 1 or 4, or a pharmaceutically acceptable prodrug or salt thereof, selected from diastereomers of a stable phosphate prodrug according to formula:


and mixtures thereof, wherein Ar, R 7 , R 8 , R 9 , X 2 and X 6 are defined as in claim 1 or 4.

6. The compound of claim 1 or 4, or its pharmaceutically acceptable prodrug or salt thereof, selected from stable phosphate prodrugs and diastereomers thereof according to formulae:


wherein Ar, R9, X2 and X6 are defined as in claim 1 or 4.

7. The compound according to any of claims 1 and 4-6, selected from stable phosphate prodrugs and diastereomers thereof according to formulae:

wherein Ar and R9 are defined as in corresponding claims 1 and 4-6, respectively.

8. The compound according to any of claims 1 and 4-7, selected from compounds of formulae:


9. A pharmaceutical composition comprising a compound according to any one of claims 1-8, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, further comprising a second or more anti-HCV agents.

11. Use of a compound according to any one of claims 1-8 in the manufacture of a medicament for the treatment of hepatitis C virus infection in a patient.

12. The use of claim 11, in combination with a second or more anti-HCV agents.

13. A method of treating hepatitis C virus infection, comprising

administering a therapeutically effective amount of a compound according to any one of claims 1-8, or a pharmaceutically acceptable prodrug or salt thereof, or a pharmaceutical composition of claim 9, to a patient in need of the treatment.

14. The method of claim 13, further comprising administering to the patient a therapeutically effective amount of a second or more anti-HCV agents.

15. A method of making a nucleoside compound according to any one of claims 1-8, comprising:

a. preparing a 5-protected 2-fluoro-a-2-C-methyl-lactone compound of formula:


through stereospecific fluorination of a lactone compound of formula:


using (PhS02)NF or other fluorinating reagents in the presence of base;

b. reducing the 5-protected 2-fluoro-a-2-C-methyl-lactone with a reducing reagent to provide 5-protected 2-fluoro-a-2-C-methyl-l-a-lactol compound of formula:


c. converting the 5-protected 2-fluoro-a-2-C-methyl-l-a-lactol compound stereoselectively to an a-intermediate comprising a leaving group L (such as Br) of formula:


d. reacting the 1-L-a-intermediate with purine or modified purine in the presence of base to stereoselectively produce a β-nucleoside compound of formula:


beta-Nucleoside

wherein Pg is H or a protecting group.

16. An intermediate useful for the preparation of a compound according to any one of claims 1-8 or a composition of claim 9, selected from compounds of formulae:


wherein Pg is H or a protecting group, and L is a leaving group.