3′,5′-cyclic phosphate prodrugs for HCV infection

Patent metadata

Field	Value
Publication number	US-9296778-B2
Application number	US-201313899487-A
Country	US
Kind code	B2
Filing date	May 21, 2013
Priority date	May 22, 2012
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

First claim

What is claimed is:

1. A compound of Formula (VIII):

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, wherein:
each Base is independently

each X is independently alkoxyl, hydrogen, or hydroxyl;
each Y is independently hydroxyl, acetoxyl, or fluoro;
each Z is independently -LC(O)O(L) p C(R) 3 , -L-Ar—C(O)O(L) p C(R) 3 , —C(R)(E)(L) p OC(O)O(L) p C(R) 3 , -LSC(O)LOH, -LSC(O)LOC(O)(L) p C(R) 3 , -LSC(O)LOC(O)(L) p N(R) 2 , -LS-S(L) p C(R) 3 , -LS-SLOH, -LN(R)C(O)O(L) p C(R) 3 , -LSC(O)LN(R)C(O)O(L) p C(R) 3 , —Ar—B, -L-B, -LN(R)C(O)D, -LN(R)C(O)CH(OH)(C(R) 2 ) 2 OH, -(L) p C(R)(R A )C(O)O(L) p C(R) 3 , or -LSC(O)LC(O)O(L) p C(R) 3 ;
each B is independently an alkyl group substituted with aminocarboxylene, carboxylene, or both;
each D is independently

each E is independently alkyl, aryl, or heteroaryl;
each Ar is independently an arylene or heteroarylene;
each L is independently alkylene;
each R is independently hydrogen, alkyl, aryl, or heteroaryl; each R A is independently a carbocyclic or heterocyclic ring; and
each p is independently 0 or 1.

2. The compound of claim 1 , wherein each Z is independently —(C 1-10 )alkylene-SC(O)(C 1-10 )alkyleneC(O)O [(C 1-10 )alkylene] p C(R) 3 , —(C 1-10 )alkylene-SC(O)(C 1-10 )alkyleneN(R)C(O)O [(C 1-10 )alkylene] p C(R) 3 , —(C(R) 2 ) m C(O)O(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m ArC(O)O(C(R) 2 ) n C(R) 3 , —C(R)(E)(C(R) 2 ) n OC(O)O(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m SC(O)(C(R) 2 ) m OH, —(C(R) 2 ) m SC(O)(C(R) 2 ) m OC(O)(C(R) 2 )—C(R) 3 , —(C(R) 2 ) m S—S(C(R) 2 ) n C(R) 3 , —(C(R) 2 ) m S—S(C(R) 2 ) m OH, —(C(R) 2 ) m N(R)C(O)O(C(R) 2 )—C(R) 3 ,

—(C(R) 2 ) n B, —(C(R) 2 ) m N(R)C(O)D, —(C(R) 2 ) m N(R)C(O)CH(OH)(C(R) 2 ) 2 OH, or —(C(R) 2 ) n C(R)(R A )C(O)O(C(R) 2 ) n C(R) 3 ; wherein each m is 1-10, each n is 0-10, and each p is 0 or 1.

3. The compound of claim 1 , wherein:
each B is independently C(R) 3 (C(R) 2 ) n OC(O)C(R)(B—)N(R)C(O)O(C(R) 2 ) n C(R) 3 ;
where B— denotes the attachment position to Ar or L; and
each n is independently an integer selected over the range of 0 to 10.

4. The compound of claim 1 , wherein each E is independently C 1 -C 10 alkyl, C 5 -C 10 aryl, or C 5 -C 10 heteroaryl.

5. The compound of claim 1 , wherein each Ar is independently C 5 -C 10 arylene or C 5 -C 10 heteroarylene.

6. The compound of claim 1 , wherein each R is independently hydrogen, C 1 -C 10 alkyl, C 5 -C 10 aryl, or C 5 -C 10 heteroaryl.

7. The compound of claim 1 , wherein each R A is independently a 3-20 membered carbocyclic or heterocyclic ring.

8. The compound of claim 1 wherein Y is fluoro.

9. The compound of claim 1 wherein Y is acetoxyl.

10. The compound of claim 1 wherein Y is hydroxyl.

11. The compound of claim 1 according to Formula (IX):

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.

12. The compound of claim 11 , wherein each Z is independently -LSC(O)LC(O)O(L) p C(R) 3 or -LSC(O)LN(R)C(O)O(L) p C(R) 3 .

13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

14. The pharmaceutical composition of claim 13 , wherein the composition is an oral formulation.

15. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound or composition of claim 1 .

16. The method of claim 15 , wherein the host is a human.

17. The method of claim 15 , wherein the administration directs a substantial amount of the compound or pharmaceutically acceptable salt thereof, to a liver of the host.

18. The method of claim 15 , wherein the compound or composition is administered in combination or alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.

19. A compound of Formula (VIII):

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, wherein:
each Base is independently

each X is alkoxyl of formula —OR′, wherein R′ is C 1-10 alkyl or C 3-15 cycloalkyl;
each Y is independently hydroxyl, acetoxyl, or fluoro;
each E is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;
each Ar is independently C 5 -C 10 arylene or C 5 -C 10 heteroarylene;
each L is independently straight-chained or branched C 1 -C 10 unsubstituted alkylene or C 1 -C 10 substituted alkylene;
each R is independently C 1-10 unsubstituted alkyl, C 1-10 substituted alkyl, aryl, or heteroaryl;
each Z is independently -LC(O)O(L) p C(R) 3 , -L-Ar—C(O)O(L) p C(R) 3 , —C(R)(E)(L) p OC(O)O(L) p C(R) 3 , -LSC(O)LOH, -LSC(O)LOC(O)(L) p C(R) 3 , -LSC(O)LOC(O)(L) p N(R) 2 , -LS-S(L) p C(R) 3 , -LS-SLOH, -LN(R)C(O)O(L) p C(R) 3 , -LSC(O)LN(R)C(O)O(L) p C(R) 3 , —Ar—B, -L-B, -LN(R)C(O)D, -LN(R)C(O)CH(OH)(C(R) 2 ) 2 OH, or -(L) p C(R)(R A )C(O)O(L) p C(R) 3 ; wherein each p is 0 or 1;
wherein
each C 1-10 substituted alkyl is independently C 1-10 alkyl substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;
each aryl is independently phenyl, biphenyl, and naphthyl, unsubstituted or substituted by a moiety which is halogen fluoro, chloro, bromo, iodo, alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate
each heteroaryl is independently furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrol

Assignees

• Idenix Pharmaceuticals Inc
• Centre Nat Rech Scient
• Univ Montpellier Ii

Inventors

• Parsy Christophe Claude
• Alexandre Francois-Rene
• Dousson Cyril B
• Dukhan David
• Gosselin Gilles
• Rahali Houcine
• Surleraux Dominique

Classifications

• A61P31/12

  Antivirals · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H19/213

  containing cyclic phosphate · CPC title

• C07H19/11

  containing cyclic phosphate · CPC title

• A61K31/7076 Primary

  containing purines, e.g. adenosine, adenylic acid · CPC title