Esters and malonates of SATE prodrugs

• US 9,192,621 B2
• Filed: 09/26/2013
• Issued: 11/24/2015
• Est. Priority Date: 09/27/2012
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Mayes, Benjamin Alexander, Moussa, Adel M.
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/038,617
• Publication Number:
  US 20140086873A1
• Time in Patent Office: 789 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

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. In certain embodiments, provided herein are compounds according to Formula 1001:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein Base, Y, Z, A, R^C and R^D are as described herein.

Claims

1. A compound of Formula 1001:

2. The compound of claim 1, wherein A is methyl.

3. The compound of claim 1, wherein A and Y, together with the atoms to which they are attached, combine to form an oxacyclopropyl ring.

4. The compound of claim 1, wherein Z is —

(CRR)_mC(O)O(CR^BR)_pCR^ARR.

5. The compound of claim 1, wherein Z is —

(CRR)_mOC(O)(CRR)_mCRRR.

6. The compound of claim 1, wherein Y is fluoro.

7. The compound of claim 1, wherein Y is hydroxyl.

8. The compound of claim 1, wherein R^C is —

CH₂Ph and R^D is hydrogen.

9. The compound of claim 1, wherein each R^A is independently hydrogen, halo, unsubtituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₂₀ aryl, or C₅-C₁₀ heteroaryl.

10. The compound of claim 1, wherein each R^B is independently hydrogen, halo, unsubtituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₂₀ aryl, or C₅-C₁₀ heteroaryl.

11. The compound of claim 1, wherein each Base is independently:

12. The compound of claim 1 according to of any of formulas 101-112:

13. The compound of claim 1 where

Base is a nucleobase selected from adeninyl, N⁶-alkylpurinyl, N⁶-acylpurinyl (wherein acyl is —

C(O)(alkyl), aryl, alkylaryl, or arylalkyl), N⁶-benzylpurinyl, N⁶-halopurinyl, N⁶-vinylpurinyl, N⁶-acetylenic purinyl, N⁶-acyl purinyl, N⁶-hydroxyalkyl purinyl, N⁶-alkylaminopurinyl, N⁶-thioalkyl purinyl, N²-alkylpurinyl, N²-alkyl-6-thiopurinyl, thyminyl, cytosinyl, 5-fluorocytosinyl, 5-methylcytosinyl, 6-azapyrimidinyl, 6-azacytosinyl, 2-mercaptopyrmidinyl, 4-mercaptopyrmidinyl, 2,4-dimercaptopyrmidinyl, uracilyl, 5-halouracilyl, 5-fluorouracilyl, C⁵-alkylpyrimidinyl, C⁵-benzylpyrimidinyl, C⁵-halopyrimidinyl, C⁵-vinylpyrimidinyl, C⁵-acetylenic pyrimidinyl, C⁵-acyl pyrimidinyl, C⁵-hydroxyalkyl purinyl, C⁵-cyanopyrimidinyl, C⁵-iodopyrimidinyl, C⁶-iodo-pyrimidinyl, C⁵-Br-vinyl pyrimidinyl, C⁶-Br-vinyl pyrimidinyl, C⁵-nitropyrimidinyl, C⁵-amino-pyrimidinyl, N²-alkylpurinyl, N²-alkyl -6-thiopurinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl. guaninyl, adeninyl, hypoxanthinyl, 7-deazaguaninyl, 7-deazaadeninyl, 2,6-diaminopurinyl, and 6-chloropurinyl;

where a functional oxygen group and a functional nitrogen groups on the base independently is optionally protected with a group selected from trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl groups, acetyl, propionyl, methanesulfonyl, and p-toluenesulfonyl; and

where each alkyl in Base is unsubstituted alkyl unless otherwise specified;

A is methyl;

or A and Y, together with the atoms to which they are attached, combine to form a 3-10 membered carbocyclic or heterocyclic, monocyclic, nonaromatic ring;

Z is —

(CRR)_mC(O)O(CR^BR)_pCR^ARR or —

(CRR)_mOC(O)(CRR)_mCRRR;

each of R^C and R^D is independently hydrogen, unsubstituted or substituted C₁-C₂₀ alkyl, C₆-C₂₀ arylalkyl, C₆-C₂₀ heteroaryl alkyl, C₆-C₂₀ aryl, or C₅-C₂₀ heteroaryl;

or R^Cand R^D, together with the atoms to which they are attached, combine to form a 3-20 membered heterocyclic ring;

each of R, R^A and R^B is independently hydrogen, halo, unsubstituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₀ aryl, or C₅-C₁₀ heteroaryl; and

each of m and p is independently an integer selected over the range of 0 to 20;

each substituted alkyl is alkyl substituted with moieties independently selected from halogen, hydroxyl, -NH₂, C₁-C₁₀-alkylamino, di-(C₁-C₁₀-alkyl)amino, C_3-15-cycloalkylamino, C_6-12-arylamino, di-(C_6-12-aryl)amino, —

O(C₁-C₁₀-alkyl), —

O(C_3-15-cycloalkyl), C_6-12-aryloxy, nitro, and cyano;

each aryl, either alone or as part of another group unless specified otherwise, is independently optionally substituted with moieties selected from halogen, unsubstituted alkyl, haloalkyl, hydroxyl, -NH₂, C₁-C₁₀-alkylamino, di-(C₁-C₁₀-alkyl)amino, C_3-15-cycloalkylamino, C_6-12-arylamino, di- (C_6-12-aryl)amino, —

O(C₁-C₁₀-alkyl), —

O(C_3-15-cycloalkyl), C_6-12-aryloxy, nitro, and cyano;

each heteroaryl is a monovalent monocyclic aromatic group or multicyclic aromatic group that contains at least one aromatic ring;

wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom; and

where the heteroaryl is bonded to the rest of the molecule through the aromatic ring; and

each heterocyclic ring is

     1) a monovalent, monocyclic, non-aromatic ring system which can be partially or fully saturated, or

     2) a multicyclic ring system that contains at least one non-aromatic ring which can be partially or fully saturated and where the remaining rings in the multicyclic ring can be fused or bridged and can be partially saturated, fully saturated, or aromatic;

wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N and the remaining ring atoms are carbon atoms where the nitrogen or sulfur atoms can be optionally oxidized and the nitrogen atoms can be optionally quaternized; and

where the heterocyclic group is bonded to the rest of the molecule through the non-aromatic ring at any heteroatom or carbon atom which results in the creation of a stable compound;

the aryl in each of the terms “

C_6-12-arylamino,”

“

di-(C_6-12-aryl)amino,” and

“

C_6-12-aryloxy”

is unsubstituted; and

the alkyl in each of the terms “

C₁-C₁₀-alkylamino,”

“

di-(C₁-C₁₀-alkyl)amino,”

“

—

O(C₁-C₁₀-alkyl),”

“

arylalkyl,” and

“

heteroarylalkyl”

is unsubstituted;

with the proviso that when Base is guanine, Y is OH, and p is 0, then each R^A is independently hydrogen, halo, unsubstituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₀ aryl, or C₅-C₁₀ heteroaryl; and

with the proviso that when Base is guanine, Y is OH, and p is 1, each R^B is independently hydrogen, halo, unsubstituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₁₀ aryl, or C₅-C₁₀ heteroaryl.

14. The compound of claim 13, wherein each R^A is independently hydrogen, halo, unsubstituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₂₀ aryl, or C₅-C₁₀ heteroaryl.

15. The compound of claim 13, wherein each R^A is independently hydrogen, halo, unsubstituted C₂-C₁₀ alkyl, substituted C₁-C₁₀ alkyl, C₆-C₂₀ aryl, or C₅-C₁₀ heteroaryl.

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

17. The pharmaceutical composition of claim 16, wherein the composition is an oral formulation.

18. 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 of Formula 1001:

19. The method of claim 18, wherein the host is a human.

20. The method of claim 18, wherein the administration directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.

21. The method of claim 18, wherein the compound 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.

22. The method of claim 18 where

Base is