2'-C-METHYL-RIBOFURANOSYL CYTIDINE PRODRUGS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

US 20120082645A1
Filed: 11/04/2011
Published: 04/05/2012
Est. Priority Date: 05/22/2006
Status: Abandoned Application

First Claim

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1-60. -60. (canceled)

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Abstract

The present disclosure provides 2′-C-methyl-ribofuranosyl cytidine prodrugs, methods of making 2′-C-methyl-ribofuranosyl cytidine prodrugs, pharmaceutical compositions of 2′-C-methyl-ribofuranosyl cytidine prodrugs, and methods of using 2′-C-methyl-ribofuranosyl cytidine prodrugs and pharmaceutical compositions thereof to treat viral diseases such as hepatitis C.

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80 Claims

1-60. -60. (canceled)

61. A method of treating a patient infected with hepatitis C, comprising administering to the patient a therapeutically effective amount of a compound of structural Formula (I):
- View Dependent Claims (62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80)
- - 62. The method of claim 61, wherein the second antiviral agent is selected from an interferon, ribavirin, interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a thiazolidine derivative, thiazolidine, benzanilide, phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotides, an inhibitor of IRES-dependent translation and a ribozyme.
  - 63. The method of claim 62, wherein the second antiviral agent is selected from interferon-alpha, ribavirin, thiazolidine, benzanilide, phenanthrenequinone, gliotoxin and cerulenin.
  - 64. The method of claim 63, wherein the second antiviral agent is interferon-alpha.
  - 65. The method of claim 61, wherein R¹is selected from hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, and substituted oxycarbonyl.
  - 66. The method of claim 61, wherein R²is selected from hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, and substituted oxycarbonyl.
  - 67. The method of claim 61, wherein R³is)-N═
    - C(R¹⁰)(R¹¹), wherein R¹⁰and R¹¹are independently selected from hydrogen, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkylamino, substituted alkylamino, amido, substituted amido, aryl, substituted aryl, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
  - 68. The method of claim 61, wherein R³is —
    - NHR¹², and R¹²is selected from acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, substituted oxycarbonyl, and a moiety of structural Formula (II).
  - 69. The method of claim 61, wherein R⁴and R⁷are independently selected from hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, and substituted oxycarbonyl.
  - 70. The method of claim 61, wherein R⁵and R⁸are independently selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, and substituted cycloalkyl.
  - 71. The method of claim 61, wherein R⁶and R⁹are independently selected from hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl, and substituted heteroarylalkanyl.
  - 72. The method of claim 61, wherein:
    - R¹is selected from hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, substituted oxycarbonyl, and
  - 73. The method of claim 72, wherein R²¹is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, and 3-pyridyl;
    - and R²²is hydrogen.
  - 74. The method of claim 72, wherein R²³is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methylbut-1-yl, 3-methylbut-1-yl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3-pyridyl.
  - 75. The method of claim 72, wherein R²⁴is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —
    - CH₂OH, —
      
      CH(OH)CH₃, —
      
      CH₂CO₂H, —
      
      CH₂CH₂CO₂H, —
      
      CH₂CONH₂, —
      
      CH₂CH₂CONH₂, —
      
      CH₂CH₂SCH₃, —
      
      CH₂SH, —
      
      CH₂(CH₂)₃NH₂, —
      
      CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, and 3-indolylmethyl.
  - 76. The method of claim 72, wherein:
    - X is O;
      
      q is 1;
      
      each of R¹³and R¹⁴is hydrogen;
      
      R¹⁵is hydrogen;
      
      W is NR¹⁸, wherein R¹⁸is hydrogen; and
      
      R¹⁶is
  - 77. The method of claim 72, wherein:
    - X is O;
      
      q is 1;
      
      each of R¹³and R¹⁴is hydrogen;
      
      R¹⁵is selected from hydrogen and —
      
      CO₂H;
      
      W is selected from O and NR¹⁸wherein R¹⁸is selected from hydrogen and methyl; and
      
      R¹⁶is selected from
  - 78. The method of claim 77, wherein:
    - R¹is hydrogen;
      
      R²is hydrogen;
      
      R²⁴is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —
      
      CH₂OH, —
      
      CH(OH)CH₃, —
      
      CH₂CO₂H, —
      
      CH₂CH₂CO₂H, —
      
      CH₂CONH₂, —
      
      CH₂CH₂CONH₂, —
      
      CH₂CH₂SCH₃, —
      
      CH₂SH, —
      
      CH₂(CH₂)₃NH₂, —
      
      CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, and 3-indolylmethyl; and
      
      R²⁵is hydrogen.
  - 79. The method of claim 72, wherein:
    - X is O;
      
      q is 1;
      
      each of R¹³and R¹⁴is hydrogen;
      
      R¹⁵is hydrogen;
      
      W is NR¹⁸, wherein R¹⁸is selected from hydrogen and methyl; and
      
      R¹⁶is
  - 80. The method of claim 61, wherein the compound of structural Formula (I) is selected from:
    - β
      
      -1-(4-allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-benzyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(tert-butyldimethylsilyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O—
      
      (N-tert-butyloxycarbonyl-L-valinyl)-5-O-(tert-butyldimethylsilyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-valinyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-5-β
      
      -(tert-butyldimethylsilyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-5-O—
      
      (N-tert-butoxycarbonyl-L-valinyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-valinyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(tert-butyldimethylsilyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(pentyloxycarbonyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-5-O-(pentyloxycarbonyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Phenyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(4-Methoxyphenyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(1,1,1-Trifluoroethyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(4-Methoxybenzyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(Propen-2-yl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2-Carboxy-2-methyl)ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-acetyl-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-acetyl-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Acetoxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(1-Isobutanoyloxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2,6-Dimethylbenzoyl)oxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2-Methylbenzoyl)oxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-Acetoxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-valinyl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-((2S)-Aminopropionylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-((2S)-Amino-3,3-dimethylbutyroylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-(Aminoacetylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-((2S)-Aminophenacetylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-(2-Amino-2-methylpropionylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-((2S)-(1-Amino-cyclohexanecarbonylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2-Acetoxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2-Pivaloyloxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-(4-(2-Cyclohexanecarboxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((2S)-Amino-3-methylbutyroylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((2S)-Amino-3-phenylpropionylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-(Phenyloxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-β
      
      1}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(3-(Benzyloxycarbonylamino)-propoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-[4-(2-Dimethylamino-ethoxycarbonylamino)-2-oxo-1H-pyrimidin-1-yl]-2-C-methyl-ribofuranose;
      
      β
      
      -1-[4-(4-Acetoxybutyroylamino)-2-oxo-1H-pyrimidin-1-yl]-2-C-methyl-ribofuranose;
      
      β
      
      -1-[4-(4-Pivaloyloxybutyroylamino)-2-oxo-1H-pyrimidin-1-yl]-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Pivaloyloxy-2,2-dimethylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((Isobutanoyloxymethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((Acetoxymethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Isobutanoyloxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Acetoxy-2-methylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Isobutanoyloxy-2-methylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Pivaloyloxy-2-methylpropypoxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Pivaloyloxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Acetoxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((Acetoxymethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Isobutanoyloxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Acetoxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Isobutanoyloxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Pivaloyloxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Pivaloyloxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-Acetoxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-(2,6-Dimethylbenzoyl)oxymethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-(2,6-Dimethylbenzoyl)oxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose;
      
      β
      
      -1-{[4-(2-((1-(2-Methylbenzoyl)oxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-C-methyl-ribofuranose; and
      
      a pharmaceutically acceptable salt of any of the foregoing.

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Current Assignee
XenoPort, Inc. (Arbor Pharmaceuticals LLC)
Original Assignee
XenoPort, Inc. (Arbor Pharmaceuticals LLC)
Inventors
Gallop, Mark A.

Application Number

US13/289,685
Publication Number

US 20120082645A1
Time in Patent Office

Days
Field of Search
US Class Current

424/85.2
CPC Class Codes

A61P 31/14 for RNA viruses

C07H 19/06 Pyrimidine radicals

2'-C-METHYL-RIBOFURANOSYL CYTIDINE PRODRUGS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

First Claim

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80 Claims

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2'-C-METHYL-RIBOFURANOSYL CYTIDINE PRODRUGS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

First Claim

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Abstract

11 Citations

80 Claims

Specification

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Solutions

Use Cases

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