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Patent · US7429572B2 · B2 · US

Modified fluorinated nucleoside analogues

(11) Publication number
US7429572B2
(21) Application number
US-82875304-A
(22) Filing date
2004-04-21
(30) Priority date
2003-05-30
(43) Publication date
2008-09-30
(45) Date of grant
2008-09-30
(52) CPC
  • C07H Sugars; derivatives thereof; nucleosides; nucleotides; nucleic acids: 19/00, 19/04, 19/048, 19/06, 19/14, 19/16
  • A61K Preparations for medical, dental or toiletry purposes: 31/7068, 31/7072
  • A61P Specific therapeutic activity of chemical compounds or medicinal preparations: 1/16, 31/00, 31/04, 31/12, 31/14, 31/16, 35/00, 43/00
(73) Assignee
PHARMASSET INC
(54) Title
Modified fluorinated nucleoside analogues
(57) Abstract

The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.

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Claims (19)

  1. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) or its pharmaceutically acceptable salt of the structure: wherein Base is a pyrimidine base represented by the following formula X is O; R 1 and R 7 are independently H, a monophosphate, a diphosphate, a triphosphate, a H-phosphonate, alkyl, an alkyl sulfonyl, or an arylalkyl sulfonyl; and R 3 is H and R 4 is NH 2 or OH.
  2. The (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof, wherein R 7 is H and R 1 is a monophosphate, or diphosphate, or a triphosphate.
  3. The (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) of claim 1 or its pharmaceutically acceptable salt thereof, R 7 is H and R 1 is a diphosphate or a triphosphate.
  4. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof wherein R 7 is H and R 1 is a triphosphate.
  5. (2′)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof wherein R 1 and R 7 are H.
  6. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) or its pharmaceutically acceptable salt thereof of the formula:
  7. A pharmaceutical composition comprising the nucleoside of claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  8. The pharmaceutical composition comprising the nucleoside of claim 2 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  9. The pharmaceutical composition comprising the nucleoside of claim 3 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  10. A pharmaceutical composition comprising the nucleoside of claim 4 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  11. A pharmaceutical composition comprising the nucleoside of claim 5 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  12. A pharmaceutical composition comprising the nucleoside of claim 6 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  13. A method of synthesizing a nucleoside of claim 1, which comprises glycosylating the pyrimidine with a compound having the following structure; wherein R is lower alkyl, acyl, benzoyl, or mesyl; and Pg is selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3, CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg's may come together to for a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
  14. A method of synthesizing the nucleoside of claim 1, which comprises selectively deprotecting a 3′-OPg or a 5′-OPg of a compound having the following structure: wherein each Pg is independently a protecting group selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3, CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg's may come together to for a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
  15. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) or its pharmaceutically acceptable salt thereof of the formula:
  16. A pharmaceutical composition comprising the nucleoside of claim 15 or its pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier.
  17. A liposomal composition comprising liposomes comprising the compound of claim 1 and optionally a pharmaceutically acceptable carrier.
  18. A liposomal composition comprising liposomes comprising the compound of claim 6 and optionally a pharmaceutically acceptable carrier.
  19. A liposomal composition comprising liposomes comprising the compound of claim 15 and optionally a pharmaceutically acceptable carrier.

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Record as JSON 
{
  "publication_number": "US7429572B2",
  "country": "US",
  "kind": "B2",
  "title": "Modified fluorinated nucleoside analogues",
  "abstract": "The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a (2'R)-2'-deoxy-2'-fluoro-2'-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.",
  "claims": [
    "1. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) or its pharmaceutically acceptable salt of the structure: wherein Base is a pyrimidine base represented by the following formula X is O; R 1 and R 7 are independently H, a monophosphate, a diphosphate, a triphosphate, a H-phosphonate, alkyl, an alkyl sulfonyl, or an arylalkyl sulfonyl; and R 3 is H and R 4 is NH 2 or OH.",
    "2. The (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof, wherein R 7 is H and R 1 is a monophosphate, or diphosphate, or a triphosphate.",
    "3. The (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) of claim 1 or its pharmaceutically acceptable salt thereof, R 7 is H and R 1 is a diphosphate or a triphosphate.",
    "4. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof wherein R 7 is H and R 1 is a triphosphate.",
    "5. (2′)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D or β-L) of claim 1 or its pharmaceutically acceptable salt thereof wherein R 1 and R 7 are H.",
    "6. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) or its pharmaceutically acceptable salt thereof of the formula:",
    "7. A pharmaceutical composition comprising the nucleoside of claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "8. The pharmaceutical composition comprising the nucleoside of claim 2 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "9. The pharmaceutical composition comprising the nucleoside of claim 3 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "10. A pharmaceutical composition comprising the nucleoside of claim 4 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "11. A pharmaceutical composition comprising the nucleoside of claim 5 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "12. A pharmaceutical composition comprising the nucleoside of claim 6 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.",
    "13. A method of synthesizing a nucleoside of claim 1, which comprises glycosylating the pyrimidine with a compound having the following structure; wherein R is lower alkyl, acyl, benzoyl, or mesyl; and Pg is selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3, CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg's may come together to for a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).",
    "14. A method of synthesizing the nucleoside of claim 1, which comprises selectively deprotecting a 3′-OPg or a 5′-OPg of a compound having the following structure: wherein each Pg is independently a protecting group selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3, CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg's may come together to for a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).",
    "15. A (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleoside (β-D) or its pharmaceutically acceptable salt thereof of the formula:",
    "16. A pharmaceutical composition comprising the nucleoside of claim 15 or its pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier.",
    "17. A liposomal composition comprising liposomes comprising the compound of claim 1 and optionally a pharmaceutically acceptable carrier.",
    "18. A liposomal composition comprising liposomes comprising the compound of claim 6 and optionally a pharmaceutically acceptable carrier.",
    "19. A liposomal composition comprising liposomes comprising the compound of claim 15 and optionally a pharmaceutically acceptable carrier."
  ],
  "cpc": [
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    "A61K 31/7072",
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    "C07H 19/04",
    "C07H 19/048",
    "C07H 19/06",
    "C07H 19/14",
    "C07H 19/16"
  ],
  "assignees": [
    "PHARMASSET INC"
  ],
  "filing_date": "2004-04-21",
  "publication_date": "2008-09-30",
  "grant_date": "2008-09-30",
  "priority_date": "2003-05-30",
  "application_number": "US-82875304-A",
  "family_id": "33563735",
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}

Record 2,605 of 5,000 in Patents full text (MLC-0201). Request the full dataset.