Pyrimidine nucleosides and their monophosphate prodrugs for the treatment of viral infections and cancer

• US 9,809,616 B2
• Filed: 10/29/2013
• Issued: 11/07/2017
• Est. Priority Date: 10/29/2012
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Cocrystal Pharma, Inc., Emory University
• Inventors: Amblard, Franck, Coats, Steven J., Schinazi, Raymond F.
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US14/066,461
• Publication Number:
  US 20140235566A1
• Time in Patent Office: 1,470 Days
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate

Abstract

The compounds are of the class of N4-hydroxycytidine nucleosides, modified monophosphate and phosphonates prodrugs analogs, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof, useful in treating HCV or Norovirus infections.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein each R¹ is, independently, C_1-20 alkyl, the carbon chain derived from a fatty alcohol, or C_1-20 alkyl substituted with a C₁-C₆ alkyl, alkoxy, di(C₁-C₆ alkyl)-amino, fluoro, C_3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;

wherein the substituents are C_1-6 alkyl, or C_1-6 alkyl substituted with a C₁-C₆ alkyl, C₁-C₆ alkoxy, di(C₁-C₆ alkyl)-amino, fluoro, or C_3-10 cycloalkyl.

3. The compound of claim 1, wherein R^7′

is independently selected from the group consisting of H, F, Cl, Br, I, N₃, C(O)OH, CN, CH₂OH, C(O)NH₂, C(S)NH₂, C(O)OR, and R.

4. The compound of claim 1, wherein the compounds are described herein are in the form of the β

-L- or β

-D-configuration, or a mixture thereof.

5. The compound of claim 1, wherein when the phosphorous portion of the compound described herein contains a chiral center, such chiral center is in the form of the R_p- or S_p-configuration or a mixture thereof.

9. A method for treating a host infected with hepatitis C viral infections in a host in need thereof, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

10. The method of claim 9, wherein the compound is administered in combination with another anti-HCV agent selected from the group consisting of interferons, anti-fibrotics, inosine monophosphate dehydrogenase inhibitors, apotosis regulators, vaccines, monoclonal antibodies, immunomodulators, antisense therapeutics, caspase inhibitors, polymerase inhibitors, anti-phospholipid agents, serine protease inhibitors, and immunomodulators.

11. The method of claim 9, wherein the compounds have been shown in previous test hosts to be converted in vivo to a mixture of compounds comprising mixture C or D of 4-NHOH, 4-NH₂ and 4-OH pyrimidine triphosphates:

6. A compound of one of the following formulas:

7. A compound of the formula:

8. A compound of one of the following formulas: