Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis c virus

Inactive Publication Date: 2006-10-11
ANDADYS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A second imidazoquinoline compound, resiquimod, is available for the treatment of HCV, but this compound has no anti-HCV effect at tolerated oral doses
Current evidence suggests that administered body concentrations of this class of drugs are limited by increased gastrointestinal toxicity following low oral doses

Method used

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  • Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis c virus
  • Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis c virus
  • Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis c virus

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0134] The preparation of the TLR7 ligand prodrug of the present invention is as follows: prepare (a) the amide, carbamate or amidine moiety after the TLR7 ligand amine substituent conversion, (b) the ester, carbonate after the TLR7 ligand alcohol substituent conversion , carbamate, ether, imide ester, acetal or ketal moiety, (c) acetal or ketal moiety after conversion of TLR7 ligand amine substituent, (d) carbonyl substitution of TLR7 ligand amide group (e) the deoxygenated product after conversion of the oxo substituent of the TLR7 ligand pyrimidine or guanosine, (f) amine. For example, TLR7 ligand prodrugs are prepared by (1) converting the hydroxyl (OH) substituent of the TLR7 ligand to an amino acid ester, or (2) converting the amine substituent of the TLR7 ligand to an amide or carbamate ester. Methods for preparing prodrugs are well known in the art, as described in Burger's Medicinal Chemistry and Drug Chemistry, 1, 172-178, 949-982 (1995). See also Bertolini et...

Embodiment 1

[0441] Example 1: 7-allyl-2-amino-9-β-D-ribofuranosyl-7,9-dihydro-purin-8-one (43)

[0442]

[0443] Step 1: Preparation of 7-allyl-2-amino-9-(2',3',5'-tri-O-acetyl-β-D-nucleofuranosyl)-7,9-dihydro- 1H-purine-6,8-dione (40)

[0444] 7-Allyl-2-amino-9-β-D-ribofuranosyl-7,9-dihydro-1H-purine-6,8-dione 17 was stirred in anhydrous acetonitrile (25 mL) ( 1.00 g, 2.95 mmol, prepared according to Reitz et al., JMC, 37, 3561-3578 (1994), DMAP (0.036 mg, 0.29 mmol) and NEt 3 (2.05 mL, 14.74 mmol) of a heterogeneous mixture. Acetic anhydride (0.862 mL, 9.13 mmol) was slowly added to the suspension, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (DCM). Then with saturated aqueous sodium bicarbonate (NaHCO 3 ), washed the organic phase with brine, and then washed with anhydrous magnesium sulfate (MgSO 4 )dry. The solvent was concentrated in vacuo and dried under high vacuum at r...

Embodiment 2

[0451] Example 2: 7-allyl-2-amino-6-ethoxy-9-β-D-ribofuranosyl-7,9-dihydro-purin-8-one (45)

[0452]

[0453] Step 1: Preparation of 7-allyl-2-amino-6-ethoxy-9-(2',3',5'-tri-O-acetyl-β-D-nucleofuranosyl)-7 , 9-dihydro-purin-8-one (44)

[0454] To a solution of 40 (0.30 g, 0.64 mmol) in anhydrous THF (15 mL) was added polymer-supported triphenylphosphine (0.89 g, 1.93 mmol) and EtOH (0.11 mL, 1.93 mmol) at room temperature. To the stirred mixture, diethyl azodicarboxylate (0.12 mL, 0.77 mmol) was added, and stirring was continued for 18 h. The spent polymer support was filtered off and the solvent was removed in vacuo. The residue was then purified by flash chromatography using a gradient of 10-50% ethyl acetate in hexanes. Removal of the solvent afforded 85 mg (26%) of the desired product 6 as a clear oil: 1 H NMR (400MHz, CDCl 3 )δ6.07(d, J=4.0Hz, 1H), 6.06(d, J=4.0Hz, 1H), 6.01(d, J=3.6Hz, 1H), 5.96(t, J=6.0Hz, 1H) , 5.87(m, 1H), 5.14(d, J=2.2Hz, 1H), 5.15(m, 1H), 4...

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Abstract

This invention relates to methods for treating or preventing hepatitis C virus infections in mammals using Toll-Like Receptor (TLR)7 ligands and prodrugs thereof. More particularly, this invention relates to methods of orally administering a therapeutically effective amount of one or more prodrugs of TLR7 ligands for the treatment or prevention of hepatitis C viral infection. Oral administration of these TLR7 immunomodulating ligands and prodrugs thereof to a mammal provides therapeutically effective amounts and reduced undesirable side effects.

Description

[0001] This application claims the benefits of U.S. Provisional Patent Application 60 / 500,339, filed September 5, 2003, U.S. Provisional Patent Application 60 / 518,996, filed November 10, 2003, and U.S. Provisional Patent Application 60 / 518,997, filed November 10, 2003 priority. 1. Field of invention [0002] The present application relates to methods of treating or preventing hepatitis C virus infection in mammals using Toll-like receptor (TLR) 7 ligands and prodrugs thereof. More specifically, the present invention relates to the oral administration of a therapeutically effective amount of one or more prodrugs of TLR7 ligands for the treatment or prevention of hepatitis C virus infection. Oral administration of these TLR7 immunomodulatory ligands and prodrugs thereof to mammals can provide therapeutically effective amounts with reduced adverse side effects. 2. Background of the invention [0003] Small molecule immunomodulation is achieved by identifying compounds that bin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/708A61P31/14
CPCY02A50/30
Inventor D·R·埃夫里特
Owner ANDADYS PHARMA INC
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