Tricyclic-Nucleoside Prodrugs for Treating Viral Infections
a technology of nucleosides and prodrugs, applied in the field of pharmaceutical chemistry, can solve the problems of liver failure, no compound described above has advanced beyond clinical trials, and the number of patients still has significant side effects
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Benefits of technology
Problems solved by technology
Method used
Image
Examples
example 5
Preparation of 2-(2′-methyl-β-D-ribofuanosyl)-6,7,8,9-tetrahydro-2H-2,3,5,6-tetraaza-benzo[cd]azulene (Compound 305)
[0375]
Step 1:
[0376]N-trifluoroacetyl propargylamine was synthesized as described in Tetrahedron Lett. 1988, Vol. 29, No. 41 pp. 5221-5224.
Step 2:
[0377]To a solution of the product from Example 1, Step 3 (125 mg, 0.294 mmol) in DMF (1.7 mL) and THF (5 mL) was added CuI (4.4 mg, 0.0231 mmol) and TEA (0.25 mL, 1.46 mmol). The mixture was degassed with argon under sonication for 2-3 minutes followed by the addition of Pd(PPh3)2Cl2 (4.4 mg, 0.00627 mmol) and 0.6 mL (6.86 mmol) of n-trifluoroacetyl propargylamine. The reaction was allowed to stir at room temperature overnight. The following day, the reaction mixture was concentrated and purified on Phenomenex-C18 reverse phase HPLC with a 0-80% B gradient over 30 min at 10 mL / min (Buffer A=H2O, Buffer B=acetonitrile) to afford 100 mg; MS (M+1): 449.09.
Step 3:
[0378]To a solution of the product from Example 5, Step 2 (30 mg, 0...
example 7
Preparation of 2-(2′-methyl-β-D-ribofuanosyl)-9-methylamino-2,6-dihydro-2,3,5,6-tetraaza-benzo[cd]azulen-7-one (Compound 307)
[0381]
[0382]The product from Example 1, Step 5 (225 mg, 0.598 mmol) in methylamine (9 mL, 1 M in THF) was sealed in an autoclave bomb and heated to 80° C. for 1 hour. The reaction mixture was concentrated and the residue was taken up in 11.6 mL of 0.5 M NaOEt and heated to 80° C. for 1 hour. The reaction mixture was concentrated and purified on Phenomenex-C18 reverse phase HPLC with a 0-40% B gradient over 20 min at 10 mL / min (Buffer A=H2O, Buffer B=acetonitrile) to afford 110 mg; 1H NMR (DMSO-d6): δ 0.76 (s, 3H), 2.82 (d, 3H, J=4.2) 3.72-3.98 (m, 4H), 4.81 (d, 1H), 4.88 (t, 1H) 5.24 (d, 1H, J=8.1), 5.25 (s, 1H), 6.20 (s, 1H), 7.08 (d, 1H, J=4.8), 7.80 (s, 1H), 8.32 (s, 1H), 10.16 (s, 1H); MS (M+1): 362.15.
BIOLOGICAL EXAMPLES
example 1
Anti-Hepatitis C Activity
[0383]Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes needed in the replication cycle, or by other pathways. A number of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture was disclosed in U.S. Pat. No. 5,738,985 to Miles et al. In vitro assays have been reported in Ferrari et al. Jnl. of Vir., 73:1649-1654, 1999; Ishii et al., Hepatology, 29:1227-1235, 1999; Lohmann et al., Jnl of Bio. Chem., 274:10807-10815, 1999; and Yamashita et al., Jnl. of Bio. Chem., 273:15479-15486, 1998.
[0384]WO 97 / 12033, filed on Sep. 27, 1996, by Emory University, listing C. Hagedorn and A. Reinoldus as inventors, which claims priority to U.S. Provisional Patent Application Ser. No. 60 / 004,383, filed on September 1995, described an HCV polymerase assay that can be used to evaluate the activity of the of the compounds described herein. Another HCV ...
PUM
| Property | Measurement | Unit |
|---|---|---|
| temperature | aaaaa | aaaaa |
| temperature | aaaaa | aaaaa |
| temperature | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More