Patent
Substituted purine nucleosides, phosphoroamidate and phosphorodiamidate derivatives for treatment of viral infections
| العنوان: | Substituted purine nucleosides, phosphoroamidate and phosphorodiamidate derivatives for treatment of viral infections |
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| Patent Number: | 9,351,989 |
| تاريخ النشر: | May 31, 2016 |
| Appl. No: | 13/988354 |
| Application Filed: | December 29, 2011 |
| مستخلص: | This invention is directed to phosphoroamidate and phosphorodiamidate derivatives including the compounds of formula (I) having the structure [chemical expression included] wherein U, V, W, Z, R1, X1, X2, and Y are defined herein. These compounds and pharmaceutical compositions containing these compounds are useful in the treatment of viral infections in mammals infected by a virus in the Flaviviridae family of viruses, in particular hepatitis C virus (HCV). The compounds of this invention may be prepared by various methods known in the art of organic chemistry in general and nucleoside and nucleotide analog synthesis in particular. |
| Inventors: | McGuigan, Chris (Cardiff, GB); Madela, Karolina (Cardiff, GB); Bourdin, Claire (Cardiff, GB); Vernachio, John (Canton, GA, US); Chamberlain, Stanley (Chapel Hill, NC, US) |
| Assignees: | INHIBITEX, INC. (Alpharetta, GA, US), UNIVERSITY COLLEGE CARDIFF CONSULTANTS LIMITED (Cardiff, GB) |
| Claim: | 1. A compound of formula (I) having the structure: [chemical expression included] wherein U and V are each independently selected from the group consisting of H OH Cl Br I OR 1 NH 2 NHR 2 NR 2 R 2 SH and SR 3 wherein R 1 , R 2 , and R 3 are independently C 1 -C 6 alkyl or alkyl(C 1 -C 3)aryl; W is independently selected from the group consisting of I OH NH 2 SH SR 4 OR 5 NHR 6 and NR 6 R 6 , wherein R 4 , R 5 and R 6 are independently C 1 -C 6 alkyl or alkyl(C 1 -C 3)aryl; X 1 is OH or F; X 2 is OH; Y is hydrogen or N 3 (azido); Z is selected from the group consisting of H —P(O)(OAr)NHR 7 —P(O)(NHR 7) 2 —P(O)(O −)NHR 7 —P(O)O − 2 (monophosphate) and —PO 2 —O—PO 2 —O—PO 3 (triphosphate) wherein R 7 is —C(R 8)(R 9)C(O)OR 10 wherein R 8 and R 9 are independently hydrogen, alkyl, aryl(C 1 -C 6)alkyl, or phenyl, R 10 is C 1 -C 6 alkyl aryl(C 1 -C 6)alkyl, [chemical expression included] and Ar is independently selected from the group consisting of phenyl 1-naphthyl 2-naphthyl [chemical expression included] and [chemical expression included] wherein the compound has a specific formula selected from the group consisting of the following: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] and the pharmaceutically acceptable salts thereof. |
| Claim: | 2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent. |
| Claim: | 3. The compound according to claim 1 wherein the compound is selected from the group consisting of the following: (2R,3R,4R,5R)-2-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; 2-amino-9-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-8-iodo-1H-purin-6(9H)-one; benzyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)propanoate; (2S)-2,4-difluorobenzyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-propyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-butyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-pentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-cyclobutyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-cyclopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-cyclohexyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-benzyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-4-(methylthio)butanoate; (2S)-benzyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S,2′S)-benzyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-bis(3,3-dimethylbutyl) 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-neopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-dicyclohexyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; ((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-oxo-1H-purin-9(6H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl phosphate; ((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-oxo-1H-purin-9(6H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl triphosphate; (S)-2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)oxidophosphorylamino)propanoate; 1(S)-phenylethyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)propanoate; (2S)-2,3-dihydro-1H-inden-2-yl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-3,3-dimethylbutyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-isobutyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (S)—P 2,2-dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)propanoate; (R)—P 2,2-dimethylpropyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)propanoate; (2S)-isopropyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-2,4-difluorobenzyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)propanoate; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)propanoate; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; (2S)-2,4-difluorobenzyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-methyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-cyclopropylmethyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-cyclobutyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-cyclopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-cyclohexyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-tetrahydro-2H-pyran-4-yl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-2,4 difluorobenzyl 2-((((2R,3R,4R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-5-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(quinolin-6-yloxy)phosphorylamino)-3-methylbutanoate; (2R)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)—((S)-1-phenylethyl) 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-4-(methylthio)butanoate; (2S)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-4-(methylthio)butanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-4-methylpentanoate; (2S,3R)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylpentanoate; (2S)-benzyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2S)-propyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2S)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2S)-cyclohexyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2R)-benzyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2R)-propyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2R)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (2R)-cyclohexyl 2-(((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate; (3R,4R,5R)-2-(2-amino-6-ethoxy-8-iodo-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; benzyl 2(S)-((((2R,3R,4R,5R)-5-(2-amino-6-ethoxy-8-iodo-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy(naphthalene-1-yloxy)phosphorylamino)-3-methylbutanoate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-8-iodo-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-isopropyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-8-iodo-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-6-ethoxy-8-iodo-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-3-methylbutanoate; (2R,3R,4R,5R)-2-(2-amino-8-iodo-6-(methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate (2S)-benzyl 2-((((2R,3R,4R,5R)-5-(2-Amino-8-iodo-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2R,3R,4R,5R)-2-(2-amino-6-(benzylamino)-8-iodo-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-6-(benzylamino)-8-iodo-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2R,3R,4R,5R)-2-(2-amino-8-iodo-6-(phenethylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-(phenethylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2R,3R,4R,5R)-2-(2-amino-8-iodo-6-(methylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2S)-benzyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-(methylthio)-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-(methylthio)-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2R,3R,4R,5R)-2-(2-(4-fluorobenzylamino)-8-iodo-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-(4-fluorobenzylamino)-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate; (2S,2′S)-dimethyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-diethyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-dipropyl-((((2R,3S,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-(2,2′)-bis-amino-dipropanoate; (2S,2′S)-dibutyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate (2S,2′S)-dipentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-diisobutyl-((((2R,3S,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)(2,2′)-bis-amino-dipropanoate; (2S,2′S)-bis (cyclopropylmethyl) 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-diisopropyl-((((2R,3S,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-(2,2′)-bis-amino-dipropanoate; (2S,2′S)-sec-butyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-dicyclobutyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-dicyclopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-bis (tetrahydro-2H-pyran-4-yl) 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)—(S)-phenylethyl-((((2R,3S,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-(2,2′)-bis-amino-dipropanoate; (2S,2′S)-bis(2,3-dihydro-1H-inden-2-yl) 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S)-benzyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((S)-1-(neopentyloxy)-1-oxopropan-2-ylamino)phosphorylamino)propanoate; (2S)-cyclohexyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((S)-1-(neopentyloxy)-1-oxopropan-2-ylamino)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(benzylamino)phosphorylamino)propanoate; (2S)-neopentyl 2-((((2R,3R,4R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-ylamino)phosphorylamino)propanoate; benzyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)diacetate; neopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)diacetate; (2R,2′R)-neopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate; (2S,2′S)-benzyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(4-methylpentanoate); (2R,2′R)-neopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(4-methylthiobutanoate; (2S,2′S)-benzyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(3-methyl butanoate); (2S,2′S)-dicyclohexyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(3-methylbutanoate); (2S,2′S)-neopentyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(2-phenylacetate); and (2S,2′S)-dicyclohexyl 2,2′-((((2R,3R,4R,5R)-5-(2-amino-8-iodo-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)bis(2-phenylacetate); and the pharmaceutically acceptable salts thereof. |
| Claim: | 4. A method for treating a viral infection in a mammal infected by a virus in the Flaviviridae family of viruses comprising administering to a mammal in need thereof an effective amount of the compound of claim 1 ; and wherein said virus is hepatitis C virus. |
| Claim: | 5. A method for treating a hepatitis C viral infection in a mammal comprising administering to a mammal in need thereof an effective amount of the pharmaceutical composition of claim 2 . |
| Claim: | 6. A composition comprising a compound of formula (I) having the structure: [chemical expression included] wherein U and V are each independently selected front the group consisting of H OH Cl Br I OR 1 NH 2 NHR 2 NR 2 R 2 SH and SR 3 wherein R 1 , R 2 , and R 3 are independently C 1 -C 6 alkyl or alkyl(C 1 -C 3)aryl; W is independently selected from the group consisting of I OH NH 2 SH SR 4 OR 5 NHR 6 and NR 6 R 6 , wherein R 4 , R 5 and R 6 are independently C 1 -C 6 alkyl or alkyl(C 1 -C 3)aryl; X 1 is OH or F; X 2 is OH; Y is hydrogen or N 3 (azido); Z is selected from the group consisting of H —P(O)(OAr)NHR 7 —P(O)(NHR 7) 2 —P(O)(O −)NHR 7 —P(O)O − 2 (monophosphate) and —PO 2 —O—PO 2 —O—PO 3 (triphosphate) wherein R 7 is —C(R 8)(R 9)C(O)OR 10 wherein R 8 and R 9 are independently hydrogen, alkyl, aryl(C 1 -C 6)alkyl, or phenyl, R 10 is C 1 -C 6 alkyl aryl(C 1 -C 6)alkyl, [chemical expression included] and Ar is independently selected from the group consisting of phenyl 1-naphthyl 2-naphthyl [chemical expression included] and [chemical expression included] and the pharmaceutically acceptable salts thereof, wherein the composition comprises a mixture of at least two different diastereomers around phosphorous in formula I. |
| Claim: | 7. The composition according to claim 6 wherein the mixture comprises at least two phosphorous diastereomers in any proportion from 1:99 to 99:1. |
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| Other References: | European Search Report dated Jun. 4, 2014 in corresponding European Application No. 11852610.2. cited by applicant International Search Report for PCT/US2011/067862; Aug. 30, 2012. cited by applicant |
| Primary Examiner: | Crane, Lawrence E |
| Attorney, Agent or Firm: | Schulman, Esq., B. Aaron Stites & Harbison, PLLC. |
| رقم الانضمام: | edspgr.09351989 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |