US2018200280A1PendingUtilityA1
4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication
Est. expiryMay 16, 2033(~6.9 yrs left)· nominal 20-yr term from priority
A61K 45/06A61K 31/4178A61K 31/4184A61K 31/7056A61K 2300/00A61K 31/7072A61K 31/4188A61K 31/4709A61P 1/16C07H 19/20A61P 31/14A61K 31/683
62
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Claims
Abstract
Cytidine nucleoside analogues of Formula I, wherein the variables are as described herein, in combination with uridine nucleoside analogues of Formula II, wherein the variables are as described herein, produce a synergistic effect on the inhibition of HCV polymerase.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of treatment of HCV by administering to a patient in need thereof a combination of a compound of Formula I in and a compound of Formula II
wherein:
each R is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R′ is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R 1 is independently phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkoxy, halo, lower haloalkyl, or cyano;
each R 2a and R 2b are independently H or lower alkyl;
each R 3 is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;
each X is independently O or S;
each Y is independently H or F; and
each Y′ is independently F or OH;
or a pharmacologically acceptable salt thereof.
2 . The method of claim 1 , wherein Formula I is
3 . The method of claim 1 , wherein Formula I is
4 . The method of claim 1 , wherein Formula I is
5 . The method of claim 1 , wherein Formula I is
6 . The method of claim 1 , wherein Formula I is
7 . The method of claim 1 , wherein Formula I is
8 . The method of claim 1 , wherein Formula I is
9 . The method of claim 1 , wherein Formula I is
10 . The method of claim 1 , wherein Formula I is
11 . The method of claim 1 , wherein Formula I is
12 . The method of claim 1 , wherein Formula I is
13 . The method of claim 1 , wherein Formula I is
14 . The method of claim 1 , wherein Formula I is
15 . The method of claim 1 , wherein Formula I is
16 . The method of claim 1 , wherein Formula I is
17 . The method of claim 1 , wherein the compound of Formula II is Sofosbuvir
18 . The method of claim 1 , wherein Formula II is
19 . The method of claim 1 , wherein compound of Formula II is
20 . The method of claim 1 , wherein compound of Formula II is
21 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
22 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
23 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
24 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
25 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
26 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
27 . The method of claim 1 , wherein the compound of Formula I and the compound of Formula II are, respectively,
28 . The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
(S)-2-{[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-[((S)-1-isopropoxycarbonyl-ethylamino)-(naphthalen-2-yloxy)-phosphoryloxy]-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-4-methyl-3-propionyloxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-{(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-{(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; and (S)-2-[[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester.
29 . The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
2′-Deoxy-2′,4′-difluoro-2′-methycytidine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-3′,5′-cyclic phosphoric acid isopropyl ester; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-3′,5′-cyclic thiophosphoric acid isopropyl ester; 4′-Fluoro-2′-methylcytidine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-cytidine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-methylcytidine-5′-(O-1-naphthyl-N—(S)-2-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-methylcytidine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methylcytidine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methylcytidine-5′-(O-1-naphthyl-N—(S)-2-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methylcytidine-3′,5′-cyclic phosphoric acid isopropyl ester; 4′-Fluoro-2′-methylcytidine-3′,5′-cyclic thiophosphoric acid isopropyl ester; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate; 2′-Deoxy-2′,4′-difluoro-2′-methylcytidine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate; 4′-Fluoro-2′-methylcytidine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate; and 4′-Fluoro-2′-methylcytidine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate.
30 . The method of claim 1 , wherein the compound of Formula II is selected from the group consisting of:
2′-Deoxy-2′,4′-difluoro-2′-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate; 2′-Deoxy-2′,4′-difluoro-2′-methyluridine-5′-(O-2-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate; 2′-Deoxy-2′,4′-difluoro-2′-methyluridine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate 2′-Deoxy-2′,4′-difluoro-2′-methyluridine-3′,5′-cyclic phosphoric acid isopropyl ester; 4′-Fluoro-2′-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-methyluridine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-methyluridine-5′-(O-1-naphthyl-N—(S)-2-(isopropoxycarbonyl)ethyl phosphoramidate; 4′-Fluoro-2′-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methyluridine-5′-(O-1-naphthyl-N—(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methyluridine-5′-(O-1-naphthyl-N—(S)-2-(isopropoxycarbonyl)ethyl thiophosphoramidate; 4′-Fluoro-2′-methyluridine-3′,5′-cyclic phosphoric acid isopropyl ester; 4′-Fluoro-2′-methyluridine-3′,5′-cyclic thiophosphoric acid isopropyl ester; 2′-Deoxy-2′,4′-difluoro-2′-methyluridine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate; 2′-Deoxy-2′,4′-difluoro-2′-methyluridine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate; 4′-Fluoro-2′-methyluridine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate; and 4′-Fluoro-2′-methyluridine-5′-{N,N′-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate.
31 . The method of claim 1 , wherein the compound of Formula II is selected from the group consisting of:
(S)-2-{[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-[((S)-1-isopropoxycarbonyl-ethylamino)-(naphthalen-2-yloxy)-phosphoryloxy]-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-4-methyl-3-propionyloxy-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-{(S)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-{(R)-[(2S,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(S)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester; (S)-2-[(R)-[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester; and (S)-2-[[(2S,3S,4R,5R)-5-(5-Bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-2-yloxy)-phosphorylamino]-propionic acid isopropyl ester.
32 . The method of claim 1 , wherein the combination of a compound of Formula I and a compound of Formula II further comprises one or more of ribavirin, peginterferon-α, simeprevir, ledipasvir, daclatasvir, and velpatasvir.
33 . A composition comprising a compound of Formula I and a compound of Formula II, admixed with at least one carrier, diluent or excipient
wherein:
each R is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R′ is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R 1 is independently phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkoxy, halo, lower haloalkyl, or cyano;
each R 2a and R 2b are independently H or lower alkyl;
each R 3 is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;
each X is independently O or S;
each Y is independently H or F; and
each Y′ is independently F or OH;
or a pharmacologically acceptable salt thereof.
34 . A method of treatment of HCV by administering to a patient in need thereof a compound of Formula I, or a combination of Formula I and Formula II, further in combination with a NS3A HCV protease inhibitor
wherein:
each R is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R′ is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R 1 is independently phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkoxy, halo, lower haloalkyl, or cyano;
each R 2a and R 2b are independently H or lower alkyl;
each R 3 is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;
each X is independently O or S;
each Y is independently H or F; and
each Y′ is independently F or OH;
or a pharmacologically acceptable salt thereof.
35 . A method of treatment of HCV by administering to a patient in need thereof a compound of Formula I, or a combination of Formula I and Formula II, further in combination with an additional NS5B HCV polymerase inhibitor
wherein:
each R is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R′ is independently O—R 1 or NHC(R 2a )(R 2b )C(═O)OR 3 ;
each R 1 is independently phenyl or naphthyl, optionally substituted with one or more lower alkyl, lower alkoxy, halo, lower haloalkyl, or cyano;
each R 2a and R 2b are independently H or lower alkyl;
each R 3 is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;
each X is independently O or S;
each Y is independently H or F; and
each Y′ is independently F or OH;
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