US2003225037A1PendingUtilityA1
Method for the treatment or prevention of Flaviviridea viral infection using nucleoside analogues
Est. expiryNov 4, 2019(expired)· nominal 20-yr term from priority
Inventors:Richard Storer
A61K 38/21A61K 31/505A61K 31/52A61P 31/14A61K 31/53A61K 31/415A61K 45/06A61K 38/208
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Claims
Abstract
In accordance with the present invention there is provided a method for treating or preventing a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound of formula (I) or (II) or or a pharmaceutically acceptable salts thereof, wherein Ra, R, Z and Y are defined in the application.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for treating or preventing a Flaviviridae viral infection in a host comprising administering a therapeutically effective amount of at least one compound having the formula I or a pharmaceutically acceptable salt thereof:
wherein:
R is H, —NR 2 R 3 or OR 4 wherein
R 2 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl;
R 3 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; and
Ra is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl and
wherein each Rc is independently chosen from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and an hydroxy protecting group;
wherein said nucleoside is present in the form of the (−) enantiomer, (+) enantiomer and mixtures thereof, including racemic mixtures.
2 . The method of claim 1 wherein R is NH 2 , H or OH.
3 . The method of claim 1 wherein R is NH 2 or OH.
4 . The method of claim 1 wherein R is OH.
5 . The method of claim 1 wherein R is —NR 2 R 3 wherein R 2 is cycloropyl and R 3 is H.
6 . The method of claim 1 wherein Ra is chosen from H, monophosphate, diphosphate, and triphosphate.
7 . The method of claim 1 wherein Ra is chosen from monophosphate, diphosphate, and triphosphate.
8 . The method of claim 1 wherein Ra is triphosphate.
9 . The method of claim 1 wherein Ra is H.
10 . The method as defined in claim 1 wherein said compound of formula I of the present invention is substantially in the form of the (−) enantiomer.
11 . The method of claim 1 which comprises administering at least one compound chosen from:
Compound 1 cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane;
Compound 2 cis-2-hydroxymethyl-4-(2′-amino-6′-cyclobutylamino-purine-9′-yl)-1,3-dioxolane;
Compound 3 cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopentylamino-purine-9′-yl)-1,3-dioxolane;
Compound 4 -cis-2-hydroxymethyl-4-(2′-6′-diamino-purin-9′-yl)-1,3-dioxolane;
Compound 5 cis-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane;
Compound 6 cis-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane;
Compound 7 cis-2-hydroxymethyl-4-(2′amino-6′-chloro-purin-9′-yl)-1,3-dioxolane; or
Compound 8 cis-2-hydroxymethyl-4-(2′amino-purin-9′-yl)-1,3-dioxolane.
12 . The method of claim 1 which comprises administering at least one compound chosen from
Compound 1(−) cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopropylamino-purine-9′-yl)-1,3-dioxolane;
Compound 2(−) cis-2-hydroxymethyl-4-(2′-amino-6′-cyclobutylamino-purine-9′-yl)-1,3-dioxolane;
Compound 3(−) cis-2-hydroxymethyl-4-(2′-amino-6′-cyclopentylamino-purine-9′-yl)-1,3-dioxolane;
Compound 4(−) -cis-2-hydroxymethyl-4-(2′-6′-diamino-purin-9′-yl)-1,3-dioxolane;
Compound 5(−) cis-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane;
Compound 6) (−) cis-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane;
Compound 7(−) cis-2-hydroxymethyl-4-(2′amino-6′-chloro-purin-9′-yl)-1,3-dioxolane; or
Compound 8(−) cis-2-hydroxymethyl-4-(2′amino-purin-9′-yl)-1,3-dioxolane.
13 . The method as defined in claim 1 wherein said Flaviviridae viral infection is hepatitis C (HCV).
14 . The method as defined in claim 10 wherein said Flaviviridae viral infection is hepatitis C (HCV).
15 . The method as defined in claim 11 wherein said Flaviviridae viral infection is hepatitis C (HCV).
16 . The method as defined in claim 12 wherein said Flaviviridae viral infection is hepatitis C (HCV).
17 . A method for treating or preventing a hepatitis C viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula I as defined in claim 1 and at least one further antiviral agent.
18 . The method according to claim 17 wherein the antiviral agent is chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
19 . The method according to claim 17 wherein the antiviral agent chosen from interferon (IFN), interferon α-2a, interferon α-2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.
20 . The method according to claim 17 wherein the antiviral agent chosen from interferon α and ribavirin.
21 . A pharmaceutical composition for treating or preventing a hepatitis viral C infection comprising administering at least one compound according to formula I as defined in claim 1 together with at least one pharmaceutically acceptable carrier or excipient.
22 . A method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of at least one compound having the formula I:
or a pharmaceutically acceptable salts thereof, wherein:
R is H, —NR 2 R 3 or OR 4 wherein
R 2 is H, C 1-6 alkyl, C 2-6 alkenyl,or C 2-6 alkynyl;
R 3 is H or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; and
Ra is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl and
wherein each Rc is independently chosen from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and an hydroxy protecting group;
wherein said nucleoside is present in the form of the (−) enantiomer,(+) enantiomer and mixtures thereof, including racemic mixtures.
23 . The method of claim 22 wherein said viral polymerase is a HCV polymerase.
24 . A method for treating or preventing a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound having the formula II or a pharmaceutically acceptable salt thereof:
wherein
Z is H, —NR′ 2 R 3′ or OR 4′ wherein
R 2′ is H, C 1-6 alkyl, C 2-6 alkenyl,or C 2-6 alkynyl;
R 3′ is H or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R 4′ is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; and
Y is N or C—X;
X is chosen from of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, CF 3 , N 3 , NO 2 , C 6-10 aryl, C 6-10 heteroaryl and CORb wherein Rb is chosen from of H, OH, SH, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy and C 1-6 thioalkyl;
and Ra is chosen from of H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and
wherein each Rc are independently chosen from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and an hydroxy protecting group, wherein said compound is in the form of a single enantiomer or a mixture thereof including racemic mixtures.
25 . The method of claim 24 wherein said compound of formula II of the present invention is substantially in the form of the (+) enantiomer.
26 . The method of claim 24 wherein sais-compound of formula II of the present invention is substantially in the form of the (−) enatiomer.
27 . The method of claim 24 wherein Ra is chosen from H, monophosphate, diphosphate, and triphosphate.
28 . The method of claim 24 wherein Ra is chosen from monophosphate, diphosphate, and triphosphate.
29 . The method of claim 24 wherein Ra is triphosphate.
30 . The method of claim 24 wherein Ra is H.
31 . The method of claim 24 wherein Y is C—X.
32 . The method of claim 24 wherein Y is C—X and X is H, methyl, or Halogen.
33 . The method of claim 24 wherein Y is C—X and X is H, methyl or halogen.
34 . The method of claim 24 wherein Y is C—X and X is H, methyl or F.
35 . The method of claim 24 wherein Y is C—X and X is H or F.
36 . The method of claim 24 wherein Y is C—X and X is H.
37 . The method of claim 24 wherein Y is C—X and X is F.
38 . The method of claim 24 wherein Z is OH.
39 . The method of claim 24 wherein Z is NH 2 .
40 . The method of claim 25 wherein Ra is chosen from H, monophosphate, diphosphate, and triphosphate.
41 . The method of claim 25 wherein Ra is chosen from monophosphate, diphosphate, and triphosphate.
42 . The method of claim 25 wherein Ra is triphosphate.
43 . The method of claim 25 wherein Ra is H.
44 . The method of claim 25 wherein Y is C—X.
45 . The method of claim 25 wherein Y is C—X and X is H, methyl, or Halogen.
46 . The method of claim 25 wherein Y is C—X and X is H, methyl or halogen.
47 . The method of claim 25 wherein Y is C—X and X is H, methyl or F.
48 . The method of claim 25 wherein Y is C—X and X is H or F.
49 . The method of claim 25 wherein Y is C—X and X is H.
50 . The method of claim 25 wherein Y is C—X and X is F.
51 . The method of claim 25 wherein Z is OH.
52 . The method of claim 25 wherein Z is NH 2 .
53 . The method of claim 26 wherein Ra is chosen from H, monophosphate, diphosphate, and triphosphate.
54 . The method of claim 26 wherein Ra is chosen from monophosphate, diphosphate, and triphosphate.
55 . The method of claim 26 wherein Ra is triphosphate.
56 . The method of claim 26 wherein Ra is H.
57 . The method of claim 26 wherein Y is C—X.
58 . The method of claim 26 wherein Y is C—X and X is H, methyl, or Halogen.
59 . The method of claim 26 wherein Y is C—X and X is H, methyl or halogen.
60 . The method of claim 26 wherein Y is C—X and X is H, methyl or F.
61 . The method of claim 26 wherein Y is C—X and X is H or F.
62 . The method of claim 26 wherein Y is C—X and X is H.
63 . The method of claim 26 wherein Y is C—X and X is F.
64 . The-method of claim 26 wherein Z is OH.
65 . The method of claim 26 wherein Z is NH 2 .
66 . The method of claim 24 wherein the compound of formula II is (+)Cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-Dioxolane (Compound #17 (+)).
67 . The method of claim 24 wherein the compound of formula II is (+)Cis-2-hydroxymethyl-4-(5′-fluorocytosin-1′-yl)-1,3-Dioxolane (Compound #18 (+)).
68 . The method of claim 24 wherein the compound of formula II is (−)Cis-2-hydroxymethyl-4-(5′-fluorocytosin-1′-yl)-1,3-Dioxolane (Compound #18 (−)).
69 . The method of claim 24 wherein the compound of formula II is (+)Cis-2-hydroxymethyl-4-(5′-azacytosin-1′-yl)-1,3-Dioxolane (Compound #19 (+)).
70 . The method of claim 24 wherein the compound of formula II is (+)-cis-2-hydroxymethyl-4-(5′-methylcytosin-1′-yl)-1,3-dioxolane(β-D-) (compound#20) (+)
71 . The method of claim 24 wherein the compound of formula II is (+)-cis-2-hydroxymethyl-4-(N-1′-thiminyl)-1,3-dioxolane (-D-) (compound#21) (+)
72 . The method of claim 24 wherein said Flaviviridea viral infection is hepatitis C.
73 . A method for treating or preventing a hepatitis C viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula II as defined in claim 24 and at least one further antiviral agent.
74 . The method according to claim 73 wherein the further antiviral agent is chosen from of viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.
75 . The method according to claim 73 wherein the antiviral agent is chosen from interferon (IFN), interferon αx-2a, interferon α-2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.
76 . The method according to claim 73 wherein the antiviral agent chosen from interferon α and ribavirin.
77 . A pharmaceutical composition for treating or preventing a hepatitis viral C infection comprising administering at least one compound according to formula II as defined in claim 73 together with at least one pharmaceutically acceptable carrier or excipient.
78 . A method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of at least one compound having the formula II or a pharmaceutically acceptable salt thereof:
wherein
Z is H, —NR 2′ R 3′ or OR 4′ wherein
R 2′ is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R 3′ is H or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R 4′ is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; and
Y is N or C—X;
X is chosen from of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, CF 3 , N 3 , NO 2 , C 6-10 aryl, C 6-10 heteroaryl and CORb wherein Rb is chosen from of H, OH, SH, C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkoxy and C 1-6 thioalkyl;
and Ra is chosen from of H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and
wherein each Rc are independently chosen from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and an hydroxy protecting group, wherein said compound is in the form of a single enantiomer or a mixture thereof including racemic mixtures.
79 . The method of claim 78 wherein said viral polymerase is a HCV polymerase.Cited by (0)
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