US2007225317A1PendingUtilityA1
Rsv polymerase inhibitors
Est. expiryOct 30, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 31/12A61K 31/4353A61K 31/437C07D 471/04A61P 11/00
52
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Claims
Abstract
Compounds or enantiomers of formula (I) or a salt thereof: wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, are useful for the manufacture of a medicament for the treatment or prevention of respiratory syncytial virus infection in a mammal.
Claims
exact text as granted — not AI-modified1 .- 8 . (canceled)
9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ia) below, or an enantiomer or a salt thereof, in association with at least one pharmaceutically-acceptable carrier:
wherein R 1 is —(CH═CH) 0-1 —(C 6 or C 10 )aryl or —(CH═CH) 0-1 -5-, 6-, 9- or 10-membered heteroaryl, said aryl or heteroaryl being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl optionally substituted with amino, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, nitro, azido, cyano, amino, (C 1-6 )alkylamino di((C 1-6 )alkyl)amino, aryl and heteroaryl;
R 2 is H, (C 1-6 )alkyl, hydroxy, halo, (C 1-6 )haloalkyl, amino, (C 1-6 )alkylamino di((C 1-6 )alkyl)amino, or (C 2-6 )alkynyl:
R 3 is (C 6 , C 10 or C 14 )aryl or 5-, 6-, 9- or 10-membered heteroaryl, each of which being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 6- )alkylthio, nitro amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino and COO(C 1-6 )alkyl- and
R 4 and R 5 are each independently H or (C 1-6 )alkyl; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a (C 3-7 )cycloalkyl group; with the proviso that R 1 is not 2-methoxyphenyl when R 2 is H, R 3 is 3,4-dimethoxyphenyl, R 4 is CH 3 and R 5 is CH 3 .
10 . The pharmaceutical composition according to claim 9 for use in the treatment or prevention of respiratory syncytial virus infection.
11 . The pharmaceutical composition according to claim 10 additionally comprising a therapeutically effective amount of at least one other antiviral agent.
12 . The pharmaceutical composition according to claim 11 wherein the antiviral agent is selected from an immunomodulatory agent, an inhibitor of RSV polymerase or an inhibitor of another target in the RSV life cycle.
13 . A method of treating or preventing a respiratory syncytial virus infection in a mammal comprising administering to the mammal an anti-respiratory syncytial virally-effective amount of a composition according to claim 9 .
14 . The method according to claim 13 wherein the composition additionally comprises a therapeutically effective amount of at least one other antiviral agent.
15 . The method according to claim 14 wherein the antiviral agent is selected from an immunomodulatory agent, an inhibitor of RSV polymerase or an inhibitor of another target in the RSV life cycle.
16 . A method of inhibiting replication of a respiratory syncytial virus comprising exposing virus-infected cells to an anti-respiratory syncytial virally-effective amount of a composition according to claim 9 .
17 . A packaged pharmaceutical comprising a pharmaceutical composition according to claim 9 and directions identifying an administration regimen therefor.
18 . The packaged pharmaceutical according to claim 17 for use for the treatment or prevention of respiratory syncytial virus infection in a mammal.
19 . An article of manufacture comprising packaging material contained within which is a composition effective to inhibit a respiratory syncytial virus, the packaging material comprising a label which indicates that the composition can be used to treat or prevent infection by a respiratory syncytial virus, wherein said composition is a composition according to claim 9 .
20 . A method of treating or preventing a respiratory syncytial virus infection in a mammal comprising administering to the mammal an anti-respiratory syncytial virally-effective amount of a compound of formula (I), or an enantiomer or a salt thereof or a composition thereof:
wherein R 1 is —(CH═CH) 0-1 —(C 6 or C 10 C)aryl or —(CH═CH) 0-1 -5-, 6-, 9- or 10-membered heteroaryl, said aryl or heteroaryl being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl optionally substituted with amino, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, nitro, azido, cyano, amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino, aryl and heteroaryl;
R 2 is H, (C 1-6 )alkyl, hydroxy, halo, (C 1-6 )haloalkyl, amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino, or (C 2-6 )alkynyl;
R 3 is (C 6 , C 10 or C 14 )aryl or 5-, 6-, 9- or 10-membered heteroaryl, each of which being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, nitro, amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino and COO(C 1-6 )alkyl; and
R 4 and R 5 are each independently H or (C 1-6 )alkyl; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a (C 3-7 )cycloalkyl group.
21 . The method according to claim 20 wherein the composition additionally comprises a therapeutically effective amount of at least one other antiviral agent.
22 . The method according to claim 21 wherein the antiviral agent is selected from an immunomodulatory agent, an inhibitor of RSV polymerase or an inhibitor of another target in the RSV life cycle.
23 . A method of inhibiting replication of a respiratory syncytial virus comprising exposing virus-infected cells to an anti-respiratory syncytial virally-effective amount of a compound, wherein the compound is of formula (I) of claim 20 or an enantiomer or a salt thereof.
24 . A packaged pharmaceutical for use for the treatment or prevention of respiratory syncytial virus infection in a mammal comprising a pharmaceutical composition containing a compound and directions identifying an administration regimen, wherein the compound is of formula (I) of claim 20 or an enantiomer or a salt thereof.
25 . An article of manufacture comprising packaging material contained within which is a composition effective to inhibit a respiratory syncytial virus, the packaging material comprising a label which indicates that the composition can be used to treat or prevent infection by a respiratory syncytial virus, wherein said composition includes a compound of formula (I) of claim 20 or an enantiomer or a salt thereof.
26 . The composition according to claim 9 , wherein, in the compound of formula (Ia):
R 1 is —(CH═CH) 0-1 —(C 6 or C 10 )aryl or 5-, 6-, 9- or 10-membered heteroaryl, said aryl or heteroaryl being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl optionally substituted with amino, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, nitro, azido, cyano, amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino, aryl and heteroaryl;
R 2 is H, (C 1-6 )alkyl, hydroxy, halo, (C 1-6 )haloalkyl, amino, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino, or (C 2-6 )alkynyl; R 3 is (C 6 , C 10 or C 14 )aryl or 5-, 6-, 9- or 10-membered heteroaryl, each of which being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, amino, (C 1-6 )alkylamino and di((C 1-6 )alkyl)amino; and
R 4 and R 5 are each independently (C 1-6 )alkyl; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a (C 3-7 )cycloalkyl group; with the proviso that R 1 is not 2-methoxyphenyl, when R 2 is H, R 3 is 3,4-dimethoxyphenyl, R 4 is CH 3 and R 5 is CH 3 .
27 . The composition according to claim 9 , wherein, in the compound of formula (Ia):
R 1 is (CH═CH) 0-1 -phenyl, the phenyl being optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl optionally substituted with amino, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, amino, nitro, cyano, azido, (C 1-6 )alkylamino, di((C 1-6 )alkyl)amino, and heteroaryl;
or R 1 is a 5-, 6-, 9- or 10-membered heteroaryl optionally substituted with one, two or three substituents, each independently selected from nitro, (C 1-6 )alkyl optionally substituted with amino, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, halo, (C 1-6 )alkylthio, cyano and heteroaryl; R 2 is H, (C 1-6 )alkyl, hydroxy, halo, amino, (C 1-6 )alkylamino, or (C 2-6 )alkynyl; R 3 is naphthyl, anthryl, or phenyl optionally substituted with one, two or three substituents, each independently selected from:
(C 1-6 )alkyl, halo, (C 1-6 )haloalkyl, hydroxy, (C 1-6 )alkoxy, and (C 1-6 )alkylthio;
or R 3 is a 5-, 6-, 9- or 10-membered heteroaryl optionally substituted with (C 1-6 )alkyl; and R 4 and R 5 are each independently Me or Et; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a (C 3-7 )cycloalkyl group; with the proviso that R 1 is not 2-methoxyphenyl, when R 2 is H, R 3 is 3,4-dimethoxyphenyl, R 4 is CH 3 and R 5 is CH 3 .
28 . The composition according to claim 9 , wherein, in the compound of formula (Ia):
R 1 is phenyl, 2-pyridyl, quinolinyl or benzofuranyl, the phenyl and 2-pyridyl each being optionally substituted with one or two substituents, each independently selected from:
methyl, hydroxy, methoxy, nitro, cyano, methylthio, fluoro, 2-aminoethyl and CF 3 ;
R 2 is H, NH 2 , bromo, chloro, or OH; R 3 is naphthyl, or phenyl optionally substituted with one, two or three substituents, each independently selected from:
methyl, iodo, hydroxy, methoxy, ethoxy and methylthio; and
R 4 and R 5 are each independently Me; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a cyclopentyl or cyclohexyl group; with the proviso that R 1 is not 2-methoxyphenyl, when R 2 is H, R 3 is 3,4-dimethoxyphenyl, R 4 is CH 3 and R 5 is CH 3 .
29 . The composition according to claim 9 , wherein, in the compound of formula (Ia):
R 1 is phenyl, 2-pyridyl, quinolinyl or benzofuranyl, the phenyl and 2-pyridyl each being optionally substituted with one or two substituents, each independently selected from:
methyl, methoxy, fluoro, CF 3 , nitro, cyano, and methylthio;
R 2 is H, NH 2 , bromo, chloro, or OH; R 3 is phenyl optionally substituted with one, two or three substituents, each independently selected from:
hydroxy, methoxy, ethoxy, methyl, iodo and methylthio; and
R 4 and R 5 are each independently Me; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a cyclopentyl or cyclohexyl group; with the proviso that R 1 is not 2-methoxyphenyl, when R 2 is H, R 3 is 3,4-dimethoxyphenyl, R 4 is CH 3 and R 5 is CH 3 .
30 . The composition according to claim 9 , wherein, in the compound of formula (Ia):
R 1 is R 2 is NH 2 or bromo; R 3 is phenyl substituted with one or two substituents each independently selected from hydroxy, methoxy, and iodo; and R 4 and R 5 are each independently Me; or R 4 and R 5 are linked, together with the carbon atom to which they are attached, to form a cyclohexyl group.
31 . The composition according to claim 9 , wherein, the compound of formula (Ia) is selected from the compounds of the following formula:
wherein R 1 , R 2 and R 3 are defined as in the table below:
Cpd
entry #
R 1
R 2
R 3
1002
H
1003
H
1004
H
1005
H
1006
H
1007
H
1008
H
1009
H
1010
H
1011
H
1012
H
1013
H
1014
H
1015
H
1016
H
1017
H
1018
H
1019
H
1020
H
1021
H
1022
H
1023
H
1024
H
1025
H
1026
H
1027
H
1028
H
1029
H
1030
H
1031
H
1032
H
1033
H
1034
H
1035
H
1036
H
1037
H
1038
H
1039
H
1040
H
1041
H
1042
H
1043
H
1044
H
1045
H
1046
Br
1047
H
1048
NH 3
1049
C≡CH
1050
NHMe
1051
Me
1052
Br
1053
Br
1054
Cl
1055
OH
1056
Br
1057
Br
1058
NH 3
1059
NH 3
1060
Br
1061
Br
1062
Br
1063
Br
1064
Br
1065
Br
1066
Br
1067
Br
1068
Br
1069
Br
1070
Br
1071
Br
1072
Br
1073
Br
1074
Br
1075
NH 3
1076
NH 3
1077
NH 3
1078
NH 3
1079
NH 3
1080
NH 3
1081
NH 3
1082
NH 3
1083
NH 3
1084
NH 3
1085
NH 3
1086
NH 3
1087
NH 3
1088
NH 3
1089
NH 3
1090
Br
1091
Br
1092
Br
1093
Br
1094
Br
1095
Br
1096
Br
1097
Br
1098
Br
1099
Br
1100
Br
1101
Br
1102
Br
1103
Br
1104
Br
1105
Br
1106
Br
1107
Br
1108
Br
1109
Br
1110
Br
1111
Br
1112
Br
1113
Br
1114
Br
1115
Br
1116
Br
1117
Br
1118
Br
1119
Br
1120
Br
1121
Br
1122
Br
1123
Br
1124
Br
1124
Br
1125
Br
1126
Br
1127
Br
1128
Br
1129
Br
1130
NH 3
1131
NH 3
1132
H
32 . The composition according to claim 9 , wherein, the compound of formula (Ia) is selected from the compounds of the following formula:
wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined as in the table below:
Cpd entry #
R 1
R 2
R 3
2001
H
2002
H
2003
H
2004
H
2005
Br
2006
NH 2
2007
H
2008
Br
2009
NH 2
2010
NH 2
2011
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