US2013035328A1PendingUtilityA1
Antiviral compounds and methods
Est. expiryJun 26, 2023(expired)· nominal 20-yr term from priority
Inventors:Peter William GageGary Dinneen EwartLauren Elizabeth WilsonWayne Morris BestAnita Premkumar
A61P 31/18A61P 31/00A61P 31/16A61P 31/14A61P 31/12A61P 11/00A61P 1/16A61K 31/15A61K 31/4406A61K 31/381A61K 31/47A61K 31/55C07D 241/34C07C 279/22A61K 45/06A61K 31/4965A61K 31/165Y02A50/30C07D 277/46
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Claims
Abstract
The invention relates to compounds having antiviral activity and methods utilizing the compounds to treat viral infections.
Claims
exact text as granted — not AI-modified1 - 168 . (canceled)
169 . A method for the therapeutic or prophylactic treatment of a subject infected with or exposed to a virus, comprising administering to the subject a compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein,
R 2 , R 3 and R 4 are independently hydrogen,
and wherein
X=hydrogen, hydroxy, nitro, halo, C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyl, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkyloxy, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo;
R a , R b , R c , R d , R e , R f , R h , R k , R l , R m , R n , R o , R p independently=hydrogen, amino, halo, C 1-5 alkyi, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino,
or PrS;
R g , R i independently=hydrogen, hydroxy, halo, or C 1-5 alkyl;
R j =hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS,
and wherein
when R 1 is
R a and R c are amino, and R b is halo, R 2 , R 3 or R 4 cannot be hydrogen, benzyl or substituted benzyl or BODIPY-Fl;
when R 1 is C 6 H 5 CH═CH, R 2 is hydrogen and R 3 is phenyl, R 4 cannot be phenyl;
when R 1 is phenyl, R 2 is hydrogen, and R 3 is benzoyl, R 4 cannot be benzoyl;
when R 1 is phenyl, R 2 is substituted benzyl, R 3 is hydrogen and R 4 is hydrogen, R a , R o and R p cannot all be hydrogen;
when R 1 is phenyl, R 3 is hydrogen and R 4 is hydrogen, R 2 cannot be benzyl or phenyl;
when R 1 is phenyl, R 2 is hydrogen, R 3 cannot be phenyl together with R 4 as benzoyl; and
when R 1 is phenyl, R 2 is hydrogen, R 3 and R 4 cannot both be benzyl.
170 . The method according to claim 169 wherein the compound is selected from the group consisting of:
(2-Bromocinnamoyl)guanidine,
(2-Chlorocinnamoyl)guanidine,
(2-Furanacryloyl)guanidine,
(2-Methoxycinnamoyl)guanidine,
(2-Nitrocinnamoyl)guanidine,
(3-Bromocinnamoyl)guanidine,
(3 -Chlorocinnamoyl)guanidine,
(3 -Methoxycinnamoyl)guanidine,
(3-Nitrocinnamoyl)guanidine,
(3-phenylpropanoyl)guanidine,
(4-Bromocinnamoyl)guanidine,
(4-Chlorocinnamoyl)guanidine,
(4-Hydroxycinnamoyl)guanidine,
(4-Methoxycinnamoyl)guanidine,
(4-Phenoxybenzoyl)guanidine,
(5-Phenyl-penta-2,4-dienoyl)guanidine,
(a-Methylcinnamoyl)guanidine,
(Phenylacetyl)guanidine,
(Quinoline-2-carbonyl)guanidine,
(trans-2-Phenylcyclopropanecarbonyl)guanidine,
[(4-Chlorophenoxy-acetyl]guanidine,
[(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,
[3-(3-Pyridyl)acryloyl]guanidine,
1-bromo-2-naphthoylguanidine,
1-naphthoylguanidine,
2-(1-naphthyl)acetoylguanidine,
2-(2-naphthyl)acetoylguanidine,
2-(cyclohex-1-en-lyl)cinnamoylguanidine,
2-(trifiuoromethyl)cinnamoylguanidine,
2,3,5,6,-tetramethylcinnamoylguanidine,
2,3-difiuorocinnamoylguanidine,
2,3-dimethylcinnamoylguanidine,
2,4,6-trimethylcinnamoylguanidine,
2,4-dichlorocinnamolyguanidine,
2,5-dimethylcinnamoylguanidine,
2,6-dichlorocinnamoylguanidine,
2′4 DichloroBenazamil HCl,
2-chloro-6-fluorocinnamoylguanidine,
2-cyclohexylcinnamoylguanidine,
2-ethoxycinnamoylguanidine,
2-ethylcinnamoylguanidine,
2-fluorocinnamoylguanidine,
2-methylcinnamoylguanidine,
2-naphthoylguanidine,
2-phenylcinnamoylguanidine,
2-t-butylcinnamoylguanidine,
3-(2-naphthyl)acryloylguanidine,
3-(cyclohex-1-en-1-yl)cinnamoylguanidine,
3 -(trans-hept-1-en-1-yl)cinnamoylguanidine,
3-(trifiuoromethoxy)cinnamoylguanidine,
3-(trifluoromethyl)cinnamoylguanidine,
3,4-(methylenedioxy)cinnamoylguanidine,
3,4,5-trimethoxycinnamoylguanidine,
3,4-dichlorocinnamoylguanidine,
3,4-difluorocinnamoylguanidine,
3-ethoxycinnamoylguanidine,
3-fluorocinnamoylguanidine,
3-isopropylcinnamoylguanidine hydrochloride,
3-methoxy-HMA,
3-methoxy-amiloride,
3-methylcinnamoylguanidine,
3-phenylcinnamoylguanidine,
3-t-butylcinnamoylguanidine,
4-(trifluoromethyl)cinnamoylguanidine,
4-ethoxycinnamoylguanidine,
4-fluorocinnamoylguanidine,
4-isopropylcinnamoylguanidine,
4-methylcinnamoylguanidine,
4-phenylbenzoylguanidine,
4-phenylcinnamoylguanidine,
4-t-butylcinnamoylguanidine,
5-(2′-bromophenyl)penta-2,4-dienoylguanidine,
5-(3′-bromophenyl)penta-2,4-dienoylguanidine,
5-(4-fluorophenyl)amiloride,
5-(N,N-Dimethyl)amiloride hydrochloride,
5-(N,N-hexamethylene)amiloride,
5-(N-Ethyl-N-isopropyl)amiloride,
5-(N-Methyl-N-isobutyl)amiloride,
5-bromo-2-fluorocinnamoylguanidine,
5-bromo-2-methoxycinnamoylguanidine,
5-tert-butylamino-amiloride,
6-bromo-2-naphthoylguanidine,
6-Iodoamiloride,
6-methoxy-2-naphthoylguanidine,
Benzamil hydrochloride,
Benzyoylguanidine,
cinnamoylguanidine hydrochloride,
Cinnamoylguanidine,
N-(2-naphthoyl)-N′-phenylguanidine,
N-(3-phenylpropanoyl)-N′-phenylguanidine,
N-(3-phenylpropanoyl)-N′-phenylguanidine,
N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,
N-(cinnamoyl)-N′phenylguanidine,
N,N′-Bis(3-phenylpropanoyl)guanidine,
N,N′-bis(3phenylpropanoyl)-N″-phenylguanidine,
N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,
N,N′-bis-(cinnamoyl)-N″-phenylguanidine,
N-amidino-3,5-diamino-6-phynyl-2-Pyrazinecarboxamide,
N-amidino-3-amino-5-hexamethyleneimino-6-phenyl-2-pyrazinecarboxamide,
N-amidino-3-amino-5-phenyl-6-chloro-2-pyrazinecarboxamide,
N-Benzoyl-N′-cinnamoylguanidine,
N-Cinnamoyl-N′,N′-dimethylguanidine,
Phenamil methanesulfonate salt,
trans-3-(1-naphthyl)acryloylguanidine and
trans-3 -Furanacryoylguanidine,
or a pharmaceutically acceptable salt thereof.
171 . The method according to claim 169 , wherein said virus is a Lentivirus.
172 . The method according to claim 171 , wherein said Lentivirus is Human Immunodeficiency Virus (HIV).
173 . The method according to claim 172 , wherein said HIV is HIV-1.
174 . The method according to claim 169 wherein said virus is a Coronavirus.
175 . The method according to claim 174 , wherein said Coronavirus is the Severe Acute Respiratory Syndrome virus (SARS), human Coronavirus 229E, human Coronavirus OC43, porcine respiratory Coronavirus (PRCV) or bovine Coronvirus (BCV).
176 . The method according to claim 174 , wherein said Coronavirus is any one of the coronavirus isolates listed in Table 1.
177 . The method according to claim 169 , wherein said virus is the Hepatitis C virus.
178 . The method according to claim 169 , wherein said virus is Equine Arteritis virus.
179 . A method for preventing the infection of a cell exposed to a virus or for reducing, retarding or otherwise inhibiting growth and/or replication of a virus in a cell infected with said virus comprising contacting the cell with a compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein,
R 2 , R 3 and R 4 are independently hydrogen,
and wherein
X=hydrogen, hydroxy, nitro, halo, C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyl, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkyloxy, phenyl, C 1-6 alkeneyl, C 3-6 dycloalkeneyl, C 1-6 alkeneoxy, or benzo;
R a , R b , R c , R d , R e , R f , R h , R k , R l , R m , R n , R o , R p independently = hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino,
or PrS;
R g , R i independently=hydrogen, hydroxy, halo, or C 1-5 alkyl;
R j =hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS,
and wherein
when R 1 is
R a and R c are amino, and R b is halo, R 2 , R 3 or R 4 cannot be hydrogen, benzyl or substituted benzyl or BODIPY-Fl;
when R 1 is C 6 H 5 CH═CH, R 2 is hydrogen and R 3 is phenyl, R 4 cannot be phenyl;
when R 1 is phenyl, R 2 is hydrogen, and R 3 is benzoyl, R 4 cannot be benzoyl;
when R 1 is phenyl, R 2 is substituted benzyl, R 3 is hydrogen and R 4 is hydrogen, R n , R o and R p cannot all be hydrogen;
when R 1 is phenyl, R 3 is hydrogen and R 4 is hydrogen, R 2 cannot be benzyl or phenyl;
when R 1 is phenyl, R 2 is hydrogen, R 3 cannot be phenyl together with R 4 as benzoyl; and
when R 1 is phenyl, R 2 is hydrogen, R 3 and R 4 cannot both be benzyl.
180 . The method according to claim 179 wherein the compound is selected from:
(2-Bromocinnamoyl)guanidine,
(2-Chlorocinnamoyl)guanidine,
(2-Furanacryloyl)guanidine,
(2-Methoxycinnamoyl)guanidine,
(2-Nitrocinnamoyl)guanidine,
(3-Bromocinnamoyl)guanidine,
(3-Chlorocinnamoyl)guanidine,
(3-Methoxycinnamoyl)guanidine,
(3-Nitrocinnamoyl)guanidine,
(3-phenylpropanoyl)guanidine,
(4-Bromocinnamoyl)guanidine,
(4-Chlorocinnamoyl)guanidine,
(4-Hydroxycinnamoyl)guanidine,
(4-Methoxycinnamoyl)guanidine,
(4-Phenoxybenzoyl)guanidine,
(5-Phenyl-penta-2,4-dienoyl)guanidine,
(a-Methylcinnamoyl)guanidine,
(Phenylacetyl)guanidine,
(Quinoline-2-carbonyl)guanidine,
(trans-2-Phenylcyclopropanecarbonyl)guanidine,
[(4-Chlorophenoxy-acetyl]guanidine,
[(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,
[3-(3-Pyridyl)acryloyl]guanidine,
1-bromo-2-naphthoylguanidine,
1-naphthoylguanidine,
2-(1-naphthyl)acetoylguanidine,
2-(2-naphthyl)acetoylguanidine,
2-(cyclohex-1-en-lyl)cinnamoylguanidine,
2-(trifluoromethyl)cinnamoylguanidine,
2,3,5,6,-tetramethylcinnamoylguanidine,
2,3-difluorocinnamoy lguanidine,
2,3-dimethylcinnamoylguanidine,
2,4,6-trimethylcinnamoylguanidine,
2,4-dichlorocinnamolyguanidine,
2,5-dimethylcinnamoylguanidine,
2,6-dichlorocinnamoylguanidine,
2′4 DichloroBenazamil HCl,
2-chloro-6-fluorocinnamoylguanidine,
2-cyclohexylcinnamoylguanidine,
2-ethoxycinnamoylguanidine,
2-ethylcinnamoylguanidine,
2-fluorocinnamoylguanidine,
2-methylcinnamoylguanidine,
2-naphthoylguanidine,
2-phenylcinnamoylguanidine,
2-t-butylcinnamoylguanidine,
3-(2-naphthyl)acryloylguanidine,
3-(cyclohex-1-en-1-yl)cinnamoylguanidine,
3-(trans-hept-1-en-1-yl)cinnamoylguanidine,
3-(trifluoromethoxy)cinnamoylguanidine,
3-(trifluoromethyl)cinnamoylguanidine,
3,4-(methylenedioxy)cinnamoylguanidine,
3,4,5-trimethoxycinnamoylguanidine,
3,4-dichlorocinnamoylguanidine,
3,4-difluorocinnamoylguanidine,
3-ethoxycinnamoylguanidine,
3-fluorocinnamoylguanidine,
3-isopropylcinnamoylguanidine hydrochloride,
3-methoxy-HMA,
3-methoxy-amiloride,
3-methylcinnamoylguanidine,
3-phenylcinnamoylguanidine,
3-t-butylcinnamoylguanidine,
4-(trifluoromethyl)cinnamoylguanidine,
4-ethoxycinnamoylguanidine,
4-fluorocinnamoylguanidine,
4-isopropylcinnamoylguanidine,
4-methylcinnamoylguanidine,
4-phenylbenzoylguanidine,
4-phenylcinnamoylguanidine,
4-t-butylcinnamoylguanidine,
5-(2′-bromophenyl)penta-2,4-dienoylguanidine,
5-(3′-bromophenyl)penta-2,4-dienoylguanidine,
5-(4-fluorophenyl)amiloride,
5-(N,N-Dimethyl)amiloride hydrochloride,
5-(N,N-hexamethylene)amiloride,
5-(N-Ethyl-N-isopropyl)amiloride,
5-(N-Methyl-N-isobutyl)amiloride,
5-bromo-2-fluorocinnamoylguanidine,
5-bromo-2-methoxycinnamoylguanidine,
5-tert-butylamino-amiloride,
6-bromo-2-naphthoylguanidine,
6-Iodoamiloride,
6-methoxy-2-naphthoylguanidine,
Benzamil hydrochloride,
Benzyoylguanidine,
cinnamoylguanidine hydrochloride,
Cinnamoylguanidine,
N-(2-naphthoyl)-N′-phenylguanidine,
N-(3-phenylpropanoyl)-N′-phenylguanidine,
N-(3-phenylpropanoyl)-N′-phenylguanidine,
N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,
N-(cinnamoyl)-N′phenylguanidine,
N,N′-Bis(3-phenylpropanoyl)guanidine,
N,N′-bis(3phenylpropanoyl)-N″-phenylguanidine,
N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,
N,N′-bis-(cinnamoyl)-N″-phenylguanidine,
N-amidino-3,5-diamino-6-phynyl-2-Pyrazinecarboxamide,
N-amidino-3-amino-5-hexamethyleneimino-6-phenyl-2-pyrazinecarboxamide,
N-amidino-3-amino-5-phenyl-6-chloro-2-pyrazinecarboxamide,
N-Benzoyl-N′-cinnamoylguanidine,
N-Cinnamoyl-N′,N′-dimethylguanidine,
Phenamil methanesulfonate salt,
trans-3-(1-naphthyl)acryloylguanidine and
trans-3 -Furanacryoylguanidine,
or a pharmaceutically acceptable salt thereof.
181 . The method according to claim 179 , wherein said virus is a Lentivirus, Human Immunodeficiency Virus (HIV), a Coronavirus, the Hepatitis C virus or Equine Arteritis virus.
182 . A compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein,
R 1 =
R 2 , R 3 and R 4 are independently hydrogen,
and wherein
X=hydrogen, C 2-6 alkyl, C 3-6 cycloalkyl, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo;
R d , R e , R f , R h , R l , R m , R n , R o , R p independently = hydrogen, amino, C2_salkyl, aryl, substituted aryl, aryl-substituted amino,
or PrS;
R g , R i independently=hydrogen, hydroxy, or C 1-5 alkyl;
R k =amino, C 1-5 alkyl, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino,
or PrS;
R j =hydrogen, amino, C 1-5 alkyl, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS,
and wherein
when R 1 is C 6 H 5 CH═CH, R 2 is hydrogen and R 3 is phenyl, R 4 cannot be phenyl;
when R 1 is phenyl, R 2 is hydrogen, and R 3 is benzoyl, R 4 cannot be benzoyl;
when R 1 is phenyl, R 2 is substituted benzyl, R 3 is hydrogen and R 4 is hydrogen, R n , R o and R p cannot all be hydrogen;
when R 1 is phenyl, R 3 is hydrogen and R 4 is hydrogen, R 2 cannot be benzyl or phenyl;
when R 1 is phenyl, R 2 is hydrogen, R 3 cannot be phenyl together with R 4 as benzoyl; and
when R 1 is phenyl, R 2 is hydrogen, R 3 and R 4 cannot both be benzyl.
183 . A compound of Formula I
or a pharmaceutically acceptable salt thereof,
wherein,
R 2 , R 3 and R 4 are independently hydrogen,
and wherein
X=hydrogen, C 2-6 alkyl, C 3-6 cycloalkyl, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo;
R d , R e , R f , R h , R l , R m , R n , R o , R p independently=hydrogen, amino, C 2-5 alkyl, aryl, substituted aryl, aryl-substituted amino,
or PrS;
R g , R i independently=hydrogen, hydroxy, or C 1-5 alkyl;
R k =hydrogen, amino, C 1-5 alkyl, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino,
or PrS;
R j =amino, C 1-5 alkyl, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS,
and wherein
when R 1 is C 6 H 5 CH═CH, R 2 is hydrogen and R 3 is phenyl, R 4 cannot be phenyl;
when R 1 is phenyl, R 2 is hydrogen, and R 3 is benzoyl, R 4 cannot be benzoyl;
when R 1 is phenyl, R 2 is substituted benzyl, R 3 is hydrogen and R 4 is hydrogen, R n , R o and R p cannot all be hydrogen;
when R 1 is phenyl, R 3 is hydrogen and R 4 is hydrogen, R 2 cannot be benzyl or phenyl;
when R 1 is phenyl, R 2 is hydrogen, R 3 cannot be phenyl together with R 4 as benzoyl; and
when R 1 is phenyl, R 2 is hydrogen, R 3 and R 4 cannot both be benzyl.
184 . A compound according to claim 183 selected from the group consisting of:
cinnamoylguanidine,
4-phenylbenzoylguanidine,
N-(cinnamoyl)-N′phenylguanidine,
N,N′-bis-(cinnamoyl)-N″-phenylguanidine,
N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,
N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,
N″-Cinnamoyl-N,N′-diphenylguanidine,
(Phenylacetyl)guanidine,
benzyoylguanidine,
N-benzoyl-N′-cinnamoylguanidine,
[(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,
(5-Phenyl-penta-2,4-dienoyl)guanidine,
[3-(3-Pyridyl)acryloyl] guanidine,
(4-Hydroxycinnamoyl)guanidine,
(Quinoline-2-carbonyl)guanidine,
or a pharmaceutically acceptable salt thereof.
185 . A pharmaceutical composition comprising a compound according to claim 183 and optionally one or more pharmaceutical acceptable carriers or derivatives.
186 . The pharmaceutical composition according to claim 185 , further comprising one or more other antiviral agents.Join the waitlist — get patent alerts
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