Method For Treating COVID-19 and Related Viral Infections

Abstract

A group of known compounds has been found to have polymerase inhibitor qualities and are presumed to be efficacious in the protection of human cells from damage by the SARS-CoV-2 virus, which causes the COVID-19 disease. These compounds, referred to herein as Special Phenyl Compounds, provide such protection by inhibiting replication of the virus, which is done by interfering with its RNA transcription process. These compounds can also be used to treat diseases caused by structurally related viruses such as West Nile virus, Marburg virus, Ebola virus, dengue virus, HIV, hepatitis C virus (HepC), and coronaviruses other than SARS-CoV2. Patients are treated by administering effective doses of one or more of the compounds.

Claims

1. A method for treating a patient diagnosed with or suffering from infection by the SARS-CoV-2 virus, comprising the steps of: administering to the patient an effective dose of a substance consisting of a phenyl group containing organic compound selected from the group consisting of 2-(4-oxo-3H-phthalazin-1-yl)-N-(2-phenylquinolin-4-yl)acetamide, [3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)phenyl]-[2-(4-fluorophenyl)morpholin-4-yl]methanone, 2-[[2-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)pyrolidin-1-yl]methyl]-5-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-1,3,4-oxadiazole, N-dibenzofuran-2-yl-4-(4-oxo-1H-quinazolin-2-yl)but-anamide, N-(9H-fluoren-2-yl)-2-[(4-oxo-1H-quinazolin-2-yl)meth-oxy]acetamide, N-(9H-fluoren-9-yl)-2-[(4-methyl-5-oxo-[1,2,4]triazolo[4,3-a]quinazolin-1-yl)sulfanyl]acetamide, (2S)—N-methyl-4-(3-methyl-4-oxo-2-phenylchromene-8-carbonyl)-2,3-dihydro-1,4-benzoxazine-2-carboxamide, 3-[3-[5-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydroindol-1-yl]-3-oxopropyl]-2H-phthalazine-1,4-dione, (7S)-7-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[3-(tetrazol-1-yl)phenyl]-2-(trifluoromethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine, 3-[[(2S)-2-methyl-2,3-dihydroindol-1-yl]sulfonyl]-N-(2-methyl-4-oxoquinazolin-3-yl)benzamide, (2R)-4-[2-[5-(4-flu-orophenyl)-4-oxothieno[2,3-d]pyrimidin-3-yl]acetyl]-2,3-dihydro-1,4-benzoxazine-2-carboxamide, (2R)-4-[2-(4-oxo-5-thiophen ylthieno[2,3-d]pyrimidin-3-yl)acetyl]-2,3-dihydro-1,4-benzoxa-zine-2-carboxamide, [(1S)-1-(4-oxo-3H-quinazolin-2-yl)ethyl] 6-cyclopropyl-3-methyl-[1,2]oxazolo[5,4-b]pyridine-4-carboxylate, and 4-[2-[4-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)piperazin-1-yl]acetyl]-1,3-dihydroquinoxalin-2-one, (3R)—N-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]-2-(furan-2-carbonyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide, [(3S)-3-(1,3-benzoxazol-2-yl)piperidin-1-yl]-[3-(2,3-dihydroindo1-1-ylsulfonyl)phenyl]methanone, [(2S)-1-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl)-1-oxopropan-2-yl]9-oxo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazoline-6-carboxylate, 1-[4-[3-[(2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrrolidine-1-carbonyl]phenyl]sulfonylpiperazin-1-yl]ethenone, 13-[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl]-4,8-dioxa-12,14,16,18-tetrazatetracyclo[9.7.0.03,9.012,17]octadeca-1,3(9),10,14,16-pentaen-15-amine, 3-[2-[(2S)-2-(4-methylpiperazine-1-carbonyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-2-oxoethyl]quinazolin-4-one, (3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-1-yl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridin-1-yl]methanone, N-(1,3-benzodioxol-5-yl)-1-[2-(4-fluorophenyl)quinoline-4-carbonyl]piperidine-4-carboxamide, [2-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl) oxoethyl] 2-(furan-2-yl)quinoline-4-carboxylate, (4S)-4-methyl [2-[(4-oxo-1-phenyl-5H-pyrazolo[3,4-d]pyrimidin yl)sulfanyl]acetyl]-3,4-dihydro-1H-1,5-benzodiazepin-2-one, [2-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl)-2-oxoethyl] 3-benzyl oxophthalazine-1-carboxylate.

2. The method of claim 1 wherein the patient is human.

3. A method for treating a patient diagnosed with or suffering from infection by the SARS-CoV-2 virus or a structurally similar virus, comprising the steps of: administering to the patient an effective dose of a substance consisting of a phenyl containing group organic compound selected from the group consisting of 2-(4-oxo-3H-phthalazin-1-y1)—N-(2-phenylquinolin-4-yl)acetamide, [3-(3,4-dihydro-1H-iso-quinolin-2-ylsulfonyl)phenyl]-[2-(4-fluorophenyl)morpholin-4-yl]methanone, 2-112-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)pyro-lidin-1-yl]methyl1-5-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-1,3,4-oxadiazole, N-dibenzofuran-2-yl-4-(4-oxo-1H-quinazolin-2-yl)but-anamide, N-(9H-fluoren-2-yl)-2-[(4-oxo-1H-quinazolin-2-yl)meth-oxy]acetamide, N-(9H-fluoren-9-yl)-2-[(4-methyl-5-oxo-[1,2,4]triazolo[4,3-a]quinazolin-1-yl)sulfanyl]acetamide, (2S)—N-methyl-4-(3-methyl-4-oxo-2-phenylchromene-8-carbonyl)-2,3-dihydro-1,4-benzoxazine-2-carboxamide, 3-[3-[5-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydroindol-1-yl]-3-oxopropyl]-2H-phthalazine-1,4-dione, (7S)-7-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-[3-(tetrazol yl)phenyl]-2-(trifluoromethyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine, 3-[[(2S)-2-methyl-2,3-dihydroindol-1-yl]sulfonyl]-N-(2-methyl-4-oxoquinazolin-3-yl)benzamide, (2R)-4-[2-[5-(4-flu-orophenyl)-4-oxothieno[2,3-d]pyrimidin-3-yl]acetyl]-2,3-dihydro-1,4-benzoxazine-2-carboxamide, (2R)-4-[2-(4-oxo-5-thiophen-2-yl-thieno[2,3-d]pyrimidin-3-yl)acetyl]-2,3-dihydro-1,4-benzoxazine-2-carboxamide, [(1S)-1-(4-oxo-3H-quinazolin-2-yl)ethyl] 6-cyclo-propyl-3-methyl-[1,2]oxazolo[5,4-b]pyridine-4-carboxylate, and 4-[2-[4-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)piperazin-1-yl]acetyl]-1,3-dihydroquinoxalin-2-one, (3R)—N-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]-2-(furan-2-carbonyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide, [(3S)-3-(1,3-benzoxazol-2-yl)piperidin-1-yl]-[3-(2,3-dihydroindo1-1-ylsulfonyl)phenyl]methanone, [(2S)-1-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl)-1-oxopropan-2-yl]9-oxo-2,3-dihydro-1H-pyrrolo[2,1-b]quinazoline-6-carboxylate, 1-[4-[3-[(2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)pyrrolidine-1-carbonyl]phenyl]sulfonylpiperazin-1-yl]ethenone, 13-[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl]-4,8-dioxa-12,14,16,18-tetrazatetracyclo[9.7.0.03,9.012,17]octadeca-1,3(9),10,14,16-pentaen-15-amine, 3-[2-[(2S)-2-(4-methylpiperazine-1-carbonyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-2-oxoethyl]quinazolin-4-one, (3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-1-yl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridin-1-yl]methanone, N-(1,3-benzodioxol-5-yl)-1-[2-(4-fluorophenyl)quinoline-4-carbonyl]piperidine carboxamide, [2-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl) oxoethyl] 2-(furan-2-yl)quinoline-4-carboxylate, (4S)-4-methyl [2-[(4-oxo-1-phenyl-5H-pyrazolo[3,4-d]pyrimidin yl)sulfanyl]acetyl]-3,4-dihydro-1H-1,5-benzodiazepin-2-one, [2-(2,2-dimethyl-3-oxo-4H-quinoxalin-1-yl)-2-oxoethyl] 3-benzyl-4-oxophthalazine-1-carboxylate.

4. The method of claim 3 wherein the patient is human.

Description

IN THE DRAWING

[0011] FIGS. 1A to 1K show the structures of the compounds utilized in the treatment method of the present invention.

[0012] FIG. 2 shows a bar graph of relative activity of HIV reverse transcriptase in the presence of vehicle (dmso) or 10 μM compound.

[0013] FIG. 3 shows the numeric quantitation of the data in FIG. 2.

DETAILED DESCRIPTION

[0014] The aforementioned compounds (hereafter the “Special Phenyl Compounds”) have been found to strongly bind the SARS-CoV-2 nsp12 active site in a computational theoretical model. Additionally, compounds from this group have been shown to inhibit the activity of the distantly related polymerase, HIV reverse transcriptase (RT). This anti-viral effect was observed in an in vitro enzymatic assay where each trial consisted of a triplicate of reactions that was averaged and presented as a percentage of vehicle (dmso) treated control from same day/same set of reactions.

[0015] The RNA genome of the SARS-CoV-2 and aforementioned related viruses is replicated by an RNA-dependent RNA polymerase (RdRp), or other polymerase, which is non-structural protein 12 (nsp12) in SARS-CoV-2, and is similar to reverse transcriptase in HIV and NS5B in HepC. The Special Phenyl Compounds interfere with this nucleic acid replication by inhibiting the polymerase. These compounds do this somewhat differently than remdesivir, however.

[0016] Inhibition of RdRp has proven effective in treatment of other viruses, such as HIV and HepC, and has led to compassionate use of remdesivir, in the case of SARS-CoV-2.

[0017] While remdesivir gets incorporated into the nucleotide chain as a nucleotide analog and shuts down the nsp12 enzyme, the Special Phenyl Compounds are believed to bind to areas in and around the catalytic site, inhibiting the binding of the catalytic metal ions and perhaps the binding of template strands and nucleotides as well.

[0018] The Special Phenyl Compounds are listed in the ZINC 12 Database (zincl2.docking.dorg) and are available from Enamine, a Ukrainian company having a U.S. location at 1 Distribution Way Monmouth Jct., NJ 08852.

[0019] The effective dose can be determined in the usual manner, that is, by clinical testing.