Substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, pharmaceutical composition, method for the production and use thereof

Inventors

Ivachtchenko, Alexandre Vasilievich • Ivashchenko, Andrey Alexandrovich • Mitkin, Oleg Dmitrievich

Assignees

Viriom Inc • ASAVI LLC

Abstract

Influenza is an acute infectious respiratory disease caused by the influenza virus. It is part of the group of Acute Respiratory Viral Infections (ARVI). It occasionally spreads in the form of epidemics and pandemics. Currently, more than 2000 variants of the influenza virus differing in the antigen spectrum have been identified. Given that influenza is a serious threat to public health (worldwide, these annual epidemics lead to 3-5 million cases of severe illness, millions of hospitalizations, and up to 650,000 deaths), it seems appropriate to search for new anti-influenza drugs with improved characteristics.The inventors surprisingly found out that the previously unknown substituted 3,4,12,12a-tetrahydro-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione of general formula 1, its stereoisomer, their prodrug, pharmaceutically acceptable salt, solvate, hydrate, and a crystalline or polycrystalline form thereof are effective agents for prophylaxis and treatment of viral diseases, including influenza where R1 is (6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, (7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)-methyl; R2 is hydrogen or a protective group selected from a series comprising (C1-C3 alkyl) oxycarbonyloxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, {[2-(C1-C3 alkyl) oxyethoxy]carbonyl}oxy, ({[(1R)-2-[(C1-C3alkyl)oxy]-1-methylethoxy} carbonyl)oxy, {[(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy) carbonyl]oxy, {[(1-acetylazetidine)-3-yloxy]carbonyl}oxy, {[(C1-C3alkyl) oxycarbonyl]-oxy}methoxy, ({[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy) methoxy.

Core Innovation

The invention relates to stereochemically defined substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione derivatives, including stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms. The compounds include (12aR) stereochemistry, with 10S or 10R stereoisomers, and the R2 substituent is hydrogen or {[(C1-C3alkyl)oxycarbonyl]-oxy}methoxy.

The described compound set includes formula 1.1, 1.2, and 1.3 members bearing a 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl substituent. The disclosure further includes 7-benzyloxy and 7-hydroxy derivatives, corresponding (oxy)methyl methyl carbonate forms, and specific (10S) and (10R) stereochemical variants within the tetrahydro-oxazino-fused pyrido[2,1-f][1,2,4]triazine-6,8-dione scaffold.

The invention relates to influenza virus inhibitors and addresses the need for anti-influenza agents for prophylaxis and treatment. The experimental support includes XRD-confirmed solvates, oral availability, mouse pharmacokinetics, and in vitro EC50 antiviral activity in MDCK cell culture for influenza, with reference to baloxavir and baloxavir marboxil.

Claims Coverage

The independent claims cover 3 explicitly listed stereochemically defined compound selections, and dependent claims further narrow the scaffold to a 7-hydroxy series and specific methyl carbonate derivatives. The core inventive features center on the defined tetrahydro-oxazino-fused pyrido-triazine-6,8-dione framework, the 6,7-difluoro thieno-benzothiepin substituent, and the constrained R2 group.

The claim coverage focuses on stereochemically defined substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione derivatives with R2 constrained to hydrogen or {[(C1-C3alkyl)oxycarbonyl]-oxy}methoxy, further narrowed to a 7-hydroxy series and specific stereodefined members including a particular (10R) methyl carbonate derivative and a particular (10R) 7-hydroxy compound.

Stated Advantages

Documented Applications