DNA polymerase IIIC inhibitors and use thereof
Inventors
Yu, Xiang Y. • Xing, Li H. • Wang, Minghua • McComas, Casey • Silverman, Michael • Soll, Richard
Assignees
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Publication Number
US-10836772-B2
Publication Date
2020-11-17
Expiration Date
Abstract
The present invention relates to compounds and methods useful for inhibiting the DNA polymerase IIIC enzyme. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of Gram-positive bacterial infections.
Core Innovation
The invention relates to compounds corresponding to formula I and to selected pyrazolo[4,3-d]pyrimidin-7-one/7(6H)-one derivatives for inhibiting the growth of Gram-positive bacteria and for treating a Gram-positive bacterial infection. The disclosed compound set includes substituted pyrazolo[4,3-d]pyrimidin-7-one and 7(6H)-one derivatives, including hydrochloride and other salt forms.
The structure is defined by A and B being N and n being 1, with R1 comprising a (CH2)m-(V)o-(CH2)p segment and W, and with V selected from CH2, CH=CH, C≡C, CO, O, S, SO, SO2, NR4, CHR5, OC(O), (O)CO, CONR6-NR7CO, SO2NH, and NHSO2. The formula further includes R2 as H, CN, F, or Cl, R3 as selected substituted phenyl and benzo[d][1,3]dioxole variants, and R0 as selected phosphonate/phosphate-like groups and linked oxygen-bearing structures.
The document also describes analytical characterization and provided compound examples for multiple pyrazolo[4,3-d]pyrimidinone derivatives, including 1H NMR, HPLC purity, LC-MS, and ESI-MS data. It further reports compound classes bearing oxadiazole, phosphonate/phosphate-like, piperidine, morpholine, piperazinyl, hydroxyethyl, hydroxyethoxyethyl, quinuclidine-containing, oxysulfonamide, and ethanesulfonamide side-chain variants, together with optical isomers, isotopic isomers, and pharmaceutically acceptable salts.
Claims Coverage
The consolidated claim coverage includes methods of inhibiting Gram-positive bacterial growth and methods of treating Gram-positive bacterial infection in a subject. In total, the consolidated coverage includes four inventive feature groupings: Formula I contact inhibition, Formula I treatment, and selected enumerated pyrazolo[4,3-d]pyrimidinone derivatives for growth inhibition and treatment.
Formula I contact inhibition of Gram-positive bacteria
A method of inhibiting the growth of Gram-positive bacteria by contacting a medium with an effective amount of a compound corresponding to formula I, with A and B being N, n being 1, and detailed definitions for R1, V, W, R2, R3, and R0, including optical isomers, isotopic isomers, and pharmaceutically acceptable salts.
Formula I treatment of Gram-positive bacterial infection
A method of treating a Gram-positive bacterial infection in a subject in need thereof by administering a therapeutically effective amount of a compound corresponding to formula I, with A and B being N, n being 1, and detailed definitions for R1, V, W, R2, R3, and R0, including optical isomers, isotopic isomers, and pharmaceutically acceptable salts.
Selected pyrazolo[4,3-d]pyrimidinone derivatives for Gram-positive growth inhibition
A method of inhibiting the growth of Gram-positive bacteria by contacting a medium with an effective amount of a compound selected from an explicitly enumerated group of pyrazolo[4,3-d]pyrimidin-7(6H)-one/7-one derivatives and salt forms, including 5-((3,4-dichlorobenzyl)amino)-substituted compounds and other named variants.
Selected pyrazolo[4,3-d]pyrimidinone derivatives for treating infection
A method of treating a Gram-positive bacterial infection in a subject in need thereof by administering a therapeutically effective amount of a compound selected from an explicitly enumerated group of pyrazolo[4,3-d]pyrimidin-7(6H)-one/7-one derivatives and salt forms.
The independent claims cover Gram-positive antibacterial growth inhibition and infection treatment using either Formula I compounds or an explicitly enumerated set of substituted pyrazolo[4,3-d]pyrimidin-7-one/7(6H)-one derivatives, including pharmaceutically acceptable salts and, for Formula I, optical and isotopic isomers.
Stated Advantages
Inhibiting the growth of Gram-positive bacteria.
Treating a Gram-positive bacterial infection in a subject.
Documented Applications
Inhibiting the growth of Gram-positive bacteria by contacting a medium with an effective amount of a compound corresponding to Formula I or selected enumerated derivatives.
Treating a Gram-positive bacterial infection in a subject in need thereof by administering a therapeutically effective amount of a compound corresponding to Formula I or selected enumerated derivatives.
DNA polymerase IIIC inhibition evaluation including Ki targets.
Gram-positive MIC determination using Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae, and Bacillus subtilis.
Parenteral, veterinary, tissue culture, and medical device surface treatment context.
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