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-10723741-B1
Publication Date
2020-07-28
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 bacteria infections.
Core Innovation
The disclosure relates to substituted pyrazolo[4,3-d]pyrimidin-7-one and pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives. The compounds include a pyrazolo[4,3-d]pyrimidin-7-one core, often with a 5-((3,4-dichlorobenzyl)amino) substituent or related benzyl/aryl amino variants, and variable substituents at the 1-position and other positions, including halo, alkyl, heteroalkyl, oxadiazole, oxazole, thiazole, and phosphate-related forms.
The document also describes a broader formula I compound family in which A and B are N, n is 1, and R1 is defined by a variable linker pattern with selectable V and W groups, together with defined choices for R2, R3, and R0. The scope includes optical isomers, isotopic isomers, and pharmaceutically acceptable salts, and in some embodiments prodrug-like phosphate structures are explicitly listed.
The partial content further reports synthesis, isolation, and characterization of multiple named compounds and intermediates, including hydrochloride, dihydrochloride, and phosphate salt forms. Reported analytical data include 1H NMR, HPLC purity, LC-MS, and ESI-MS for the prepared derivatives.
Claims Coverage
The consolidated claim coverage includes two independent claim themes: a broad formula I compound definition and a selected group of specifically named substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds. Across the provided items, the main inventive features are the defined pyrazolo[4,3-d]pyrimidin scaffold, variable linker/substituent selections, explicit salt or isomer embodiments, and composition and coating embodiments.
Formula I substituted pyrazolo[4,3-d]pyrimidin-7-one compound family
A compound corresponding to formula I wherein A and B are N, n is 1, and R1 is defined by a variable linker pattern with selected V and W groups and specified ranges for the linker indices; R2, R3, and R0 are selected from the enumerated substituent options, including optional optical isomers, isotopic isomers, and pharmaceutically acceptable salts.
Selected substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds
A compound selected from a defined group of specific substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one or related oxo/one structures, including embodiments bearing (3,4-dichlorobenzyl)amino or related benzyl/aryl amino substituents, halo variants, varied 1-position substituents, and hydrochloride or other salt forms.
Pharmaceutical composition including pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound of formula I together with at least one pharmaceutically acceptable carrier.
Surface coating with an adhering coating agent
A surface coating formed by combining the compound of formula I with a coating agent that can adhere the compound to a medium.
Overall, the claims cover a broad formula I pyrazolo[4,3-d]pyrimidin-7-one chemical space and a narrower enumerated set of substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds, with explicit salt, isomer, pharmaceutical composition, and surface-coating embodiments.
Stated Advantages
Documented Applications
A pharmaceutical composition including the compound together with at least one pharmaceutically acceptable carrier.
A surface coating formed by combining the compound with a coating agent that adheres the compound to a medium.
Antibacterial therapy against low G:C Gram-positive pathogens, including drug-resistant strains and Gram-positive anaerobes, by selective targeting of DNA polymerase IIIC (pol IIIC).
Treating animals by administration.
Inhibiting bacterial growth by contacting surfaces or media.
Use as a pharmaceutical composition including a pharmaceutically acceptable carrier.
Use as a surface coating with a coating agent that adheres the compound to a medium.
Ki testing against DNA Polymerase IIIC.
Antimicrobial MIC testing against multiple Gram-positive strains, including MRSA and VRE.
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