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-11001592-B2
Publication Date
2021-05-11
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 disclosure relates to substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds corresponding to formula I, in which A and B are N and n is 1. The compounds include a substituent framework defined by R1 as (CH2)m-{(V)o-(CH2)p}q-W, with broad selection of V and W groups, and additional variable substituents R2, R3, R0, R4, R5, R6, R7, X, and Y as specified in the inputs.
The core structure further includes phosphate-containing or hydrolysable-ester R0 motifs, along with optical isomers, isotopic isomers, prodrugs, and pharmaceutically acceptable salts. The disclosed examples and selected groups center on pyrazolo[4,3-d]pyrimidin-7(6H)-one members bearing (3,4-dichlorobenzyl)amino or related substituted amino motifs and diverse side chains, including phosphonate, phosphate, hydrochloride, and dihydrochloride salt forms.
The provided content also includes preparation and characterization of multiple specific compounds within this scaffold, with named examples spanning oxazolyl, piperidyl, pyrrolidinyl, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, fluorobenzyl, difluorobenzyl, sulfonyl-pyridyl, and dimethylphosphoryl-containing variants. Analytical support is reported by NMR, HPLC purity, LC-MS, and ESI-MS, and several examples are presented as isolated salt forms.
Claims Coverage
The consolidated claim coverage centers on one broad Formula I compound class and one selected group of specific pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds, together covering at least two inventive feature sets. The compound claims emphasize extensive structural variability in R1/V/W and defined R2/R3/R0 patterns, including prodrug and salt forms, while dependent claim contexts address Gram-positive antibacterial use and a surface-coating format.
Formula I pyrazolo[4,3-d]pyrimidin-7-one compound scaffold with variable substituents
A compound corresponding to formula I wherein A and B are N, n is 1, and R1 is (CH2)m-{(V)o-(CH2)p}q-W, with the listed options for V and W, together with specified constraints for R2, R3, R0, R4, R5, R6, R7, X, and Y, including optical isomers, isotopic isomers, prodrugs, and pharmaceutically acceptable salts.
Selected substituted pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds including prodrugs and salts
A compound selected from specified pyrazolo[4,3-d]pyrimidin-7(6H)-one members, including compounds bearing (3,4-dichlorobenzyl)amino and related substituted side chains, together with prodrugs thereof and pharmaceutically acceptable salts thereof.
Treating a Gram-positive bacterial infection
A method of treating a Gram-positive bacterial infection by administering a therapeutically effective amount of the compound to a subject in need.
Inhibiting growth of Gram-positive bacteria by contacting a medium
A method for inhibiting the growth of Gram-positive bacteria by contacting a medium with an effective amount of the compound.
Surface coating comprising the compound and a coating agent
A surface coating comprising the compound together with a coating agent capable of adhering the compound to a medium.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition including the compound together with at least one pharmaceutically acceptable carrier.
Overall, the claims cover a broad Formula I pyrazolo[4,3-d]pyrimidin-7(6H)-one chemical space, a selected set of specific substituted compounds, and explicit use or format claims for treating Gram-positive bacterial infection, inhibiting Gram-positive bacterial growth, forming a surface coating, and providing a pharmaceutical composition.
Stated Advantages
Inhibits the growth of Gram-positive bacteria.
Allows treating a Gram-positive bacterial infection by administering to a subject in need.
Enables a surface coating in which the compound adheres to a medium.
Evaluated as DNA polymerase IIIC inhibitors with Ki targeting less than 5 μM.
Antimicrobial efficacy is described by MIC targeting less than 4 μg/mL against Gram-positive bacteria.
Documented Applications
Treating a Gram-positive bacterial infection by administering a therapeutically effective amount of the compound to a subject in need.
Inhibiting the growth of Gram-positive bacteria by contacting a medium with an effective amount of the compound.
A surface coating comprising the compound together with a coating agent capable of adhering the compound to a medium.
Pharmaceutical compositions comprising the compound and at least one pharmaceutically acceptable carrier.
Compounds evaluated as DNA polymerase IIIC inhibitors.
Antimicrobial efficacy testing against Gram-positive bacteria.
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