Substituted xanthines and methods of use thereof

Inventors

Chenard, Bertrand L. • Gallaschun, Randall J.

Assignees

Boehringer Ingelheim International GmbH

Abstract

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.

Core Innovation

The disclosure describes substituted 1H-purine-2,6-dione derivatives, substituted xanthine compounds, and related heterocyclic compounds as a recurring scaffold family. The compounds vary in N-substitution and in C7/C8 or analogous aryl ether substitution patterns, including 4-chlorobenzyl and 4-fluorobenzyl, 1-(3-hydroxypropyl), hydroxypropyl, hydroxybutyl, hydroxycyclopropyl, and hydroxy-terminated alkoxy groups, together with phenoxy, alkoxy, aryl/heteroaryl ether, and other heteroaryl motifs.

The 8-position is diversified with aryl, aryl-oxy, and heteroaryl substituents, including substituted phenoxy, benzonitrile, biphenyl, pyridylmethyl, thiazolyl, and fluorinated or halogenated motifs. Explicit examples include trifluoromethoxy, trifluoromethyl, chlorophenoxy, fluorophenoxy, difluoromethoxy, difluoro, chloro, methoxy, methyl, ethyl, isopropyl, and pyridyl substitutions, as well as compounds described as 8-bromo, 8-mercapto, 8-sulfide, or 8-sulfonyl chloride intermediates.

The content also describes substituted xanthine compounds of Formula I, Formula I(a), Formula II, and Formula III that function as TRPC5 antagonists. The disclosure relates these compounds to TRPC5-mediated ion flux and currents and defines performance targets including IC50 ≤ 10 nM and 95% inhibition at ≥1 μM. Pharmaceutical compositions comprising a compound and a pharmaceutically acceptable carrier are also described.

The remaining material presents synthetic preparation, purification, and characterization of multiple analog series, including thiazole acrylate and propanoic acid intermediates, chloromethyl pyridine salts, sulfonyl and thioether purine derivatives, and additional substituted purine-2,6-dione compounds. The examples are supported by 1H NMR, LCMS retention times, MH+ values, yields, and preparative HPLC purification, with variations that include oxo, hydroxy, amino, methanesulfonamide, sulfonyl, sulfinyl, cycloalkoxy, and ether-linked side chains.

Claims Coverage

The supplied independent claims are incomplete across the input items and repeatedly state only “A compound that is …” without further limitations. As a result, the inventive features cannot be determined exactly from the claim language provided, although the repeated disclosure centers on substituted heterocyclic compounds, especially substituted 1H-purine-2,6-dione derivatives and substituted xanthine compounds.

Not explicitly described in patent. The independent claim text supplied in the inputs is incomplete, so no specific claim limitations or fully defined inventive features can be extracted.

Stated Advantages

Documented Applications