Substituted pyrazole-pyrimidines, variants thereof, and uses therefore
Inventors
Hawley, Ronald Charles • Ibrahim, Prabha • Ford, Anthony P. • Gever, Joel R.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11591315-B2
Publication Date
2023-02-28
Expiration Date
Abstract
Disclosed herein are substituted pyrazole-pyrimidine compounds of Formula I and variants thereof for the treatment, for example, of diseases associated with P2X purinergic receptors: In one embodiment, the P2X3 and/or P2X2/3 antagonists disclosed herein are potentially useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.
Core Innovation
The disclosure provides compounds of Formula I or Formulae 1-5, including substituted pyrazole-pyrimidine compounds and pharmaceutically acceptable salts, with defined structural variables such as W, X1, X2, X3, X4, X6, Y, D, R1, R2, Rf, and R7 selected from specified groups. The exemplified compounds correspond to specific selections within this chemical framework, presenting representative chemical structures and a single formula framework with multiple allowable structural motifs.
The compounds are described as P2X receptor antagonist compounds, with particular emphasis on P2X3 receptor antagonism and P2X2/3 receptor antagonism, and with selectivity for P2X3 over P2X2/3. The disclosure further frames these compounds as P2X3 and/or P2X2/3 antagonists and states therapeutic use for diseases associated with P2X3/P2X2/3.
The disclosure further includes biological data presented as in vitro assay measurements of antagonist potency for human P2X2/3 and P2X3 channels. Antagonist potency values are provided for the listed compounds using a calcium fluorescence assay format, linking the defined P2X antagonist compounds to measured in vitro potency and receptor-related activity profiles.
Claims Coverage
The claim coverage includes independent compound claims defining compounds of Formula I or a pharmaceutically acceptable salt thereof. The inventive coverage is centered on the Formula I structural selection space, with dependent refinements narrowing structural variables, narrowed subsets by fixing W to O or CH2, and at least one further claim shifting the definition to therapeutic use.
Formula I substituted pyrazole-pyrimidine compounds
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein ring and heteroatom variables are selected, including W selected from CH2, NH, N-C1-6 alkylene, O or S; X6 is N; Y is hydrogen or -NHRd; and D is an optional oxygen, with R1, R2, Rf, and R7 selected from specified groups and optional substitution patterns.
Therapeutic use of a formula I compound
A compound of Formula I or a pharmaceutically acceptable salt thereof for use in therapy.
Fixed W to O subset
A compound, or a pharmaceutically acceptable salt, defined by the earlier structural definition where W equals O.
Fixed W to CH2 subset
A compound, or a pharmaceutically acceptable salt, defined in the refined subset where W is CH2.
Overall, the claim coverage concentrates on defining a structural class of P2X antagonist compounds via Formula I structural variables and substituent options. The coverage includes narrowed subsets by fixing W to O or CH2 and includes at least one use-in-therapy formulation tied to the structural definitions.
Stated Advantages
Emphasis on P2X3 selectivity to reduce side effects, including taste effects.
Reduced side effects, including reduced taste effects.
Selectivity for P2X3 over P2X2/3.
Documented Applications
Therapeutic treatment for diseases associated with P2X3/P2X2/3, particularly pain-related diseases and other conditions listed in the disclosure.
Use of the compounds as P2X3 and/or P2X2/3 antagonists.
Treating genitourinary disease and urinary tract disease, including overactive bladder and benign prostatic hypertrophy (BPH), via P2X3 or P2X2/3 receptor antagonism.
Treating cough and urge to cough.
Treating pain conditions.
Pharmaceutical compositions including carriers or excipients.
Methods of treating disease using the disclosed compounds.
Interested in licensing this patent?