Amino quinazoline derivatives as P2X3 inhibitors
Inventors
BRUNO, PAOLO • Biagetti, Matteo • FIORELLI, Claudio • Pizzirani, Daniela • PALA, Daniele • RONCHI, Paolo • Baker-Glenn, Charles • VAN DE POËL, Hervè • Hirst, Kim Louise • GUARIENTO, Sara
Assignees
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Publication Number
US-12466820-B2
Publication Date
2025-11-11
Expiration Date
Abstract
The present invention relates to compounds of formula I inhibiting P2X purinoceptor 3; particularly the invention relates to compounds that are amino quinazoline derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of many disorders associated with P2X3 receptors mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
Core Innovation
The invention relates to compounds of formula (I), related formula (Ia), and related formula (Ib) in which the quinazoline core is defined by variable substituent selections including Z, R1, R2, RC, Y, RD, and J. The chemical space includes heterocycloalkyl, heteroaryl, aryl, and optionally substituted variants, with ring-forming options where RA and RB may form a 5- or 6-membered saturated heterocyclic monocyclic ring system.
The disclosure also includes quinazolin-4-amine and quinazolin-4-ol related structures as example compounds and intermediates. The compounds are presented in stereochemically defined and salt-containing forms, including single enantiomers, (R) forms, hydrochloride, dihydrochloride, and formate salts.
The examples include substituted quinazoline derivatives bearing oxadiazole, pyrimidinyl, pyridazinyl, pyrazolyl, thiadiazole, thiazole, methoxy, fluoro, trifluoromethyl, aryl, and morpholine-containing motifs. The disclosure also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, optionally with other active ingredients and pharmaceutically acceptable carriers or excipients.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim defining compounds of formula (I) through extensive substituent selections, with dependent claims narrowing key variables and adding selected enumerated compounds, stereochemical embodiments, salt forms, and pharmaceutical composition coverage. In total, the claim set reflects four main inventive features around the formula (I) scaffold.
Formula (I) quinazoline scaffold with variable substituent selections
A compound of formula (I) in which Z, R1, R2, RC, Y, RD, and J are defined by extensive enumerated groups, including heterocycloalkyl, heteroaryl, aryl, and optionally substituted variants, with ring-forming options for RA and RB where applicable.
Fixed Y as -OR_D and J as H
A compound of formula (I) where Y equals -OR_D and is represented by formula (Ia), with J fixed as H and the remaining variables set according to the listed substituent options.
Selected stereochemical compounds and salts
A compound of formula (I), as defined in claim 1, selected from listed specific substituted quinazolin-4-amine and related structures, including single enantiomers, (R) forms, and salts such as dihydrochloride, hydrochloride, and formate.
Pharmaceutical composition containing the claimed compound
A pharmaceutical composition containing a compound as defined in claim 1, or a pharmaceutically acceptable salt, optionally with other active ingredients and pharmaceutically acceptable carriers or excipients.
Overall, the claims cover a broad formula (I) chemical space for quinazoline-derived compounds, narrower embodiments with Y fixed to -OR_D and J fixed as H, specific enumerated stereochemical and salt forms, and a pharmaceutical composition claim incorporating the defined compound or its pharmaceutically acceptable salt.
Stated Advantages
Selective P2X3 receptor inhibition or antagonism relative to P2X2/3 heteromeric targets is emphasized.
Treatment of respiratory diseases, including cough and chronic cough, COPD, asthma, bronchospasm, and idiopathic pulmonary fibrosis, is explicitly described.
Pharmaceutical compositions suitable for oral administration and inhalation are described.
Documented Applications
Treating respiratory diseases using compounds of formula (I)/(Ib) described as selective P2X3 receptor inhibitors or antagonists, including cough and chronic cough, treatment-resistant and idiopathic cough, COPD, asthma, bronchospasm, and idiopathic pulmonary fibrosis.
Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt for oral administration or inhalation.
In vitro electrophysiology assay for P2X3 using whole-cell patch clamp with [procedural detail omitted for safety].
Selectivity testing against P2X2/3 using in vitro electrophysiology.
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