Pyridopyrimidines derivatives as P2X3 inhibitors
Inventors
BRUNO, PAOLO • Biagetti, Matteo • FIORELLI, Claudio • Baker-Glenn, Charles • Van De Poel, Hervè • Penrose, Stephen David • LANARO, Roberta
Assignees
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Publication Number
US-12606562-B2
Publication Date
2026-04-21
Expiration Date
Abstract
The present invention relates to compounds of formula I inhibiting P2X purinoceptor 3 (hereinafter P2X3 inhibitors); particularly the invention relates to compounds that are pyridopyrimidines 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 document describes compounds within a pyrido[3,2-d]pyrimidin-4-amine scaffold series, including formula (I) embodiments in which X1, X2, and X3 are independently CH or N, at least one of X1, X2, and X3 is N, and X1 is N when X3 is N. Z is selected from heteroaryl and aryl, with heteroaryl including thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and triazinyl, and with optional substitution by groups including (C1-C3)alkyl, halo, CN, and (RA RB)NC(O)—.
In formula (I), R1 is H, R2 is selected from heteroaryl(C1-C4)alkyl and (C3-C8)heterocycloalkyl-(C1-C6)alkyl, and RA and RB are independently H or (C1-C4)alkyl, or may form together with the nitrogen atom to which they are attached a 6-membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen. RC is (C1-C6)alkyl, and J is H or (RA RB)N—, with preferred substructure definitions using formula (Ia) and related subcases.
The document also presents specific listed pyrido[3,2-d]pyrimidin-4-amine derivatives, including fluorophenyl, methylpyridazinylmethyl, oxadiazolyl-ethyl, thiazolyl, and (R)-configured trifluoromethylpyrimidinyl-ethyl substitutions. It further includes named intermediates and examples, analytical characterization including 1H NMR and LCMS, and later single-enantiomer preparations, together with biological context in vitro whole-cell electrophysiology assays for P2X3 receptors and P2X2/3.
Claims Coverage
Two independent claim themes are present: a broad compound-of-formula (I) claim and a claim to an explicitly enumerated group of pyrido[3,2-d]pyrimidin-4-amine derivatives. The broad claim is defined by the constrained X1/X2/X3 heteroatom pattern, the selectable and optionally substituted Z group, and the defined R1, R2, RA/RB, RC, and J features, while the listed-compound claim confines coverage to specific named compounds, including (R)-stereochemical members.
Compound of formula (I) with constrained heteroatom pattern and selectable Z
A compound of formula (I) wherein X1, X2 and X3 are independently CH or N, at least one of X1, X2, and X3 is N, and X1 is N when X3 is N; Z is selected from heteroaryl and aryl, with heteroaryl selected from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and triazinyl; and the heteroaryl and aryl groups are optionally substituted by one or more groups selected from (C1-C3)alkyl, halo, CN, and (RA RB)NC(O)—.
Defined R1, R2, RA/RB, RC, and J substituent architecture
R1 is H; R2 is selected from heteroaryl(C1-C4)alkyl and (C3-C8)heterocycloalkyl-(C1-C6)alkyl; any of the alkyl, heteroaryl, and heterocycloalkyl groups may be optionally substituted by defined groups; RA and RB are independently H or (C1-C4)alkyl or may form together with the nitrogen atom to which they are attached a 6-membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen; RC is (C1-C6)alkyl; and J is H or (RA RB)N—.
Selected pyrido[3,2-d]pyrimidin-4-amine compounds
A compound selected from the group consisting of the explicitly listed pyrido[3,2-d]pyrimidin-4-amine derivatives, including 6-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine; N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine; N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)pyrido[3,2-d]pyrimidin-4-amine; N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylthiazol-2-yl)pyrido[3,2-d]pyrimidin-4-amine; and multiple (R)-configured members bearing (2-(trifluoromethyl)pyrimidin-5-yl)ethyl substituents.
The claims collectively define a broad formula (I) scaffold with constrained heteroatom placement and substituent architecture, together with a second claim limited to explicit pyrido[3,2-d]pyrimidin-4-amine compounds, including specific aryl/heteroaryl substitutions and (R)-stereochemical variants.
Stated Advantages
Inhibits P2X3 receptors.
Selectivity over P2X2/3 heteromeric receptors as stated in the provided summary context.
Selectivity over P2X3 homomeric receptor as stated in the provided summary context.
Provides P2X3 potency classification (Table 8) for the described compounds.
Provides P2X3 versus P2X2/3 selectivity classification (Table 9) supporting selectivity toward P2X3.
Documented Applications
Therapeutic treatment of disorders associated with P2X3 receptor mechanisms by administering a therapeutically effective amount of a compound according to claim 1.
Use in respiratory disease indications including cough and chronic cough, and conditions including COPD and asthma, as stated in the provided summary context.
Use as part of a pharmaceutical composition or medicament including pharmaceutically acceptable carriers or excipients.
Treatment and prevention of diseases where P2X3 receptors are involved, especially respiratory diseases and cough subtypes, including sub-acute/chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).
Pharmaceutical composition use comprising a compound of claim 1 or a pharmaceutically acceptable salt with pharmaceutically acceptable carriers or excipients, optionally with one or more other active ingredients.
In vitro whole-cell electrophysiology (patch clamp) assays used to classify antagonism potency for P2X3 receptors and P2X3 versus P2X2/3 selectivity.
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