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Aminoquinazoline derivatives as P2X3 inhibitors

An alkyl and aryl technology, applied in the direction of compounds containing elements of Group 3/13 of the periodic table, pharmaceutical combinations, medical preparations containing active ingredients, etc., can solve the problem of aminoquinazoline derivative compounds that are not described or suggested And other issues

Pending Publication Date: 2022-04-01
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] It is worth noting that the prior art does not describe or suggest the aminoquinazoline derivative compounds of the general formula (I) of the present invention that represent the solution to the above needs

Method used

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  • Aminoquinazoline derivatives as P2X3 inhibitors
  • Aminoquinazoline derivatives as P2X3 inhibitors
  • Aminoquinazoline derivatives as P2X3 inhibitors

Examples

Experimental program
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preparation example Construction

[0442] Inhalable preparations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable preparations.

[0443] For administration as dry powder, single or multidose inhalers known from the prior art can be used. In this case the powder may be filled in gelatin, plastic or other capsules, cartridges or blister packs or in a depot.

[0444] Diluents or carriers that are chemically inert to the compounds of the invention, such as lactose or any other suitable additive for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0445] Inhalation aerosols comprising a propellant gas such as a hydrofluoroalkane may contain a compound of the invention in solution or dispersion. Propellant driven formulations may also contain other ingredients such as co-solvents, stabilizers or optional other excipients.

[0446] The propellant-free inhalable formulations containing the compounds of the invention may be...

Embodiment 1

[0588] 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4- Oxadiazol-5-yl)ethyl)quinazolin-4-amine

[0589] Preparation of intermediate 1,2-amino-5-bromo-3-methoxybenzoic acid hydrobromide

[0590]

[0591] A solution of bromine (6.0 g, 1.9 mL, 37.70 mmol) in chloroform (15 mL) was added dropwise to 2-amino-3-methoxybenzoic acid (6.0 g, 35.90 mmol) in chloroform ( 180mL) in suspension. The reaction was stirred for another 5 hours and allowed to warm slowly to room temperature. The solvent was removed in vacuo and the residue was triturated with ether. The reaction was filtered to give the title compound (11.3 g, 96%) as a beige solid.

[0592] LCMS (Method 4): [MH+] = 247 at 4.07 min.

[0593] Preparation of intermediate 2 6-bromo-8-methoxyquinazolin-4-ol

[0594]

[0595] A solution of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (Intermediate 1) (10.0 g, 30.60 mmol) in formamide (40 mL) was heated to 165 °C for 18 hours. After returning to room temperature...

Embodiment 114

[0646] N-(((1r,4r)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine

[0647]

[0648] Step 1: Benzyl ((1r,4r)-4-(((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate preparation of

[0649]

[0650] To a solution of 6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol (Intermediate 3) (80mg, 0.30mmol) in N,N-dimethylformamide (2mL) (Benzotriazol-1-yloxy)tripyrrolidinophosphorus Hexafluorophosphate (169 mg, 0.32 mmol) and diisopropylethylamine (0.32 mL, 1.85 mmol). The resulting mixture was heated to 40 °C and stirred for 20 min, then benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (93 mg, 0.36 mmol) was added and heating was maintained at 40 °C for 18 min. Hour. After returning to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine (2 x 20 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was used directly i...

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PUM

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Abstract

The present invention relates to compounds of formula I that inhibit P2X purine receptor 3; in particular, the present invention relates to compounds that are aminoquinazoline derivatives, processes for preparing such compounds, pharmaceutical compositions comprising them and therapeutic uses thereof. The compounds of the invention are useful in the treatment of many disorders associated with the P2X3 receptor mechanism, such as respiratory diseases, including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).

Description

[0001] field of invention [0002] The present invention relates to the inhibition of P2X purinoceptor 3 (hereinafter referred to as P2X 3 Inhibitors); in particular, the present invention relates to compounds that are aminoquinazoline derivatives, methods for preparing such compounds, pharmaceutical compositions containing them and their therapeutic use. [0003] The compounds of the present invention are useful in the treatment of many 3 Disorders related to the receptor mechanism, such as respiratory diseases, including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). [0004] Background of the invention [0005] P2X receptors are cell surface ion channels activated by extracellular adenosine 5-triphosphate (ATP). The P2X receptor family is a trimeric assembly composed of seven distinct subunit subtypes (P2X1-7) that assemble into homomeric and heteromeric channels. All subunits share a common topology that contains an i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P11/00A61P11/14C07D239/94C07D401/12C07D403/12C07D405/12C07D409/12C07D413/04C07D413/12C07D413/14C07D417/12C07D487/04A61K31/517A61K31/519A61K31/5355A61K31/5377
CPCC07D403/12C07D401/12C07D487/04C07D401/14C07D417/14C07D405/14C07D413/14C07D413/12C07D417/12C07D239/95C07D239/94C07D403/14C07D409/14C07D405/12C07D409/12C07D471/04C07D471/08A61P11/06A61P11/14A61P11/00C07D413/04C07D451/00A61K31/517A61K31/5377C07F5/02
Inventor P·布鲁诺M·比亚杰蒂C·费奥莱里D·皮齐拉尼D·帕拉P·龙奇C·贝克-格伦H·范德波尔K·L·赫斯特
Owner CHIESI FARM SPA
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