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Pcsk9 inhibitors and methods of use thereof

A technology of inhibitors and residues, applied in the field of PCSK9 inhibitors and its use, can solve problems such as allergic reactions and harmful immune responses

Pending Publication Date: 2021-09-17
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, both antibody drugs require intravenous administration and can cause anaphylaxis or other deleterious immune responses in the body

Method used

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  • Pcsk9 inhibitors and methods of use thereof
  • Pcsk9 inhibitors and methods of use thereof
  • Pcsk9 inhibitors and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example

[0268] Examples of compounds of formula (I) or pharmaceutically acceptable salts thereof that have useful biological activities are listed in Tables 1-10. 1 H NMR spectroscopy was performed on a Varian MR-400 mass spectrometer operating at 400 MHz (proton frequency) equipped with: self-shielded z-gradient coil 5 mm 1H / nX reverse detection broadband probe, deuterium digital channel lock unit, with transmitter bias A frequency-shifted quadrature digital detection unit. Chemical shifts are reported as delta values ​​in ppm relative to trimethylsilane (TMS) as internal standard. Coupling constants (J values) are given in Hertz (Hz) and diversity is reported using the following abbreviations (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined).

[0269] A. Analysis method

[0270] Method 1 (Acid FA)

[0271] UPLC settings

[0272] Solvent: -A water (high purity via PureLab Option unit) with 0.1% formic acid

[0273] B Acetonitrile with 0.1%...

example 302B

[0821] A solution of Example 302A (6.77 g, 21 mmol) in THF (200 mL) was cooled to -65 °C under N2 atmosphere. MeMgBr (21 mL, 63.1 mmol, 3M in THF) was added dropwise, then stirred at -65 °C for 0.5 h. The reaction was warmed to room temperature for 2 h, quenched by the addition of water (200 mL). After extraction with EtOAc (200 mL x 2), the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / EtOAc = 3 / 1) to give the desired product Example 302B (4 g, 56% yield) as a yellow oil. LCMS[M+H] + =339

[0822] Step 2: Instance 302C

[0823] To the reactor, a suspension of Pd / C (400 mg) catalyst was introduced into a solution of Example 302B (4 g, 0.012 mmol) in MeOH (40 mL). The vessel was purged with nitrogen, then hydrogen, and the reaction mixture was stirred at room temperature for 18 h. Consumption of starting material was detected b...

example 303

[0846] To Example 303G (563 mg, 1.14 mmol) and K at room temperature 2 CO 3 (940 mg, 6.82 mmol) in DMF (10 mL) was added Example 301A (183 mg, 1.14 mmol). The reaction was then heated to 60 °C and stirred for 16 h. TLC showed that the starting material was consumed. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 4), and the combined organic layers were washed with brine (20 mL x 2), washed with Na2SO 4 Dry, filter and concentrate. The residue was purified by silica gel chromatography (eluting with petroleum ether / EtOAc = 3 / 1 to 1 / 9) to provide the crude product, which was purified by preparative HPLC to provide the product Example 303 as a pale yellow solid ( 75.2 mg, yield: 12.93%). LCMS[M+H] + =511

[0847] 1H NMR (400MHz, CDCl3) δ 8.37(s, 2H), 7.96(s, 1H), 7.66-7.58(m, 2H), 6.82(s, 1H), 5.87(s, 1H), 3.83-3.73(m , 5H), 3.59-3.44 (m, 5H), 3.01 (s, 4...

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Abstract

The invention relates to a novel inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of priority from US Provisional Patent Application No. 62 / 794,239, filed January 18, 2019, which is hereby incorporated by reference in its entirety. Background technique [0003] PCSK9, also known as "proprotein convertase subtilisin / kexin9", is a member of the secreted proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases circulating LDL cholesterol levels by enhancing the degradation of the LDL receptor independent of its catalytic activity. Secreted PCSK9 binds to the epidermal growth factor domain A (EGFA) of the LDL receptor (LDLR) on the cell surface, and the PCSK9 / LDL receptor complex is internalized into the endosomal / lysosomal compartment. Enhanced binding affinity of PCSK9 to the LDL receptor at the acidic pH of late endosomes / lysosomes reduces LDL receptor recycling, whereas targeting the LDL receptor for lysosomal degradation. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/02C07D401/12C07K16/40C07K16/28C07D231/10C07D231/38A61K31/435A61K31/395A61P3/06
CPCC07D403/12C07D413/12C07D417/12C07D417/14A61K31/506A61K31/5377A61K31/541A61P9/00A61K45/06A61P3/06C12N9/0012C12N9/6424C07D491/107C07D487/10C07D498/04C07D471/10C07D403/14C07D401/14C07D498/10C07D495/04C07D239/42C07D235/30C07D253/075C07D263/58C07D271/07C07D401/12C07D471/04
Inventor M·H·塞拉诺-吴B·K·哈巴德V·考施克D·丹尼尔斯
Owner ASTRAZENECA AB
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