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Quinazoline and indole compounds to treat medical disorders

A compound and pharmacy technology, applied in the fields of compounds, chemical instruments and methods, drug combinations, etc. of Group 5/15 elements of the periodic table, can solve the problem of no small molecule factor B inhibitors, etc.

Inactive Publication Date: 2019-03-01
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although initial attempts have been made to develop inhibitors of factor B, there are currently no small molecule factor B inhibitors in clinical trials

Method used

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  • Quinazoline and indole compounds to treat medical disorders
  • Quinazoline and indole compounds to treat medical disorders
  • Quinazoline and indole compounds to treat medical disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0576] The preparation method of the compound of the present invention

[0577] abbreviation

[0578] ACN acetonitrile

[0579] Acetyl

[0580] Ac 2 O acetic anhydride

[0581] AcOEt ethyl acetate

[0582] AcOH acetic acid

[0583] Boc 2 O di-tert-butyl dicarbonate

[0584] Butyl

[0585] CBz benzyloxycarbonyl

[0586] CH 3 OH, MeOH Methanol

[0587] DCM,CH 2 Cl 2 Dichloromethane

[0588] DMA N,N-Dimethylacetamide

[0589] DMAP 4-Dimethylaminopyridine

[0590] DMF N,N-Dimethylformamide

[0591] DMS Dimethyl Sulfide

[0592] DMSO Dimethyl Sulfoxide

[0593] Et ethyl

[0594] Et 3 N,TEA Triethylamine

[0595] EtOAc ethyl acetate

[0596] EtOH ethanol

[0597] HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate

[0598] HCl hydrochloric acid

[0599] HMTA Hexamethylenetetramine

[0600] iBu, i-Bu, isoBu isobutyl

[0601] iPr, i-Pr, isoPr isopropyl

[0602] i PR 2 NEt N,N-Diisopropylethylamine

[0603] K 2 CO 3 potassium c...

Embodiment 1

[0659] Embodiment 1. General synthetic route

[0660] Scheme 1-1

[0661]

[0662] Scheme 1-1: Compounds of the present invention can be prepared from, for example, central core moieties. In Step 1, the central core is coupled with an appropriately substituted quinazoline known in the art to provide species of formula A-C. In step 2, species A-C are coupled with an appropriately substituted linker with the B moiety to provide a compound of formula I.

[0663] Scheme 1-2

[0664]

[0665] Scheme 1-2: Compounds of the invention can be prepared from eg protected piperazines. In Step 1, piperazine is coupled with an appropriately substituted quinazoline known in the art to provide species of formula A-C. In step 2, piperazine is deprotected as known in the art to provide the nucleophilic amine. In step 3, piperazine is subjected to appropriately substituted acid chlorides to provide compounds of formula I.

[0666]

[0667] Schemes 1-3: Compounds of the invention ca...

Embodiment 2

[0680] Embodiment 2. The synthesis of quinazoline (A) part

[0681] Scheme 2-1

[0682]

[0683] Scheme 2-1: Ring A of the present invention can be prepared from, for example, aniline. In step 1, an appropriately substituted aniline is converted to a urea as known in the art. In step 2, an appropriately substituted urea is cyclized by nucleophilic attack of the carbonyl moiety, followed by loss of R to provide a heterocycle. In step 3, an appropriately substituted heterocycle is arylated as known in the art to provide a halogenated quinazoline which can optionally be further modified in steps 4 and 5. In step 4, an appropriately substituted quinazoline is reduced as known in the art to the halogenated species, which can be used as described in Example 1. In step 5, the appropriately substituted dihalide is instead further derivatized as known in the art to provide the halogenated species, which can be used as described in Example 1.

[0684] Scheme 2-2

[0685]

[0...

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PUM

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Abstract

Compounds, methods of use, and processes for making inhibitors of Complement Factor B are provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Application No. 62 / 355,273, filed June 27, 2016, and U.S. Application No. 62 / 471,799, filed March 15, 2017, each of which is hereby incorporated by reference for all purposes . Background technique [0003] The complement system is part of the innate immune system that does not adapt to changes in the course of a subject's life, but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to clear pathogens. This complex regulatory pathway allows rapid responses to pathogenic organisms while simultaneously protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act by opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (disruption of membranes of foreign cells) an...

Claims

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Application Information

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IPC IPC(8): A61K31/517A61K31/395C07D401/14
CPCC07D401/14A61K31/517C07D403/12A61K45/06A61K31/454A61K31/662C07D401/04C07D401/06C07D403/04C07D239/94C07D417/12C07D487/08C07F9/3834C07D491/056C07D403/14C07D417/14C07D451/02C07D471/02A61P11/00A61P11/08A61P13/02A61P13/12A61P19/02A61P25/28A61P27/02A61P29/00A61P9/00A61P13/00
Inventor J·A·怀尔斯A·帕德克
Owner ACHILLION PHARMA INC
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