Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders

A technology of compounds and obstacles, applied in the directions of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problem of no small molecule factor D inhibitors and so on

Pending Publication Date: 2018-05-11
ACHILLION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although initial attempts have been made to develop inhibitors of factor D, there are currently no small molecule factor D inhibitors in clinical trials

Method used

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  • Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
  • Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
  • Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0580] VII. Methods of Preparation of Active Compounds

[0581] Acronym

[0582] (Boc) 2 O di-tert-butyl dicarbonate

[0583] CAN acetonitrile

[0584] AcOEt, EtOAc ethyl acetate

[0585] CH 3 OH, MeOH Methanol

[0586] CsF Cesium fluoride

[0587] CuI Cuprous iodide

[0588] DCM,CH 2 Cl 2 Dichloromethane

[0589] DIEA,DIPEA N,N-Diisopropylethylamine

[0590] DMA N,N-Dimethylacetamide

[0591] DMF N,N-Dimethylformamide

[0592] DMSO Dimethyl Sulfoxide

[0593] DPPA diphenylphosphoryl azide

[0594] Et 3 N,TEA Triethylamine

[0595] EtOAc ethyl acetate

[0596] EtOH ethanol

[0597] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0598] HCl hydrochloric acid

[0599] i PR 2 Net N,N-Diisopropylethylamine

[0600] K 2 CO 3 potassium carbonate

[0601] LiOH lithium hydroxide

[0602] MTBE methyl tert-butyl ether

[0603] Na 2 SO 4 sodium sulfate

[0604] NaCl sodium chloride

[0605] NaH sodium hy...

Embodiment 1

[0660] Embodiment 1. General synthetic route

[0661] Compounds of the invention can be prepared, for example, from a central core. In one embodiment, the central core structure 1 is, for example, an N-protected amino acid, wherein X 1 is nitrogen and PG = protecting group. In one embodiment, the central core is coupled to an amine to generate an amide of structure 2 (where L-B includes a C(O)N moiety). Structure 2 can then be deprotected to generate Structure 3 . Structure 3 is coupled to structure 4 (A-COOH) to generate a second amide bond to form a compound within formula I. This chemical process is schematically shown in scheme 1.

[0662]

[0663] Route 1

[0664] In an alternative embodiment, the central core structure 5 is reacted with a heterocyclic or heteroaryl compound to generate a compound of structure 6. In one embodiment, structure 6 is deprotected to generate the carboxylic acid (structure 7). In one embodiment, structure 7 is coupled to an amine to g...

Embodiment 2

[0693] Example 2. Examples of central synthons

[0694]

[0695] Z A for halogen.

[0696] In one embodiment, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, compounds such as:

[0697]

[0698] Structure A can be treated with deuterium oxide to generate structure B. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO2014 / 037480 (p.103). Structure B can be reduced to generate structure C. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be treated with Mitsunobu reaction conditions to generate structure D. Structure B can be processed with DAST to generate structure E. See WO2014 / 037480. Structure A can be treated with sodium borodeuteride to generate structure F. See Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure F can be use...

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PUM

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Abstract

Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is an aryl, heteroaryl or heterocycle (R32) are provided. The inhibitors of Factor D described herein reduce the excessive activation of complement.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of Provisional US Application No. 62 / 209,972, filed August 26, 2015, which is hereby incorporated by reference in its entirety for all purposes. Background technique [0003] Immunological disorders occur when the immune system does not function in the normal way. Inflammation is a protective response involving the immune system, blood vessels, and molecular mediators. A wide variety of medical disorders result from deleterious immune or inflammatory responses or the inability of cells to respond to normal immune or inflammatory processes. [0004] 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 instead 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 respo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40C07D401/14C07D403/14C07D471/04A61K31/167A61K31/395
CPCC07K5/06191A61P1/16A61P29/00A61P17/00A61P21/00A61P19/02A61P37/02A61P27/02A61P11/00A61P9/00A61K38/00A61K31/416A61K31/4439A61K31/506A61K31/519A61P13/00C07D401/14C07D403/06C07D403/14C07D405/14C07D409/14C07D413/14C07D417/14C07D471/04C07D487/04C07D493/04C07D495/04C07D513/04A61K31/167A61K31/395A61K31/40A61K31/444A61K31/497A61P25/00A61P27/00A61P13/02A61P25/02A61P3/06A61P43/00A61P9/10Y02A50/30
Inventor J·A·怀尔斯A·S·法德克M·德施潘德A·阿加瓦尔陈大为V·R·加德哈查恩达桥本彰宏G·派斯王秋萍王祥柱
Owner ACHILLION PHARMA INC
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