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Novel cyclic amidine compounds for treatment of autoimmune disease

A compound, selected technology, applied in allergic diseases, organic chemistry, drug combination, etc., can solve the problem of no steroid-free and non-cytotoxic oral drugs, etc.

Pending Publication Date: 2021-04-13
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

) Thus, TLR7, TLR8 and TLR9 represent novel therapeutic targets for the treatment of autoimmune and autoinflammatory diseases for which effective steroid-free and non-cytotoxic oral agents do not exist and have been developed from the very upstream Inhibition of these pathways may lead to desirable therapeutic effects

Method used

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  • Novel cyclic amidine compounds for treatment of autoimmune disease
  • Novel cyclic amidine compounds for treatment of autoimmune disease
  • Novel cyclic amidine compounds for treatment of autoimmune disease

Examples

Experimental program
Comparison scheme
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example

[0108] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

[0109] abbreviation

[0110] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

[0111] The abbreviations used in this article are as follows:

[0112] ACN: Acetonitrile

[0113] Boc 2 O: di-tert-butyl dicarbonate

[0114] Tf 2 O: trifluoroformic anhydride

[0115] DCM: dichloromethane

[0116] DDI drug-drug interactions

[0117] DIPEA diisopropylamine

[0118] DMA Dimethylacetamide

[0119] EA or EtOAc: ethyl acetate

[0120] FA: formic acid

[0121] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0122] HLM human liver microsomes

[0123] hr hours

[0124] hrs hours

[0125] IC 50 : half inhibitory concentratio...

preparation example

[0151] The following examples are intended to illustrate the implication of the present invention, but in no way represent the limitation of the implication of the present invention:

example 1

[0153] 5-[(2R,6R)-2-(5-bromo-3,4-dihydroquinazolin-2-yl)-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile

[0154]

[0155] The title compound was prepared according to the following scheme:

[0156]

[0157] Step 1: Preparation of (2R,6R)-6-methylmorpholine-2-carboxylic acid methyl ester hydrochloride (compound 1b)

[0158] At rt, to (2R,6R)-4-tert-butoxycarbonyl-6-methyl-morpholine-2-carboxylic acid (Compound 1a, CAS: 1581752-93-3, WuXi AppTec (Tianjin) New Drug Development Ltd., catalog number: RC-160325, 1.5 g, 6.1 mmol) in MeOH (20 mL) was added dropwise with SOCl 2 (1 mL). The reaction mixture was heated to reflux for 2 hrs, then cooled to rt, and concentrated under vacuum to give crude compound 1b (1.2 g, 100% yield) as a white solid. 1 HNMR (400MHz, DMSO-d 6 ) δ = 9.63 (br s, 2H), 4.55 (br d, J = 10.88Hz, 1H), 3.95 (br dd, J = 10.21, 5.93Hz, 1H), 3.41 (br d, J = 10.64Hz, 1H ), 3.22(br d, J=11.98Hz, 1H), 2.94(t, J=12.10Hz, 1H), 2.65(t, J=11.92Hz, 1H), 1.16(d,...

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Abstract

The present invention relates to compounds of formula (I), wherein R1, R2 and R3 are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds as antagonist of TLR7 and / or TLR8 and / or TLR9 in the treatment of autoimmune diseases as well as auto- inflammation diseases.

Description

technical field [0001] The present invention relates to an organic compound for the treatment and / or prevention of mammals, in particular to an antagonist of TLR7 and / or TLR8 and / or TLR9 for the treatment of systemic lupus erythematosus or lupus nephritis. Background technique [0002] Autoimmune connective tissue diseases (CTDs) include classic autoimmune syndromes such as systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSjS), mixed connective tissue disease (MCTD), dermatomyositis / multiple myositis (DM / PM), rheumatoid arthritis (RA) and systemic sclerosis (SSc). With the exception of RA, there are no truly effective and safe therapies for patients. SLE represents a typical CTD with a prevalence of 20-150 / 100,000 and causes widespread inflammation and tissue damage in different organs, ranging from common symptoms in the skin and joints to kidney, lung or heart failure. Traditionally, SLE has been treated with nonspecific anti-inflammatory drugs or immunos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/517A61K31/551C07D487/10A61P37/00
CPCA61P37/00C07D413/14C07D487/10C07D211/70
Inventor 仇宗兴沈宏朱伟F·戴伊邹舸许洪涛
Owner F HOFFMANN LA ROCHE & CO AG
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