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Nlrp3 inflammasome inhibitors

A -NH2, C3-C5 technology, used in anti-inflammatory agents, non-central analgesics, allergic diseases, etc., can solve problems such as poor metabolic stability

Pending Publication Date: 2021-02-26
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the major problems associated with mitochondrial modulators is their poor metabolic stability; there is therefore a need for selective and stable inhibitors of neuroinflammation of this nature (Lee et al., Eur J. Org. Chem. [European Organic Journal of Chemistry] 2017, 141, 240)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 9a

[0100] In embodiment 9a, and embodiment 9, the invention relates to a compound having any one of formulas (I) to (III), or a pharmaceutically acceptable salt thereof, wherein R 3 Choose from the following:

[0101]

[0102] where R 3e independently selected from -OH, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, halogenated, -OC(O)(C 1 -C 4 Alkyl), halogenated C 1 -C 4 Alkyl, -C(O)O(C 1 -C 4 Alkyl), hydroxyl C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halo C 1 -C 4 Alkoxy, -NH 2 、-SO 2 NH 2 、-SO 2 NH(C 1 -C 4 Alkyl), -NHSO 2 (C 1 -C 4 Alkyl), -NH(C 1 -C 4 Alkyl), -C(O)NH 2 , CO 2 H; and

[0103] R 3g Choose from H, C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, Halo and HaloC 1 -C 4 alkyl.

[0104] In embodiment 9b, and according to embodiment 9a, the invention relates to a compound having any of formulas (I) to (III), or a pharmaceutically acceptable salt thereof, wherein R is preferred 3e selected from the group consisting of: halo, OH, CH 3 、CH 2 OH, -NHS(O) 2...

example

[0450] Example of the invention

[0451] The disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed to limit the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure thereby. It should be further understood that various other embodiments, modifications and their equivalents that can occur to those skilled in the art themselves can be employed without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0452] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. In all methods, it is understood that protecting groups for sensitive or reactive groups may be used where necessary according to general chemistry principles. Protective groups were ma...

example 1

[0688] 2-(2-Chloro-5-isopropyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine-7 (8H)-yl)-N-(pyrimidin-4-yl)acetamide

[0689]

[0690] A solution of Intermediate 5 (70 mg, 0.261 mmol) in DMF (5 mL) was cooled to 0 °C in an ice bath and LiHMDS (1M in THF, 0.680 mL, 0.680 mmol) was added dropwise. The mixture was stirred at 0 °C for 20 min, then a solution of 2-chloro-N-(pyrimidin-4-yl)acetamide (65.3 mg, 0.314 mmol) in DMF (1 mL) was added slowly. The ice bath was removed and the solution was stirred overnight at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with Na 2 SO 4 Dry, filter and evaporate. The residue was purified by preparative RP chromatography to afford the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.24 (s, 1H), 8.92 (d, 1H), 8.67 (d, 1H), 8.00 (dd, 1H), 7.82 (s, 1H), 7.50 ( s,1H), 4.90(s,2H), 3.62(sept,1H), 1.31(d,6H). LC-MS: Rt=1.0min; MS m / z[M+H] + 403.2

[0691] Simi...

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Abstract

The present invention relates to novel thienopyrrolotriazinacetamide compounds of Formula (I): wherein R1, R2 and R3 are defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasomeactivity. The invention further relates to the processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.

Description

technical field [0001] The present invention relates to novel thienopyrrolotriazine acetamide compounds useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to methods for the preparation of the compounds, pharmaceutical compositions comprising the compounds, methods of using the compounds in the treatment of various diseases and disorders, and medicaments containing the compounds, and their use in the treatment of various diseases and disorders Uses in NLRP3-mediated diseases and disorders. Background technique [0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene: the protein belongs to the nucleotide-binding and oligomerization domain-like receptor (NLR) family and is also known as a "pyrin" domain-containing protein. 3" (Inoue et al., Immunology [immunology], 2013, 139, 11-18). The gene encodes a protein containing a thermal protein domain, a nucleotide binding site domain (NBD), and a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/14C07D513/14A61K31/53A61P29/00
CPCA61P29/00C07D513/14A61K31/53C07D495/14A61K45/06A61K2300/00A61P37/00A61K31/616
Inventor C·法拉第N·戈默曼P·扬泽A·麦凯H·马特斯N·J·施蒂夫尔J·韦尔奇茨基
Owner NOVARTIS AG
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