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Compounds and compositions for treating conditions associated with nlrp activity

A compound, the technology of -Z-Q, applied in the treatment of a kind of anti-TNFα resistance, the pathology and/or symptoms and/or fields of the disease, disease or disorder, can solve the low permeability, poor systemic biological Utilization etc.

Pending Publication Date: 2021-08-27
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NLRP3 antagonists that are potent in NLRP3-inflammasome-driven cytokine secretion assays in cells but have low permeability in vitro in permeability assays such as the MDCK assay have pharmacokineti

Method used

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  • Compounds and compositions for treating conditions associated with nlrp activity
  • Compounds and compositions for treating conditions associated with nlrp activity
  • Compounds and compositions for treating conditions associated with nlrp activity

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[1930] Racemic compounds of the present invention can be resolved into the individual enantiomers using a variety of known methods. For example, chiral stationary phases may be used, and elution conditions may include normal phase or supercritical fluids with or without acidic or basic additives. Enantiomerically pure acids or bases can be used to form diastereomeric salts with racemic compounds so that the pure enantiomers can be obtained by fractional crystallization. Racemates may also be derivatized with enantiomerically pure auxiliary reagents to form diastereomeric mixtures which may be separated. The auxiliary is then removed to give the pure enantiomer.

[1931] The following abbreviations have assigned meanings:

[1932] ACN = acetonitrile

[1933] BTC = trichloromethyl chloroformate

[1934] Boc = tert-butoxycarbonyl

[1935] Davephos=2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

[1936] DCM = dichloromethane

[1937] DEA = Diethylamine

[1938] DMF...

example 1-3

[2160]

[2161] Step 1: N'-((1,2,3,5,6,7-hexahydro-symmetricindacene-4-yl)carbamoyl)-N,N-dimethylmethane-sulfonimide Amide

[2162] Into a 50 mL round bottom flask purged and maintained with a nitrogen inert atmosphere was placed N,N-dimethylmethanesulfonylimide amide (220 mg, 1.8 mmol, 1.0 equiv) and TEA (0.75 mL, 5.4 mmol, 3.0 equiv ) in THF (15.0 mL). To the solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-symmetric indacene (286 mg, 1.4 mmol, 0.8 equiv). The solution was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC with the following conditions: Column: XBridge Prep OBD C18 column, 30×150mm, 5um; Mobile phase A: water (10mmol / L NH 4 HCO 3 +0.1% NH 4 OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; detector, UV 220 / 254 nm. This yielded 80 mg of N'-((1,2,3,5,6,7-hexahydro-symmetricindacen-4-yl)carbamoyl)-N,N-dimethylmetha...

example 10-12

[2171]

[2172] Step 1: N-(tert-butyldiphenylsilyl)-3-(dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-symmetric indacene -4-yl)carbamoyl)propane-1-sulfonylimide amide

[2173] Put N-(tert-butyldiphenylsilyl)-3-(dimethylamino)propane-1-sulfonylimide amide (300mg , 0.7 mmol, 1.0 equiv) and NaH (60% wt in mineral oil, 44 mg, 1.1 mmol, 1.5 equiv) in THF (10 mL). To the solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-symmetric indacene (148 mg, 0.7 mmol, 1.0 equiv) at 0°C. The resulting solution was stirred for another 1 h at 0 °C in a water / ice bath, then quenched by addition of water. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were concentrated to give 300 mg of N-(tert-butyldiphenylsilyl)-3-(dimethylamino)-N '-((1,2,3,5,6,7-hexahydro-symmetricindacen-4-yl)carbamoyl)propane-1-sulfonylimide amide. MS-ESI: 602.9 (M+1).

[2174] Step 2: 3-(Dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-symmetricindacene-4-yl)carbamoyl)propane-1-sulfo ...

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PUM

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Abstract

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: Formula (AA) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.

Description

technical field [0001] The disclosure features chemical entities (e.g., compounds that modulate (e.g., antagonize) NLRP3, or pharmaceutically acceptable compounds of such compounds) that are useful, for example, in the treatment of conditions, diseases or disorders in a subject (e.g., a human) Accepted salts and / or hydrates and / or co-crystals and / or pharmaceutical combinations) in which NLRP3 activity is reduced or increased (e.g., increased, e.g., in conditions associated with NLRP3 signaling, disease or disorder) contributes to the pathology and / or symptoms and / or progression of said condition, disease or disorder. The present disclosure also features compositions and other methods of using and making the compositions. [0002] This disclosure also relates in part to methods and compositions for treating anti-TNFα resistance in a subject with an NLRP3 antagonist. The present disclosure also relates in part to methods, combinations and compositions for treating TFNα-associa...

Claims

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Application Information

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IPC IPC(8): C07C311/33C07D231/12C07D333/22A61K31/18A61P35/00C07C311/60
CPCC07C311/60C07D231/12C07D333/22C07C381/10C07C2603/10C07C2602/08C07C2601/04C07C2601/14C07C2601/08C07C2601/02C07C2602/38C07C311/51C07C311/56C07D207/12
Inventor J·卡茨沈东明
Owner NOVARTIS AG