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A compound, benzo technology, applied in the field of compounds, can solve problems such as limited effectiveness

Inactive Publication Date: 2020-09-29
GLAXOSMITHKLINE INTPROP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Inhibitors of apoptosis (IAP) have been proposed, but with limited success, see eg Okuhira et al., Cell Death and Disease, 2014, 5, e1513

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0506] (S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinoline-7- Base)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino ) C Amino)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 2 hydrochloric acid Salt

[0507]

[0508] ((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((4-(benzo[d]thiazol-5-yl Amino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2 ,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutanyl- A solution of 2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (65 mg, 0.055 mmol) in THF (1.5 mL) was washed with hydrochloric acid (4M at 1, 4-dioxane) (3 mL, 12 mmol) and allowed to stand overnight. The solution was evaporated to dryness and the residual product was subjected to purification by mass controlled automated preparative HPLC (ammonium bicarbonate modifier). The recovered material was di...

Embodiment 2

[0510] (S)-7-(2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinoline-7- Base)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino ) C Amino)butanoyl)-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 2 hydrochloric acid Salt

[0511]

[0512] In analogy to (S)-7-(2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinoline -7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-3,3-dimethyl-2-((S)-2-( Methylamino)propionamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxamide, 2 hydrochloride (Example 1) using (S)-1,2,3,4-tetrahydronaphthalene-1-amine instead of (R)-1,2,3,4-tetra Hydronaphthalene-1-amine to prepare the title compound. LCMS RT = 0.74 min, ES+ve 1093.

Embodiment 3

[0514] (S)-7-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl )ammonia Base) quinazolin-7-yl) oxy) ethoxy) ethoxy) ethoxy) ethoxy) -2-((S)-3,3-dimethyl-2-((S )-2- (Methylamino)propionamido)butanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline -3- Formamide, 2 hydrochloride

[0515]

[0516] ((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-( (4,5-Dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3- (((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-di Methyl-1-oxobut-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (380 mg, 0.33 mmol) in dichloromethane (5 mL ) was treated with trifluoroacetic acid (5 mL) and stirred at ambient temperature for 30 min. The mixture was evaporated to dryness; the residue was then dissolved in 4 mL THF and treated with 4M HCl in 1,4-dioxane (5 mL). After 18 hours, the resulting suspension was diluted with d...

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Abstract

The present invention relates to compounds, compositions containing said compounds, combinations and medicaments, and methods for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, e.g. as inhibitors of RIP2 kinase activity, including degrading RIP2 kinase, for the treatment of diseases and disorders mediated by RIP2 kinase, in particular for the treatment of inflammatory diseases or illness.

Description

[0001] field of invention [0002] The present invention relates to compounds, compositions containing said compounds, combinations and medicaments, and methods for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, e.g. as inhibitors of RIP2 kinase activity, including degradation of RIP2 kinase, for the treatment of diseases and conditions mediated by RIP2 kinase, in particular for the treatment of inflammatory diseases or illness. [0003] Background of the invention [0004] Receptor interacting protein-2 (RIP2) kinase, which is also known as CARD3, RICK, CARDIAK, or RIPK2, is a TKL family serine / threonine protein kinase involved in innate immune signaling. RIP2 kinase consists of an N-terminal kinase domain and a C-terminal caspase recruitment domain (CARD) linked via an intermediate (IM) region ((1998) J Biol. Chem. 273, 12296-12300; (1998) Current Biology 8, 885-889; and (1998) J Biol Chem. 273, 16...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/86C07D403/12C07D207/09
CPCC07D401/14C07D417/14C07D487/04C07D403/14A61P29/00A61K31/4725A61K45/06
Inventor L.N.卡西拉斯J.D.哈林A.H.米亚M.D.拉克哈姆I.E.D.史密斯
Owner GLAXOSMITHKLINE INTPROP