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Modulators of alpha-1 antitrypsin

A C1-C8, C1-C6 technology, applied in the field of α-1 antitrypsin regulators, can solve problems such as delay and insufficient

Pending Publication Date: 2021-07-23
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although infusions of plasma proteins have been shown to improve survival or slow the rate of progression of emphysema, boosting therapy is often insufficient in challenging conditions
Similarly, although enzyme replacement therapy has shown promise in delaying disease progression, only 2% of administered drug reaches the lungs

Method used

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  • Modulators of alpha-1 antitrypsin
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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0667] III. Preparation of compounds

[0668] All generic, sub-generic and specific compound formulas disclosed herein are considered to be part of this invention.

[0669] A. Formula I compound

[0670] The compounds of the invention can be prepared according to standard chemical practice or as described herein. In the following synthetic scheme and for the preparation of formula I, 1-6, 3-4, 3-5, 3-6, 4-3, 5-3, 6-4, 7-4, 8-4, 12-1 , 12-2, compounds II and III, compounds 1-215, tautomers of said compounds, pharmaceutically acceptable salts of said compounds and tautomers thereof, and any of the foregoing In the description of the deuterated derivatives, the following abbreviations are used:

[0671] abbreviation

[0672]BrettPhos Pd G4 = dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tris(prop-2-yl)phenyl]phenyl]phosphine; methanesulfonic acid; N-methyl yl-2-phenylaniline; palladium

[0673] CBzCl = benzyl chloroformate

[0674] DIPEA = N, N-diisopropylethylamine or N-and-N-isop...

example

[1408]So that the disclosure set forth herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any way.

example 1

[1409] Example 1. Synthetic compounds

[1410] All specific and general compounds, methods for preparing said compounds, and intermediates disclosed for making said compounds are considered to be part of the invention disclosed herein.

[1411] A. Synthetic Starting Materials

[1412] Preparations of S1-S12 describe synthetic routes for the synthesis of intermediates for compounds 1-215.

[1413] Prepare S1

[1414] 5-(4-fluoro-3-methylphenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3-f]indazole (S1)

[1415]

[1416] Step 1. Synthesis of 5-chloro-6-(3-methylbut-1-yn-1-yl)-1H-indazole (C2)

[1417] Pd(PPh 3 ) 2 Cl 2 (1.7g, 2.4mmol) was added to 3-methylbut-1-yne (10.7mL, 104.6mmol), 6-bromo-5-chloro-1H-indazole C1 (10.4g, 44.9mmol) and CuI (497mg , 2.6mmol) in Et 3 N (100 mL) and 1,4-dioxane (100 mL) in a nitrogen-purged solution. The solution was stirred overnight at 90 °C in a Parr bottle, after which the and methanol, and the mixture was concentrated in vacuo. Purif...

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PUM

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Abstract

Novel compounds, compositions, and methods of using and preparing the same, which may be useful for treating alpha-1 antitrypsin deficiency (AATD) are disclosed.

Description

technical field [0001] This application claims the benefit of U.S. Provisional Application No. 62 / 742,148, filed October 5, 2018, and U.S. Provisional Application No. 62 / 768,662, filed November 16, 2018, the contents of each of which are Incorporated by reference in its entirety. [0002] The present disclosure provides compounds capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more of the compounds. Background technique [0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments for AATD are continually improving, there is currently no cure. AAT is mainly produced in the liver and secreted into the blood. AAT inhibits a number of serine proteases (most notably neutrophil elastase [NE]) secreted by inflammatory cells, and thus protects organs such as the lungs from protease-induced damage, especially during inflammation. [0004] The most...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P1/16A61P11/00C07D471/14C07D487/04C07D487/14C07D519/00A61K31/5377A61K31/4985A61K31/496A61K31/4162A61K31/4439A61K31/427A61K31/4178A61K31/4196A61K31/437
CPCC07D487/04C07D487/14C07D471/14C07D519/00A61P11/00A61P1/16A61K31/4162A61K31/5377A61K31/496C07B2200/05C07B2200/13C07D403/04
Inventor C·M·布利M·A·布罗尼M·E·埃克莱斯K·J·加农S·C·胡德J·K·赫西A·卢克J·P·梅克西维尔A·梅德克M·纳瓦马尔S·罗代S·雷珀R·萨万特Y·施Q·唐M·瓦尔多U·K·班达拉奇D·M·布彻尔M·J·博伊德V·达马内斯L·T·德维芬宁R·F·小菲莫纳里P·M·加西亚巴兰特斯S·吉鲁R·L·小格雷A·B·霍尔D·J·赫利M·A·小约翰逊P·琼斯S·克萨文P·M·努汉特R·J·斯维特T·L·塔普利S·A·汤普森J·徐B·D·梅克西维尔K·M·科特雷尔
Owner VERTEX PHARMA INC
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