Aminomethyl-biaryl derivatives as complement factor D inhibitors and uses thereof

A technology of heteroaryl and alkyl, applied to aminomethyl-biaryl derivatives as complement factor D inhibitors and application fields thereof, can solve problems such as blindness in patients

Inactive Publication Date: 2016-05-04
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There is currently no proven medical therapy for dry AMD, and despite current therapy with anti-VEGF agents such as Lucentis, many patients with neovascular AMD become legally blind

Method used

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  • Aminomethyl-biaryl derivatives as complement factor D inhibitors and uses thereof
  • Aminomethyl-biaryl derivatives as complement factor D inhibitors and uses thereof
  • Aminomethyl-biaryl derivatives as complement factor D inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1189] Biological Example 1: Human Complement Factor DELISA Assay

[1190] Recombinant human factor D (expressed in E. coli and purified using standard methods) was treated at a concentration of 10 nM together with various concentrations of test compounds in 7.5 mM MgCl 2Incubate with 0.075% (w / v) CHAPS in 0.1 MPBS pH 7.4 for 1 hour at room temperature. Cobra venom factor and human complement factor B substrate complex were added to a final concentration of 200 nM. After incubation at room temperature for 1 hour, the enzyme reaction was stopped by adding 0.1 M sodium carbonate buffer, pH 9.0, containing 0.15 M NaCl and 40 mM EDTA. The reaction product Ba was quantified by enzyme-linked immunosorbent assay. ICs were calculated as percent inhibition of Factor D-activity as a function of test compound concentration 50 value.

Embodiment 2

[1191] Biological Example 2: Human Complement Factor DTR-FRET Assay

Embodiment 21

[1192] Biological Example 2.1.2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-(tert-butoxycarbonyl)-5-((3- Chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfodihydro Indole-2-ylidene)pent-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indole-1-

[1193]

[1194] To 2-((1E,3E,5E)-5-(1-(5-carboxypentyl)-3,3-dimethyl-5-sulfoindoline-2-ylidene)pentyl-1 ,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indole-1- To a solution of potassium salt (Cy-5, CAS#449175-58-0) (162 mg, 0.233 mmol) in DMF (1 mL) was added HBTU (112 mg, 0.295 mmol) at room temperature. After stirring for 10 minutes, (2S,4S)-4-(aminomethyl)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert Butyl ester (Intermediate B15 of WO2012093101, Step C) (129 mg, 0.32 mmol) and DIEA (86 μL, 0.491). The blue solution was stirred for 12 hours and then purified by preparative HPLC (WatersSunFire C18OBD, 5 μm, 30*100 mm, eluent A:H 2 O+0.1% TFA, B:...

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Abstract

The present invention provides a compound of formula (I), a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

field of invention [0001] The present invention relates to inhibition of the alternative complement pathway, in particular inhibitor D, in patients suffering from conditions and diseases associated with activation of the alternative complement pathway, such as age-related macular degeneration, diabetic retinopathy and related eye diseases. Background of the invention [0002] The complement system is an important component of the innate immune system and includes a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical pathway, the lectin pathway and the alternative pathway (V.M. Holers, Clinical Immunology: Principles and Practice, edited by R.R. Rich, Mosby Press; 1996, 363-391) . Molecules, antibodies or cellular components from microorganisms can activate these pathways, resulting in the formation of protease complexes known as C3-convertase and C5-convertase. The classical pathway is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81C07C311/21C07C233/75C07C229/06
CPCA61P1/04A61P1/16A61P3/04A61P7/00A61P7/06A61P7/08A61P9/00A61P9/10A61P11/00A61P11/06A61P11/08A61P13/12A61P21/04A61P25/00A61P25/16A61P27/02A61P29/00A61P31/00A61P31/02A61P31/04A61P33/00A61P35/00A61P37/06A61P37/08A61P43/00C07C217/48C07C217/58C07C217/64C07C217/74C07C217/76C07C229/34C07C229/36C07C229/42C07C233/43C07C233/47C07C233/63C07C235/34C07C235/46C07C237/20C07C237/38C07C237/40C07C237/42C07C255/16C07C255/43C07C255/57C07C255/59C07C257/18C07C311/37C07C317/32C07D205/04C07D213/56C07D213/82C07D215/12C07D231/12C07D231/56C07D233/90C07D239/26C07D257/04C07D263/32C07D265/30C07D267/10C07D277/56C07D305/06C07D307/16C07D309/06C07D309/14C07D311/42C07D317/60C07D405/12C07D417/12C07C2601/02C07C2601/08C07C2601/14C07C2602/08C07C2602/10C07D213/81
Inventor D·B·毕兰格尔S·弗洛尔C·F·格林K·珍德扎嵇楠刘东雷E·L·J·洛蒂瓦R·G·卡尔基N·马伊诺尔菲J·J·鲍尔斯S·A·兰德尔O·罗格尔A·伍尔佩蒂尹泰荣
Owner NOVARTIS AG
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