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C5ar antagonists

A technology selected from and compounds, applied in the direction of anti-inflammatory agents, antibacterial drugs, anti-tumor drugs, etc., can solve the problem of reducing pDC infiltration

Active Publication Date: 2013-04-24
CHEMOCENTRYX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, C5aR expression has been demonstrated in plasmacytoid dendritic cells (pDC) isolated from cutaneous lupus erythematosus lesions, and these cells have been shown to display chemotactic behavior for C5a, suggesting that C5aR on pDC Blockade of β may be effective in reducing pDC infiltration into inflamed skin in SLE and psoriasis

Method used

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[0101] Compound preparation

[0102] Those skilled in the art will recognize that there are a variety of methods that can be used to synthesize the molecules shown in the claims. In general, the method available for the synthesis of the compounds shown in the claims consists of four parts, which can be performed in any order: formation of the piperidine ring, installation of two amide bonds, and installation and / or modification of C 1 、C 2 and C 3 functional groups on the .

[0103] Several methods of preparing the claimed compounds are illustrated below (Schemes 1-6).

[0104] Reaction 1

[0105] Reaction 2

[0106] Reaction 3

[0107] Reaction 4

[0108] Schemes 1-4 show some methods for forming piperidine rings. Coupling at the 2-position of the pyridine ring can be achieved by transition metal-mediated coupling as shown in Schemes 1-2, or by metal-catalyzed addition of organometallic species such as zincate or magnesium salts (reaction Equation 3) to achie...

Embodiment 1

[0167] Synthesis of cis-1-(2-fluoro-6-methylbenzoyl)-2-phenylpiperidine-3-carboxylic acid (3-trifluoromethylphenyl)amide

[0168]

[0169] a) Pd(PPh 3 ) 4 (3.0g, 2.6mmol) was added to 2-chloro-3-carboxyethylpyridine (25g, 134.7mmol), phenylboronic acid (21.04g, 172.6mmol) and K 2 CO 3 (55.1 g, 399 mmol) in a solution in 1,4-dioxane (200 mL) and water (200 mL). The reaction mixture was heated at 100°C for 2 hours. The solution was then cooled to room temperature and dioxane was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na 2 SO 4 ), filtered through celite, and concentrated under reduced pressure. By flash chromatography (SiO 2 , 10-100% EtOAc / hexanes) to obtain 2-phenylpyridine derivatives (yield 91%, 27.98 g). LC-MS R t (Retention time): 2.45 minutes, MS: (ES) m / z 228 (M+H + ).

[0170] b) PtO 2 (800 mg, 3.52 mmol) was added to a solution of ethyl 2-phenyl-nicotinate...

Embodiment 2

[0176] Synthesis of N-(3-tert-butylphenyl)-1-(5-chloro-3-methylpicolyl)-2-phenylpiperidine-3-carboxamide

[0177]

[0178] a) 2-Chloronicotinoyl chloride (1.05 equiv) dissolved in anhydrous dichloromethane (0.5M) was added to 3-tert-butylaniline (1 equiv) and 2M K over 30 min at 0 °C 2 CO 3 aqueous solution (2.2 equiv) in anhydrous dichloromethane (0.5M) and the reaction mixture was stirred at room temperature for an additional 1.5 hours. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated to afford the desired amide as a foamy solid which was used in the next step without further purification. MS: (ES) m / z289.1 (M+H + ).

[0179] b) Pd(PPh 3 ) 4 (2-5mol%) to the above pyridine amide (1 eq), phenylboronic acid (1.4 eq) and 2M K 2 CO 3 aqueous solution (2.4 eq) in toluene (0.7 M) and heated the reaction mixture at 100° C. overnight (about 12...

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Abstract

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of C5a receptors.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Application Serial No. 12 / 823,039, filed June 24, 2010, and U.S. Application Serial No. 13 / 072,616, filed March 25, 2011; for all purposes, the contents of Incorporated herein by reference in its entirety. [0003] Claims for Inventions Made Under Federally Sponsored Research and Development Not Applicable. [0004] "Sequence Listings", tables or computer program attachments submitted on CD-ROM are not applicable. Background technique [0005] The complement system plays a central role in the clearance of immune complexes and the immune response to infectious agents, foreign antigens, virus-infected cells and tumor cells. Inappropriate or overactivation of the complement system can lead to harmful and potentially life-threatening consequences due to severe inflammation and tissue destruction. These consequences manifest clinically in a variety of conditions, including septic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/445C07D211/06
CPCC07D211/60C07D413/14A61K31/454C07D405/10C07D401/06C07D405/12A61K31/5377A61K31/445C07D413/12C07D401/10C07D401/14C07D401/12A61K31/451A61K31/4545A61P1/04A61P1/18A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P21/00A61P21/04A61P25/00A61P25/28A61P27/00A61P27/02A61P29/00A61P3/12A61P31/04A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00A61P7/02A61P7/04A61P9/00A61P9/08A61P9/10A61P3/10
Inventor 樊平臣凯文·洛伊德·格林曼曼莫汉·雷迪·莱莱蒂李延东杰伊·鲍尔斯田中裕子杨菊曾一斌
Owner CHEMOCENTRYX INC
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