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Substituted piperazines

A substituent and representative technology, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulations, organic chemistry, etc., can solve the problems of short half-life and the risk of degradation

Inactive Publication Date: 2007-02-14
CHEMOCENTRYX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although function-blocking antibodies and small peptide therapeutics hold promise, once administered, they risk degradation, extremely short half-lives, and the intolerable cost of developing and manufacturing them, which characterize most protein drugs

Method used

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  • Substituted piperazines
  • Substituted piperazines
  • Substituted piperazines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] The piperazine ring can be formally attached to the terminal aryl unit in a variety of ways: through aromatic nucleophilic substitution reactions, metal-catalyzed coupling reactions (arylation of secondary amines), ring expansion, rearrangement, and cyclization reactions, among others. Different protection / deprotection strategies can also be employed. Thus, all or only a portion of the final molecular structure may be present at the critical aryl coupling step. Examples of various such aryl coupling methods are listed below.

[0209] Scheme A: Metal-catalyzed arylation of secondary amines

[0210] Synthesis of (5-chloro-2-piperazin-1-yl-phenyl)-phenyl-methanone

[0211]

[0212] At room temperature, piperazine (3.6g, 42.5mmol), palladium(II) acetate (0.007g, 0.043mmol), sodium tert-butoxide (0.22g, 2.4mmol) and BINAP (0.042g, 0.068mmol) were dissolved in 10 mL of anhydrous Stir in toluene for 15 minutes. Then, a solution of (2-bromo-5-chloro-phenyl)-phenyl-methan...

Embodiment 2

[1298] The protocol mentioned in the following examples is that described in Example 2.

[1299] Scheme A: Metal-catalyzed arylation of secondary amines

[1300] Synthesis of tert-butyl 1-[4-(4-chloro-3-methoxy-phenyl)-[1,4]diazepane-1-carboxylate:

[1301]

[1302] 5-Bromo-2-chloroanisole (1.10g, 5mmol, 1.0equiv), N-Boc-homopiperazine (1.0g, 1equiv), NaOtBu (0.72g, 1.5eq), rac-BINAP (58mg , 0.015 equiv) and Pd2Dba3 (28 mg, 0.005 eq) was heated in 3 mL of toluene at 90 °C overnight. After cooling to room temperature, the residue was dissolved in EtOAc and washed with water and brine. Na for organic layer 2 SO 4 Drying, filtration, evaporation, and flash column chromatography (1:4 EtOAc / hexanes) gave 1-[4-(4-chloro-3-methoxy-phenyl)-[1,4]diazepine tert-Butyl Hepane-1-carboxylate. 1 H NMR (400MHz, CDCl 3 )δ7.13(d, 1H), 6.22(d, 1H), 6.20(dd, 1H), 3.86(s, 3H), 3.45(m, 6H), 3.32(m, 2H), 3.20(m, 2H ), 1.95 (m, 2H), 1.20 (s, 9H). LCMS observed for (M+H-Boc)+: 241.

[130...

Embodiment 3

[2109] The preferred protocol in the following examples is that described in Example 3.

[2110] Scheme A: Metal-catalyzed arylation of secondary amines

[2111] Synthesis of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-piperazin-1-yl- Pyrazol-1-yl)-ethanone

[2112]

[2113] According to protocol A of Example 1, at 70 ° C, heat 2-(3-iodo-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4- Chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (204mg, 1eq), piperazine (430mg, 10eq, 9,9-dimethyl-4,5-bis(benzene phosphino) xanthene (Xantphos) (40mg, 0.3eq), Pd 2 (dba) 3 (72mg, 0.1eq) and Cs 2 CO 3 (200mg, 1.5eq) mixture overnight, then cooled to room temperature, dissolved in EtOAc and washed with water. The organic layer was purified by reverse phase HPLC (acetonitrile-H with 0.1% TFA 2 O as eluent), resulting in the title compound: LCMS retention time: 3.07 min (Agilent Zorbax SB-C18, 2.1 x 50 mm, 5 μ, 35 °C) using a 4.5 min gradient from 20-95% B at 95% ...

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Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of U.S. Patent Application No. 10 / 979,882, filed November 1, 2004, which is a continuation in part of U.S. Patent Application No. 10 / 979,882, filed December 9, 2003 A continuation-in-part, U.S. Patent Application No. 10 / 732,897 is a continuation-in-part of U.S. Patent Application No. 10 / 460,752, filed June 11, 2003, which claims the benefit of June 12, 2002 The contents of each patent application are incorporated herein by reference for the benefit of filed US Patent Provisional Application No. 60 / 453,711 (USSN 10 / 171,398 originally filed June 12, 2002). [0003] Claims Regarding Inventions Made Under Federally Sponsored Research or Development [0004] Not applied [0005] "Sequence Listings", tables or computer programs submitted as attachments on high-density diskettes [0006] none. Background of the invention [0007] The present invention provides compounds and pharmac...

Claims

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Application Information

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IPC IPC(8): A61K31/496C07D403/06
Inventor A·M·K·朋内尔J·B·阿根J·J·K·莱特S·森B·E·麦克马斯特D·J·戴拉吉陈伟张朋烈
Owner CHEMOCENTRYX INC
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