Trisubstituted chiral lactam derivative and preparation method and application thereof

A lactam and substituent technology, applied in the field of tri-substituted chiral γ-lactam derivatives, can solve the problems of ineffectiveness of disease development and potential safety hazards.

Inactive Publication Date: 2010-06-23
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs used to treat allergic dermatitis mainly include antihistamines and bronchodilators, but they can only improve symptoms and have no effect on

Method used

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  • Trisubstituted chiral lactam derivative and preparation method and application thereof
  • Trisubstituted chiral lactam derivative and preparation method and application thereof
  • Trisubstituted chiral lactam derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0145] The present invention is further illustrated below through specific intermediates and examples, but it should be understood that these intermediates and examples are only used for more detailed description, and should not be interpreted as being used to limit the present invention in any form. invention.

[0146] The present invention provides general and / or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. It will be clear to those skilled in the art that in the following, unless otherwise specified, the materials and operation methods used in the present invention are well known in the art.

[0147] The melting points of the compounds were determined by a YRT-3 melting point apparatus, and the temperature was not corrected. 1 The H-NMR spec...

Embodiment 1

[0222] Example 1 : α(R)-{[(2-methyl-3-chloro)phenyl]carbamoylmethyl}-γ(R)-(4-bromophenyl)-N-{[3-(2- Oxo-pyrrolidin-1-yl)propyl]carbamoylmethyl}-γ-lactam

[0223]

[0224] Dissolve intermediate 20 (300mg, 0.625mmol) in 20mL of anhydrous dichloromethane, add carbonyldiimidazole (CDI, 122mg, 0.75mmol), stir at room temperature for 2-3 hours, then add 1-(3- Aminopropyl)pyrrolidin-2-one (84mg, 0.594mmol), stirred overnight at room temperature. After the reaction was completed, saturated brine was added thereto for extraction, and the combined organic phases were dried (Na 2 SO 4 ), filtered, concentrated and separated by column (eluent: dichloromethane / methanol / ammonia water system) to obtain a white solid product.

[0225] 1 H-NMR (400MHz, CDCl 3 )δppm: 8.62 (1H, s), 7.58 (1H, d, J = 7.56Hz), 7.49 (3H, m), 7.20 (1H, d, J = 7.84Hz), 7, 12 (1H, m), 7.05(2H, m), 4.78(1H, d, J=7.29Hz), 4.44(1H, d, J=16.53Hz), 3.14-3.45(8H, brm), 2.98(1H, m), 2.87(1H , m), 2.59 (1H, m), 2.0...

Embodiment 2

[0226] Example 2 : α(R)-{[(2-methyl-3-chloro)phenyl]carbamoylmethyl}-γ(R)-(4-bromophenyl)-N-[(1-phenylpiper Pyridin-4-yl)carbamoylmethyl]-γ-lactam

[0227]

[0228] Starting from intermediate 20 and 1-benzyl-4-aminopiperidine, the title compound was prepared by the same operation as described in Example 1 to obtain a white solid product.

[0229] 1 H-NMR (400MHz, CDCl 3 )δppm: 7.56 (2H, m), 7.49 (2H, m), 7.27-7.35 (5H, brm), 6.99-7.11 (5H, brm), 4.66 (1H, dd, J=9.52, 3.08Hz), 4.47 (1H, d, J=16.75Hz), 3.70(1H, m), 3.44(2H, s), 3.16(1H, m), 3.11(1H, d, J=16.75Hz), 2.98(1H, m) , 2.74-2.79(3H, brm), 2.52(1H, m), 2.32(3H, s), 1.94-2.15(3H, brm), 1.37-1.80(4H, brm); FAB-MS(m / z) : 653.0[M+H] + .

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Abstract

The invention relates to a trisubstituted chiral lactam derivative with the antagonistic effect of a CCR4 shown in a general formula I. The definition of each substituent group in a general formula I is shown as a specification. The invention also relates to a preparation method of a compound shown in the general formula I, a medicament composition containing the compound in the general formula Iand an application of the compound in the general formula I in the preparation of medicaments. The medicaments are used for treating and preventing diseases related to the CCR4.

Description

technical field [0001] The present invention relates to novel trisubstituted chiral γ-lactam derivatives capable of antagonizing human chemokine receptor 4 (abbreviated as hCCR4), the preparation method of these compounds, the pharmaceutical composition containing the above compounds, and the use of the compounds Use in the preparation of medicines for treating and / or preventing hCCR4-mediated diseases or conditions. technical background [0002] CCR4 (Chemokine Receptor 4, Chemokine Receptor 4) was first discovered by Christine A.Power et al. in 1995 (Christine AP et al. J.Biol.Chem.1995, 270(8):19495-19500), which belongs to chemotaxis One of the members of the factor receptor (CCR) family, it is a 7-transmembrane G-protein coupled receptor. It has two naturally occurring specific ligands: MDC (Macrophage-derived chemokine) and TARC (thymus and activation regulated chemokine) (Sadatoshi Maeda et al. Veterinary Immunology and Immunopathology 2002(90): 145-154). The newly ...

Claims

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Application Information

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IPC IPC(8): C07D207/27C07D401/12C07D403/12C07D417/14A61K31/4025A61K31/454A61K31/5377A61P43/00
Inventor 李松王应孙薇马大龙肖军海凌笑梅赵芳田林杰王莉莉綦辉郑志兵孙哲钟武谢元谢云德李行舟赵国明周辛波王晓奎刘洪英
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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