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4-aminopyrimidine derivatives as histamine H4 receptor antagonists

An alkyl and group technology, which can be used in anti-inflammatory agents, drug combinations, non-central analgesics, etc., and can solve problems such as low homology

Active Publication Date: 2010-12-01
PALAU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, H 4 The receptor has low homology to the other 3 histamine receptors (see Oda T et al.); it is noteworthy that H 4 receptor and H 3 Receptors share only 35% homology

Method used

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  • 4-aminopyrimidine derivatives as histamine H4 receptor antagonists
  • 4-aminopyrimidine derivatives as histamine H4 receptor antagonists
  • 4-aminopyrimidine derivatives as histamine H4 receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0774] 2-isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine

[0775] The compound obtained in Reference Example 1 (144 mg, 0.72 mmol) was added to the compound of Reference Example 3 (89 mg, an approximately 50% mixture of two regioisomers, 0.48 mmol equivalent to 0.24 mmol of the desired region Isomer) and DIEA (0.25ml, 1.44mmol) in n-BuOH (6ml) and heated the resulting mixture in a sealed tube at 100°C overnight. Additional compounds of Reference Example 1 (96 mg, 0.48 mmol) and DIEA (0.25 ml) were added and heated at 100°C for another day. The reactant is cooled and the solvent is evaporated to a dry state. By preparative HPLC-MS (column X-Terra PREP MSC185μm (100mm×19mm), rate 20ml / min, eluent: A=AcN, B=NH 4 HCO 3 75mM, gradient: 0 minutes A 25%; 1 minute A 25%; 11 minutes A 90%; 12 minutes A 90%) Purify the resulting crude product and evaporate the product-containing fraction to dryness to form a Boc-protected intermediate Product (26.9 mg, yield 32%). To t...

Embodiment 2 to 3

[0778] Following a method similar to that described in Example 1, but using appropriate starting materials, the following compounds were obtained:

[0779]

Embodiment 4

[0781] 2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine

[0782] Method A

[0783] The compound of Reference Example 18 (2g, 6.0 mmol), benzophenone imine (1.1ml, 6.60 mmol), sodium tert-butoxide (0.86g, 9.0 mmol), racemic BINAP (0.22g) , 0.36 mmol) and toluene (60ml) were placed in a schlenk tube. The system was cleaned 3 times by vacuum / argon cycle. Then add Pd 2 (dba) 3 (0.11 g, 0.12 mmol) and vacuum / argon purge again 3 times. The reaction mixture was heated overnight at 85°C. Cool the crude reaction product at room temperature and pass through diatomaceous earth Filter and rinse the filter cake with ethyl acetate. The filtrate was evaporated to a dry state. The residue was dissolved in THF (127ml), then 3N HCl (127ml) was added and stirred at room temperature for 3 hours. Evaporate to dryness. The crude product was dissolved in water and ethyl acetate, the phases were separated and the organic layer was discarded. Add 0.5N NaOH to the acidic aqueous phase u...

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Abstract

4-Amino-pyrimidine derivatives of Formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.

Description

Technical field [0001] The present invention relates to a series of novel 4-amino-pyrimidine derivatives, methods for preparing them, pharmaceutical compositions containing these compounds, and the use of the compounds in therapy. Background technique [0002] Histamine is one of the most effective mediators of immediate allergic reactions. Although the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, the effects of histamine on the immune system are only beginning to be revealed. [0003] A few years ago, one was named H 4 The novel histamine receptor was cloned by several independently working research groups (see Oda T et al., J Biol Chem 2000, 275: 36781-6; Nguyen T et al., Mol Pharmacol 2001, 59: 427-33). Like H 4 Like other members of the receptor family, H 4 The receptor is a G protein coupled receptor (GPCR) with 7 transmembrane segments. However, H 4 The receptor has low homology with the other three...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4439
CPCC07D403/04A61P1/04A61P11/00A61P11/02A61P11/06A61P17/04A61P17/06A61P19/02A61P25/00A61P25/04A61P25/06A61P27/02A61P27/12A61P29/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor E·卡塞列尔冈萨雷斯E·M·梅迪纳福恩特斯R·索利瓦索利瓦M·维尔基里博纳多J·马蒂维亚
Owner PALAU PHARMA
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