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2-aminopyrimidine derivatives as modulators of the histamine h4 receptor activity

An alkyl and phenyl technology, which can be used in drug combinations, respiratory diseases, skin diseases, etc., and can solve problems such as low homology

Inactive Publication Date: 2008-10-01
PALAU PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, H 4 The receptor has very low homology with the other three histamine receptors; notably its association with the H 3 Receptors share only 35% amino acid homology

Method used

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  • 2-aminopyrimidine derivatives as modulators of the histamine h4 receptor activity
  • 2-aminopyrimidine derivatives as modulators of the histamine h4 receptor activity
  • 2-aminopyrimidine derivatives as modulators of the histamine h4 receptor activity

Examples

Experimental program
Comparison scheme
Effect test

example 5

[0217] Tert-Butylmethyl[(3R)-pyrrolidin-3-yl]carbamate

[0218] (a) tert-Butyl [(3R)-1-benzylpyrrolidin-3-yl] methyl carbamate

[0219] To (3R)-1-benzyl-N-methylpyrrolidin-3-amine (10g, 52.55mmol) cooled at 0°C in 115mL CH 2 Cl 2 Add 15mL CH of di-tert-butyl dicarbonate (11.6g, 53.07mmol) to the solution 2 Cl 2 Solution. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude product was chromatographed on silica gel using a hexane / AcOEt mixture of increasing polarity as an eluent to obtain 14.5 g of the title compound (yield: 95%).

[0220] LC-MS (Method 1): t R =9.55min; m / z=291(MH + ).

[0221] (b) Title compound

[0222] A solution of the compound (14.5 g, 50.14 mmol), Pd / C (10%, 50% water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) obtained as above in a mixture of MeOH (390 mL) and water (45 mL) Heat under reflux for 5 hours. The reaction was filtered through celite, and the filtrate was washed with AcOEt and MeOH. ...

example 6

[0225] Tert-Butylazetidin-3-yl (methyl) carbamate

[0226] (a) tert-Butyl[1-(diphenylmethyl)azetidin-3-yl]methyl carbamate

[0227] Follow the procedure similar to that described in section 5a of the reference example, but use 1-(diphenylmethyl)-N-methylazetidine-3-amine instead of (3R)-1-benzyl-N-methyl Pyrrolidine-3-amine to obtain the desired compound with a yield of 73%.

[0228] LC-MS (Method 1): t R =10.14min; m / z=353(MH + ).

[0229] (b) Title compound

[0230] A solution of the compound (6.18 g, 17.53 mmol) obtained above in 60 mL MeOH and 15 mL AcOEt was purged with argon. Pd / C (10%, 50% water) (929mg) was added, then the solution was purged again with argon, and the 2 Stir under the atmosphere for 18 hours. The reaction was filtered through celite, and the filtrate was washed with AcOEt and MeOH. The solvent was evaporated to dryness to obtain a mixture of 5.66 g of the title compound and one equivalent of diphenylmethane, which was used directly.

[0231] 1 H NMR (300MH...

example 7

[0233] Tert-Butylazetidin-3-yl (ethyl) carbamate

[0234] (a) tert-Butyl [1-(diphenylmethyl)azetidin-3-yl] carbamate

[0235] Follow the similar process as described in section 5a of the reference example, but use 1-(diphenylmethyl)azetidine-3-amine instead of (3R)-1-benzyl-N-methylpyrrolidine-3 -Amine to obtain the title compound with a yield of 61%.

[0236] LC-MS (Method 1): t R =9.07min; m / z=339(MH + ).

[0237] (b) tert-butyl [1-(diphenylmethyl)azetidin-3-yl] ethyl carbamate to 55% NaH (985 mg, 22.5 mmol), THF cooled at 0°C (40 mL) and EtI (2.34 mL, 28.7 mmol) were added to the compound (6.9 g, 20.5 mmol) obtained above, and the resulting mixture was stirred at room temperature for 18 h. Then additional 55% NaH (500 mg, 11.45 mmol) and EtI (1.3 mL, 16.2 mmol) were added, and the mixture was stirred at room temperature for 18 h. A few drops of water are added and the mixture is partitioned between AcOEt and water. Pass the organic phase through Na 2 SO 4 Dry and concentrate to...

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Abstract

2-Aminopyrimidine derivatives of formula (I), wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as modulators of the H4 receptor.

Description

Technical field [0001] The present invention relates to a series of new 2-aminopyrimidine derivatives, methods for preparing them, pharmaceutical compositions containing these compounds, and their use in therapy. Background technique [0002] Histamine is one of the most powerful mediators of direct allergic reactions. Although histamine's effects on muscle contraction, vascular permeability, and gastric acid secretion are well known, its effects on the immune system are gradually becoming apparent. [0003] Recently, several independent working groups have cloned a novel histamine receptor called H 4 . As another member of its family, it is a G-protein coupled receptor (GPCR) that contains 7 transmembrane fragments. However, H 4 The homology of the receptor to the other three histamine receptors is very low; 3 The receptors share only 35% amino acid homology. Although H 3 The expression of the receptor is limited to the cells of the central nervous system, but H 4 The expression...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D405/12C07D409/12C07D239/50C07D403/04C07D471/04C07D401/04A61K31/506A61P11/00A61P17/00
CPCA61K31/506C07D403/12C07D239/50C07D405/12C07D409/12C07D471/04
Inventor E·卡塞列尔冈萨雷斯J·萨拉斯索拉纳R·索利瓦索利瓦E·M·梅迪纳福恩特斯J·马蒂维亚
Owner PALAU PHARMA SA
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