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1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

A kind of phenyl, phenoxy technology, applied in 1-phenyl-substituted heterocyclic derivatives and their uses as prostaglandin D2 receptor modulators, can solve problems such as limited efficacy

Inactive Publication Date: 2015-03-18
ACTELION PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, treatment with antihistamines and leukotriene antagonists has limited efficacy, and long-term use of corticosteroids often produces undesired side effects

Method used

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  • 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
  • 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
  • 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 110

[0547] Example 110: (±)-{4-chloro-2-[5-(2-methoxy-benzylthiocarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c]Pyridin-4-yl]-phenoxy}-acetic acid (C23H22N3O4ClS2, MW=503.07)

[0548] To (±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-ethyl acetate hydrochloric acid Salt (50mg, 0.13mmol, 1.00eq.) and NEt 3 (54 μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL) was added 2-methoxybenzyl isothiocyanate (24 mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL). The mixture was stirred at room temperature for 18 hours. An aqueous solution of 1M NaOH (0.5 mL) was added. The mixture was stirred at room temperature for 18 hours. The solution was neutralized with formic acid, purified by preparative HPLC (column: Atlantis, 30×75 mm, 10 μm, UV / MS, acidic conditions) and concentrated in vacuo to obtain the desired acid as a white solid.

[0549] LC-MS 1FA: t R =0.95min; [M+H] + =504.2

Embodiment 111

[0550] Example 111: (±)-4-(2-carboxymethoxy-5-chloro-phenyl)-2-propyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine -5- Benzyl carboxylate (C25H25N2O5ClS, MW=500.12)

[0551] In N 2 Downward (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine Benzyl-5-carboxylate (50mg, 0.09mmol, 1.00eq.) and 0.5M propyl zinc bromide in THF (0.36mL, 0.18mmol, 2.00eq.) in THF (10mL) were added Tetrakis(triphenylphosphine)palladium(0) (5.1mg, 4μmol, 0.05eq.). The mixture was stirred at 50°C for 18 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DMF, filtered, and purified by preparative HPLC (column: Atlantis, 30×75 mm, 10 μm, UV / MS, acidic conditions) and concentrated in vacuo. The obtained ester was dissolved in DMF (0.5 mL), and 1M NaOH aqueous solution (0.5 mL) was added. The resulting solution was stirred for 18 hours at room temperature. The solution was neutralized with formic acid (1 mL), fil...

Embodiment 112

[0553] Example 112: (±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine -5- Benzyl carboxylate (C28H23N2O5ClS, MW=534.10)

[0554] In N 2 Downward (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine -5-carboxylic acid benzyl ester (63mg, 0.12mmol, 1.00eq.), phenylboronic acid (15mg, 0.12mmol, 1.00eq.) and sodium carbonate (50mg, 0.47mmol, 4.00eq.) in toluene / methanol / Tetrakis(triphenylphosphine)palladium(0) (6.8 mg, 6 μmol, 0.05 eq.) was added to the mixture in water 20:4:1 (4 mL), and the mixture was stirred at 100°C for 18 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (25 mL) and water (25 mL). Separate the layers. The organic phase was washed with a saturated aqueous NaCl solution (1×12 mL), and subjected to MgSO 4 Dry and filter through celite. The filtrate was concentrated in vacuo. The residue was dissolved in DMF (0...

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Abstract

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I), wherein Y, Z, R1, R2, R3 and R4 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

Description

Technical field [0001] The present invention relates to 1-phenyl-substituted heterocyclic derivatives of formula (I) and their use as prostaglandin receptor modulators (especially as prostaglandin D 2 The use of receptor ("DP receptor") modulators) in the treatment of various prostaglandin-mediated diseases and disorders, and relates to pharmaceutical compositions containing these compounds and methods for their preparation. Specifically, such derivatives can be used alone or in a pharmaceutical composition for the treatment of chronic allergic / immune diseases / disorders and acute allergic / immune diseases / disorders such as the following diseases: asthma, allergic Asthma, eosinophilic asthma, critically ill asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergy, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma , Food allergy, systemic mast cell disease, anaphylactic shock, urticaria, eczema, ulcerativ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61K31/4353A61P11/00A61P17/00A61P37/00
CPCC07D513/04A61P1/04A61P11/00A61P11/06A61P17/00A61P19/02A61P29/00A61P37/00A61P37/06A61P37/08A61P43/00A61K31/429A61K31/4353
Inventor 汗默德·艾萨维克里斯托弗·博斯西尔维娅·里卡德-比尔德斯滕罗曼·西格里斯特
Owner ACTELION PHARM LTD
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