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Novel tricyclic spiropiperidine compounds, their synthesis and their uses as modulators of chemokine receptor activity

A compound, piperidine technology, applied in the field of preparation of the compound, can solve problems such as dyspnea, insufficient blood oxygen supply, etc., and achieve a good effect of inhibiting activity

Inactive Publication Date: 2009-10-07
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This causes difficulty breathing and may result in insufficient oxygen supply to the blood

Method used

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  • Novel tricyclic spiropiperidine compounds, their synthesis and their uses as modulators of chemokine receptor activity
  • Novel tricyclic spiropiperidine compounds, their synthesis and their uses as modulators of chemokine receptor activity
  • Novel tricyclic spiropiperidine compounds, their synthesis and their uses as modulators of chemokine receptor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0522] (4-(acetylamino)-2-chloro-5-{[(2S)-3-(5-chloro-1’H,3H-spiro[1-benzofuran-2,4’-piper Pyridine]-1'-yl)-2-hydroxypropyl]oxy}phenoxy)acetic acid

[0523] Step 1: {5-Chloro-4-[(4-methoxybenzyl)oxy]-2-[((2S)-oxiran-2-yl)methoxy]phenyl}carbamate tert-butyl ester

[0524] To a solution of tert-butyl {5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]phenyl}carbamate (2.9 g) in NMP (20 ml) was added cesium carbonate ( 2.6 g) and 3-nitrobenzenesulfonic acid (2S)-oxiran-2-ylmethyl ester (1 equivalent). The reaction mixture was stirred at room temperature for 18 h, then partitioned between diethyl ether and water. The organic phase was dried over sodium sulfate, and then the solvent was removed to obtain 3.3 g (99%) by APCI-MS (m / z 435 (M + )) identified subtitle compound as a flowable oil.

[0525] Step 2: 5-chloro-2-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl) -2-Hydroxypropyl]oxy}-4-hydroxyphenylcarbamate tert-butyl ester

[0526] To {5-chloro-4-[(4-met...

Embodiment 2

[0534] (4-(acetylamino)-3-{[(2S)-3-(5-chloro-1’H,3H-spiro[1-benzofuran-2,4’-piperidine]-1’- base)-2-hydroxypropyl]oxy}phenoxy)acetic acid

[0535] Method A

[0536] Step 1: (4-Acetylamino-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidine]-1' -yl)-2-hydroxypropyl]oxy}phenoxy)methyl acetate

[0537] To N-[2-[(2S)-3-(5-chlorospiro[benzofuran-2(3H),4'-piperidin]-1'-yl)-2-hydroxypropoxy]-4 To a solution of -hydroxyphenyl]acetamide (45 mg) in DMF (1 ml) was added cesium carbonate (49 mg) and methyl bromoacetate (15 mg). The reaction mixture was stirred at room temperature for 6 h after which time the mixture was filtered and then purified by reverse phase HPLC (water: acetonitrile with 1% TFA) to afford 21 mg (33%) of the subtitle compound as a white solid.

[0538] 1 H-NMR (d6-DMSO) δ9.57-9.48 (m, H), 8.94 (d, J=8.3, NH), 7.67-7.64 (m, H), 7.31-7.29 (m, H), 7.17- 7.15 (m, H), 6.82-6.78 (m, H), 6.69-6.68 (m, H), 6.51-6.48 (m, H), 6.03 (b, OH), 4.78 (s, 3H), 4...

Embodiment 3

[0548] (4-(acetylamino)-2-chloro-5-{[(2S)-3-(5-fluoro-1’H,3H-spiro[1-benzofuran-2,4’-piper Pyridine]-1'-yl)-2-hydroxypropyl]oxy}phenoxy)acetic acid hydrochloride

[0549] Step 1: N-(5-chloro-2-{[(2S)-3-(5-fluoro-1'H,3H-spiro[1-benzofuran-2,4'-piperidine]-1' -yl)-2-hydroxypropyl]oxy}-4-hydroxyphenyl)acetamide

[0550] N-{5-chloro-4-methoxy-2-[((2S)-oxiran-2-yl)methoxy]phenyl}acetamide (1g) and 5-fluoro-3H- A solution of spiro[1-benzofuran-2,4'-piperidine] (0.75 g) in ethanol (20 ml) was heated at 80° C. for 1 h, then concentrated in vacuo. The residue was redissolved in dichloromethane, then boron tribromide (1.0M solution in dichloromethane, 3.6ml) was added dropwise. The reaction mixture was stirred at 30 °C for 1 h. Then add the second batch of BBr 3 (1.0M solution in dichloromethane, 3.6ml). The mixture was stirred at 30 °C for 18 h. The reaction was quenched with methanol (20ml) then concentrated in vacuo. The residue was redissolved in dichloromethane (10ml) an...

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Abstract

Compounds of formula (I) wherein R, R, R, R, R, R, and R are as defined in the specification, are described. The present invention also relates to pharmaceutical composition comprising said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof. Beside, the invention relates to salts and polymorphic forms of the new compounds as well as the preparation thereof.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions containing said compounds and the use of said compounds in therapy. The invention also relates to processes for the preparation of said compounds and novel intermediates useful in the preparation of said compounds. Furthermore, the present invention relates to salts and polymorphic forms of said novel compounds and to the preparation of salts and polymorphic forms of said novel compounds. Background technique [0002] The intrinsic function of the lung exposes the delicate structure to a wide range of environmental conditions including pollutants, microorganisms, allergens, and carcinogens. Host factors resulting from the interaction of lifestyle choices and genetic makeup influence the response to the above exposures. Injury or infection to the lungs can produce a wide range of respiratory disorders (or respiratory diseases). Many of these diseases are of enormous public ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107A61K31/438A61P11/00C07C235/60C07D211/48C07D303/23
CPCC07D491/107C07C235/60C07D303/23C07C233/25C07D211/48C07C69/92A61P11/00A61P11/06A61P11/08A61P29/00A61P35/00A61P37/00A61K31/438
Inventor 巴里·埃尔金斯戴维·恩尼斯托马斯·埃里克森斯科特·吉布森顾虹伊恩·哈索尔马丁·黑默林博-戈兰·约瑟夫森斯维特拉纳·伊万诺瓦桑托什·卡维塔克赛撒纳·S·库马维诺德·库马西达·林格沙玛格丽特·门索尼德斯-哈西马埃里克·梅里菲尔德约翰·莫约翰·佩维奥斯汀·皮姆詹姆斯·鲁伯森迈克·罗杰斯哈肯·舒尔茨珀·斯特兰德伯格王振玉马丁·库珀
Owner ASTRAZENECA AB
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