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Spirocyclic compounds as modulators of chemokine receptor activity

A compound, cycloalkyl technology, applied in the fields of rheumatoid arthritis and transplant rejection, allergic diseases and autoimmune diseases, treatment and prevention of inflammatory diseases, can solve the problem of mobilizing monocytes and so on

Inactive Publication Date: 2012-08-22
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

MIP-1α- / - mice have normal numbers of lymphocytes but fail to mobilize monocytes to sites of viral inflammation after immune challenge

Method used

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  • Spirocyclic compounds as modulators of chemokine receptor activity
  • Spirocyclic compounds as modulators of chemokine receptor activity
  • Spirocyclic compounds as modulators of chemokine receptor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] (2R)-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methanol Base-1-oxo-but-2-yl)-7-oxo-8-oxa-6-azaspiro[4.5]decane-2-carboxamide

[0174]

[0175] Step A: (R)-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)- 3-Methyl-1-oxo-but-2-yl)-3-oxocyclopentanecarboxamide

[0176]

[0177] To (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxyl-3,3-dimethylpiperidin-1-yl)-3-methanol at room temperature To a solution of butan-1-one hydrochloride (WO 2007092681, 300 mg, 0.799 mmol) in THF (2 mL) was added (R)-3-oxocyclopentanecarboxylic acid (WO 2007092681, 102 mg, 0.799 mmol) , triethylamine (0.223 mL, 1.599 mmol) and BOP (354 mg, 0.799 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and 1N hydrochloric acid (1 mL). The organic layer was washed with water (3 mL), brine (2 mL), washed with anhydrous Na 2 SO 4 Drying,...

Embodiment 2

[0199] (2R)-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methanol Base-1-oxo-but-2-yl)-7-oxo-6,8-diazaspiro[4.5]decane-2-carboxamide

[0200]

[0201] Step A: Benzyl (1R)-3-allyl-3-aminocyclopentanecarboxylate

[0202]

[0203] To a solution of benzyl (R)-3-oxocyclopentanecarboxylate (WO 2007092681, 1 g, 4.58 mmol) in methanol (5 mL) was added 2-allyl-4,4,5,5-tetra Methyl-1,3,2-dioxaborolane (1.155 g, 6.87 mmol) and ammonia solution (7N in MeOH, 8 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Shimadzu VP-ODS 20x100 mm, 8 min gradient, solvent A: 10% MeOH, 90% H 2 O, 0.1% TFA; Solvent B: 90% MeOH, 10% H 2 O, 0.1% TFA; wavelength: 220 nM). The desired fractions were collected, concentrated and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The organic layer was washed with anhydrous...

Embodiment 3

[0223] N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1- Oxo-but-2-yl)-7-oxo-6-oxa-8-azaspiro[4.5]decane-1-carboxamide

[0224]

[0225] Step A: Benzyl 2-oxocyclopentanecarboxylate

[0226]

[0227]To ethyl 2-oxocyclopentanecarboxylate (4 g, 25.6 mmol) was added benzyl alcohol (3.6 g, 33.3 mmol) and the resulting mixture was heated to 175° C. for 1 hour. The reaction mixture was concentrated under reduced pressure using a high vacuum pump to obtain benzyl 2-oxocyclopentanecarboxylate (5.2 g, 23.84 mmol, 93% yield) as an oil. This compound was used in the next step without further purification.

[0228] Step B: Benzyl 2-allyl-2-hydroxycyclopentanecarboxylate (homochiral)

[0229]

[0230] 3-Bromoprop-1-ene (8.31 g, 68.7mmol) and indium (1.081ml, 68.7mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and 1N hydrochloric acid (15 mL) was added to the residue and stirred a...

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Abstract

The present application describes modulators of chemokine receptor activity of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using modulators of formula (I) are disclosed.

Description

technical field [0001] The present invention generally relates to spiro compounds as modulators of chemokine receptor activity, pharmaceutical compositions containing said compounds, and the use of said compounds as medicaments for the treatment and prevention of inflammatory diseases, allergic Methods of allergic disease and autoimmune disease and especially rheumatoid arthritis and transplant rejection. Background technique [0002] Chemokines are chemotactic cytokines with a molecular weight of 6-15 kDa that are released by many types of cells to attract and activate many types of cells including monocytes, macrophages, T and B lymphocytes, Eosinophils, basophils, and neutrophils. There are two main classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or adjacent (CC). CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth-s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/12C07D413/12C07D471/04A61K31/4427
CPCA61K31/4427C07D405/12C07D413/12C07D471/04C07D401/12C07D471/10A61P1/00A61P1/04A61P11/00A61P11/06A61P13/12A61P17/02A61P17/06A61P19/02A61P25/00A61P25/28A61P29/00A61P29/02A61P31/18A61P35/00A61P37/02A61P37/06A61P43/00A61P9/00A61P9/04A61P9/10Y02A50/30
Inventor T.G.M.达尔J.V.邓西亚D.S.加德纳郭伟巍J.海因斯
Owner BRISTOL MYERS SQUIBB CO
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