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Tetrahydropyran heterocyclic cyclopentyl heteroaryl modulators of chemokine receptor activity

A technology of heterocycle and cycloalkyl is applied in the field of tetrahydropyran heterocyclopentyl heteroaryl modulation agent with chemokine receptor activity, which can solve the problems of low sensitivity of rheumatoid arthritis and the like

Inactive Publication Date: 2006-09-13
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Those humans homozygous for the 32-base pair deletion of the CCR-5 gene appear to be less susceptible to rheumatoid arthritis (Gomez et al. Arthritis & Rheumatism. 42, 989-992 (1999)

Method used

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  • Tetrahydropyran heterocyclic cyclopentyl heteroaryl modulators of chemokine receptor activity
  • Tetrahydropyran heterocyclic cyclopentyl heteroaryl modulators of chemokine receptor activity
  • Tetrahydropyran heterocyclic cyclopentyl heteroaryl modulators of chemokine receptor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0295]

[0296] Step A

[0297]

[0298] To a solution of Intermediate 2 (500 mg, 1.84 mmol) in dichloromethane (25 mL) was added Intermediate 6 (358, 2.03 mmol), N,N-diisopropylethylamine (1.06 mL, 6.08 mmol), 1-Hydroxy-7-azabenzotriazole (276 mg, 2.03 mmol) and EDC (583 mg, 3.04 mmol) and the solution was stirred overnight. The mixture was extracted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by MPLC (0-60% ethyl acetate / hexanes). 4N hydrochloric acid was added and the solution was concentrated in vacuo to give the desired product (660 mg, 90%).

[0299] Step B

[0300]

[0301] To a solution of the product obtained in Step A (168 mg, 0.42 mmol) in dichloromethane (20 mL) was added tetrahydro-4H-pyran-4-one (50 mg, 0.50 mmol) and N,N-diisopropyl Ethylamine (260 uL, 1.5 mmol). After addition of molecular sieves (25 mg), sodium triacetoxyborohydride (1.06 g, 5.00 mmol) was added and ...

Embodiment 2

[0303]

[0304] Step A

[0305]

[0306] To a solution of Intermediate 2 (500 mg, 1.84 mmol) in dichloromethane (25 mL) was added Intermediate 6 (358, 2.03 mmol), N,N-diisopropylethylamine (1.06 mL, 6.08 mmol), 1-Hydroxy-7-azabenzotriazole (276 mg, 2.03 mmol) and EDC (583 mg, 3.04 mmol), and the solution was stirred overnight. The mixture was extracted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by MPLC (0-60% ethyl acetate / hexanes). 4N hydrochloric acid was added, and the solution was concentrated in vacuo to give the desired product (660 mg, 90%).

[0307] Step B

[0308]

[0309] To a solution of the product from Step A (50 mg, 0.39 mmol) in dichloromethane (15 mL) was added intermediate 4 (128 mg, 0.32 mmol) and N,N-diisopropylethylamine (203 uL, 1.17 mmol). After addition of molecular sieves (15 mg), sodium triacetoxyborohydride (827 mg, 3.9 mmol) was added and the mixture was st...

Embodiment 3

[0311]

[0312] Step A

[0313]

[0314] To a solution of Intermediate 2 (500 mg, 1.84 mmol) in diazomethane (25 mL) was added Intermediate 6 (358, 2.03 mmol), N,N-diisopropylethylamine (1.06 mL, 6.08 mmol), 1-Hydroxy-7-azabenzotriazole (276 mg, 2.03 mmol) and EDC (583 mg, 3.04 mmol), and the solution was stirred overnight. The mixture was extracted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by MPLC (0-60% ethyl acetate / hexanes). 4N hydrochloric acid was added, and the solution was concentrated in vacuo to give the desired product (660 mg, 90%).

[0315] Step B

[0316]

[0317] To a solution of Intermediate 3 (17 mg, 0.150 mmol) in anhydrous dichloromethane (15 mL) was added the product of Step A (50 mg, 0.125 mmol) and N,N-diisopropylethylamine (65 uL, 0.375 mmol ). After addition of molecular sieves (10 mg), sodium triacetoxyborohydride (185 mg, 0.875 mmol) was added and the mixt...

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PUM

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Abstract

The present invention is further directed to compounds of the formulas: (I) (II) (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, R19, R24 and R25 are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.

Description

Background of the invention [0001] Chemokines are a family of small (70-120 amino acids) pro-inflammatory cytokines with potent chemotactic activity. Chemokines are chemotactic cytokines released by various cells that attract different cells such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (in Schall, Cytokine , 3, 165-183 (1991) and Murphy, Rev. Immun ., 12, 593-633 (1994)). These molecules were originally identified by 4 conserved cysteines and were divided into two subfamilies based on the arrangement of the first cysteine ​​pair. In the CXC-chemokine family, which includes IL-8, GROα, NAP-2, and IP-10, the two cysteines are separated by one amino acid, while in the CC-chemokine family, which includes RANTES, MCP -1, MCP-2, MCP-3, MIP-1α, M1I′-1β and eotaxin, these two residues are adjacent. [0002] α-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth-stimulatin...

Claims

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Application Information

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IPC IPC(8): C07D407/12C07D
CPCC07D405/12C07D417/12A61P19/02A61P29/00A61P37/02A61P43/00
Inventor G·布托拉杨立虎S·D·戈布尔
Owner MERCK & CO INC
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