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3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

An alkyl, amino technology, applied in the field of chemokine receptor modulators

Inactive Publication Date: 2007-01-10
INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Therefore, drugs that inhibit the binding of chemokines, such as MCP-1 and / or MIP-1α, to these receptors, such as chemokine receptor antagonists, can be used to inhibit the binding of chemokines, such as MCP-1 and / or MIP -1α is a pharmaceutical ingredient that acts on target cells, but there is no report in the prior art that 3-cycloalkylaminopyrrolidine derivatives have such pharmacological effects

Method used

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  • 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors
  • 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors
  • 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0240] Step A

[0241]

[0242] (3-Trifluoromethyl-benzamido)acetic acid. At 0°C, to a rapidly stirring solution of glycine (15.014g, 0.20mol) in MeCN (400mL) and 2M NaOH (250mL) was slowly added 3-(trifluoromethyl)-benzoyl chloride (41.714) over 30 min. g, 0.20 mol) in 75 mL of MeCN solution. The turbid yellow solution was stirred at 0°C for 30 min. The reaction mixture was acidified with 3M HCl to pH=3, followed by removal of MeCN on a rotary evaporator. Then the resulting mixture was extracted with EtOAc (400 mL×3). The organic layers were combined, dried, filtered, and concentrated to obtain a pale yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After drying under high vacuum over the weekend, 44.60 g (90%) of a white powder product was obtained. MS(M+H + )=248.1. 1 H NMR(DMSO-d 6 ) δ 12.70 (br s, 1H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H)...

Embodiment 2

[0259] Step A

[0260]

[0261] 8-pyridin-2-yl-1,4-dioxaspiro[4.5]decane-8-ol. To a solution of 2-bromopyridine (14g, 88.6mmol) in anhydrous ether (300mL) cooled at -78°C was slowly added 2.5M n-butyllithium solution (36mL). After the addition, stirring was continued for 1 hour at -78°C. A solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL) was slowly added thereto. When the addition is complete, the mixture is warmed to 0°C and stirring is continued for 1 hour. The reaction was quenched by adding aqueous ammonium chloride (4.5 g) (100 mL). The organic phase was separated, and the aqueous phase was extracted 4 times with methylene chloride. Combine the organic phases and pass MgSO 4 Dry and concentrate. Crystallization from EtOAc gave 7 g of the desired product. The mother liquor was purified on silica gel and eluted with 10% MeOH / EtOAc to give 3 g of the desired product. MS(M+H) + 236.0.

[0262] Step B

[0263]

[0264] 4-hydroxy-...

Embodiment 3

[0269]

[0270] N-(2-{(3S)-3-[(4-Hydroxy-4-pyridin-2-ylcyclohexyl)(methyl)amino]pyrrolidin-1-yl}-2-oxoethyl)- 3-(Trifluoromethyl)benzamide. To N-(2-{(3S)-3-[(4-hydroxy-4-pyridin-2-ylcyclohexyl)amino]pyrrolidin-1-yl}-2-oxoethyl)-3-( Trifluoromethyl)benzamide (49mg, 0.1mmol) and formaldehyde (0.3mL, 37% aqueous solution) in THF (2mL) solution was added Na(OAc) 3 BH (64 mg, 0.3 mmol). After stirring overnight at room temperature, add saturated NaHCO 3 The solution quenches the reaction. The resulting solution was extracted with EtOAc, and the EtOAc layer was dried (MgSO 4 ),concentrate. After preparative HPLC purification, the title compound was obtained as the TFA salt. MS(M+H) + 505.

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Abstract

The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula 1: (wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, X, Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and / or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and / or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and / or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis.

Description

Invention field [0001] The present invention relates to modulators of chemokine receptors, such as antagonists, and their use as pharmaceutical ingredients. The invention further relates to novel compounds and medical methods for the treatment of inflammation and other disorders, especially those related to the accumulation of lymphocytes or monocytes, such as rheumatoid arthritis, lupus, graft-versus-host disease and / Or transplant rejection. More precisely, the present invention relates to 3-cycloalkylaminopyrrolidine derivatives and their use as modulators of chemokine receptors. [0002] More specifically, the present invention relates to novel compounds with anti-inflammatory and immunomodulatory biological activities and their pharmaceutical compositions, which act via the antagonism of the CCR2 receptor (also known as MCP-1 receptor), thereby causing a single Inhibition of nuclear chemotactic protein-1 (MCP-1). The new compound is a 3-cycloalkylaminopyrrolidine derivative. ...

Claims

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Application Information

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IPC IPC(8): A61K31/44C07D401/12C07D401/14A61K31/4025A61K31/427A61K31/4439A61K31/506C07D417/02
CPCC07D403/12C07D413/14C07D401/12C07D413/12C07D401/14C07D207/14C07D417/14C07D417/12A61K31/454A61K31/4025C07D277/24C07D417/04A61K31/40A61K31/427A61K31/4439A61K31/497A61K31/501A61K31/506A61K31/5377A61P15/00A61P17/00A61P19/00A61P19/02A61P25/00A61P25/04A61P29/00A61P3/04A61P31/12A61P31/18A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61P9/08A61P9/10A61P3/10
Inventor 薛楚标B·迈特卡夫A·Q·韩D·J·罗宾逊郑长胜王安来张迎新
Owner INCYTE
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