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Prodrugs of a piperidinyl derivative as modulators of chemokine receptor activity

A chemokine receptor and chemokine technology, applied in the fields of rheumatoid arthritis and transplant rejection, treatment and prevention of inflammatory diseases, allergic diseases and autoimmune diseases, can solve the problem of mobilizing monocytes, etc. question

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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  • Prodrugs of a piperidinyl derivative as modulators of chemokine receptor activity
  • Prodrugs of a piperidinyl derivative as modulators of chemokine receptor activity
  • Prodrugs of a piperidinyl derivative as modulators of chemokine receptor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Step 1: tert-Butyl 3,3-Dimethyl-4-oxopiperidine-1-carboxylate

[0109]

[0110] A solution of tert-butyl 4-oxopiperidine-1-carboxylate (52.47 g, 263 mmol) in THF (1000 mL) was cooled to 0 °C and treated with sodium hydride (60% in mineral oil) at 5 min intervals suspension) (22.12 g, 553 mmol) was processed in 4 equal portions. The resulting suspension was stirred at 0 °C for 45 minutes ("min."), and then treated by dropwise addition of iodomethane (41.2 ml, 658 mmol). The mixture was stirred for 1 hour ("h" or "hr"), and then allowed to come to room temperature ("rt"). Ninety minutes after the ice bath was removed, a rapid exotherm (20-40° C. within 3 minutes) and vigorous evolution of gas was observed. The ice bath was changed, and the mixture was stirred overnight, at which time the mixture was slowly warmed to room temperature. The reaction mixture was quenched with saturated ammonium chloride (200 mL), then treated with sufficient water to dissolve the precip...

Embodiment 2

[0139]

[0140] Compound 1 (200 mg, 0.396 mmol), BOC-L-alanine (188 mg, 0.991 mmol) were treated with a solution of N,N'-dicyclohexylcarbodiimide (229 mg, 1.110 mmol) in DCM (2 mL) . , a solution of 4-(dimethylamino)pyridine (121 mg, 0.991 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered to remove N,N-dicyclohexylurea and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in EtOAc (15 mL), cooled to 0 °C and additional N,N-dicyclohexylurea was filtered off. Use 1M KHSO 4 (3 times), water and 5% NaHCO 3 (3 times) wash filtrate, dry (Na 2 SO 4 ) and concentrate. Purification of the crude product by flash chromatography using a 12 g silica gel column and eluting with 0-75% EtOAc / hexanes afforded (S)-2-(tert-butoxycarbonylamino)propanoic acid 1-(3-((R )-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutane-2 -yl)ureido)-2-methylpropan-2-yl ester...

Embodiment 3

[0147]

[0148] Compound 1 (215 mg, 0.426 mmol), BOC-L-valine (231 mg, 1.066 mmol) were treated with a solution of N,N'-dicyclohexylcarbodiimide (246 mg, 1.193 mmol) in DCM (2 mL) and 4-(dimethylamino)pyridine (130 mg, 1.066 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove N,N-dicyclohexylurea and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in EtOAc (15 mL), cooled to 0 °C and additional N,N-dicyclohexylurea was filtered off. Use 1M KHSO 4 (3 times), water and 5% NaHCO 3 (3 times) wash filtrate, dry (Na 2 SO 4) and concentrate. Purification of the crude product by flash chromatography using a 12 g silica gel column and eluting with 0-75% EtOAc / hexanes afforded the desired product (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid 1 -(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl- 1-oxobut-2-yl)ureido)-2-methylpropan-2...

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Abstract

The present application describes prodrugs of the compound 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 using the prodrug compounds of the invention are disclosed.

Description

technical field [0001] The present invention relates generally to prodrugs of piperidinyl modulators of chemokine receptor activity, pharmaceutical compositions containing said prodrugs, and the use of said prodrugs as medicaments for the treatment and prevention of inflammatory diseases , allergic disease and autoimmune disease and in particular 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, among other cell types, monocytes, macrophages, T and B lymphocytes, phagocytes, Acid cells, 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-stimulati...

Claims

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Application Information

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IPC IPC(8): C07D211/52
CPCC07D211/52C07F9/59C07D211/60A61P1/04A61P11/00A61P11/06A61P13/12A61P17/06A61P19/00A61P19/02A61P25/00A61P25/04A61P25/28A61P29/00A61P31/18A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61P9/00A61P9/04A61P9/10C07D211/20A61K31/4418
Inventor J.海因斯P.H.卡特L.A.M.科内利厄斯T.G.M.达尔J.V.邓西亚S.奈尔J.B.桑特拉J.S.瓦里尔吴红
Owner BRISTOL MYERS SQUIBB CO
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