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Radioligands for imaging lpa1 receptor

A technology of radioactive labeling and receptors, applied in the direction of radioactive carriers, radioactive preparations in vivo, and instruments for radiological diagnosis, etc., which can solve problems such as undesired side effects, limited treatment options, and no cure

Pending Publication Date: 2021-08-13
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no cure for IPF, and the available treatment options are very limited and have unwanted side effects

Method used

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  • Radioligands for imaging lpa1 receptor
  • Radioligands for imaging lpa1 receptor
  • Radioligands for imaging lpa1 receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Example 1. (1S, 3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0123]

[0124] The title compound was prepared according to the synthetic sequence described for the preparation of the corresponding isopropyl ester (Example IE) or ethyl ester (Example 10F) from patent application US 2017 / 0360759. The starting material used to prepare the title compound was (1S,3R)-methyl 3-hydroxycyclohexane-1-carboxylate (instead of the corresponding cyclohexane isopropyl or ethyl ester).

Embodiment 2

[0125] Example 2. (1R,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0126]

[0127] To a clear solution of the compound of Example 1 (1.95 g, 5.41 mmol) in MeOH (38.6 mL) was added 5.4M NaOMe solution (4.0 mL, 21.64 mmol). The reaction was heated at 60 °C for 6 h and then cooled to room temperature. The reaction was placed in an ice bath, neutralized with 1 N HCl, and then partially concentrated to remove MeOH. The resulting cloudy mixture was partitioned at 1.0MK 2 HPO 4 with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (1x). The organic layers were combined and washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to give a white solid, weighing 1.66 g. Purification by chiral SFC Prep (column: Chiralpak IA, 21x250mm, 5 microns; mobile phase: 20% MeOH / 80% CO 2 ; flow conditions: 85 mL / min, 150 bar, 40° C.; detector wavelength: 254 nm...

Embodiment 3

[0128] Example 3. (1S,3S)-3-((2-methyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester

[0129]

[0130] To a solution of the compound of Example 1 (970 mg, 2.69 mmol) and pyridine (1.09 mL, 13.5 mmol) in DCM (17.9 mL) at 0 °C was added dropwise over 1 h 4-nitrophenyl chloroformate (1.09 g, 5.38 mmol) in DCM (3 mL). The reaction was then allowed to warm to room temperature and stirred at room temperature for 20 h, then concentrated in vacuo to give a solid. A minimal amount of DCM was added to give a suspension and the solid (pyridine hydrochloride) was removed by filtration. The filtrate was concentrated in vacuo. The residue was chromatographed (120 g SiO 2 column; continuous gradient from 0-50% EtOAc in hexanes) to give the title compound (1.12 g, 79% yield) as a pale yellow solid. LCMS,[M+H] + = 526.3. 1 H NMR (500MHz, CDCl 3 )δ8.33-8.28(m,2H),8.03(d,J=8.5Hz,1H),7.43-7.38(m,...

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Abstract

The present invention relates to radiolabeled LPA1 receptor antagonists of Formula (I) or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein, which are useful for the quantitative imaging of LPA1 receptors in mammals.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 745,524, filed October 15, 2018; the entire contents of which are incorporated herein by reference. technical field [0003] The present invention relates to novel radiolabeled lysophosphatidic acid (LPA) receptor 1 antagonists and their use for labeling and diagnostic imaging of the LPA1 receptor in mammals. Background technique [0004] Positron emission tomography (PET) is a non-invasive imaging technique that can provide functional information about biological processes in living subjects. The ability to image and monitor molecular events in vivo is of great value for gaining insight into biochemical and physiological processes in living organisms. This in turn is crucial for the development of novel methods for the treatment of diseases, early detection of diseases and design of new drugs. PET relies on the design and synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61B6/00A61B6/03A61K51/04
CPCA61K51/0455A61B6/037A61B6/481A61B6/5217A61K2123/00C07D401/04
Inventor 郑泰华J·R·考特D·J·唐纳利金俊英史俊陶式微T·特兰
Owner BRISTOL MYERS SQUIBB CO
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