Molecular probe derived from calcium-sensitive receptor protein antagonist and application of molecular probe in parathyroid gland resection surgery

A technology of molecular probes and calcium sensitive proteins, applied in the field of molecular probes, can solve the problems of large number, high failure rate, and small tissue, and achieve the effects of small molecular weight, high safety, and high selectivity

Inactive Publication Date: 2021-07-27
THE SECOND HOSPITAL OF DALIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the main problems at present are: 1) Due to the small size of the parathyroid gland tissue, the large number (5-7 or more), the wide distribution, and the difficulty of distinguishing it from the surrounding lymph nodes and adipose tissue, etc., the parathyroid gland tissue The failure rate of resection is high (10-15%), and it is not easy to remove completely; 2) In thyroidectomy, especially radical thyroid cancer resection, lymph node dissection is required, because lymph nodes and parathyroid glands are difficult to distinguish in many cases , can lead to incorrect removal of the parathyroid glands in up to 2% of cases
[0003] The parathyroid glands are difficult to identify with the naked eye
In 1971, methylene blue was used to stain the parathyroid glands, but the results of the operation did not show better than the operator's visual judgment, and the dye showed certain neurotoxicity
In 2006, the biosynthetic prodrug of heme protoporphyrin IX (PpIX), 5-aminolevulinic acid, was shown to selectively accumulate in the parathyroid glands, thereby achieving the effect of fluorescence imaging. Although there was one surgical application, according to A 50% probability of staining failure is reported1 as the method requires isolation of the patient for 48 hours to avoid photobleaching and phototoxic reactions
In 2015, nature medicine reported a synthetic near-infrared dye molecule that can identify parathyroid glands in the Yorkie pig animal model, but exogenous staining reagents need to be injected into the tail vein.

Method used

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  • Molecular probe derived from calcium-sensitive receptor protein antagonist and application of molecular probe in parathyroid gland resection surgery
  • Molecular probe derived from calcium-sensitive receptor protein antagonist and application of molecular probe in parathyroid gland resection surgery
  • Molecular probe derived from calcium-sensitive receptor protein antagonist and application of molecular probe in parathyroid gland resection surgery

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of Compound A

[0051] 2-Azidocyclohexan-1-ol ((1R,2R)-2-azidocyclohexan-1-ol) synthesis procedure: epoxycyclohexane (15.5mL, 153mmol) and NaN 3 (25.2g, 387mmol) dissolved in H 2 In a mixed solution of O and acetone (1:1, 160 mL), heat to reflux for 17 hours (the reaction temperature is set to 75° C.). After the reaction was completed, the acetone was evaporated away, and the remaining aqueous system was extracted with ether (3*80mL). The combined extracts were washed twice with water (2*20mL) and then washed with MgSO 4 dry. The solvent was evaporated to dryness to obtain 2-azidocyclohexanol as a yellow oil (yield 99%), which was directly used in the next synthesis reaction. Rf0.6 (petroleum ether: ethyl acetate, 9:1). 1HNMR (500MHz, Chloroform-d) δ3.41(q, J=6.9Hz, 1H), 2.04(q, J=6.9Hz, 1H), 1.97(s, 1H), 2.01–1.89(m, 1H), 1.77–1.67(m,1H),1.71–1.61(m,2H),1.64–1.57(m,1H),1.52–1.40(m,1H),1.39(dt,J=12.6,6.7Hz,1H), 1.32 (dt, J = 12.5, 6.9 Hz, 1H). 13C NMR...

Embodiment 2

[0055] Preparation of Compound B

[0056] Boc-7-azabicyclo[4.1.0]heptane-7-carboxylic acid tert-butyl ester (tert-butyl 7-azabicyclo[4.1.0]heptane-7-carboxylate) B compound synthesis: under nitrogen atmosphere, Compound A (0.194g, 2mmol), triethylamine (0.525g, 5.2mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP) were dissolved in 3mL of anhydrous dichloromethane, and the solution was cooled to 0°C and then added with di Di-tert-butyl carbonate (0.905 g, 5.2 mmol). After the solution was stirred at 0°C for 10 minutes, the reaction was stirred at room temperature for an additional 2 hours. After the reaction was completed, the reaction was quenched with 20 mL of water. This system was diluted with saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with ether (2*25mL) and the combined extracts were washed with saturated KHSO 4 (20mL) solution, saturated Na 2 CO 3 (20 mL) and saturated NaCl (20 mL), the organic phase was then dried. ...

Embodiment 3

[0058] Synthesis of compound C (tert-butyl (2-(((S)-1-(naphthalen-1-yl)ethyl)amino)cyclohexyl)carbamate):

[0059] Compound B (1 mmol) and LiClO 4 (0.1 mmol) was dissolved in anhydrous acetonitrile (6 mL), and (S)-(-)-1-(1-naphthyl)ethylamine (1.25 mmol) was added to the solution under an inert atmosphere at room temperature. The reaction solution was refluxed until the reaction was complete (check the reaction with TLC, it takes about 4-8 hours). After the reaction system was spun to remove most of the acetonitrile, the crude product was distributed in a two-phase system of ethyl acetate and water, and the organic phase was washed with water and brine, then dried with anhydrous sodium sulfate, concentrated and then used as ethyl acetate and petroleum ether. The pure product was separated by mobile phase chromatography column. There are two configurations, SSR and RRR, which are separated by silica gel chromatography (dichloromethane: methanol volume ratio = 100: 10-20), and...

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Abstract

The invention discloses a molecular probe derived from a calcium-sensitive receptor protein antagonist and application of the molecular probe in parathyroid gland resection surgery. The molecular probe is specifically a molecular probe which is derived from a chiral calcium-sensitive protein inhibitor antagonist Calhex 231 and contains a fluorophore as shown in a general formula A1 or a molecular probe containing a chromophore as shown in a general formula A2, wherein the structures of general formula A1 and general formula A2 are shown in specification.

Description

technical field [0001] The present invention relates to a method capable of quickly and specifically identifying parathyroid glands during parathyroidectomy, synthesis and application of image-guided molecular probes, in particular to design, synthesis and application of a calcium-sensing receptor protein Antagonist (Calhex 231)-derived molecular probes that may facilitate parathyroidectomy in secondary hyperparathyroidism surgery. Background technique [0002] Secondary hyperparathyroidism is an important complication of uremia, which greatly reduces the survival rate and quality of life of patients. Parathyroidectomy is an ideal treatment for secondary hyperparathyroidism in uremia. However, the main problems at present are: 1) Due to the small size of the parathyroid gland tissue, the large number (5-7 or more), the wide distribution, and the difficulty of distinguishing it from the surrounding lymph nodes and adipose tissue, etc., the parathyroid gland tissue The failur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D279/18C07C311/43C07C303/38A61K49/00
CPCC07D279/18C07C311/43C07C303/38C07C209/62C07C269/00C07D203/26A61K49/0021A61K49/003A61K49/006C07B2200/07C07C2601/14
Inventor 郑丰刘晓燕张博宇
Owner THE SECOND HOSPITAL OF DALIAN MEDICAL UNIV
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