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Prostate specific membrane antigen inhibitor, metal marker thereof, preparation method and application

A prostate-specific, metal-labeled technology, which is applied in the field of biomedicine, can solve problems such as insufficient cell internalization rate and cell uptake rate, changes in inhibitor affinity, and structure-activity relationships that have yet to be established, achieving novel structures and physical and chemical properties. Stable and high marking effect

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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

177 Lu-labeled PSMA-617 and PSMA-I&T drugs still have the problem of insufficient cell internalization rate and cellular uptake rate (uptake rate is about 20%, internalization rate is less than 10%), and there is still a lot of room for improvement
In terms of linking groups, it is usually used in drug design to control the metabolic properties of drugs, 225 Ac-PSMA-617 and 177 Lu-PSMA-617 uses aminocaproic acid, while 177 The linking groups used by Lu-PSMA-I&T are much more complicated; in terms of targeting groups, most of the small molecule inhibitors of PSMA currently entering the clinical stage use Lys-Urea-GLu structural fragments to inhibit dipeptides, of which the lysine branch The chain amino group is usually directly connected to the linking group by an amide bond, and the structure-activity relationship between the branched chain modification and its properties has yet to be established
Due to the steric selectivity of the binding of the targeting group and the PSMA enzyme, even minor structural modifications to the inhibitor can lead to large changes in the affinity of the inhibitor

Method used

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  • Prostate specific membrane antigen inhibitor, metal marker thereof, preparation method and application
  • Prostate specific membrane antigen inhibitor, metal marker thereof, preparation method and application
  • Prostate specific membrane antigen inhibitor, metal marker thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] This embodiment discloses the synthesis of compound S-1, and its reaction formula is:

[0098]

[0099] Specifically: add triethylamine (4.11g, 40.7mmol) to a solution of S (6.0g, 20.3mmol) in dichloromethane (50mL) at room temperature, then add triphosgene (2.00g, 6.71mmol), and react for 30 Minutes later, additional R1 (5.30 g, 14.2 mmol) and triethylamine (1.44 g, 14.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was followed by TLC. The reaction mixture was poured into 200 mL of ice water, extracted with ethyl acetate (3×60 mL), washed with brine three times, and dried over anhydrous sodium sulfate for two hours. The organic solvent was removed by rotary evaporation under reduced pressure, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 7.5 g of yellow oily compound, yield: 59.4%.

Embodiment 2

[0101] This embodiment discloses the synthesis of compound S-2, and its reaction formula is:

[0102]

[0103] Get the ethyl acetate (100mL) mixture of compound S-1 (4.0g, 6.44mmol) and Pd / C (0.322mmol) prepared by the method of Example 1 in 1 atm atmospheric pressure of H 2 Stir at room temperature for 16 hours. Filter out unreacted Pd / C. The filtrate was collected, ethyl acetate was distilled off under reduced pressure, and the obtained oily liquid was passed through a silica gel column (mobile phase: petroleum ether / ethyl acetate=1 / 1) 2.7 g of dark green oil, yield: 86.1%.

Embodiment 3

[0105] This example discloses the synthesis of compound S-3-3 (i.e. in compound S-3, X=3), and its reaction formula is:

[0106]

[0107]. Take compound S-2 (2.5g, 5.13mmol) prepared by the method of Example 2, R2 (2.27g, 7.70mmol) and potassium carbonate (1.42g, 10.3mmol) were mixed and dissolved in N,N-dimethyl Formamide (40 mL), stirred at 60°C for 16 hours. After the reaction was completed, the reaction mixture was poured into ice water, extracted with ethyl acetate and washed 3 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate for two hours. After removing the desiccant by filtration, the organic phase was concentrated under reduced pressure, and then purified by a silica gel column (petroleum ether / ethyl acetate=1:1) to obtain 2.8 g of a yellow solid product with a yield of 77.7%.

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Abstract

The invention discloses a prostate specific membrane antigen inhibitor, a metal marker, a preparation method and application thereof, and belongs to the technical field of biological medicines. The structure of the prostate specific membrane antigen inhibitor is shown as a formula I, the structure of the metal marker is shown as a formula II, and the prostate specific membrane antigen inhibitor isused for preparing a prostate cancer diagnosis reagent / drug or / and a treatment drug. The compound is novel in structure and stable in physicochemical property, and can be applied to the fields of diagnosis, staging, curative effect evaluation and treatment of prostate cancer in preparation of prostate cancer diagnosis and treatment medicines.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a prostate-specific membrane antigen inhibitor, a metal marker thereof, a preparation method and an application. Background technique [0002] Prostate cancer is a common malignant tumor in men and accounts for the second leading cause of cancer-related death in men. As the population ages, the threat of prostate cancer will grow. Once prostate cancer develops to an advanced stage, the 5-year survival rate is only about 30%. In developed countries, prostate cancer ranks first in the incidence of male malignant tumors, and prostate cancer is prone to biochemical recurrence, bone metastasis, and lymph node metastasis. Once metastasis occurs, the effect of traditional radiotherapy and chemotherapy is very limited (ChatalicKLS , Konijnenberg M, Nonnekens J, et al., Theranostics, 2016, 6, 104-117). [0003] Prostate-specific membrane antigen (PSMA) is a transmembrane...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02A61K31/395A61K31/555A61P35/00A61K51/04
CPCA61K51/044A61K51/0482A61P35/00C07B2200/05C07D257/02
Inventor 周志军刘楠陈跃陈环宇孙占良赵岩冯悦刘洋
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