Psma-targeted radiopharmaceutical for diagnosing and treating prostate cancer

A radioactive and pharmaceutical technology, used in radioactive carriers, in vivo radioactive preparations, drug combinations, etc., can solve the problem of prostate cancer having no therapeutic effect.

Active Publication Date: 2020-11-27
FUTURECHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, Drug used to treat prostate cancer with bone metastases, but it is 223 Ra-RaCl 2 (radium dichloride, radium dichloride) injection, which has no therapeutic effect on prostate cancer formed other than bone

Method used

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  • Psma-targeted radiopharmaceutical for diagnosing and treating prostate cancer
  • Psma-targeted radiopharmaceutical for diagnosing and treating prostate cancer
  • Psma-targeted radiopharmaceutical for diagnosing and treating prostate cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] Preparation of Compound 3b, 3c

[0266]

[0267] Preparation of compound 3b

[0268] Compound 3a (5.2 g, 10.66 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and then tert-butyl bromoacetate (1.9 mL, 12.8 mmol) was added slowly. The mixture was maintained at 0 °C, triethylamine (2.2 mL, 16 mmol) was slowly added, and the temperature was slowly raised to room temperature with stirring. After stirring for 3 hours, water (50 mL) was added and the organic compounds were extracted with dichloromethane (50 mL, twice). The collected organic layer was treated with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by column chromatography (5% methanol / dichloromethane) to obtain compound 3b (3.36 g, 52%).

[0269] 1 H NMR (400MHz, CDCl 3 )δ1.39-1.53(m,36H),1.55-1.89(m,5H),2.02-2.10(m,1H),2.22-2.37(m,2H),2.54-2.58(m,2H),3.27( s,2H),4.28-4.36(m,2H),5.07-5.10(m,2H);

[0270] 13 C NMR (100MHz, CDCl 3 )δ22.6,...

Embodiment 2

[0277] Preparation of Compound 2a, 2b

[0278]

[0279] Step 1: Preparation of Compound 5a

[0280] After dissolving triphosgene (107mg, 0.36mmol) in acetonitrile (5.0mL), compound 3a (500mg, 1.03mmol) dissolved in acetonitrile (10mL) was slowly added thereto at 0°C, and then triethylamine was added (0.50 mL, 3.61 mmol) and stirred for 30 minutes. Added propargylamine (4a, 0.072mL, 1.13mmol) at 0°C, stirred at room temperature for 1 hour after 15 minutes, concentrated under reduced pressure, added water, and repeated extraction of the organic compound with ethyl acetate three times. The collected organic solvent was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (2% methanol / dichloromethane) to obtain white solid compound 5a (492 mg, 84%).

[0281] 1 H NMR (400MHz, CDCl 3)δ1.25-1.30(m,2H),1.44(s,18H),1.48(s,9H),1.51-1.60(m,3H),1.67-1.76(m,1H),1.80-1.90(m, 1H),2.05-2.13(m,1H),2.18(t,J=2.6Hz,1H),2.29-2.40...

Embodiment 3

[0311] Compound 2c, preparation of 2d

[0312]

[0313] Step 1: Preparation of compound 5c

[0314] Dissolve 4-pentanoic acid (82mg, 0.83mmol) in dichloromethane (10mL), cool to 0°C, then add N,N'-dicyclohexylcarbodiimide (190mg, 0.91mmol) and compound 3c (0.5 g, 0.83 mmol) and stirred at room temperature for 1 hour. After the organic layer was filtered several times, the solvent was removed under reduced pressure, and the concentrate was separated by column chromatography (30% ethyl acetate / n-hexane) to obtain compound 5c (0.29 g, 52%).

[0315] 1 H NMR (400MHz, CDCl 3 )δ1.34-1.67(m,39H),1.68-2.02(m,5H),2.16-2.32(m,2H),2.37-2.56(m,5H),3.22(t,J=7.2Hz,1H) ,3.29(t,J=7.6Hz,1H),3.82-3.90(m,2H),4.17-4.29(m,2H),5.49-5.52(m,1.5H),5.60(d,J=8.0Hz, 0.5Hz);

[0316] MS(ESI) m / z 704[M+Na] +

[0317] Step 1: Preparation of compound 5d

[0318] Except using 4-pentanoic acid (32mg, 0.32mmol), N,N'-dicyclohexylcarbodiimide (74mg, 0.36mmol), compound 3c (0.20g, 0.32mmol), in order...

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Abstract

The present invention relates to a pharmaceutical composition for diagnosing and treating prostate cancer, capable of targeting PSMA, and a compound provided by one aspect of the present invention hasa glutamine-urea-lysine compound to which a radioactive metal-coupled chelator is structurally coupled and to which an aryl group that can additionally bind to PSMA protein is coupled.Coupling between the glutamine-urea-lysine compound and the chelator includes a polar spacer so as to serve the role of reducing in vivo nonspecific coupling and exhibit an effect of being rapidly removed from vitalorgans, but not from prostate cancer. These characteristics lower the radiation exposure, which is caused by a therapeutic radioisotope-coupled compound, to normal tissue and organs, and thus reduceside effects. In addition, a compound that contains a phenyl group having a coupling force with albumin has an increased residence time in the blood, thereby becoming more accumulated in prostate cancer.

Description

technical field [0001] The present invention relates to PSMA-targeted radiopharmaceuticals for the diagnosis and treatment of prostate cancer. Background technique [0002] Prostate cancer is the most common cancer in men in the world and the second leading cause of death. Prostate cancer is characterized by a high incidence in men over the age of 50, and the number of patients increases rapidly with age. It usually progresses slowly, but if it becomes malignant and metastasizes, it is an extremely difficult disease to treat. Metastasis mainly starts from the lymph nodes around the prostate cancer, pelvic bone, spine and bladder, and gradually spreads to the whole body. [0003] At present, the diagnostic methods mainly used for prostate cancer include prostate specific antigen detection method (PSAtest), rectal digital detection, etc., as well as transrectal ultrasound, CT, MRI, WBBS (Whole body bone scan, whole body bone scintigraphy) imaging diagnosis and treatment , a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K51/04A61P35/00
CPCA61P35/00C07D403/12C07D257/02A61K51/0402A61K51/0497A61K51/0474A61K51/0487C07F5/003
Inventor 池大润李炳世秋昭映郑玹填金玟焕
Owner FUTURECHEM
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