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Method for preparing conjugate

A technology of conjugates and drugs, applied in the field of medicine, can solve problems such as the inability to obtain stable pentafluorophenol esters

Active Publication Date: 2019-08-06
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Through in-depth research, it is surprising to find a new method of coupling targeted drugs and bioactive molecules in the present invention, that is, the use of a new carboxyl activation method greatly improves the stability of the activated carboxyl group in the linker, successfully overcoming the The problem that the stable pentafluorophenol ester cannot be obtained by using the coupling technology of pentafluorophenol to activate the carboxyl group, and at the same time realize the coupling of biologically active molecules and targeted drugs with a high coupling ratio

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0250] 1-(4-(((S)-1-(((S)-1-((4-(((S)-2-((2R,3R)-3-((S)-1-( (3R,4S,5S)-4-((S)-2-((S)-2-(Dimethylamino)-3-methylbutanylamino)-N,3-dimethylbutanylamino) -3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-3-phenylpropionamido)methyl)phenyl )amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-4-oxobutyl)-1- Synthesis of Methyl-4-((2,3,5,6-Tetrafluorophenoxy)carbonyl)piperidin-1-ium Iodide (Compound 1)

[0251]

[0252] step one:

[0253] Synthesis of ethyl 1-(4-(tert-butoxy)-4-oxobutyl)piperidine-4-carboxylate (compound 1-2)

[0254] At room temperature, compound 1-1 (1.0g, 6.4mmol) was dissolved in N,N-dimethylformamide (10mL), and tert-butyl 4-bromobutyrate (1.7g, 7.6mmol) was added to the reaction solution ), potassium carbonate (1.77g, 12.8mmol) and potassium iodide (0.53g, 3.2mmol). After addition, stir at room temperature for 5 h, pour the reaction solution into water, extract with ethyl acetate (20 mL×3), wash with saturate...

Embodiment 2

[0271] 1-(4-(((S)-1-(((S)-1-((4-(((S)-2-((2R,3R)-3-((S)-1-( (3R,4S,5S)-4-((S)-2-((S)-2-(Dimethylamino)-3-methylbutanylamino)-N,3-dimethylbutanylamino) -3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-3-phenylpropionamido)methyl)phenyl )amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-4-oxobutyl)-4- Synthesis of ((2,4,6-trifluorophenoxy)carbonyl)piperidine-1-oxide (Compound 2)

[0272]

[0273] step one:

[0274] Synthesis of 1-(4-(tert-butoxy)-4-oxobutyl)-4-(ethoxycarbonyl)piperidine-1-oxide (compound 2-2)

[0275] Compound 1-2 (700 mg, 2.34 mmol) was dissolved in dichloromethane (10 mL) at room temperature, m-chloroperoxybenzoic acid (808 mg, 4.68 mmol) was added under nitrogen protection, and stirred overnight at room temperature. Use high-performance liquid chromatography-mass spectrometry to monitor the complete reaction of the raw materials, the reaction solution is quenched with saturated aqueous sodium bicarbonate, ...

Embodiment 3

[0289] 1-(4-(((S)-1-(((S)-1-((4-(((S)-2-((2R,3R)-3-((S)-1-( (3R,4S,5S)-4-((S)-2-((S)-2-(Dimethylamino)-3-methylbutanylamino)-N,3-dimethylbutanylamino) -3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-3-phenylpropionamido)methyl)phenyl )amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobut-2-yl)amino)-4-oxobutyl)-1- Synthesis of Methyl-4-((2,4,6-trifluorophenoxy)carbonyl)piperidin-1-ium Iodide (Compound 3)

[0290]

[0291] Using the similar operation described in Step 6 of Example 1, substituting 2,4,6-trifluorophenol for 2,3,5,6-tetrafluorophenol, 21 mg of the title compound was obtained. ESI-MS(m / z):1448.2[M] + .

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Abstract

The invention belongs to the technical field of medicines, and relates to a method for preparing conjugate. Specifically speaking, a method for preparing conjugate of a general formula (II) a productprepared by the method and applications of the product in the prevention and / or treatment of proliferative diseases associated with abnormal cellular activity (including but not limited to cancer diseases) are related.

Description

technical field [0001] The invention belongs to the technical field of medicine. Specifically, the present invention relates to a method for preparing a targeted drug-biologically active molecule conjugate, a product prepared by the method, and the product is useful in preventing and / or treating proliferative diseases related to abnormal cell activity (including but Not limited to use in cancer diseases). Background technique [0002] Chemotherapy was once the standard treatment for cancer, but highly lethal bioactive molecules can accidentally kill normal cells, causing serious side effects. Targeted anti-tumor drugs have become a hot spot in the field of tumor research because they have both targeting and anti-tumor activities. Since the 20th century, breakthroughs have been made in the development of antitumor drugs and targeted tumor therapy by using biomacromolecular drugs (such as therapeutic antibodies or antibody fragments) and targeting small molecule ligands. Ho...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K45/00A61P35/00
CPCA61K45/00A61K47/68A61P35/00A61K38/08
Inventor 宋帅田强唐祖建邓汉文汪静刘登念胡瑞斌肖亮薛彤彤蔡家强王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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