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Pyrrolopyrimidine derivatives or conjugates thereof, and preparation method and application thereof

A technology of drug conjugates and mixtures, which can be used in drug combinations, pharmaceutical formulations, medical preparations of non-active ingredients, etc., and can solve problems such as systemic toxicity

Pending Publication Date: 2021-12-17
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the biggest problem with systemic administration is systemic toxicity. It can be seen that two of the approved drugs are administered locally, and one is an immune adjuvant

Method used

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  • Pyrrolopyrimidine derivatives or conjugates thereof, and preparation method and application thereof
  • Pyrrolopyrimidine derivatives or conjugates thereof, and preparation method and application thereof
  • Pyrrolopyrimidine derivatives or conjugates thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0286] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) in 10 -6 (ppm) units are given. NMR was measured with a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d). 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS).

[0287] For MS measurement, Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector / waters SQ Detector), THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0288] High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high pressure liquid chromatograph.

[0289] Chiral HPLC analysis was ...

Embodiment 2-11

[0307] 4-Amino-2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile 1

[0308]

[0309] first step

[0310] (9H-Fluoren-9-yl)methyl(4-(bromomethyl)benzyl)carbamate 1b

[0311] (9H-fluoren-9-yl)methyl(4-(bromomethyl)benzyl)carbamate

[0312] Weigh (4-(bromomethyl)benzyl)carbamate tert-butyl ester 1a (5.16g, 17.19mmol, supplier Bide) and place it in a reaction flask, add acetonitrile (30mL) and 1, 4M of hydrochloric acid successively. 4-dioxane solution (20 mL) was reacted at room temperature for 1 hour under vigorous stirring. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and then 50 mL of n-hexane was added and concentrated under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (50 ml) and water (10 ml), followed by sodium bicarbonate (8.66 g, 103.14 mmol) and 9-fluorenylmethyl chloroformate (4.00 g, 15.46 mmol) ), and the reaction was stirred at room temperature for 1 h...

Embodiment 2-22

[0340] (S)-4-Amino-7-(4-((3-aminopyrrolidin-1-yl)methyl)benzyl)-2-butoxy-7H-pyrrolo[2,3-d]pyrimidine -6-carbonitrile 2

[0341]

[0342] first step

[0343] (S)-(1-(4-(((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)methyl)benzyl)pyrrolidin-3-yl)carbamate tert-butyl ester 2b

[0344] 1b (400 mg, 0.947 mmol) was added to 8 mL of acetonitrile, potassium carbonate (193 mg, 1.42 mmol) was added, (S)-3-tert-butoxycarbonylaminopyrrolidine 2a (264.6 mg, 1.42 mmol, supplier Ark) was added , and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with water (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered to remove the drying agent , the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatograp...

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Abstract

The invention relates to pyrrolopyrimidine derivatives or conjugates thereof, and a preparation method and application thereof. Specifically, the invention provides a ligand-drug conjugate with a structure as shown in a general formula (D-), the preparation method and the application of the ligand-drug conjugate and a pharmaceutical composition containing the ligand-drug conjugate in preparation of drugs for treating cancers through receptor regulation, and substituent groups in the general formula (D-) are as defined in the specification.

Description

technical field [0001] The present disclosure relates to a new class of structural pyrrolopyrimidine derivatives or conjugates thereof. Specifically, the present disclosure relates to a pyrrolopyrimidine derivative, a ligand-drug conjugate containing the structure, a preparation method thereof, a pharmaceutical composition comprising the conjugate, and the conjugate or Use of the pharmaceutical composition. Background technique [0002] Antibody drug conjugates (antibody drug conjugates, ADCs) link monoclonal antibodies or antibody fragments to biologically active drugs through stable chemical linker compounds, making full use of the specificity and The high efficiency of the drug avoids defects such as low curative effect of the former and excessive side effects of the latter. This means that, compared with traditional chemotherapy drugs in the past, antibody drug conjugates can precisely bind tumor cells and reduce the impact on normal cells (Mullard A, (2013) Nature Rev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K31/519A61P35/00
CPCA61K47/6803A61K47/6851A61K31/519A61P35/00
Inventor 许建烟贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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