Hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs)

A technology of compounds and mesoforms, applied in the field of protein degradation targeting chimera compounds, can solve the problems of poor water solubility of fulvestrant, increased dosage, and low bioavailability

Pending Publication Date: 2021-06-18
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poor water solubility and low bioavailability of fulvestrant, it is difficult to further increase the dosage by intramuscular injection.

Method used

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  • Hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs)
  • Hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs)
  • Hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0490] (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-(4-methylthiazole-5- Base) phenyl) cyclobutyl) pyrrolidine-2-carboxamide 1

[0491]

[0492]

[0493] first step

[0494] (1-(4-(4-methylthiazol-5-yl)phenyl)cyclobutyl)carbamate tert-butyl ester 1b

[0495] (1-(4-Bromophenyl) cyclobutyl) tert-butyl carbamate (300mg, 0.92mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.) and palladium acetate (20.6mg, 0.092mmol), potassium acetate (181mg, 1.84mmol), 4-methylthiazole (182mg, 1.84mmol) was dissolved in N,N-dimethylacetamide (6mL), and heated to 90°C under the protection of argon to react overnight. Concentrate under reduced pressure to remove the solvent, and purify by thin-layer chromatography with developer system B to obtain the title compound 1b (300 mg), yield: 94%.

[0496] MS m / z(ESI):345[M+1]

[0497] second step

[0498] 1-(4-(4-methylthiazol-5-yl)phenyl)cyclobutan-1-amine hydrochloride 1c

[0499] Compound 1b (300mg, 0.87mmol) wa...

Embodiment 2

[0521] (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutyryl)-4-hydroxy-N-(3-(4-(4-methylthiazole-5- Base) phenyl) oxetan-3-yl) pyrrolidine-2-carboxamide 2

[0522]

[0523]

[0524] first step

[0525] 2-Methyl-N-(3-(4-(4-methylthiazol-5-yl)phenyl)oxetan-3-yl)propane-2-sulfinamide 2b

[0526] N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide 2a (300mg, 0.903mmol, using a known method Org.Lett., 2011 , 13,3912-3915) and 4-methylthiazole (179mg, 1.81mmol), palladium acetate (20mg, 0.090mmol), pivalic acid (28mg, 0.027mmol), potassium carbonate (187mg, 1.35mmol) , Tricyclohexylphosphine tetrafluoroborate (33mg, 0.090mmol) was mixed and dissolved in N,N-dimethylformamide (10mL), filled with argon, and heated to 110°C for 17 hours. After the reaction solution was cooled to room temperature, it was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtrate, concentrate under red...

Embodiment 3

[0550] (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-(4-methylthiazole-5- Base) phenyl) cyclopropyl) pyrrolidine-2-carboxamide 3

[0551]

[0552] first step

[0553] (1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamate tert-butyl ester 3b

[0554] (1-(4-bromophenyl)-cyclopropyl) tert-butyl carbamate 3a (250mg, 0.801mmol, Shanghai Bi De Pharmaceutical Co., Ltd.), 4-methylthiazole (159mg, 1.60mmol), acetic acid Palladium (18mg, 0.08mmol) and potassium acetate (157mg, 1.60mmol) were mixed and dissolved in N,N-dimethylacetamide solvent (10mL). The reaction was heated to 100°C and stirred overnight. The reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. Filtrate, concentrate under reduced pressure to remove the solvent, and purify by thin-layer chromatography with developer system B to obtain ...

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Abstract

The invention relates to a hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs). Particularly, the invention relates to a novel micromolecule E3 ubiquitin ligase protein binding ligand compound and a compound of PROTACs, a preparation method thereof, and application of the novel micromolecule E3 ubiquitin ligase protein binding ligand compound and the compound of PROTACs in medicine. The invention relates to an E3 ubiquitin ligase protein binding ligand compound as shown in a general formula (IM) and a compound of PROTACs as shown in a general formula (I), a preparation method thereof, and application of the E3 ubiquitin ligase protein binding ligand compound as shown in the general formula (IM) and the compound of PROTACs as shown in the general formula (I) in medicine.

Description

Technical field [0001] The present disclosure belongs to the field of medicine and relates to a novel small molecule E3 ubiquitin ligase protein-binding ligand compound and a protein degradation targeting chimera (PROTACs) compound, its preparation method, and its application in medicine. Specifically, the present disclosure relates to an E3 ubiquitin ligase protein-bound ligand compound represented by the general formula (IM) and a protein degradation targeting chimera (PROTACs) compound represented by the general formula (I), and their preparation methods, and their applications in medicine. The use of the present disclosure in medicine demonstrates, but is not limited to, its use as an estrogen receptor degrader for the treatment of estrogen receptor mediated or dependent diseases or conditions. Background technique [0002] The concept of protein degradation targeting chimera PROTACs (PROteolysis TArgeting Chimeras) technology was proposed in 2001. Early PROTACs recruit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P35/00A61P35/02
CPCC07K5/06034A61P35/00A61P35/02A61K38/00
Inventor 杨方龙贾敏强何卫明王伟民许建烟张利敏贺峰白昌陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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