Phthalazinone compound as well as preparation method and medical application thereof

A technology of compounds and medicinal effects, which is applied in the field of phthalazinone compounds and their preparation and medical application, and can solve problems such as not necessarily applicable

Active Publication Date: 2021-12-17
SHANGHAI JEMINCARE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the molecular design idea of ​​PROTAC is completely different from that of small molecules, and there is no obvious regularity at all. Common medicinal strategies, such as equivalent replacement of effective fragments, are not necessarily applicable in the design of such molecules.

Method used

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  • Phthalazinone compound as well as preparation method and medical application thereof
  • Phthalazinone compound as well as preparation method and medical application thereof
  • Phthalazinone compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0165] Reference Example 1: Preparation of Intermediate I-1

[0166]

[0167] 2-Bromo-4-fluorobenzoic acid (7.00 g, 31.9 mmol) was dissolved in thionyl chloride (30.0 mL), and N,N-dimethylformamide (0.25 mL) was added. The reaction solution was stirred at 80° C. for 2 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, and after removing thionyl chloride under reduced pressure, the residue was dissolved in dichloromethane (100 mL). Diethylamine (11.7 g, 159.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was washed with saturated aqueous sodium bicarbonate (30.0 mL), water (30.0 mL), saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-1, which was directly used in the next reaction without purification.

[0168] LC-MS(ESI)[M+H] + 274.0.

[0169] 1 H NMR...

reference example 2

[0170] Reference Example 2: Preparation of Intermediate I-2

[0171]

[0172] Intermediate I-1 (8.50g), potassium vinylfluoroborate (4.98g, 37.2mmol) and potassium carbonate (10.7g, 77.5mmol) were dissolved in dioxane (80.0mL) / water (20.0mL) To the mixed solution, bistriphenylphosphinepalladium dichloride (1.09g, 1.55mmol) was added. The reaction solution was stirred overnight at 90° C. under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (100.0 mL), washed successively with water (30.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-2, which was directly used in the next reaction without purification.

[0173] LC-MS(ESI)[M+H] + 222.2.

[0174] 1H NMR (400MHz, Chloroform-d) δ7.2...

reference example 3

[0175] Reference Example 3: Preparation of Intermediate I-3

[0176]

[0177] Intermediate I-2 (7.00g) was dissolved in a mixed solvent of dioxane (70.0mL) / water (30.0mL), and potassium osmate dihydrate (466.0mg, 1.27mmol) and sodium periodate ( 13.5 g, 63.2 mmol). The reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was dissolved in ethyl acetate (100.0 mL), washed successively with water (30.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-3.

[0178] 1 H NMR (400MHz, Chloroform-d) δ9.99 (d, J = 2.3Hz, 1H), 7.63–7.57 (m, 1H), 7.38–7.28 (m, 2H), 3.59 (q, J = 7.1Hz, 2H), 3.11(q, J=7.1Hz, 2H), 1.27(t, J=7.1Hz, 3H), 1.02(t, J=7.1Hz, 3H).

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Abstract

The invention discloses a phthalazinone compound as well as a preparation method and medical application thereof, and particularly discloses a compound as shown in a formula (I) defined in the description and pharmacologically acceptable salt thereof, and application of the compound as an androgen receptor (AR) for degradation.

Description

technical field [0001] The present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and the application of the compound as an androgen receptor (AR) degradation agent. Background technique [0002] Prostate cancer (PCa) is one of the most common cancers worldwide and the second leading cancer killer of adult males worldwide. Prostate cancer has no obvious symptoms in the early stage and grows slowly. When it reaches the advanced stage, symptoms such as frequent urination, dysuria, hematuria, and painful urination will appear, and may metastasize to other parts. Generally, when the cancer is discovered, the patient is already in the advanced stage. In the United States, the incidence of prostate cancer has surpassed that of lung cancer and has become the first cancer that endangers men's health. In 2016, there were 120,000 new prostate cancer patients in my country. It is estimated that by 2030, the number of new pros...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D487/08A61P35/00A61P13/08A61P15/14A61P21/00A61K31/502A61K31/506A61K31/55
CPCC07D401/14C07D487/08A61P35/00A61P13/08A61P15/14A61P21/00A61P35/04A61P5/26Y02P20/55A61K31/502A61K31/55C07D471/04A61K31/506C07B2200/07
Inventor 陆洪福邢唯强吕永聪齐保建彭建彪郭海兵
Owner SHANGHAI JEMINCARE PHARMA CO LTD
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