Difunctional MDM2 protein degradation agent as well as preparation method, pharmaceutical composition and application thereof

A technology of protein degradation and MDM2, which is applied in the direction of drug combination, antidote, antipyretic, etc., can solve the problems of decreased apoptosis function and cell cycle arrest, etc.

Pending Publication Date: 2022-08-05
SHANGHAI LONGWOOD PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In support of this concept, some p53 wild-type tumors appear to display reduced apoptotic function, yet their ability to undergo cell cycle arrest remains intact

Method used

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  • Difunctional MDM2 protein degradation agent as well as preparation method, pharmaceutical composition and application thereof
  • Difunctional MDM2 protein degradation agent as well as preparation method, pharmaceutical composition and application thereof
  • Difunctional MDM2 protein degradation agent as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135]2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3-methyl-1- Synthesis of (propyl-2-sulfonamidino)butyl-2-)-2-oxopiperidin-3-yl)acetic acid

[0136]

[0137] Step 1: Methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate

[0138]

[0139] 4-(3-Chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoic acid methyl ester (36.5g) was dissolved in ethanol (300ml), cooled to 0~ 5°C, add NaBH in batches 4 (2.85g), react at 0~10 ℃ for 2 hours, TLC tracking reaction is basically complete, add acetic acid (~8ml) dropwise until no hydrogen is released, concentrate the solvent, add 300ml of ethyl acetate, wash with water and saturated sodium bicarbonate successively, After drying over anhydrous magnesium sulfate, it was concentrated to obtain 37 g of methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate.

[0140] Step 2: 4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic acid

[0141]

[0142] Diss...

Embodiment 2

[0185] Compound 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl yl-1-((S)-2-propylsulfonamidino)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)benzoic acid

[0186]

[0187] Step 1: 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3 -Methyl-1-(N-(2,2,2-trifluoroacetyl)-2-propylsulfonamidino)butyl-2-)-2-oxopiperidin-3-yl)acetamide Synthesis of methyl) benzoate

[0188]

[0189]2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)- 3-Methyl-1-(N-(2,2,2-trifluoroacetyl)-2-propylsulfonamidino)butyl-2-)-2-oxopiperidin-3-yl)acetic acid (800mg), methyl p-aminobenzoate (219mg), DMAP (324mg) and EDC.HCl (508.4mg) were successively added to the DCM (16ml) solution and stirred at room temperature overnight. The reaction was complete as detected by TLC. Water was added dropwise to the reaction solution under ice bath to quench the reaction, the cold 1N HCl solution was adjusted to pH=2, the layers were separated, ...

Embodiment 3

[0195] 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3-methyl -1-(Propan-2-ylthiamidinyl)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)-N-(5-(2-(2,6- Synthesis of Dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)pent-4-yn-1-yl)-2-methoxybenzamide

[0196]

[0197] step 1:

[0198]

[0199] 3-Bromo-2-bromomethyl-benzoic acid methyl ester (5.00 g, 16.2 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (2.94 g, 17.9 mmol) were added to acetonitrile (50 ml) ), then added triethylamine (8.21g, 81.1mmol), heated to reflux overnight, the reaction solution turned dark purple, cooled to room temperature and filtered, the solid was washed with water (20ml) and MTBE (20ml), and dried in vacuo to give 2.70 g solid, 52% yield. 1 H NMR (400MHz, DMSO-d 6 )δ11.03(s, 1H), 7.88(d, J=7.9Hz, 1H), 7.78(d, J=7.5Hz, 1H), 7.52(t, J=7.7Hz, 1H), 5.16(dd, J=13.3, 5.1Hz, 1H), 4.43 (d, J=17.6Hz, 1H), 4.27 (d, J=17.6Hz, 1H), 2.92 (ddd, J=18.1, 13.6, 5.4Hz, 1H), 2.65–2.51 (m, 1H)...

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Abstract

The invention provides a protein degradation targeting chimera as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the protein degradation targeting chimera comprises the following structure: an MDM2 target protein inhibitor-C (O) NH-L2-Y1-B1, and the definition of each group is described in the specification. The compounds are useful in the treatment of conditions or disorders (e.g., cancer) responsive to degradation of the MDM2 protein.

Description

technical field [0001] The present invention relates to the field of small molecule medicines, in particular, the present invention provides an MDM2 protein degrading agent, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] The p53 gene is the most tumor suppressor gene related to human tumors. It has the functions of maintaining genome stability and inhibiting or preventing cell transformation, thereby inhibiting the occurrence of tumors. The research on new anti-tumor drugs targeting p53 has become a hot spot in this field. The research results show that MDM2 (murine double minute 2) is a key negative regulator of p53, p53 activates the transcription of MDM2, and MDM2 in turn inhibits the activity of p53, The two form an autoregulatory feedback loop to keep both p53 and MDM2 at low levels under normal circumstances. The abnormal expression of MDM2 in tumor cells leads to the rapid degradation of p53 and the inacti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/4545A61P35/00A61P35/02A61P5/14A61P11/06A61P11/00A61P17/06A61P17/00A61P27/02A61P11/02A61P37/08A61P37/06A61P19/02A61P1/00A61P9/10A61P25/14A61P29/00A61P39/00A61P31/04A61P31/12
CPCC07D401/14A61P35/00A61P35/02A61P5/14A61P11/06A61P11/00A61P17/06A61P17/00A61P27/02A61P11/02A61P37/08A61P37/06A61P19/02A61P1/00A61P9/10A61P25/14A61P29/00A61P39/00A61P31/04A61P31/12A61K31/4545A61K31/4745C07D401/04C07D487/10
Inventor 王喆曾志宏江荣珍赖满庆
Owner SHANGHAI LONGWOOD PHARMA
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