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An anti-tumor apoptosis protein inhibitor

A compound, pharmaceutical technology, applied in the field of medicinal chemistry

Active Publication Date: 2020-09-15
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] IAP inhibitors have a very good market value, but there are still many major challenges in the development of this variety

Method used

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  • An anti-tumor apoptosis protein inhibitor
  • An anti-tumor apoptosis protein inhibitor
  • An anti-tumor apoptosis protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062]

[0063] Step 1: Dissolve 12.73g of diphenylmethylamine in 200ml of DMF, add 40.69g of Fmoc-Cys(Trt)-OH, 39.49g of HBTU and 13.47g of DIEA in sequence, stir at room temperature for 2h, and detect by TLC (PE:EA=2: 1) until the raw material reacts completely. Add 20ml of piperidine to the reaction solution, stir the reaction at room temperature, and check by TLC (PE:EA=2:1) ​​until the reaction of the raw materials is complete. The reaction solution was poured into 1L of water, extracted twice with ethyl acetate (500ml*2), the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (eluent DCM:MeOH) to obtain compound I-1-1 (30.02g yellow oily liquid, [M+H] + = 529.7);

[0064] Step 2: Dissolve 30.00g of compound I-1-1 in 150ml of DMF, add 19.15g of Fmoc-proline, 32.26g of HBTU and 11.00g of DIEA in sequence, sti...

Embodiment 2

[0072]

[0073]Step 1: Dissolve 1.40g of compound I-1-6 in 40ml of DCM, add 8ml of trifluoroacetic acid, and react at room temperature for 2.5h. After the reaction, adjust the pH to 7-8 with saturated aqueous sodium bicarbonate solution, separate the liquid, and use it for the aqueous phase 40ml of DCM was stripped once, and the organic phases were combined. The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Add 30ml of tertiary methyl ether and beat at room temperature for 0.5h, and filter to obtain compound I-2-1 (2.41g, white solid);

[0074] Step 2: Dissolve 1.0 g of compound I-2-1 in 40 ml of DMF, add 0.44 g of N-Boc-2-methylalanine, 1.22 g of HBTU and 0.55 g of DIEA in sequence, react at room temperature for 1.0 h, and detect by TLC (DCM: MeOH=15:1), until the reaction of raw materials is complete. Add 8ml of piperidine to the reaction solution, react at room tempe...

Embodiment 3

[0078]

[0079] Step 1: Dissolve 0.21g of compound I-2-2 in 10ml of DMF, add 0.2g of compound 2, and react at room temperature for 1.5h. After the reaction is over. Pour the reaction solution into 100ml of water, extract 40ml*2 with ethyl acetate, combine the organic phases, wash the organic phase once with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, and perform column chromatography (eluent DCM : MeOH) purified to give compound I-3 (0.15g, white solid, [M+H] + = 1021.7).

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Abstract

The invention relates to compounds shown as a formula (I) or pharmaceutically acceptable salts, isomers or prodrugs thereof, wherein R1, R2, R3 and R4 are defined in a specification. The compounds canbe used for inhibiting IAP, and thus can be used for treating diseases related to overexpression of IAP protein, such as cancers. The invention further relates to medicinal compositions containing the compounds and a method of preparing the compounds. The compounds have relatively good activity, potential medicinal values and wide market prospects.

Description

technical field [0001] This field belongs to the field of medicinal chemistry, and in particular relates to an (apoptotic protein) IAP inhibitor that can be used to treat cancer and a preparation method thereof. Background technique [0002] Apoptosis, or programmed cell death, is a genetically and biochemically regulated mechanism that plays an important role in development and homeostasis in both invertebrates and vertebrates. Abnormalities in apoptosis leading to premature cell death have been linked to a variety of developmental disorders. Defects in apoptosis leading to a lack of cell death have been linked to cancer and chronic viral infection. [0003] Current cancer therapies, including chemotherapeutics, radiation and immunotherapy, indirectly induce apoptosis in cancer cells. Thus, the inability of cancer cells to execute the apoptotic program due to defects in the normal apoptotic machinery is often associated with increased resistance to chemotherapy-, radiatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04C07D519/00A61K31/407A61K31/454A61K31/4245A61K31/4178A61K31/4188A61K31/5377A61K31/506A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D513/04C07D519/00
Inventor 张孝清宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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