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Macrocyclic ketone peptide compound as well as preparation method and medical purpose thereof

A technology of epoxy ketones and compounds, applied in the field of macrocyclic epoxy ketone peptide derivatives, macrocyclic peptide compounds, macrocyclic peptide proteasome inhibitor derivatives, can solve problems such as side reactions

Inactive Publication Date: 2018-06-05
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ixazomib is transformed from Bortezomib. Through prodrug design and structural adjustment, the absorption and stability of the compound are greatly improved. Due to its good oral effect, the compound was approved by the FDA in 2015 for the treatment of at least A treatment for multiple myeloma patients, however the drug still does not prevent peripheral neuropathy caused by boronic acid groups
Therefore, the design of orally active analogs of the epoxy ketone compound Carfilzomib has become the focus of research, among which Oprozomib transformed from Carfilzomib has attracted widespread attention, and the oral bioavailability of this compound in beagle dogs reaches 39%. , is currently in the second phase of clinical research, but according to relevant literature reports, the compound can cause serious dose-related gastrointestinal side effects during oral administration, and corresponding dosage forms are currently being developed to solve this problem

Method used

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  • Macrocyclic ketone peptide compound as well as preparation method and medical purpose thereof
  • Macrocyclic ketone peptide compound as well as preparation method and medical purpose thereof
  • Macrocyclic ketone peptide compound as well as preparation method and medical purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0159] Preparation Example 1 Methyl 2-(allyloxy)benzoate (1a)

[0160] Methyl salicylate (4.2ml, 33mmol), potassium carbonate (13.8g, 99mmol) and 3-bromopropene (4.0ml, 46mmol) were placed in a 100mL three-necked flask, 50mL of acetone was added, and the reaction solution was refluxed The reaction was carried out for 18 hours. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, 100ml of ethyl acetate was added, washed with water (2×100ml) and saturated brine (2×100ml) successively, dried over anhydrous sodium sulfate and then decompressed The solvent was removed and separated by column chromatography to obtain 5.9 g of a colorless oily liquid with a yield of 93%. 1 H NMR (500MHz, CDCl 3 )δ7.80(dd,J=8.0,2.0Hz,1H),7.44(ddd,J=8.0,7.5,2.0Hz,1H),7.01–6.94(m,2H),6.11–6.02(m,1H) ,5.54–5.48(m,1H),5.32–5.27(m,1H),4.63(dt,J=5.0,1.5Hz,2H),3.90(s,3H)ppm; ESI-MS: m / z=193 [M+H] + .

preparation Embodiment 2

[0161] Preparation Example 2 Methyl 2-(3-buten-1-yloxy)benzoate (1b).

[0162] Using 4-bromo-1-butene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 4.0 g of a colorless oily liquid with a yield of 88%. 1 H NMR (500MHz, CDCl 3 )δ7.77(dd,J=7.5,1.5Hz,1H),7.47–7.38(m,1H),7.00–6.91(m,2H),6.00–5.88(m,1H),5.22–5.07(m, 2H), 4.08(t, J=6.5Hz, 2H), 3.88(s, 3H), 2.62–2.54(m, 2H)ppm; ESI-MS: m / z=207[M+H] + .

preparation Embodiment 3

[0163] Preparation Example 3 Methyl 2-(4-penten-1-yloxy)benzoate (1c)

[0164] Using 5-bromo-1-pentene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 5.8 g of a colorless oily liquid with a yield of 80%. 1 H NMR (500MHz, CDCl 3)δ7.78(dd, J=7.5,1.5Hz,1H),7.44(ddd,J=8.0,7.5,1.5Hz,1H),6.99–6.94(m,2H),5.92–5.80(m,1H) ,5.09–5.04(m,1H),5.02–4.98(m,1H),4.05(t,J=6.5Hz,2H),3.89(s,3H),2.34–2.25(m,2H),1.98–1.88 (m,2H)ppm; ESI-MS: m / z=221[M+H] + .

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Abstract

The invention provides a novel macrocyclic ketone peptide derivative, an optical isomer or pharmaceutically acceptable salt or solvolyte thereof. Carboxyl protection compounds are used as starting rawmaterials to be subjected to condensation with amino protection amino acid, deamination protection, olefin ring closing double decomposition and decarboxylizing protection, and condensation with epoxy ketone fragment. The macrocyclic ketone peptide compound with a fire-new framework has high protease body inhibition activity; the high in vitro proliferation inhibition effect is achieved on multiple myeloma such as RPMI 8226, MM.1S and NCI-H929 and various other solid tumor cell strains; meanwhile, the compound has good oral administration effects, and can also be applied to preparation of anti-tumor and immune disease medicine. The compound has the advantages that raw materials required for synthesis can be easily obtained; the route design is reasonable; the reaction conditions are mild;the yield in each step is high; the operation is simple and convenient; the compound is suitable for industrial production. The compound has a structure shown by a formula (I) shown in the description.

Description

technical field [0001] The present invention relates to the field of medicine, and relates to a class of macrocyclic peptide compounds, in particular to a macrocyclic epoxy ketone peptide derivative, in particular to macrocyclic peptide proteasome inhibitor derivatives, salts of the compound and the The compound or its salt is a drug with active ingredients, which can be used for treating tumor-related diseases such as multiple myeloma and mantle cell lymphoma. Background technique [0002] Malignant tumors are one of the major diseases that threaten human health. In 2008, there were about 12.7 million new cancer patients and 7.6 million cancer deaths worldwide. It is estimated that by 2020, there will be 15 million new cancer patients worldwide, and cancer deaths The number is also skyrocketing globally and could reach 13.2 million. With the continuous increase of the population and the aging trend of the population, coupled with the widespread existence of various unhealt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/08C07K5/117A61K38/06A61K38/07A61P35/00A61P35/02
CPCY02P20/55C07K5/08A61K38/00C07K5/1024
Inventor 刘滔李佳胡永洲周宇波李大强高立信董晓武胡小蓓余建均张小团
Owner ZHEJIANG UNIV
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