Unlock instant, AI-driven research and patent intelligence for your innovation.
Macrocyclic ketone peptide compound as well as preparation method and medical purpose thereof
What is Al technical title?
Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
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
View PDF1 Cites 3 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
Smart Image
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), potassiumcarbonate (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 anhydroussodiumsulfate 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] + .
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More
PUM
Login to View More
Abstract
The invention provides a novel macrocyclic ketonepeptide 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 epoxyketone fragment. The macrocyclic ketonepeptide 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 diseasemedicine. 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 peptideproteasome 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 celllymphoma. 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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.
Login to View More 
Login to View More