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Compound wez series and its preparation method and use for preparing medicine

A compound and pharmaceutical technology, applied in the field of chemical drugs, can solve the problems of aggravated lung tissue damage, complex etiology and pathogenesis, and less than 50% effective rate of treatment

Active Publication Date: 2021-02-09
NANJING WELLBEST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The etiology and pathogenesis of this type of disease are quite complex, with recurrent attacks, and there is still no cure at present, and long-term treatment is needed to control the progression of the disease
The commonly used clinical drugs are mainly glucocorticoids and immunosuppressants, etc., but the effective rate of these drugs is less than 50%, and the adverse reactions are large, including bone marrow suppression, liver and kidney function damage, osteoporosis, easy to induce infection and Tumor etc.
At the same time, it may inhibit the expression of VEGF in tissues, reduce the permeability of pulmonary microvessels, inhibit the division and proliferation of vascular endothelial cells and angiogenesis, aggravate lung tissue damage, and eventually lead to diffuse pulmonary interstitial disease pulmonary fibrosis
At present, there is no effective anti-fibrosis drug, and glucocorticoids are commonly used for anti-inflammation to reduce the anti-fibrosis process, but the curative effect is limited and there are many adverse reactions
[0008] For the above-mentioned diseases, the current treatment methods are far from meeting the clinical needs, and it is necessary to find more new drugs with good curative effect, less side effects and low price to control the progression of the disease, reduce recurrence and complications, and reduce mortality

Method used

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  • Compound wez series and its preparation method and use for preparing medicine
  • Compound wez series and its preparation method and use for preparing medicine
  • Compound wez series and its preparation method and use for preparing medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1 prepares the method for the compound of formula IV, V, VI structure

[0076] 1. Synthesis line:

[0077]

[0078]

[0079]

[0080] 2. Specific synthesis steps:

[0081] (1) Synthesis of ETH-1

[0082] Add 11.8 grams of (R)-1-tert-butoxycarbonyl-3-aminopyrrolidine, 11.0 grams of 2-bromo-3-chloropyridine, 10.0 grams of sodium tert-butoxide, and 70 ml of toluene into a 250 ml three-necked bottle, protect it with nitrogen, and open it Stir, add 0.1 g of palladium acetate, 1,1'-bi-2-naphthol, tris(dimethylamino)phosphine, heat to 100°C, react for 7 hours, stop the reaction, pour into 500ml of water, add 1000ml of ethyl acetate Extracted several times, combined the ethyl acetate layer, washed with 200*3 water, recovered the ethyl acetate layer to obtain a residual paste, mixed the sample with silica gel, and obtained about 7 grams of ETH-1 through silica gel column chromatography.

[0083] (2) Synthesis of pyrrolidine amide

[0084] 4-(3H-[1,2,3]tri...

Embodiment 2

[0088] Embodiment 2 Rat Pharmacokinetic Properties Research

[0089] 1. Experimental method:

[0090] 36 male SD rats were purchased and randomly assigned to 3 compound groups (WEZ-4, WEZ-5, WEZ-6). The 12 rats used for each compound test were randomly divided into two groups, of which 6 were Rats were administered intravenously (1 mg / kg), blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and plasma was separated, and the other 6 rats were administered by intragastric administration (5 mg / kg), blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration and plasma was separated. Adopt LC / MS / MS method to measure the concentration of each compound in plasma, and use Phocnix WinNonlin 6.2.1 software to calculate relevant pharmacokinetic parameters, calculate its bioavailability in male SD rats, evaluate each compound's Pharmacokinetic properties.

[0091] 2. Experimental results

[0092] The bioavailability of compo...

Embodiment 3

[0093] Embodiment 3, the influence of compound WEZ-4, WEZ-5, WEZ-6 on NK / T cell lymphoma

[0094] 1. Experimental method

[0095] (1) Cell culture and grouping: NK / T cell lymphoma cell line YTS cells were purchased, cultured on the wall with DMEM cell culture medium containing 10% fetal bovine serum, and digested and passaged with trypsin after the cells were 90% confluent. The passaged cells continued to expand and culture, and grouped after obtaining a sufficient number of cells. The control group was treated with DMEM without drug, and the WEZ-4, WEZ-5, and WEZ-6 treatment groups were treated with DMEM containing different concentrations (10µM, 20µM, 30µM) for 24 hours continuously.

[0096] (2) Animal grouping and modeling

[0097] Grouping of animals: select SPF grade male C57 mice (18-20) g, feeding environment temperature (18-23) ℃, moderate 45%-55%, free access to water and food. They were randomly divided into control group, WEZ-4 treatment group, WEZ-5 treatment g...

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PUM

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Abstract

The invention discloses compound WEZ series and its preparation method and application for preparing medicines. The compound WEZ series are compounds represented by formulas I, II and III. Drugs for immunological disorders.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and specifically relates to the WEZ series of compounds with the structures of formulas I, II, and III or pharmaceutically acceptable salts thereof, a preparation method thereof, and an application for preparing medicines. Background technique [0002] NK / T cell lymphoma is a common non-Hodgkin's lymphoma in my country, and its incidence has been increasing in recent years. Immune factors play an important role in pathogenesis, and patients with autoimmune diseases (eg, lupus erythematosus, dermatomyositis, Sjogren's syndrome, sarcoidosis) have an increased risk of developing lymphoma. The disease is difficult to treat and the prognosis is poor. The traditional CHOP regimen for the treatment of aggressive non-Hodgkin's lymphoma is less effective in the treatment of NK / T cell lymphoma. Even if a short-term remission can be obtained, the subsequent recurrence rate is high. Currently, there is stil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/444A61P35/00A61P19/02A61P19/08A61P29/00A61P1/00A61P1/04A61P17/06A61P17/00A61P17/10A61P17/08A61P3/06A61P9/10A61P11/00
CPCA61P1/00A61P1/04A61P3/06A61P9/10A61P11/00A61P17/00A61P17/06A61P17/08A61P17/10A61P19/02A61P19/08A61P29/00A61P35/00C07D471/04
Inventor 陈敏其他发明人请求不公开姓名
Owner NANJING WELLBEST PHARM CO LTD