Urea transporter inhibitors, and preparation method and application thereof
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A straight-chain, compound technology, applied in the field of urea channel protein inhibitors, can solve problems such as the lack of increased urine osmotic pressure
Inactive Publication Date: 2012-10-31
PEKING UNIV
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Embodiment 1
[0045] Example 1, Preparation of 1-[2-(3-amino-6-methylthieno[2,3-b]quinolyl)]ethanone (Youte, A-04)
[0046]
[0047] 1) Add 130ml of acetic anhydride to a three-neck flask, dissolve compound 1 (100g, 0.93mol) with 200ml of DCM (dichloromethane), add it dropwise to the acetic anhydride, and control the temperature at 30-40°C. After the dropwise addition, the temperature was kept for half an hour, and the reaction was monitored by TLC. Heat 600ml of water to 50°C, pour the reaction solution into hot water, stir for half an hour, and concentrate to DCM. The solid was filtered off with suction, and the solid was washed twice with 200 ml of water each time. Compound 2 (125 g) was obtained by drying, with a yield of 90%.
[0048] 2) Add 110ml of DMF (dimethylformamide) into the three-necked flask, cool down to 0°C, and dropwise add 360ml of POCl 3 , temperature control 0-10 degrees, there is solid precipitation in the middle, unable to stir, continue to add dropwise, the sys...
Embodiment 2
[0054] Example 2, Screening and Pharmacodynamic Evaluation of UT-B Inhibitors
[0055] 1. Screening test method
[0056] 1) Take blood, put it in a 15ml graduated centrifuge tube (suspended in PBS containing sodium heparin), centrifuge at 3000r / min for 10min, discard the supernatant;
[0057] 2) Add the same amount of PBS as the blood, centrifuge at 3000r / min for 10min, discard the supernatant;
[0058] 3) Dilute the red blood cells with hypertonic PBS containing 1.25M acetamide to a cell suspension with a specific volume of about 2%;
[0059] 4) The erythrocyte suspension was incubated at room temperature for 2 hours to balance the concentration of acetamide inside and outside the cells, and mixed with a pipette at regular intervals;
[0060] 5) Take 99 μl of the above-mentioned erythrocyte suspension and place it in each well of a 96-well round-bottom microplate, then add 1 μl of the compound to be tested (such as Utyl), mix well, and incubate at room temperature for 6 min (...
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Abstract
The invention discloses a series of urea transporter inhibitors of which the structural formula is disclosed in the specification. An erythrocyte model is used for screening to obtain compounds for inhibiting urea transporters. The experimental result indicates that the compounds (such as Youti) can inhibit the permeation of urea transporter UT-B mediated erythrocyte membranes for urea, and the action forms a dosage dependency relationship; Youti within effective dose range has no cytotoxic action on the MDCK (Madin-Darby Canine Kidney) cells, which indicates that the action of Youti for inhibiting cell permeable urea is irrelevant to cytotoxicity; the inhibiting action of Youti on the urea transporter UT-B gradually increases; the inhibiting action of Youti on the urea transporter UT-B is reversible; and the in-vivo test result proves that Youti can obviously increase the uresis amount of a rat, lower the concentration of urea in the urine of the rat, and lower the osmotic pressure, which indicates that Youti has selective diuresis action on urea in vivo.
Description
technical field [0001] The invention relates to a class of urea channel protein inhibitors, a preparation method and application thereof. Background technique [0002] 1. Current applications and R&D hotspots of diuretics [0003] Diuretics act on the kidneys to increase water excretion. Clinically, it is mainly used to treat edema caused by various reasons, and it can also be used to treat some non-edematous diseases. For example, as a first-line drug, it can be used alone or in combination with other drugs to treat hypertension, reduce the incidence of cardiovascular and cerebrovascular diseases and mortality Rate. Currently, the commonly used diuretics are mainly divided into three categories: high-potency diuretics, moderate-potency diuretics, and low-potency diuretics. High-potency diuretics and moderate-potency diuretics mainly inhibit Na + / K + / 2Cl - common transporter and distal convoluted tubule Na + / Cl - Common transporter, inhibits the reabsorption of Na...
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