Polysubstituted thieno[2,3-b]pyridine derivatives, and preparation method and application thereof
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An unsubstituted and pyrrole technology, applied in the field of multi-substituted thieno[2,3-b]pyridine derivatives and their preparation, can solve the problem of no increase in urine osmotic pressure
Active Publication Date: 2019-12-31
PEKING UNIV
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Embodiment 1
[0117] The preparation of compound shown in embodiment 1, formula I-1
[0118] refer to Figure 13 The shown flow chart prepares the compound shown in formula I-1, and concrete operation steps are as follows:
[0119] Weigh ethyl acetoacetate (1.302g, 10mmol), add DMF-DMA (1.430g, 12mmol) and 5mL dichloromethane, reflux and stir at 40°C. After reacting for 8 h, TLC detected that the reaction was complete. Cool to room temperature, remove the solvent and volatile solutes by rotary evaporation, then add 10 mL×3 toluene, and remove the volatile solutes by rotary evaporation three times to obtain a rose-red oily liquid.
[0120] Weigh sodium ethoxide (0.34g, 5mmol) and dissolve it in 15mL of ethanol, slowly add 2-cyanothioacetamide (0.463g, 5.5mmol) under ice bath, stir for 10 minutes, then add dropwise the ethanol solution of the above intermediate , rose to room temperature and reacted overnight, the solution was gradually cloudy from clear. After the reaction was detected b...
Embodiment 2
[0128] Example 2, Screening and Pharmacodynamic Evaluation of UT-B Inhibitors
[0129] 1. Screening test method
[0130] 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;
[0131] 2) Add the same amount of PBS as the blood, centrifuge at 3000r / min for 10min, discard the supernatant;
[0132] 3) Dilute the erythrocytes with hypertonic PBS containing 1.25M acetamide to a cell suspension whose specific volume is 2%;
[0133]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;
[0134] 5) Take 99 μl of the above 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 the compound shown in formula I-1), mix well, and incubate at room temperature f...
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Abstract
The invention discloses polysubstituted thieno[2,3-b]pyridine derivatives, and a preparation method and an application thereof. The structural formula of the derivatives are represented by formula I shown in the description. A compound for inhibiting a urea transporter is screened by using an erythrocyte model. Experimental results show that the compounds (represented by formula I-1) can inhibit the permeation of a urea transporter UT-B mediated erythrocyte membrane to urea, and the effect of the compounds has a dose-dependent relationship; the compounds represented by the formula I-1 have nocytotoxic effect on MDCK cells within an effective dose range, so the effect of the compounds represented by the formula I-1 on inhibiting cell permeation urea is irrelevant to the cytotoxicity of thecompounds; the inhibition effect of the compounds represented by the formula I-1 on the urea transporter UT-B is gradually enhanced; the inhibiting effect of the compounds represented by the formulaI-1 on the UT-B is reversible; and in-vivo test results show that the compounds represented by the formula I-1 can significantly increase the urination volume of rats, reduce the concentration of ureain rat urine and reduce the osmotic pressure, so that the compounds represented by the formula I-1 generate a urea selective diuresis effect in vivo.
Description
technical field [0001] The invention relates to the field of diuretic and antihypertensive drugs, in particular to multi-substituted thieno[2,3-b]pyridine derivatives and their preparation methods and applications. Background technique [0002] 1. Current applications and research and development 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 transpo...
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