Conjugates of 1-amino-1,1-bisphosphonates with betulin, method of preparation and use

Abstract

The subject of the application are conjugates of 1-amino-1,1-bisphosphonates with betulin, which are characterized in that the carboxyacyl derivative of betulin of general formula 1, where R1=Me, CH2CH2COOH, R2=H,Me, is connected via an amide group to 1-amino-1,1-bisphosphonate of general formula 2, where R3=H,Me. The application also covers a method for preparing conjugates of 1-amino-1,1-bisphosphonates with betulin of the general formula 3, where R1=Me, CH2CH2CONHCH(PO(OEt)2)2, R2=H,Me, R3=H,Me, which consists in contacting a betulin derivative of the general formula 1, where R1=Me, CH2CH2COOH in the amount of 0.10 mmol in an inert gas environment with N,N'-dicyclohexylcarbodiimide (DCC) in the amount of 0.11 to 0.22 mmol DCC / 0.10 mmol 1, in the presence of 1-hydroxybenzotriazole (HOBt) in the amount of 0.11 to 0.22 mmol HOBt / 0.10 mmol 1, in organic solvents, preferably in dichloromethane (DCM) in the amount of 4.5 to 5 mmol 4.7 mL DCM / 0.10 mmol 1, the whole is stirred at a temperature from 0°C to 5°C for 15 minutes,then at room temperature for 2 h, then at a temperature from 0°C to 5°C 1-amino-1,1-bisphosphonate of the general formula 2, where R3=H, Me in a molar ratio from 0.13 to 0.40 mmol 2 / 0.10 mmol 1, dissolved in dichloromethane in an amount from 2.0 to 2.5 mL of DCM / 0.10 mmol 1, methanol is added in an amount from 0.01 to 0.40 mL of MeOH / 0.10 mmol 1, the reaction is carried out at room temperature for from 2 days to 16 days, then the organic solvent is evaporated under a pressure from 10 mmHg to 20 mmHg, extracted with organic solvents, preferably ethyl acetate, the organic solvent is evaporated again under a pressure from 10 mmHg to 20 mmHg, purified by column chromatography. The subject of the application is also the use of conjugates obtained by the specific method described above for the production of potential pharmaceuticals intended to inhibit the proliferation of stomach, lung, and osteosarcoma cancer cells.