Prospects for further implementation in 2021 – 2022: completed.

Research level: no analogues in the world.

Availability of a patent: No

What additional actions does further research require: additional funding, modern scientific equipment.

Brief characteristics, advantages, further application perspective.

Analysis of the relationship between the structure and activity of a series of previously synthesized fibrinogen receptor antagonists demonstrated the importance of the optimal distance between two positively charged ligand centers. Compounds containing a γ-aminobutyric acid fragment are leaders in affinity and antiaggregation properties. The introduction of β-alanine or γ-aminobutyric acid into the α-position of the residue has a positive effect on the functional activity and affinity for αIIbβ3. It was shown that compounds derived from quinazolin-4-one are more active than 4-phenylquinazolines in in vitro tests for antiaggregatory activity. Optically active 3-alkyl-5 – [(E) -2 (aryl) vinyl] -1,2-dihydro-3H-1,4-benzodiazepin-2-ones has been synthesized. It has been shown that the reaction of N-carboxyanhydrides of amino acids with 1- (2-aminophenyl) -3-phenylprop-2-en-1-ones is the optimal method for obtaining the above compounds. The optical purity of the synthesized compounds was determined by HPLC using a Chira Dex column. It was shown that the use of the N-carboxyanhydride method made it possible to obtain the target compounds with a high degree of optical purity, in contrast to the method based on the condensation of 1- (2-aminophenyl) -3-phenylprop-2-en-1-ones with the hydrochloride amino acid chlorides. A number of new 1,2-dihydro-3H-1,4-benzodiazepin-2-ones containing piperazine benzoic acid residues at position 3 have been synthesized. The molecular and crystal structure of two representatives of this series has been established by XRD. It was found that the benzodiazipine ring in both molecules takes the bath conformation. However, in the case of 5- (o-chlorophenyl) -substituted benzodiazipine, the piperazine fragment has the conformation of a chair, twisted bath, and in the case of 5-phenyl-substituted benzodiazipine, the piperazine ring is in the conformation of a twisted bath. Using the immobilized microsomal fraction, enantioselective hydrolysis of 3-acetoxy-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one was carried out and the S-enantiomer of the studied substrate was obtained within 5 cycles of using the biocatalyst in periodic mode. The method for isolation of the S-enantiomer of 3-acetoxy-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzdiazepin-2-one has been improved due to the use of methyl cellosolve and modification of the column carrier with activated zinc silicate. The synthesized derivatives of 1,4-benzodiazepin-2-one exhibit analgesic activity with ED50 values ​​from 0.028 to 0.072 mg / kg, which is significantly higher than the analgesic activity of the standard drug diclofenac sodium (ED50 10.1 mg / kg). The affinity of the synthesized 3-arylidene-1,2-dihydro-3H-benzodiazepin-2-ones to the central benzodiazepine receptors was established by the method of radioligand analysis. When studying the acute toxicity of PROPOXAZEPAM, it was found that PROPOXAZEPAM belongs to the 5th class of toxicity (practically non-toxic substances). The results of observations of the behavioral reactions of male rats, which were injected with PROPOXAZEPAM for 90 days (the number of crossed peripheral squares and the latency period), fluctuated in the experimental groups, but did not statistically significantly differ from those of the control group. Exploratory activity in terms of the number of crossed central squares decreased 2.8 times for animals that were injected with a 10-fold dose of PROPOXAZEPAM compared to controls. In the Ames test, PROPOXAZEPAM did not detect potential mutagens in Salmonella typhimurium strains TA98 and TA100, neither in the variant without activation (“direct” mutagen), nor in the test with metabolic activation (“indirect” mutagen).




Leave a Reply

Your email address will not be published. Required fields are marked *