New Antihemostatic Substances
Development of New Antihemostatic Substances and Medicines and Rodenticides on Their Basis
Tech Area / Field
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
8 Project completed
Senior Project Manager
State Institute of Technology of Organic Synthesis (GITOS), Russia, Saratov reg., Shikhany
- US Army's Edgewood Chemical Biological Center, USA, MD, Aberdeen Proving Ground
Project summaryThe cardiovascular diseases are the most widespread and complex forms of pathological changes in human organism.
Myocardial infarction, insult, various exhibitions of a stenocardia, thrombosis, haemophilia, change of a permeability of blood vessels, the lesions of hemopoietic organs result not only in a disability, but can cause lethal outcome.
In clinical medicine for prophylaxis and treatment of thromboembolic diseases in combination with various cardiological drugs now are widely applied also anticoagulants of indirect prolonged action.
The adjustment in a blood coagulation system and, especially, reduction in a coagulability is the important problem. The chemical substances lowering a blood coagulability, antihemostatics or anticoagulants, in assignment are sectioned into two types:
– medicinal preparations used at diseases of cardiovascular system for prophylaxis and treatment of thromboembolic complications;
– agents for combatting against the synanthropic gnawers used in practice of deratization of inhabited and industrial premises.
The medicinal anticoagulants of cumarine and indandione series, at complex examination have found many negative properties. It, first of all, their toxicity, large stage of latency, tendency to a cumulation, presence of the remote consequences etc. Just these factors also have resulted in restriction of application of similar drugs in anticoagulant therapy.
On the other hand, the anticoagulants used for destruction of the synanthropic gnawers, demand periodic renovation of assortment. It is produced by that the long application of the same drugs develops the appearance of resistance with the gnawers to them. Besides, the rodenticides produced in Russia, were developed long ago, and are not effective enough; production of modern drugs with a high activity is absent.
Therefore, development of new compounds in examined series and search of essentially new chemical compounds is a urgent problem having the important theoretical and applied meaning at synthesis of medicinal and rodenticide drugs of new generation.
Within the framework of SITOS transition on civil directions of works, the group of the experts, engaging earlier in development of chemical weapons, began study of anticoagulants for the purposes of combatting against the gnawers. In development of these works, conducted at SITOS in sphere of rodenticide drugs of anticoagulant action, it is represented expedient to carry out researches of new anticoagulants and their complex study. Proceeding from properties, which will show such anticoagulants, they can be recommended for use or as pharmaceuticals, or rodenticides. Proceeding from results of own preliminary researches with the count of literary data, we have chosen for study heterocyclic derivatives keeping in structure a fragment - imidazole:
As heterocycles, it is supposed to use an imidazole, purine derivatives - purine, theophyllinum etc., and as a fragment R - various function groups. They are supposed to be compared in antithrombic action, and also in the mechanism of influence on a coagulability of a blood to new substances of purine series of the general formula:
At a finding of fragments imparting to compounds high physiological activity, it is supposed to study the insertion of these fragments to structure of cumarines and indandiones.
The purposes of the project:
– synthesis of compounds having high anticoagulant properties;
– determination of their toxic and anticoagulant properties;
– building of a database of substances having anticoagulant activities;
– choice of compounds on the best indexes of high activity and low price;
– model building of active transport of substances from stands of a mesomorphic state of biological structures;
– development of obtaining technology of the chosen compounds.
The description of works under the project.
All works on the project are pided on three parts:
1. Synthesis and study of properties of compounds. The synthesis roughly up to 100 chosen compounds, their analysis, and identification will be carried out. For all obtained compounds will be studied a toxicity and anticoagulant activity on mice and rats by standard procedures. Calculations of an electron and geometrical structure of investigated molecules by semiempirical methods of quantum chemistry will be carried out, the maps of molecular electrostatic potential will be constructed, and the conformational transitions will be studied. Were based on received results, the questions of structure-property correlation (QSAR) will be surveyed, databases for investigated physiologically active compounds will be created. The obtained data will be used for a choice of structures for the further synthesis of compounds. Experimental works on study of influence of obtained substances on experimental animals also will be carried out, the mechanism of anticoagulant action will be considered. On the set of the characteristics, the best samples of rodenticides and medicinal anticoagulants will be selected.
2. Optimization of methods of obtaining of the chosen samples. It is planned to find the cheapest and technologically convenient methods of synthesis. The optimization of methods of obtaining of the chosen substances will be carried out by criteria of receiving of a maximal yield of target substances and minimization of cost of a product. The method of planning of extreme experiment will be used. Obtaining of mathematical model - equation of process, finding of optimal range of carrying out of process are supposed.
3. Development of technology of obtaining of substances on the chosen methods. It is planned to develop technologies, applicable for introduction in production. A choice of basic flow diagram of process, improvement of technology in laboratory scale and obtaining of data for projection of pilot installation by capacity 0.5 t/years.
The significance of the project for the decision of a problem.
The carried out research will have scientific meaning for study of problems of creation of new anticoagulants of a blood of various purpose. The complex study of new substances of anticoagulant action as pharmaceuticals, and as agents combatting against the gnawers will be carried out. The database together with the structure – property relationships, which are supposed to be built during the project, will form the basis for the further works in this direction. The building of the production technology of a high performance rodenticide agent will allow solving a problem of absence of a modern Russian drug.
Expected results and their application.
The offered elaboration falls into the applied researches. The carrying out of the specified works should lead to following results:
– it will be obtained up to 100 substances having anticoagulant activities;
– the study of properties of these compounds will allow to give away the references on possible practical application of obtained substances;
– the database of substances having anticoagulant activities both known and for the first time obtained will be built. This database can be used in the further researches, and in aggregate with results of study of structure - property dependences can serve as mean of unexperimental evaluation of new anticoagulants;
– the model of active transport of substances from point of view of a mesomorphic state of biological structures will be offered;
– the elaboration of technology of obtaining of the most perspective substances will allow to implant them in production.
Meeting ISTC goals and objectives.
The present project will give the scientists of SITOS, connected with development of chemical weapon, an opportunity for reorientation of the abilities to peace activity. Also, work within the framework of the programs of ISTC will result in integration of the experts of SITOS to international scientific assemblage. The applied researches directed to building of pharmaceuticals and agents of combatting against the gnawers will be supported. The building of technologies of obtaining of anticoagulants, which can be realized in SITOS, will support transferring of the enterprise to the market economy.
Scope of activities.
The work consists of 5 problems:
1. Carrying out of synthesis of potential anticoagulants:
– development of methods of synthesis;
– synthesis of potential anticoagulants (about 100 substances);
– analysis and identification;
– updating of a choice of target substances in process of receiving data about a biological activities and calculated structure-property data.
2. Carrying out of a primary pharmacological screening of first synthesized substances:
– evaluation of toxic properties of obtained substances in acute experiment;
– evaluation of anticoagulant properties of obtained substances by clinical methods;
– evaluation of toxic properties of obtained substances in chronic experiment
3. Carrying out of calculating works:
– calculation of a structure by semiempirical methods;
– study of structure - property correlation;
– building of a database of anticoagulants.
4. Study of influence of substances on system of coagulation of a blood:
– study of laws of distribution of anticoagulants in an organism;
– study of mesomorphic properties of obtained compounds;
– model building of active transport of anticoagulants through membranes from positions of a mesomorphic state;
– model building of a competitive replacement of vitamin K from active centers of transport albuminum.
5. Elaboration of technology of obtaining of perspective anticoagulants:
– optimization of methods of obtaining of the chosen samples;
– elaboration of technology of obtaining of substances by the chosen methods.
Technical approach and methodology.
The methodology includes the following:
– the direction of synthetic works will be based on experience of preceding works of SITOS and will be corrected by data of quantum-chemical calculations executed during the project;
– the choice of substances from synthesized compounds will be based on high anticoagulant activity and hypotoxicity for the medical purposes, and on high anticoagulant activity and of enough high toxicity for goals of the combatting against the gnawers;
– the study of influence of substances on system of coagulation of a blood will be based on model of active transport of substances from positions of a mesomorphic state;
– the optimization of methods of obtaining of the chosen substances will be carried out by criteria of obtaining of a maximal yield of target substances, minimization of cost of a product, and diminution of waste products.
The technical approach includes the following:
– the synthesis of compounds will be carried out on the standard labware with use of known methods or developed during realization of the project;
– the analysis and identification of compounds will be carried out by methods of an element analysis, IRS, UVS, NMR, and MS, by GLC and HPLC methods;
– for study of a toxicity of the obtained compounds on various species of laboratory animals the standard procedures will be used;
– the definition of anticoagulant properties of substances will be carried out both by in vitro (Quick's method etc.), and by in vivo (method of preliminary action of studied substances in relation to an experimental thrombus caused mice by intravenous entering of thrombin);
– the calculations of an electron and geometrical structure of studied molecules, construction of maps of molecular electrostatic potential, study of conformational transitions will be carried out with use of semiempirical methods of quantum chemistry (CNDO, MNDO, PM-3). The building of structure - property relationships (QSAR), and database for studied physiologically active compounds will be based on developments executed during the project;
– for revealing the mechanism of allocation in an organism of obtained compounds, the method of UVS will be used;
– for study of mesomorphic properties of substances, the method of polarization microscopy and DSC will be used.
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