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The Use of Aza- and Diazabicyclononanes for Human Life Maintenance

#2602


Synthesis, Studies, and Application of Aza- and Diazabicyclononanes as Complexing Agents, Preparations for Radiation Hygiene, and Medicines

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • ENV-RED/Remediation and Decontamination/Environment
  • ENV-RWT/Radioactive Waste Treatment/Environment

Status
3 Approved without Funding

Registration date
11.09.2002

Leading Institute
Russian Academy of Sciences / Ufa Scientific Centre / Institute of Organic Chemistry, Russia, Bashkiria, Ufa

Supporting institutes

  • Institute of Organic Chemistry, Russia, Moscow\nVNIITF, Russia, Chelyabinsk reg., Snezhinsk

Collaborators

  • University of Oklahoma / Institute for Science and Public Policy, USA, OK, Norman\nUniversity of Maryland / Department of Chemistry and Biochemistry, USA, MD, College Park\nUniversity of Arizona / Department of Chemistry, USA, AZ, Tucson

Project summary

The goal of the present Project is systematic investigations into the synthesis and chemical transformations of aza- and diazabicyclononanes and their derivatives, as well as production of novel highly efficient preparations indispensable for human life maintenance, resulting from basic research. Development of novel scintillation compositions for the detection of radionuclides in medicine, radiation hygiene, and radioecology. Creation of a technology for the preparation of aza- and diazabicyclononanes of predetermined structures starting from basic organic chemicals.

Compounds containing 3-aza- and 3,7-diazabicyclo[3.3.1]nonane fragment manifest insecticidal, antiarrythmic, and antitumor properties and belong to the class of compounds indispensable for human life maintenance. Therefore, complex studies aimed at the development of original, highly selective methods for the preparation of these compounds and synthesis of novel, potent pharmacologically and biologically active substances based on them seem topical. It is expedient to focus attention on the identification of factors favoring enhanced efficiencies and selectivities of the chemical processes that proceed under conditions of a ‘parallel synthesis’ without accumulation and evolution of toxic and explosive reagents.

This will allow realization of a directed synthesis of 3-aza- and 3,7-diazabicyclo[3.3.1]nonane derivatives of predetermined structures and develop technologies for their production. Asymmetric syntheses involving aza- and diazabicyclo[3.3.1]nonane ligands seem promising. These investigations will deal with the studies of catalytic activities and stereodifferentiating abilities of novel, transition- and non-transition-metal chiral complexes in model cyclopropanation, isomerization, and hydrogenation reactions of prochiral substrates. The results of this research will serve as the basis for development of technologies for manufacture of optically active compounds for medicinal purposes.

Nowadays, cardiovascular diseases have acquired threatening scale. According to the WHO data, the highest mortality rate of the human population is connected with disorders of the cardiovascular system. With this in mind, the search for, and development of, novel efficient antiarrythmic drugs seems extremely urgent. Preliminary studies have already revealed research along this line to have great potential. In particular, the authors of this Project participated in the preparation of a novel highly efficient antiarrythmic drug based on alkaloid lappaconitine containing the 3-azabicyclo[3.3.1]nonane fragment. In its antiarrythmic and antifibrillation activities, toxicity, strength of the effect exerted, duration and the range of therapeutic actions, this medicine excels numerous antiarrythmic drugs currently in practice. Compounds comprising aza- and diazabicyclononane fragments are of undoubted interest as ligands for complex formation with d- and f-element salts, which is important for the solution of problems of their extraction and sorption, as well as for practical uses in hydrometallurgy, radiochemistry, medicine, etc. The Project has mainly the medicinal and environmental orientation, hence, development of specific chemically resistant and mechanically strong hemosorbents, on the one hand, and, on the other hand, of extractants for concrete radionuclides enabling their selective extraction, together with perfection of detoxification monitoring systems, belong to the priority lines of research.

It is known that the detection of a-radiation of transuranium elements in human and animal blood by a scintillation method involves extraction, concentration, and conversion of radionuclides into forms suitable for subsequent registration, e.g., into thin films or suspensions. New procedures for the formation of gels, sols, and complexes of radionuclides with a series of novel ligands will be studied aiming at homogenization of solutions of metal complexes in a liquid scintillator, which in turn will allow counting under conditions of 4p geometry. This will make possible the detection of ultrasmall amounts of transuranium elements in blood and environment with minimum expenses for sampling.

The concentration effect of colored complexes and complicated systems, e.g., blood hemoglobin, on the scintillation properties will be investigated and the detection limits of a-radiators will be determined.

Studies are intended to construct finely dispersed scintillator emulsions based on nanoparticles superior in efficacy the present-day dioxane systems for tritium detection.

Construction of new-generation neutron-sensitive liquid scintillators based on gadolinium complexes to be employed in medical and biological studies is expected.

In the framework of the proposed Project, research will be carried out along the following principal lines:

1. Basic research in the field of directed synthesis of 3-aza- and 3,7-diazabicyclo[3.3.1]nonanes and development of new methods for the preparation thereof in a lesser number of steps starting from both the available natural sources and basic organic chemicals. Synthesis of aza- and diazabicyclononane analogs comprising annelated and spiro-fused cyclopropane fragments and other small heterocycles is intended based on reactions of unsaturated compounds with in situ generated diazo compounds.

2. Identification of the structure – antiarrythmic activity relationships in the series of heterocyclic compounds synthesized, detailed pre-clinical studies on the most promising representatives and development of novel highly efficient antiarrythmic drugs. Directed search for effective fungicides, insecticides, analgesics, antiviral and antibacterial preparations, and drugs against Alzheimer disease amongst aza- and diazabicyclononanes.

3. Synthesis, structure elucidation of transition-metal complexes comprising aza- and diazabicyclononanes including optically active ones, and studies of their catalytic activities and stereodifferentiating abilities in hydrogenation, isomerization, and cyclopropanation reactions. Development of novel technologies of the catalytic synthesis of optically active compounds for medicinal use.

4. Development of highly selective extractants for hydrometallurgy, radiochemistry, and medicine involving oligomeric and polymeric materials based on 3-aza- and 3,7-diazabicyclononanes and analogs thereof. Design and testing of highly efficient hemosorbents biocompatible with blood, plasma, and lymph and specific for certain radionuclides.

5. Production and studies of highly efficient sorbents for extraction of uranium and plutonium isotopes and their scission products from liquid radioactive media (liquid radioactive waste and environmental objects).

6. Development of procedures for cleaning of territories polluted with radionuclides.

7. Construction and studies of novel liquid scintillation compositions comprising f-element complexes with sulfur-, phosphorus- and nitrogen-containing ligands (including alkaloids and aza- and diazabicyclononanes) for registration of a-, b-, and g-radiators in medicine, radiation hygiene, and radioecology.

Previous Results.

Virtually all of the problems contemplated in the Project have sound theoretical backgrounds and definite experimentation in the respective areas, which allows us to state with confidence that, in case of support, its implementation is realistic. The participants have longstanding experience in the field of chemistry and technology of directed organic synthesis of compounds with predetermined properties, polycyclic hydrocarbons, alkaloids, biologically active compounds, homogeneous metal-complex catalysis, coordination chemistry, and radiochemistry. New approaches to the synthesis of aza- and diazabicyclononanes have been developed, a novel antiarrythmic drug allapinine has been designed and applied in medicinal practice; this is involved in the 1992 Index of the most important medicines of the Russian Federation. A liquid scintillator containing gadolinium complexes for the registration of neutrino and neutron radiation in a remote power control system of nuclear reactors has been developed. In the course of implementation of the Project # 419 “Creation of scientific grounds, techniques and technologies for the transformation of the explosive 2,4,6-trinitrotoluene (trotyl, TNT) into valuable civil products (polymeric materials, dyes, biologically active substrances, etc.”, researchers of the N. D. Zelinsky Institute of Organic Chemistry RAS have developed a common methodology for the synthesis of 1-X-3,5-dinitrobenzenes starting from the most abundant explosive, viz., 2,4,6-trinitrotoluene (trotyl), subject to demilitarization. The 1-X-3,5-dinitrobenzenes obtained represent the necessary starting synthons for the accomplishment of the proposed Project.

The research area related to the proposed Project is highly topical in this country and abroad.

The Project participants have at their disposal fairly extensive experimentation facilities and scientific instrumentation (NMR and IR spectrometers, instruments for high-performance chromatography, etc.) indispensable for successful research in the fields of organic and physical chemistry, radiochemistry, and development of advanced chemical technologies.

Expected Results.

The proposed Project will allow development of the basis for original, highly selective and practicable methods for the synthesis of compounds containing aza- and diazabicyclo[3.3.1]nonane fragments and analogs thereof, which are promising as complex-forming agents and preparations for radiation hygiene and medicine. The development of one-pot methods for the synthesis of 3-aza- and 3,7-diazabicyclo[3.3.1]nonanes of predetermined structures based on directed multiple condensations of amines and carbonyl compounds with 1,3-dinitropropanes will also help solution of a problem of trinitrotoluene utilization and processing into perse substances practically useful for the world community.

The present Project envisages the search for novel design principles of important building blocks and valuable compounds which simplify the overall chemical process by combining the steps of generation of toxic and hazardous intermediates with their simultaneous conversion into the target products.

Synthesis of novel transition-metal complexes with optically active ligands based on aza- and diazabicyclononanes together with their use as catalysts for the enantiospecific synthesis of preparations of medicinal use is planned. This involves, in particular, synthesis of drug substances of celastatin, a highly efficient inhibitor of kidney dihydropeptidase, which is a component of an antimicrobial drug “Thienam”, and (S)-(+)-Ibuprofen, a modern non-steroidal antiinflammatory drug.

In the course of the Project implementation, attention of the participants will be largely paid to the identification of factors favoring enhanced efficiencies and selectivities of the chemical processes under study involving metal complexes of aza- and diazabicyclononanes so that these processes did become promising for synthetic organic chemistry.

Structure elucidation of the compounds synthesized will be carried out with extensive use of high-resolution NMR spectroscopy on various nuclei involving two-dimensional techniques. X-Ray diffraction analysis will be an important tool in structure determination of various forms of aza- and diazabicyclononanes (in the case of substituted macrocycles). The use of X-ray diffraction analysis, X-ray photoelectron spectroscopy, and electron paramagnetic resonance methods will shed light on the persity of putative existing forms of transition- and non-transition-metal complexes with aza- and diazabicyclononanes including those of the ‘host-guest’ type.

As regards practical application of the proposed Project, it is expected to develop technology and to patent the methods for the synthesis of aza- and diazabicyclononanes based on both the available natural sources and basic organic chemicals.

Development of novel methods for the synthesis of biologically active compounds containing aza- and diazabicyclononane structural fragments will allow enlargement of the assortment of highly efficient medicines for treatment of cardiovascular diseases and creation of a new class of environmentally friendly insecticides. Our studies will result in construction of practicable highly efficient novel catalysts, composites for polymeric materials possessing unique properties (light transformation, detection of various radiation types, etc.), novel efficient extractants for the isolation and separation of heavy metals, new-generation a-, b-, and g-sensitive liquid scintillators for medical and biological, as well as radioecological and physical studies. Comparative parameters of the known and novel sorbents, viz., partition, concentration, and purification coefficients, etc., will be obtained.

The availability of pilot plants and highly skilled personnel gives grounds to suggest that the Project team will be able to propose, by the end of the Project term, a number of technologies aimed at preparing practically important aza- and diazabicyclononanes for their application in medicine, for the solution of radioecological problems, and in radiochemical and physical research.

The proposed Project meets completely the ISTC goals; this will provide weapons scientists and engineers alternative employment in peaceful activities and will support basic and applied research and development of peaceful technologies, especially in the fields of medicine, environment protection, and nuclear safety.


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