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New Spiroheterocycles for Pharmacology and Medicine


Synthesis and Research of New Spiroheterocyclic Systems and Their Polymer Derivatives, Potentially Suitable in Pharmacology and Medicine

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology

3 Approved without Funding

Registration date

Leading Institute
Yerevan Institute "Plastpolymer", Armenia, Yerevan


  • University of Crete, Greece, Heraklione\nUniversiteit Antwerpen, Belgium, Antwerpen\nLouisiana State University / School of Medicine in Shreveport, USA, CA, Shreveport\nUniversité d'Orléans / Institut de Chimie Organique et Analytique, France, Orleans\nVas Gene Therapeutics, Inc., USA, CA, Los-Angeles

Project summary

The progress in medicine and pharmacology is in many ways connected with the synthesis of new biologically active compounds and with the getting of effective medical agents on their basis. The structural basis of numerous medical remedies (MR) and biologically active compounds are nitrogen-, oxygen-, sulphur containing heterocycles. During the last three decades researches in the sphere of spiroheterocyclic compounds (SHC) have successfully developed. The practical value of the latter is proved by new information on getting different new medical remedies on their basis that have wide scope of usage [1-7].

For example, derivatives of 8-azaspiro/4,5/decan-7, 9- dione, possess psychotropic activity and are used to treat mental disorders [1]. The known active neuroleptic means- fluspirilenum is the derivative of 1,3,8- triazaspiro /4,5/ decan- 4- one [2]. Spirocompounds containing 1,2- dihydro- 4-H-3, 1- benzoxazine inhibite interleukin and are suitable both anti- inflammation agents and for treating diseases connected with enzymatic destruction of tissue [4].

Though most of the drugs used in medicine have as initial active agent low molecular weight compounds, physiologically active polymer substances have been studied as well recently [8-15]. For example, copolymers of ethylene and maleic anhydride (MA) in hydrolyzed form possess a wide specter of anti-tumor action [10]. Also have been obtained copolymers of 2 methyl- 5- vinylpiridine and N- vinylpirrolidone (VP), having anti-tumor activity [12].

The advantages of polymer medical agents are:

– controlled installation of therapeutic doze at a required rate;

– preserving of required concentration of the medicine during a long period of time;
– minimal frequency of installing the medicine at its maximal effectiveness;
– reducing of side- effects.

Our work, also, proves the perspective of researches in the field of spiroheterocycles and their derivatives in the process of new drugs discovery. The methods of preparation of series of spiroheterocyclic systems I-IV, containing heteroatoms nitrogen, oxygen and sulphur on the basis of aldehydes of six member saturated heterocycles are worked out by the author while writing his candidate theses [16-22].

X=O, S, N-R, n = 1,2; R and R1- hydrocarbon radicals

Among the received derivatives of spiroheterocycles there are both potential anti-depressive substances and activators monoaminoxidaz of the brain [23-25]. Among them are revealed the substances with mutational and anti-mutational activities [26,27]. The analyses of the proposed data prove that the derivatives of spiroheterocycles can, for sure, be applied in medicine particularly as psychotropic and anti- inflammation agents. The proposed work is a development of our research in the field of O-, S- and N-containing spiroheterocycles and their polymer derivatives.

The aim of the given project is getting new psychotropic, anti-inflammation and anti-tumor agents with the least side-effects and low toxic on the basis of bioactive compounds of the spiroheterocycles class and their polymer derivatives, potentially suitable in pharmacology and medicine. As a result of the fulfillment of the project new spiroheterocyclic systems (V-XXII) containing, particularly tetrahydropyran, piperidine, piperazine, 1,3- thiazine and benzothiazine (V-IX),dihydro-1,4-thiazine (X,XI), 2H-1,4- benzothiazine (XII, XIII), thiamorpholine (XIV),di - and tetrahydropteridine (XVII,XVIII), thiazolidino[3,2-a]piperazine and thiazolidino[3,2-c]thiamorpholine (XIX,XX), dihydro-2H- 1,4- benzothiazine (XXI, XXII), also their polymer derivatives (XX III) will be obtained.

X= O, N- R, R and R1- hydrocarbon radicals

Through biological testing of the series of the above mentioned SHC doubtless substances with psychotropic activity and anti-inflammation properties, potentially suitable in pharmacology and medicine, will be revealed. We supposed that the anti-tumor activity will be observed in those SHC that are connected with copolymers of VP and MA. The expected results are based on the analysis of the existing and our data on the synthesis and properties of the compounds of a class of spiroheterocycles.

The participants of the project have a great experience in the sphere of the synthesis of heterocyclic compounds and their biological trial, have long studied copolymers of vinylacetate (VA), N-vinylpirrolidone (VP), unsaturated carbonic acids and of MA [28-35].

The work proposed in the given project concerns the type of ''Applied Research'' and will allow to receive the following main results.

Scientific aspect:

– to work out methods of obtaining a series of new spiroheterocyclic systems, containing tetrahydropyran, piperidine, piperazine, thiazolidine, 1,3- and 1,4- thiazine and benzothiazine, tetrahydroquinoxaline, di- and tetrahydropteridine and to study of their chemical properties;

– to synthesis the derivatives 2',2'- dimethyl- 3,4- dihydro-2H- 1,4- benzothiazin-2-spiro- 4'- tetrahydropyran (XV) and 1'-methyl-3,4- dihydro-2H- 1,4- benzothiazin-2-spiro- 4'-piperidine (XVI) with different pharmacofor substitutes;

– to study the biological properties of the obtained compounds for revealing their psychotropic activities, anti- inflammation, anesthetic and antihistaminic action;

– to obtain the water-soluble copolymers of VP and MA with definite composition and molecular weight (MW) satisfying the demands of medicine towards biopolymers;

– through the polymer-analogical transformation of copolymers VP and MA to obtain new polymer derivatives of SHC to reveal their supposed anti-tumor activities;

– to research the relationship between the structure and biological activity SHC by modern methods of quantum chemistry.

Industrial aspect:

– the work out the medical substances on the basis of biologically active compounds of the spiroheterocyclic class and their derivatives, including polymer forms, potentially suitable for medical usage to cure several forms of mental disease or malignant tumor.

The expected results will give certain contribution to the development of SHC chemistry and will support the creation of new pharmaceutical agents on their basis.

Fulfillment of work will provide partial engagement of the scientists involved in defensive themes and use their potential in solving peaceful problems in the sphere of medicine and pharmacology, and also will promote the integration of the participants of the project into the international scientific society.

The main volume of the proposed project consists of the following tasks:

– The scientific research works on working up methods of synthesis of new spiroheterocyclic systems and their derivatives containing tetrahydropyran,piperidine, piperazine, tetrahydroquinoxaline, di - and tetrahydropteridine, thiazolidine, 1,3- and 1,4- thiazine and benzothiazine and the study of their chemical properties.

– The synthesis of polymer derivatives of SHC through polymer-analogical transformations of copolymers VP with MA and the study of their physiochemical properties.

– Biological tests of the derivatives of spiroheterocycles and revealing compounds potentially suitable to be used in pharmacology and medicine as psychotropic, anti-inflammation and anti-tumor agents.

The plan of the works on suggested project consists of the following stages:

– Synthesis of 4- aldehydes of tetrahydropyran and piperidine series and corresponding a-bromaldehydes.

– Synthesis of spiroheterocyclic imins I, IV and their thiazine analogues X-XIV, containing dihydro-1,4-thiazine (X,XI), 2H-1,4- benzothiazine (XII, XIII), thiamorpholine (XIV).

– Synthesis of spiroheterocyclic systems V-XXII.

– Study of the chemical properties of spiroheterocycles, including the synthesis of the derivatives XV, XVI containing pharmacofor substitutes in the position 4: [ -(CH2)2NH2, -(CH2)2 -OH, -(CH2)2 - N(C2H5)2, -(CH2)3 -NH2, -(CH2)3-N(CH3)2, CO- (CH2)2 - N(C2H5)2].

– Biological testing of the derivatives of SHC to reveal their psychotropic activities, anti-inflammation, anesthetic and antihistaminic action.

– The study of the reactivity of spiroheterocycles and the relationships between their structure and biological activities within the framework of molecular orbital method.

– Synthesis of water-soluble copolymers VP and MA with definite composition and MW.

– Synthesis of new polymer connected SHC on the basis of copolymers VP with MA and study of their biological properties.

The project will be realized in the laboratories and with the equipment of the institute. Synthesis of SHC will be fulfilled by using the methods of halogenizing, hydrolyzing, restoring, substituting, cyclocondensing and so on, and what concerns to copolymers VP with MA- radical polymerizing.

The structure of the synthesized spiroheterocyclic systems and their derivatives will be studied by the methods of IR, 1H and 13C NMR spectroscopy and mass- spectrometry and the purity will be controlled by the methods of gas- liquid and thin- layer chromatography. Electronic structure of spiroheterocycles will be researched by the methods of quantum chemistry.

The biological tests of the obtained compounds will be carried out in specialized laboratories.

The role of the foreign collaborators is:

– mutual discussion of the results and exchange of information during the project progress;

– introducing comments to the technical account;
– conduction of joint working seminars and conferences.


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