Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/1177
Title: STUDIES OF HETEROCYCLIC NATURAL PRODUCTS COMPOUNDS ANALOGUS TO CANNABINOIDS
Authors: Sharma, Rashmi
Keywords: CHEMISTRY
HETEROCYCLIC NATURAL PRODUCTS COMPOUNDS
CANNABINOIDS
HETEROCYCLIC COMPOUNDS
Issue Date: 1985
Abstract: Heterocyclic compounds are widely distributed in nature and are essential to life, playing a vital role'in the metabolism of the living cells. Most of the heterocyclic compounds are pharmacologically active and many of these are in clinical use. Natural products like (a) antibiotics e.g. pencillin-N, sulphadiazene(s) and pencillin (b) alka loids e.g. morphine, reserpine, ellipticine and vinblastin and (c) fiavones and anthocyanines fall in this group. A large majority of synthetic heterocyclics are being used as anticancer agents, antiepleptics, analgesics, hypnotics, pesticides, weed killers and rodenticides. Alarge number of heterocyclic compounds are also found to be endowed with central nervous system activity, antifertility activity, antiinflammatory activity etc. Heterocycles therefore hold an intrinsic interest for an organic chemist. The present study deals with intensive investigation of some classes of known physiologically active compounds. The programme of research concentrates mainly on synthesis of some nitrogen and oxygen containing analogs of tetra hydrocannabinols, the active constituents of Cannabis sativa Linn, known for its central nervous system activity and also some nonsteroidal antifertility agents, which can be safely and efficaciously used as oral contraceptives. Further a few anthraquinones and flavonoids have been extracted from Cassia ii species subgenus fistula. Quaternary ammonium bases have also been isolated from thallctrum javanicum and Thalictrum neurocarpum, the two species found in India hitherto unre- _____ m ported. The present work has been divided into three parts. Part 1 The tranquilizing and hallucinogenic effects of some chemicals have led to believe that it is possible to control behaviour and mood of persons clinically. All these compounds affect the central nervous system (CMS). The cannabis prepa rations such as bhang, hashish and marijuana derived from the Indian hemp plant cannabis sativa attracted a lot of attention and their importance is due to their pronounced CNS activity. The cannabis preparations have a unique feature of causing both, CNS stimulation and depression, not exhibited by any other class of drugs. Cannabis derived drugs are also asso ciated witn analgesic properties, spontaneous changes in human behaviour and altered response to stimuli. Any one of these properties is sufficient to make the drug chemically important, but the multiplicity of activities render it useless. Efforts have been directed towards separation of the unique-tranquilizing and stimulating effect of cannabinoids, by insertion of nitrogen atom at the ring junction of pyran and alicyclic ring of tetrahydrocannabinols. On the other hand some well known CNS active agents such as tryptamine, serotinin, harmine have a indole nucleus in their structural framework and some synthetic benzimidazoles are also endowed with CNS activity. Keeping these factors in view, compounds iii having mixed features of cannabinoids (ring A and B) and that of indoles, benzimidazoles or imidazoles (ring C and D) have been prepared. In another approach it seems # possible to modify the biological properties of tetrahydro cannabinols by the insertion of oxygen atom in the ring C as it provides opportunity of repeating the structural features' of ring A and B i.e. the ring C is an oxygen heterocyclic fused with aromatic benzene ring. This part of thesis has further been divided into three sections. Section I Synthesis of some oxygen analogs (ring C) of canna binoids has been carried out. Several 8-methyl,3-hydroxy-2- alkyl-6H- benzofuro [2,3-cJ[l] benzopyrans have been prepa red. In these molecules there is opportunity of repeating the features of ring A and B of THC's. The ring C is a five membered oxygen heterocyclic fused with aromatic benzene ring (ring D). The synthesis of these compounds has been achieved by condensation of resorcinols with appropriate j3-keto ester (7-methyl, ethyl 2, 3-dihydro-3-oxobenzofuran-2- carboxylate) and the pyrans obtained were subjected to Grignard reaction with methyl magnesium halide to furnish the corresponding 8-methyl,3-hydroxy-2-alkyl-6,6 dimethyl- 6H-benzofuro [2,'3-cJ [lj benzopyran (I) IV Series 1 R - C2H5, C3H7, n-C3H7, C4H9, C5H]>1 The structure of these compounds has been established by elemental analysis, nmr and mass spectroscopy. The alkylation of these pyrans (1) with 2-chloroethyl pyrrolidine hydro chloride in the presence of anhydrous potassium carbonate in dryacetone afforded the corresponding 3-(2-pyroiidinoethylj- ethers which have been converted to hydrochlorides. Series II (2) I 2 2VJ; CHXH NMe I- 2 2 > CHCHCH NMe-, 2 2 2 2 Section II Synthesis of nitrogen analogs of cannabinoids having mixed features of cannabinoids (ring A and 3) and that of indole or imidazole (ring C and D) has been carried out. Attempts have been directed towardsthe synthesis of 7Hindolo [1,2-c] [1,3] benzoxazines (III) and 5H-imidazolo [1,2-c] [1,3] benzoxazine (IV) systems, 2-(2'-hydroxyphenyl) indoles and 2-(2'-hydroxyphenyl) imidazoles have been prepared as intermediates for the synthesis of (III) and (IV) respectively as the second hetero ring B could then easily be constructed by introducing a methylene bridge between the OH and NH groups. Series I R R; ^ Nr -o^T;;Me (in) m, Series II (IV) R=H,CH3,C2H5..... R=OCH3,H,CH3-- R2=OH,HlCH3...- R=H,CH3JC H-, C6-H4OCH3, VI The structure of these compounds have been ascertained by elemental analysis, NMR and Mass spectra studies. Section III Many synthetic benzimidazole derivatives are known to possess potent central nervous system activity. Therefore, synthesis of some cannabinoid analogs, having mixed features of benzimidazoles and cannabinolds have been carried out. Succesful attempts have been made to prepare 7H-benzimidazolo [l,2-c] [1,3] benzoxazines (V) and 7H-pyridoimidazolo [l,2-c] [1,3] benzoxazines (VJ) 2-(2'-hydroxyphenyl) benzimi dazoles and 2-(2'-hydroxyphenyl) pyridoimidazoles have been prepared as intermediates. A methylene bridge has been introduced between the -OH and -NH groups of the correspond ing benzimidazoles by treating them with dibromomethane in K2C03-DMF system. R R=CI,C0C6HR1= Cf,CH3.Br. (V) vii The structure of these compounds were confirmed by elemental analysis, mass and nmr sDectra studies. Part II Population explosion can be termed as one of the major problems facing mankind today. For centuries, world's birth and death rate had been in a sort of natural equili brium. The development of antiinfective drugs of various kinds and advances made in the medical science has reduced the effectiveness of death, as a possible means of popula tion control. This has brought us face to face with scarcity of food, material and energy resources. Not only this, it has also given birth to social evils like unemployment, juvenile delinquency, increased incidence of crime and environmental pollution. Contraceptives derived from plant and other natural sources have been used by men and women, for thousands of years. An important stimulus to research in the field of antifertility compounds was the successful employment of progestational and progestational-estrogenic steroids in the human female. The role of critical balance of estrogens and progestagens for the maintenance of preg nancy by an interplay of hypothalmic, pituitary and ovarian function is well recognised. An interference with the level of these hormones could cause termination of pregnancy, has been an attractive basis for the designing and develop ment of oral contraceptives. Inspite of remarkable efficacy Vlll of these steroidal preparations as oral contraceptives, the method Is far from ideal. They are Known to proauce undesirable effects characteristic to natural estrogens and progestations and also their continous use and compli cated administration over major part of the active repro ductive life of woman involves the risk of permanent disturbance of normal harmonal balance. This has diverted the attention towards search of non-steroidal estrogenic compounds which also possess antifertility activity and have minimized hormonal effects. The synthesis of a number of 6H-benzofuro [1,2-c] [1,3] benzopyran-6-ones and 2-(l',2'- diphenyl vinyl)-l-phenyl benzofurans has been described in this part of the thesis. This part has been divided in two sections. Section I ______ ^ Triphenylethylenes are known to possess antifertility activity in experimental animals. This activity is attributed to their estrogenic and/or estrogen antagonist activities. Lately interest has been concentrated in compounds having the triarylethylene pattern in rigid frame work and a large number of 1,2 diphenylindenes, 2,3-diphenyl indoles, 2,3 diphenylbenzofurans etc. have been synthesized and tested. During the present studies, a novel system has been developed, in which properly substituted benzofurans have a '1,2-diphenylvinyl' group attached at position 2. It was thought such IX compounds would be very suitable for further exploration in view of the incorporation of both the open and 'cyclized' triarylethylene pattern in their structural make up, in a more rigid form. This section incorporates the synthesis of some 2-(l,-2'-diphenylvinyl)-3-phenyl benzofurans (VII) and their basic ethers. For the synthesis of these compounds (VII),2-aroyl-3-arylbenzofurans have been prepared as inter mediates, which were condensed with benzyl magnesium chloride to give corresponding carbinol, which on dehydration under mild acidic conditions gave the novel triarylethylene system in which one of the phenyl group has been replaced by more potent antifertility group 3-phenyi benzofur-2-yl. Substitution of one of the hydroxy groups of both the steroidal and nonsteroidal estrogenic compounds with alkoxy groups terminating in basic nitrogen is known to improve their antiimplantation activity. Therefore, the corresponding (3-t-aminoalkoxy derivatives have been prepared and characterized. Section II Many cycliied triarylethylene system such as diphenylcoumarins, chromenes, chromans and diphenyl benzofurans etc are known to be endowed with strong antifertility activity. Introduction of dialkylaminoalkoxy function in certain estrogenic compounds is known to modify their biological properties considerably. It was thought of interest to prepare compounds having both coumarin and benzofuran ring systems in their molecular framework. The basic ethers of 8-methyl,3-hydroxy-6H-benzofuro [2,3-c][l] benzopyran-6-ones (VIII) and 9-methyl,3-hydroxy-6H-benzofuro [2,3-c][l] benzopyran-6-ones (Vlllb) have been synthe sized and reported in this part of the thesis. The close structural relationship to coumestrol and rigid triaryle thylene pattern in their molecular framework made the choice of such structure an interesting point for further exploration (VIII) a = Rx = CH3, R2 = H b = R1 = H, R2 CH3 XI These, 8-methyl,3-hydroxy-6H-benzofuro [2,3-cJ[lJ benzopyran-6-ones were prepared by condensing 8-methyl, ethyl-2,3-dihydro-3-oxobenzofuran-2-carboxylate with appropriate resorcinols in the presence of phosphorus oxychloride. The etherification of these benzopyran-6-ones was carried out with dimethyl sulphate, 2-chloroethylpyrrolidine, 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride to give the corresponding ethers. Part III The economic importance of plants in human life is immense, since the evolution of man. For centuries man has relied upon plants as a source of food and medicines. Most of the plants are known to have a medicinal folkloric background. On investigations their drug potential has been confirmed. The chemical investigation of two medicinally important species of India, Cassia and thalictrum has been taken up for present studies. This part of thesis is also divided in two sections. Section I Cassia, belonging to family Leguminosae, is large and predominantly tropical genus of about 580 species of herbs, shrubs and trees, with about twenty representatives in India. Many of them are known to possess great medicinal value. The subgenus fistula possess twenty eight tropical trees, six of these are represented in Indian flora. Their xii pytochemical investigations revealed that all the species of this subgenus contain Kaempferol and a mixture of anthraquinones. Rhein wa? found to be specifically present in all the six species, as it is absent from many other * species. This six species of the section fistula which were undertaken for study are as follows. 1. Cassia grandis L £. Cassia fistula L 3. Cassia nodosa Hamilt 4. Cassia renigera wall 5. Cassia javanita L 6. Cassia marginata Roxb The leaves of these plants were extracted with petroleum ether, benzene and methanol. Extracts were analyzed for anthraquinones and flavonoids. The studies revealed the presence of chrysophanol, physcion, rhein and Kaempferol in all the species. Section II Thalictrum Linn is a large genus of perennial herbs native of North temperate and tropical regions, belonging to family Ranunculaceae. This is an alkaloid rich genus. The alkaloids, so far isolated from thalictrum species can be classified into following chemical types, l) isoquinoline alkaloid (simple isoquinoline, oenzylisoquinoline, dimeric alkaloids belonging Xlll to bis-benzyl tetrahydroisoquinoline and benzyltetrahydroi soquinolineuporphine types, aporphii.e, oxyaporphine, protoberberine ana protopine types) and ii) diterpenoid alkaloids. Literature revealed that practically no work has been reported on T. javanicum Blume and T. neurocarpum Royle. Therefore, it was considered of interest to take tnem for present studies. The following bases have been isolated from these plants. 1. Berberine 2. Columbamine 3. Jatrorhizine 4. Palmatine 5. Thalidastine Thalidastine was found to be absent from T. neurocaroum.
URI: http://hdl.handle.net/123456789/1177
Other Identifiers: Ph.D
Appears in Collections:DOCTORAL THESES (chemistry)

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