TR2022010295A1 - SYNTHESIS OF DIHYDROXY-TETRAHYDROINDENO-IMIDAZole DERIVATIVES - Google Patents

Abstract

The invention involves the synthesis of new molecules containing a biologically active hydrazono-imidazole group. It is about the synthesis of hydrazone-containing Dihydroxy-tetrahydroindeno-imidazole derivatives from the reaction of guanylhydrazones (aminoguanidine) with Ninhydrin (2,2-dihydroxyindane-1,3-dione) derivatives and their pharmacologically acceptable structures.

Description

DESCRIPTION SYNTHESIS OF DIHYDROXY-TETRAHYDROINDENO-IMIDAZOLE DERIVATIVES Field of the Invention The present invention relates to the synthesis of hydrazone-containing Dihydroxy-tetrahydroindeno-imidazole derivatives from the reaction of guanylhydrazones (aminoguanidine) with Ninhydrin (2,2-dihydroxyindane-1,3-dione) derivatives and their pharmacologically acceptable salts, tautomers and structures. The aim of the present invention is to synthesize new molecules containing biologically active hydrazono-imidazole groups. State of the Art Related to the Invention (Prior Art) Cancer is still a big problem in the 21st century. Cancer is a complex disease influenced by genetic and environmental factors, progressing through a multistage carcinogenesis involving various physiological systems within the human body, such as cell signaling and apoptosis. Consequently, combating cancer is extremely complex. The biological activities of hydrazones, with their anticancer, antimalarial, antiviral, antifungal, antibacterial, antitubercular, and antiinflammatory properties, shed light on solving the problems caused by cancer. Furthermore, ninhydrin is of great importance due to its role in the synthesis of imidazole derivatives, which possess a wide range of biological activities. Imidazole-containing compounds exhibit various biological activities and pharmacological properties, such as antibacterial, anti-Alzheimer's, antifungal, anti-HCV, anti-HIV, antimalarial, and anticancer activities, and play a crucial role in drug discovery. These nitrogen-containing heterocyclic compounds are not only naturally occurring motifs (DNA base elements, histidine, alkaloids, biotin, vitamin B12, etc.) but can also be used in agriculture as plant growth regulators and pesticides. Imidazole compounds, nitrogen-containing heterocyclic compounds, are important compounds due to their broad pharmaceutical activity. Because the imidazole ring is electron-rich, imidazole derivatives exhibit a wide range of bioactive properties in biological systems. The imidazole pharmacophore group, found in the structures of biological molecules such as histamine, vitamin B12, DNA, and hemoglobin, is important for medicinal chemistry due to its weak interactions with enzymes and receptors. Numerous molecules containing the imidazole group possess high therapeutic potential and biologically active properties. For example, anticancer (imidazole carboxamide, zoledronic acid, dacarbazine, azathioprine, nilotnib, and tipifarnib), antifungal (clotrimazole, miconazole, ketoconazole, and oxiconazole), antiparasitic (metronidazole, benznidazole, omidazole, and secnidazole), antihistamine (cimetidine, imetidine, immepipre, and thioperamide), antineuropathic (nafimidone, fipamezole, and dexmedetomidine), and antihypertensive (losartan, eprosartan, and olmesartan) molecules, topoisomerase inhibitors (indimitecan, camptothecin), microtubule polymerization inhibitors (combretastatin A-4 and N-methylimidazole bridged analog derivatives), cytochrome P450 enzyme inhibitors (fadrozole, letrozole), RAF inhibitors. (pyrazole tricyclic derivatives), TGF-ß inhibitors (Quinoxaline-imidazoles and amides, pyridinyl imidazole), Farnesyltransferase inhibitors (Tipifamib analogs, Azaheptapyridines), and metal-imidazole complexes are biologically active compounds and are widely used to treat various disease types with high therapeutic potential. This situation is important for focusing on biological molecules containing imidazole groups, conducting new research, and synthesizing new molecules. Hydrazide-hydrazones (-NH-N=CH-) are a group responsible for various pharmaceutical applications because they contain the azomethine pharmacophore group and are also important compounds in the synthesis of different heterocycles. Isoniazid, ciprofloxacin, and pyrazinamide are some of the antituberculosis drugs containing hydrazone groups. Compounds such as nifuroxazide, verazide, and salinazide contain hydrazones and are approved as antibacterial and antimicrobial agents. Ilubiprofen, the ester hydrazide in this group of compounds, is known for its inhibition of ovarian proliferation and metastasis of carcinoma and leukemia cells. Zorubicin is an anthracycline drug with proven chemotherapy effects for various cancers. Binodenoson is a drug used as an adenosine receptor blocker. Clotrimazole, miconazole, and ketoconazole are imidazole derivatives and are broad-spectrum antifungal agents, and nimorazole is an antimicrobial agent against anaerobic bacteria and protozoa. Dihydroxy-tetrahydroindeno-thioimidazole derivatives, obtained from the reaction of ninhydrin with urea derivatives, have been found to exhibit antimicrobial and antifungal activity. Novel 3-(arylideneamino)-3a,8a-dihydroxy- l ,3 ,3a,8atetrahydroindeno[ l ,2-d]imidazole-2,8-diones and their 2-thioxo analogs were obtained from the reaction of ninhydrin with semi- and thiosemicarbazones and their antimicrobial activities were measured; the results showed that these compounds contain a carbonyl or thiol group at the atom at position 2 of the imidazole ring. Brief Description and Objectives of the Invention The present invention relates to the synthesis of hydrazone-containing dihydroxy-tetrahydroindeno-imidazole derivatives from the reaction of guanylhydrazones (aminoguanidine) with ninhydrin (2,2-dihydroxyindane-l,3-dione) derivatives and their pharmacologically acceptable salts, tautomers and structures. The purpose of this invention is to synthesize new molecules containing biologically active hydrazono-imidazole groups. Comparison of the invention with previous studies and patents revealed that no reactions have occurred between the guanylhydrazone derivatives and ninhydrin derivatives used, and that the compounds synthesized using this invention are not reported in the literature. It was also observed that the synthesized compound had not been synthesized by any other route. The present invention synthesizes new, previously unsynthesized dihydroxytetrahydroindeno-imidazole compounds containing a hydrazone group by attaching a hydrazone group to position 2 of the imidazole ring of the compounds synthesized. Literature and patent searches have revealed that the method employed in the invention, the chemical compounds used for synthesis, and the chemical structures of the resulting new compounds are distinct. The present invention is very important since the synthesized compounds are expected to show biological activity and have potential pharmacological activity for human, plant and animal health. These compounds are expected to show biological activity since their pharmacologically acceptable salts are in tautomeric and cis-diol structures and it is thought that they can be used in phase studies after cell and animal experiments. Within the framework of this invention, many new molecules containing new imidazole groups that are expected to show biological activity have been synthesized. It is envisaged that the molecules synthesized within the scope of this invention will also be used in plants for protective purposes against diseases. Detailed Description of the Invention The synthesis of the compounds of the invention occurs in two steps. The first step is the synthesis of guanylhydrazones; The relevant aldehyde/ketone compound (1 equivalent gram) and the aminoguanidine hydrochloride salt (1.1 equivalent grams) are added to the reaction flask and stirred in pure water/(ethanol or methanol) with a magnetic stirrer for approximately 6-24 hours at room temperature. The reaction progress is usually followed by controlling with the help of thin layer chromatography, and after the reaction is completed, a base solution such as NaOH or KOH (1 equivalent gram) is added to the reaction flask to neutralize the medium. The reaction flask is again allowed to stir for approximately 1 hour with the aid of a magnetic stirrer at room conditions and is purified by crystallization in methanol, ethanol, or propanol. The reaction equation is given below. The second step is the synthesis of dihydroxy-tetrahydroindeno-imidazole derivatives; the guanylhydrazone derivatives synthesized in the first step are added to the reaction flask with solvents (methylalcohol, ethyl alcohol, diocane, tetrahydrofuran, chloroform, dichloromethane, etc.) in an equivalent molar ratio to the ninhydrin derivatives and the reaction is carried out by stirring with the help of a magnetic stirrer at room temperature for approximately 1 to 24 hours. Synthesized 3a,8a-dihydroxy-8-oxo-3,3a,8,8a-tetrahydroindeno[1,2-d]imidazol-2-yl) hydrazonoyl derivatives are purified by crystallization in methanol, ethanol or propanol. The structures of the substances are determined by 1 H-NMR, 1 3 C NMR, and it is possible to synthesize an unlimited number of new compounds by connecting the above-mentioned groups (R5, R6) such as aromatic or aliphatic groups. The reaction equation is given below. R 1 O R6 R2 OH R3 /k N R3 NH2 R4HO N N/ \ R6 R4 0 H H Y Synthesis reaction equation of imidazole derivatives R groups can be hydrogen, alkyl, cycloalkyl heterocycloalkyl (Cl-ClO), aryl (C3-C10), heterocyclic C3-C10) groups instead of aryl groups. Cyclic groups can be single-ringed, fused, bridged, or heterocyclic. These rings may contain oxygen, sulfur, nitrogen, or various combinations of these. Aryl groups here can form 3- to 8-membered substituted or unsubstituted heterocyclic or heteroaryl rings. These heterocyclic or heteroaryl rings can contain 1, 2, 3, or, depending on the size of the ring, heteroatoms such as N, O, S, Se, or P, or a combination of these. Alkyl groups can range from Cl-C8, as well as C2-C10 alkenyl and C2-C10 alkynyl groups. Instead of both aryl and alkyl or cycloalkyl groups, there may be groups such as hydroxyl, nitro, carbonyl, halide, nitrile, carboxyl, amide, amine, ester, sulfonyl, sulfonyl amide, urethane, urea, thiourea, guanidine, hydrazone. Instead of alkyl and aryl groups, there may be imidazole, pyrrole, thiophene, thioazolidine, pyridine, pyrimidine and 4-8 membered heterocyclic groups containing one or more hetero atoms such as N, O, S, Se, P or combinations of these and their derivatives. Instead of hydrogens in both aryl and alkyl groups, there may be organic functional groups or a combination of these groups. The carbonyl group in the imidazole ring may also be replaced by a thiol or imine group. In a preferred embodiment of the invention: for example; further thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, quinazolinyl, pyridaZinyl, cinolinyl, phthalaZinyl, quinoxalinyl, xanthine, hypoxanthine, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, such as pyrrolidinyl, piperidinyl and piperazinyl groups may be other aromatic or non-aromatic groups. The H's given here may be replaced by organic or inorganic functional groups. In another preferred embodiment of the invention, the structures of Formula 1 shown below may be any combination of the groups indicated above. R4 H ::II Y R6 General formula of dihydroxy-tetrahydroindeno-imidazole derivatives (Formula 1) Here, optionally, one or more groups selected from halogen, hydroxyl, amino, cyano, nitro, -CHO, -COOH, -PO4, C1, -C4 and other functional groups may be substituted for the H's. Without any limitation, known groups may be substituted for the alkyl (R) and aryl (Ar) groups. Additionally, alkyl groups attached to Ar, Ar, and R groups can also be used as alkylating agents against cancer cells, such as ClCH2CH2- and ClCH2CH2O-, (ClCH2CH2)2N-, instead of H in aromatic (aryl) and non-aromatic groups. The term "aryl" as used herein includes a derived organic group. As a result of acidic and basic hydrolysis of these compounds in the hydrazone structure, the carbonyl group is separated and the imine double bond is replaced by H's. In addition, these compounds of the compound in Formula I can exist in the form of tautomeric structures, stereoisomers or pharmacologically acceptable salts or solutions. The term "tautomer" used here refers to the migration of protons between adjacent single and double bonds. The compounds described here can undergo any possible tautomerization physically and chemically. Depending on the position of the groups attached to the carbon in the formulas, the compound can be one or more racemic, as well as optically active R and S isomers or racemic and diastereomer structures. Although the OH group in the compounds is synthesized in the cis structure, it is also possible to be in the trans structure. According to the present invention, the compounds may exist in different polymorphs or modifications. The general molecular formula is given They include pharmaceutically acceptable organic or inorganic base or acid salts of compounds. The invention relates to the compound of Formula 1a or their pharmaceutically acceptable salt, solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer or polymorphic crystal structure; they may also exist as pharmacological salts or non-toxic metal complexes of these compounds. The nitrogen attached to the carbonyl group may show NH tautomer by shifting the hydrogen to the carbonyl group and the hydrazone nitrogen. According to the invention, they also include therapeutically active, non-toxic pharmacologically acceptable solution forms of these compounds. In a preferred embodiment of the invention; - The R groups (R1-R6) in the compound shown in Formula 1 are aromatic or non-aromatic cyclic structures and/or combinations of these groups, hydrogen, alkyl, aromatic, heterocyclic, 3-7 membered aromatic groups, straight or branched basic skeleton between 1-15 carbons, including amino groups, aryl groups, halogens, (-CH2-), carbonyl, -NH-, carboxyl, amide, sulfur, hydroxyl, amide, acid salts, other aromatic or non-aromatic aryl derivatives or heterocyclic structures, oxygen can be one of the groups or combinations of these, - Alkyl groups bonded to R groups can be straight chain, branched or cycloalkyl or alkenyl or alkynyl or aryl or alkylaryl or heterocyclic rings composed of nitrogen, oxygen or sulfur; in the case of rings, they can be aromatic or aromatic rings with more than one hetero atom, - Heterocyclic groups bonded to R groups can be linear alkyl, branched or cycloalkyl or alkenyl or alkynyl or aryl or alkylaryl or containing one or more different or the same hetero atoms selected from atoms such as nitrogen, oxygen, sulfur and phosphate - Hydrogen or hydrogens in the R groups can be replaced by sulfonylalkyl or sulfonylalkylaryl or sulfonylaryl groups, - Alkyl substituents bonded to the R groups; hydrogen, alkyl, aromatic, heterocyclic, 3-7 membered aromatic groups, 3-7 membered alkyl groups, aromatic or non-aromatic 10-membered monocyclic or bicyclic ring containing at least one heteroatom C can be replaced by 0, N, S, Si, P or B or combinations thereof, - NH in the imidazo ring in the compound shown in formula 1 can be replaced by S, Se, P or =NR (imine, R groups alkyl, aryl heterocyclic) groups, - N atom in the ring in the compound shown in formula 1 can be replaced by S, C, 0 and P atoms, - Formula The compound indicated with 1 can be used in an antimicrobial, antiviral, antituberculosis, anticancer, antiinflammatory, antibacterial, antiparasitic, antifungal, antiobesity, antidiabetic, antihypertensive, analgesic or anticonvulsant combination. 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