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4-Methyl-2,2-Dioxo-1H-26,1-Benzothiazine-3-Carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties

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4-Methyl-2,2-Dioxo-1H-26,1-Benzothiazine-3-Carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties Scientia Pharmaceutica Article 4-Methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties Igor V. Ukrainets 1,*, Ganna M. Hamza 1, Anna A. Burian 1, Svitlana V. Shishkina 2,3, Natali I. Voloshchuk 4 ID and Oxana V. Malchenko 4 1 Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine; [email protected] (G.M.H.); [email protected] (A.A.B.) 2 STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Nauki ave., 61001 Kharkiv, Ukraine; [email protected] 3 Department of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., 61077 Kharkiv, Ukraine 4 Department of Pharmacology, N. I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine; [email protected] (N.I.V.); [email protected] (O.V.M.) * Correspondence: [email protected]; Tel.: +38-0572-679-185 Received: 27 February 2018; Accepted: 6 March 2018; Published: 8 March 2018 Abstract: In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing CO2 both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti-inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection, the substances synthesized demonstrate a moderate anti-inflammatory action and simultaneously increase the pain threshold of the experimental animals very effectively, exceeding Lornoxicam and Diclofenac in a similar dose by their analgesic activity. Keywords: esters; hydrolysis; 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid; 2,1-benzothiazine; crystal structure; anti-inflammatory action; analgesic activity Sci. Pharm. 2018, 86, 9; doi:10.3390/scipharm86010009 www.mdpi.com/journal/scipharm Sci. Pharm. 2018, 86, 9 2 of 14 Sci. Pharm. 2018, 86, 9 2 of 14 1. Introduction Even a cursory review of reference works on drugs reveals the fact that in the arsenal of modern nonnon-narcotic-narcotic products products against against pain pain,, the the important important role role belongs belongs to tovarious various carboxylic carboxylic acids acids [1,2]. [1 ,In2]. accordanceIn accordance with with the the chemical chemical structure structure,, analg analgesicesic acids acids can can be be divided divided into into several several groups. groups. First First of all, it is, undoubtedly, derivatives of long long-known-known salicylic acid I (Figure 11).). AA separateseparate groupgroup isis derivatives ofof anthranilic anthranilic and and 2-aminonicotinic 2-aminonicotinic acids acidsII (X =II C (X and = N,C respectively)and N, respectively) that are structurally that are structcloseurally to salicylic close acid.to salicylic Especially acid. importantEspecially important and popular and analgesics popular analgesics were created were on created the basis on the of phenylaceticbasis of phenylacetic acid III. Furthermore,acid III. Furthermore, the most representativethe most representative group of analgesicsgroup of analgesics officially permitted officially permittedfor use is comprisedfor use is comprised of 2-phenylpropionic of 2-phenylpropionic acids IV .acids Derivatives IV. Derivatives of succinic of succinic acid (Fenbufen acid (FenbufenV and VSuxibuzone), and Suxibuzone), hetarylcarboxylic hetarylcarboxylic acid (Cinchophen, acid (Cinchophen, Etodolac and Etodolac clinically and important clinically drug important Ketorolac drugVI), Ketorolacand hetarylacetic VI), and acids hetarylaceticVII (Indometacin, acids VII Sulindac,(Indometacin, etc.) shouldSulindac, also etc. be) should mentioned. also be mentioned. Me R' R R COOH COOH COOH COOH O X NH R R I II III IV Acetylsalicylic acid Enfenamic acid Actarit Almiprofen 5-Bromosalicylic acid acetate Flufenamic acid Alclofenac Benoxaprofen Diflunisal Mefenamic acid Amfenac Bermoprofen Dipyrocetyl Tolfenamic acid Bromfenac Dexketoprofen Fosfosal Clonixin Diclofenac Fenoprofen Gentisic acid Flunixin Felbinac Flurbiprofen Narceine Fenclofenac Ibuprofen Salicylsulfuric acid Ibufenac Indoprofen Salsalate Ketoprofen Loxoprofen Naproxen Pranoprofen Suprofen COOH Clometacin X Indometacin R4 1 COOH COOH Y R Isofezolac N z Mofezolac O O Sulindac 3 2 V VI R R Zomepirac Fenbufen Ketorolac VII Figure 1. AnalgesicAnalgesic-acids-acids that are officially officially registered drugsdrugs [[11,,2].2]. These substances substances remain remain important important despite despite the the fact fact that that the thenegative negative impact impact of substances of substances with witha free acarboxyl free carboxyl group, group, first of first all, on of all,the gastrointestinal on the gastrointestinal tract, is tract,well known is well from known medical from practice. medical practice.However, However,the presence the of presence the acid offragment the acid (or fragment easily converted (or easily into converted it in vivo into) is often it in reflected vivo) is often very reflectedpositively veryon the positively biological on theproperties biological exhibited properties by exhibitedone or another by one molecule or another [3]. molecule Therefore, [3]. Therefore,carboxylic carboxylicacids are always acids areof particular always of interest particular for interestthe searc forh thefor new search promising for new promisingpain killers pain [4], killersand their [4], possible and their side possible effects side are effects eliminated are eliminated by subsequent by subsequent chemical chemical transformation transformation to labile to labilenon-acidic non-acidic groups groups or by the or by special the special conditions conditions of their of administration their administration [5]. [5]. Taking into account the the above, above, it it is is of of interes interestt to to study study the the structure structure and and biological biological properties properties of 6 of4-methyl 4-methyl-2,2-dioxo-1-2,2-dioxo-1H-2λH-2,1λ-benzothiazine6,1-benzothiazine-3-carboxylic-3-carboxylic acids acids IX. TheIX. Themain main prerequisites prerequisites for this for thisresearch research were were the expressed the expressed analgesic analgesic activity activity demonstrated demonstrated by their by their synthetic synthetic precursors precursors — 6 —methyl methyl-4-methyl-2,2-dioxo-1-4-methyl-2,2-dioxo-1H-2λH-2,1λ-benzothiazine6,1-benzothiazine-3-carboxylates-3-carboxylates VIIIVIII [6][ 6as] aswell well as as excellent results obtained during the transition from quinolone esters X, which are similar in terms of their structure, to acids XI [7] (Figure 2). Another incentive to study the behavior of 4-methyl-substituted benzothiazine esters VIII in alkaline hydrolysis conditions was a simple scientific curiosity: as is Sci. Pharm. 2018, 86, 9 3 of 14 results obtained during the transition from quinolone esters X, which are similar in terms XI Sci.of Pharm. their 2018 structure,, 86, 9 to acids [7] (Figure2). Another incentive to study the behavior3 of of 14 4-methyl-substituted benzothiazine esters VIII in alkaline hydrolysis conditions was a simple knownscientific [8], curiosity: the corresponding as is known acids [8], thecannot corresponding be obtained acids from cannottheir 4- behydroxy obtained analogs from theirXII since 4-hydroxy in the processanalogs XIIofsince the inir the processformation of, theirthey formation, are theyimmediately are immediately decarboxylated decarboxylated to 6 44-oxo-3,4-dihydro-1-oxo-3,4-dihydro-1H--22λλ6,1,1-benzothiazin-2,2-diones-benzothiazin-2,2-diones XIII.. Me O OH O OH O R' OMe OEt OMe S O S O N N O N O O R R R VIII X XII Me O OH O O R' OH OH S O S O N N O N O O R R R IX XI XIII Figure 2. ProbableProbable (IX (IX) )and and known known (XI (XI andand XIIIXIII) )hydrolysis hydrolysis products products of of esters esters of of 44-hydroxy-2-oxoquinoline--hydroxy-2-oxoquinoline-
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