CHEMICAL MODIFICATIONS OF 6-ALLYLSULFONYL-4-METHYL-1,2-DIHYDROQUINOLIN-2-ONE AS THE APPROACH FOR SEACHING NEW BIOLOGICALLY ACTIVE SUBSTANCES

To search biologically active substances among quinolone-2 sulfonyl derivatives the method for obtaining of the convenient intermediate, namely 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one, has been developed. The synthesis has been carried out by alkylation of the initial 4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfinic acid with allyl bromide in the acetonitrile medium and in the presence of potassium carbonate giving 73% yield of the product. The presence of the allyl fragment of 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one allowed to carry out addition reactions with some C-, N- and O-nucleophiles. Addition to allyl sulfones occurs in accordance with Markovnikov’s rule despite of the strong electron withdrawing effect of the sulfonyl group. The reaction of 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one with active methylene compounds has been carried out with diethyl malonate and ethyl cyanoacetate by refluxing in absolute ethanol in the presence of sodium ethoxide. As a result, 2-R-3-methyl-4-(4-methyl-2-оxo-1,2-dihydroquinoline-6-sulfonyl)butanoic acid ethyl esters have been obtained with 73-79% yields. 6-(2-Alkylaminopropylsulfonyl)-4-methyl-1,2-dihydroquinoline-2-ones are formed under the action of N-nucleophilic reagents, in particular primary aliphatic amines, on 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one. This reaction takes place upon heating in dimethylformamide up to 50-60 o C for 6 hours, the yields of the products are 35-40%.

According to the recent literature data, most of the studies is devoted to aryl sulfones, while heteryl sulfones have not been investigated so intensively. Nevetheless, some compounds of this class with the antimicrobial [8], antiviral [9,11], antimalarial [5], anti-inflammatory and analgesic [10,12,13], antitumor [6] action have already been found. Therefore, sulfones is a promising class for study in order to develop medicinal substances. Continuing the research of 1,2-dihydroquinoline-2-one derivatives [2] that are carried out in the National University of Pharmacy a number of new potential biologically active substances in the range of 6-sulfonyl derivatives of 4-methyl-1,2-dihydroquinoline-2-one have been obtained by the reaction of nucleophilic addition to 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one.

Materials and Methods
Methods of organic synthesis were used for obtaining new compounds. The structures of the compounds synthesized were proven by the methods of 1 H NMR spectroscopy and mass spectrometry. 1 H NMR spectra were recorded on a Varian Mercury VX-200 in DMSO-D 6 solution, the operating frequency was 200 MHz, the internal standard -TMS. Mass spectra were recorded on a Varian 1200L, the ionizing voltage was 70 eV. Melting points were measured by a Koffler device.
Compound 2 was used for further chemical modifications due to the presence of the allyl fragment. It is known that despite of the strong electron withdrawing effect of the sulfonyl group addition of nucleophiles to allyl sulfones occurs in accordance with Markovnikov's rule [3]. And the products of this reaction are interesting objects of studying from the pharmacological point of view [4]. Therefore, to continue the search of biologically active compounds in the range of sulfonyl derivatives of 4-methyl-1,2-dihydroquinoline-2-one the addition reactions of some nucleophilic reagents to allyl sulfone 2 were carried out. Several active methylene compounds, alkylamines, as well as sodium hydroxide were selected for these reactions (Scheme).
6-(2-Alkylaminopropylsulfonyl)-4-methyl-1,2-dihydroquinoline-2-ones (4a,b) were synthesized by addition of the primary aliphatic amines to compound 2. The process was performed in DMFA for 6h when heating up to 50-60 o C. The compounds 4a,b obtained can be considered as promising objects for studying their effects on energy processes in the body because of the fragment of 2-aminoethanesulfonic acid (NH 2 -(CH 2 ) 2 -SO 3 H) known as taurine that has diverse physiological effects [5].
As it was shown in our previous work [1], heating of allyl sulfone 2 in aqueous alkaline solutions caused cleavage of the C-S bond. And sodium salt of 4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfinic acid was obtained as the product. Thus, conditions of hydration of the double bond of 6-allylsulfonyl-4-methyl-1,2-dihydroquinoline-2-one (2) were investigated. It has been found that β-hydroxy derivative, namely 6-(2-hydroxy propylsulfonyl)- Compounds 3a,b, 4a,b and 5 are white crystalline substances, soluble in polar organic solvents, insoluble in water. Data of 1 H NMR spectroscopy and mass spectrometry of the compounds obtained are presented in Tab. 2.
2. To obtain new biologically active substances in the range of sulfonyl derivatives of quinolone-2 the conditions of the reactions of 6-allylsulfonyl-4-methyl-1,2dihydroquinoline-2-one with some of C-, N-and O-nucleophilic reagents have been investigated and the corresponding products of addition to the allyl fragment have been obtained.
3. The chemical transformations described can be considered as a convenient way to modify and diversify sulfonyl derivatives of 1,2-dihydroquinoline-2-one.