Synthesis of Esters of 6-(2,5-Dioxopyrrolidin-1-yl)-2- - PDF document

[c010] Synthesis of Esters of 6-(2,5-Dioxopyrrolidin-1-yl)-2- (morpholin-4-yl)hexanoic Acid as Potential Transdermal Penetration Enhancers Katerina Brychtova 1 *, Sylva Dittrichova 1 , Barbora Slaba 1,2 , Lukas Placek 1,2 , Radka Opatrilova 1 , Josef Jampilek 1,2 , Jozef Csollei 1 1 Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1/3, 61242 Brno, Czech Republic; e-mail: brychtovak@vfu.cz , tel: +420-5-41562924 2 Zentiva a.s., U kabelovny 130, 102 37 Prague 10, Czech Republic * Authors to whom correspondence should be addressed. Abstract: Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of 6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl)hexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The general synthetic approach of all newly synthesized compounds is presented. Structure confirmation of all generated compounds was accomplished by IR, 1 H, 13 C NMR and HR-MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (log k ) was determined. Keywords: Transdermal penetration enhancers; 6-Aminohexanoic acid derivatives; Lipophilicity. INTRODUCTION Transdermal penetration enhancers (also called sorption promoters or accelerants) are special pharmaceutical excipients that interact with skin components to increase the penetration of drugs from topical dosage forms to blood circulation. Numerous compounds (with different chemical structures) have been evaluated as penetration enhancers and a number of potential sites and modes of action were identified [1,2]. Some of the important penetration enhancers, as classified by Sinha and Kaur [3], are terpenes and terpenoids, pyrrolidinones, fatty acids and esters, sulfoxides, alcohols and glycerides and miscellaneous enhancers including phospholipids, cyclodextrin complexes, amino acid derivatives, lipid synthesis inhibitors, clofibric acid, dodecyl- N , N- dimethylamino acetate and enzymes. This is a follow-up paper to our previous articles [4-6] dealing with a multistep synthesis of seven alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl)hexanoates with C 6 –C 12 linear alkyl ester chains. Lipophilicity (log k ) of the compounds was determined using RP-HPLC. 1

RESULTS AND DISCUSSION The starting material ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate ( 2 ) was prepared by multistep synthesis from 6-aminohexanoic acid. This amino acid was condensed with succinic anhydride to obtain succinimide intermediate 1 , which was then transformed by means of one-pot synthesis under the optimized Schwenk and Papa procedure conditions [7,8] to α -bromocarboxylate 2 . The synthesis route is shown in Scheme 1 and was reported recently [4,5]. The problems associated with the generation of α -bromocarboxyl compounds were reported by Brychtova et al. [5]. Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl) hexanoate ( 3 ) was obtained by reaction of α -bromocarboxylate 2 and morpholine. The problems associated with this C-N coupling reaction were reported by Brychtova et al. [6]. The series of seven targeted alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl)hexanoates ( 4a-g ) was formed by conventional base-catalyzed transesterification [9] of the key intermediate 3 in the excess of corresponding primary unbranched alcohol. Scheme 1. Synthesis of target esters 4a - 4g : (a) acetone, 25 °C, 24h; (b) one pot synthesis: SOCl 2 , Br 2 , EtOH; (c) toluene, reflux, 5h; (d) Na, R-OH. Br O O O a b N COOH N COOC 2 H 5 COOH + O H 2 N O 1 O 2 O O c N H O O R = -C 6 H 13 ( 4a ) -C 7 H 15 ( 4b ) -C 8 H 17 ( 4c ) N N O O -C 9 H 19 ( 4d ) -C 10 H 21 ( 4e ) d N COOR N COOC 2 H 5 -C 11 H 23 ( 4f ) -C 12 H 25 ( 4g ) O 4a-g O 3 Hydrophobicities (log P /Clog P values) of the studied compounds 3 , 4a - 4g were calculated using two commercially available programmes (ChemOffice Ultra and ACD/ChemSketch) and measured by means of RP-HPLC determination of capacity factors k with subsequent calculation of log k . The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using end-capped non-polar C 18 stationary RP column. The results are shown in Table 1 and illustrated in Figure 1. Table 1. Comparison of calculated lipophilicities (log P /Clog P ) with determined log k values. log P /Clog P log P Comp. log k ChemOffice ACD/ChemSketch 3 –0.7951 –0.20 / 0.550 0.34 ± 0.54 4a –0.0736 1.54 / 2.666 2.47 ± 0.54 4b 0.0934 1.95 / 3.195 3.00 ± 0.54 4c 0.2613 2.37 / 3.724 3.53 ± 0.54 4d 0.4177 2.79 / 4.253 4.06 ± 0.54 4e 0.5834 3.21 / 4.782 4.59 ± 0.54 4f 0.7588 3.62 / 5.311 5.13 ± 0.54 4g 0.9221 4.04 / 5.840 5.66 ± 0.54 2

As expected, ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl)hexanoate ( 3 ) showed the lowest lipophilicity, whereas dodecyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl) hexanoate ( 4g ) possessed the highest lipophilicity. It can be assumed, that the calculated log P /Clog P data and the determined log k values correspond to the expected lipophilicity increasing within the series of the evaluated compounds (ethyl <<< hexyl < heptyl < nonyl < decyl < undecyl < dodecyl derivatives). As expected, the dependence of log k on the length of the unbranched alkyl chain is linear (r = 0.9994, n = 8). Log k data specify lipophilicity within this series of the discussed compounds. Figure 1. Comparison of the log P /Clog P values computed using two the programs with the calculated log k values. Compounds 3 and 4a - g are ordered according to the increase in log k values. 6.0 5.0 4.0 Lipophilicity 3.0 2.0 1.0 0.0 3 4a 4b 4c 4d 4e 4f 4g -1.0 Compounds log k log P [ChemOffice] Clog P [ChemOffice] log P [ACD/ChemSketch] EXPERIMENTAL General All reagents were purchased from Sigma-Aldrich (Schnelldorf, Germany) or Merck (Darmstadt, Germany). Kieselgel 60, 0.040-0.063 mm (Merck) was used for column chromatography. TLC experiments were performed on alumina-backed silica gel 40 F 254 plates (Merck, Darmstadt, Germany). The plates were illuminated under UV (254 nm) and evaluated in iodine vapour. The melting points were determined on a Mikro-Heiztisch System PolyTherm A apparatus (Wagner & Munz, Munich and Hund, Wetzlar, Germany) and are uncorrected. Infrared (IR) spectra were recorded on a Smart MIRacle™ ATR ZnSe for Nicolet™ 6700 FT-IR Spectrometer (Nicolet - Thermo Scientific, U.S.A.). The spectra were obtained by accumulation of 256 scans with 2 cm -1 resolution in the 4000-600 cm -1 region. All 1 H and 13 C NMR spectra were recorded on a Bruker Avance-500 FT-NMR spectrometer (500 MHz for 1 H and 125 MHz for 13 C, Bruker Comp., Karlsruhe, Germany). Chemical shifts are reported in ppm ( δ ) to internal Si(CH 3 ) 4 , when diffused easily exchangeable signals are omitted. Mass spectra were measured using the LTQ Orbitrap Hybrid Mass Spectrometer (Thermo Electron Corporation, U.S.A.) with direct injection into APCI source (400 °C) in the positive mode. 3