bw ‘ORIGINAL ARTICLES Faculty of Pharmacy and Biochemistry’, University of Zagreb, Zagreb, Croatia, and CENQAM®, Faculty of Pharmacy, Univer- sity of Potchefstroom, Potchefstroom, South Arica Gemfibrozil ester and amide derivatives — synthesis, spectroscopic charac- terisation and QSPR M, Lovnek!, M, Jabruevié-MLaban Taxa, B. Zon! and B. Bowescuans? ‘The synthesis and spectroscopic characterisation of various gemiibrozil esters 3 and amides 4 are described. In the first step gemfibrozil was reacted with -L-benzotriazolecarboxylic acid chloride (1) yielding gemfibrozil benzotriazolide (2). ‘Compound 2 readily reacted with alcohols and amines to form the corresponding esters 3 and ami ss 4, potential pro- drugs of the well known hypolipaemic drug gemfibrozil, The quantitative structure property relationship (QSPR) was studied in the series of gemfibrozil esters and amides. ‘The following topological descriptors and physicochemical para- met and parameters of lipophilicity (log P and Ry) 1, Introduction Investigation of lipid regulating agents and their use are constantly progressing since they reduce elevated lipid concentrations, a major risk factor for the development of atherosclerosis and ischaemic heart disease. The first-line ‘reatment for hyperlipidaemia is dietary modification com- bined with reduction of other risk factors such as smok- ing, lack of physical exercise and alcool intake [1]. Lipid regulating agents are used as an adjuvant (© these: modi cations. Gemfibrozil_(5-(2,5-dimethylphenoxy)-2,2-di methylpentanoic acid) is a drug of choice in the treatment of moderate to severe hyperlipoproteinaemia. It reduces, tiglycerides and very-low-densily lipoproteins and i creases high-density lipoproteins [2—3]. Gemfibrozil is. a clofibrate analogue with a rather short plasma half-life (about 1.5 h), so repeated doses must be given to maintain, a therapeutic effect [4]. In order to modify its pharmacoki- neties and bioavailability a number of gemfibrozil deriva- tives such as aliphatic and aromatic esters, benzamides, nicotinic acid and 3-cthoxy, acetoxy or hydroxyl deriva- lives have been synthesised [5-12]. Some of them have shown hypolipaemic activity in preliminary pharmacologi- cal evaluations (5, 8, 10} Scheme ‘were used: Wiener number (W), connectivity index (17°), relative molecular mass (i), van der Waals volume (Vs) Gemfibrozil and related compounds have also been the subject of several QSAR investigations [13-15], Craiger et al. studied the effect of structure modifications in gem fibrozil series (diferent chain spacing between phenoxy and carboxylic group, variations in substituents on the aro- matie part and changes in carboxylic moiety) on biolosi- cal activity [13]. QSAR analyses of @ number of hypoli- paemic drugs of diverse chemical structures. including gemfibrozil and other fibrate analogues, revealed a correla- tion between molecular connectivity index () and phar- rmacological properties (14, 15]. It was demonstrated that this index could be used for the predietion of protein bind- ing, reduction of total cholesterol and LD3y in rats, for a _rroup of hypolipaemic drug eandidates. The present paper reports a synthesis and spectroscopic characterisation of gemfibrozil esters and amides. A QSPR study involving their calculated topological indices and Physicochemical properties was also carried out 2. Investigations, results and discussion, ‘Anew and convenient method of gemfibrozil esters 3 and, amides 4 preparation has been developed. In the first step cH Gem ~ gordo [BUT — Benziravole TEA oy Hs © Cr Orca = CO-N” a 2 ROH] pu |B ROH) part NH) Bel ih oh hy (CH) s6-COOR -O(CH,)30—CONHR i Hs as ony Beg 4d Pharmazie $5 (2000) 11 suORIGINAL ARTICLES Table 4: Resetion conditions of synthesis and IR data of esters 3 cor a oe a OCH Rr 21 739 3047, 2976, 2872, 1728, 1615, 1585, 1509, 1473, 1388, 1264, 1192,'1146, 1131, 1048, 863 3b CHC RP +reflox 402.5 396 3024, 2954, 2925, 2871, 1732, 1615, 1586, 1509, 1472, 1389, 1310,'1265, 1197, 1147, 1130, 1049, 999, 803 Be CHYCH): RD+reflux 6246 6853044, 3013, 2970, 2864, 1725, 1615, 1585, 1509, 1472, 1302, 1264, 1192, 1130, 1048, 999, 803 3d CHyCHE)s RT + reflux" 240426 32.7 3044, 3013, 2950, 2872, 2360, 2330, 1727, 1614, 1585, 1509, 1471, 1414, 1389, 1264, 1047, 946, 803 se CHYCH RE + reflux’ 34412 539 3042, OPI, 2956, 2869, 1725, 1614, 1585, 1509, 1471 1389, 1264, 1192, 1047, 998, 803 Bf (CHy,CH RT + reflux 192416 37.9 3047, 3024, 2078, 2026, 2864, 1724, 1615, 1586, 1510, 1472, 1414, 1380, 1310, 1265. 1195, 1/57, 1108, 1048, 999, 802 3€ — CHa=C(CH)CH,-RT+reflux' G48 $1.0 3083, 3046, 3023, 2925, 2867, 1730, 1659, 1615, 1585, 1509, 1473, 1390, 1310, 1265, 1190, 1130, 1049, 994, 803, gemfibrozil was reacted with N-I-benzotriazolecarboxylic acid chloride (1) giving gemfibrozil benzottiazolide (2). ‘The reaction proceeded via a mixed anhydride, which dec- arboxylated to compound 2, ‘The henzotriazole activated gemfibrozil 2 readily reacted with nucleophiles such as alcohols and amines giving the corresponding esters 3 and amides 4 (Scheme) terification reactions were performed at elevated tem- perature in the presence of triethylamine (TEA) which ac- celerated the reactions. Amines, as stronger nucleophiles, react with benzotriazolide 2 more easily, therefore the ami dation reactions were performed at room temperature. The following gemfibrozil derivatives were synthesised: methyl Ga), ethyl Gb), propyl Ge), butyl (34), pentyl Be), iso- propyl (3f) anc! methallyl (3g) esters and benzyl (4a), phe- nylethyl (4b), cyclohexyl (4e) and 2hydroxyethyl (4d) amides, Spectral analyses. of all compounds synthesised ‘were consistent with the assigned structures. The IR spec- trum of 2 showed a carbonyl band at 1720 em! which is characteristic of reactive N-acyl azoles [16]. The carbonyl group in esters had absorption maximum at 1724— 1732 em"! and in amides at’ 1632-1642 em~! (amide 1) and 1584-1586 cm” (amide 1. Reaction conditions, and physical and IR spectroscopic data for compounds 3 and 4 are given in Tables | and 4. 'H NMR chemical shifts (® pm), coupling constants (J in Hz) and assignments are ‘aiven in Tables 2 and 5 and °C NMR chemical shifts and assignments in Tables 3 and 6. Some of the compounds from series 3, e.g. the methyl, ethyl and isopropyl esters, have previously been synthesised by other methods and described in the literature without detailed spectroscopic characterisation [6]. That is why their spectroscopic data are reported here together with the data for new com- pounds. In the QSPR study, the following topological indices and Physicochemical descriptors of gemfibrozil derivatives 3 land 4 were used: Wiener number (W), the first order va lence connectivity index ('7°), relative molecular mass (Mo), van dec Waals volume (Vs), and parameters of lipo- philicity log P and Rus obtained using f constants and the ‘TLC retention factor Ry, respectively (Table 7). To deter- mine the relationship between topological indices and physicochemical properties @ multiple regression analysis ‘was performed. A significant linear relationship between topological indices (Wor 'y") and physicochemical 812 Parameters (My Vio log P or Ry) was obtained for the series of gemfibrozil and its esters (0.9753 < r < 0,9990, P< 0.05, n=8, while the experimental parameter of lipo~ Philicty, Ry, correlated well both with the topological in- dices (W and '") and log P only in the homologue series, methyl to pentyl gemfibrozil esters (Bae) (0.9962 an extated thee tines with Wate. The organic layer as ded (No,S0q),iered an! evaporate under ‘ediced pressure. The ely product 2 obained slowly crystallised. Viel 11.590 (89.2%). Mp. 50—52°C. IR (KBr, em 3108, 308, 30. 302, 2924, 2871, 1721, 1614, 1886, 150, 1483, 1450, 144, 139, 1347, 1308, 1285, 1268, 1157, 1130, 1085, (0(3, 951, $69, 84, 783, 1H NMI (CDCR), 6, pom: 831d, TH, I= 82, HITE 8.12 UG, TH, J= 82, He 20);7.65 TH, = 7.9, He) 780 (1H, J= 77, HI, 696 (4, 1H J=74, HeiD): 661 (i 1H, J=74, HAlDy SK is) 1H Hela), 388 2H, J~ 63, 1-7), 238-231 (m, 2H, HS}, 225 (3 3H, HIS) 216 3H 1.18); 181-171 (m 2H, HO 1.666, 61, HE) CaiadOs Pharmazie 5$ (2000) 11ORIGINAL ARTICLES 9) HE 1050 oc HES SET iH ork Hew zeT-seT wo Hz 8? 16° Pu 86°F 9 HE F60 srw HOP OCT mera eager io) co HEWES I-91 He M95 T-$9"1 neta aneen «9 9) 9) co ts peony HZ 6rr HI 66'>-01's Hz so Hz) 90% a1 z0F Hebb Hes ove ue yraw 21= HES 087, Hes ECz HES 0€7 HES fz He Soft HESECT HES 6ce He s0¢¢ HES Cz, He $022 He Suz HES ire Hes rz Hesoce | He Sale Hes 407 HIS 099 HIS £99 HIS 099 HIS 099 HIS 099 HISE99 HIS 659 HI S099 wo wo wo OD wo wo wD oD HIP S99 HIP 199 HIP 299. HIP S99 HIP S99 HIPS99 HIP 199 HIP s99 on GD cD wo wD oo wo wo HIP 669 HIP Zod HIP 6% HIP 669 HIP 669 HIPEOL — HIP 69 HIP 669. co) ) (9) wr ro) HZ 6 Hz 196 Hose HS 16 Hev ies Heine HES ose Hee Hessel WPM CLI-PET Hew ZL I-ecT HPSZEL | HPWZL TEL HPSSCT HF Hp WEL 48 HOS SCL HOS 9 HOS H9S IZ HOS 71 HOStCT HOS IZT HOS SCI a © = a * © = 0 ig 9— a) 4-059 9-tHO—THD—"HO-O- 4 (wid) ¢ “wonmIOs FAD UF HOYEI ¢ $1049 JO EHUD AIN Hy rae. 813 Pharmazie 55 (2000) 11ORIGINAL ARTICLES ‘Table PC NMI data of esters 3 taken in CDCl solution, 8 (ppm) wf dino of ontn-by-tn Ene O-R 2 cH, cH ¢ 4 Een, ct bu, EH, C, Ci, a on > ie a i a a i849 1788217784 1T72.90 177.86. 17.85 17301746 4179 41814173 aT 80 4181 4182 41654199 274 88 2491 4.95 2491 2491 2U88 24.95 3606 36.84 3687 36.98 307 30.87 36N6 3693, RAST 24882499 24.99 2498 36.87 2499 2498 6173 67.60 67756798 61.70 6174 oral 6775, C8 15694 156.88 15694 156.96 15691 15691 15696 156.94 C9 sh 1238.40 12350 13:81 123.45 123.50, 12381 123:53 C10 13026 13017 1302213023 130.18 10.18 13022 13025 Cl 2065 12054 12059 120.60 12054 12056 12057 12062 Gi2 13643 1363013638 136.40 136.32 130.34 13638 136.0 Cis ss 11075 nee TL Bs 176 rs. TLA2 T118e Ci 1853 Sak 1548 158.50 15.45 Iss 15501551 Cis 219 208 2d a6 QUA 21.09 2013 21.16 C16 S143 6012 65.80. 6401 6431 6117 67.46 cir 1395 21.79 30.1 2s.08 2148 140.10 cis 0.19 18.90 2202 2r48 112.52 C19 Bar 2385 19.26 20 1367 32.2, Symes of series 3 A solution of 2 (0.381, 0.001 ot) and TEA (0405 g, 0.004 mol) in the ‘conesponding alsbol (5-10 mi) o aleoholRoiene entre as sted oom temperate or rllxed unt the stating compound 2 csappened (TLC conto). The wacion mixture was evipomted under reduced pres Sune and ehromtorapted on preparative TLC. pate (mobile phase: hex aretacetone 7:1). The il product 34-g were separted 36 pare com pounds. The deiled resction condtions and ansytcal dita for 3 ere given in Tables 1-3, 32.3, Symes of snes & Method A: A solution of 2 (0.250 g, 0.0007 nol) in wolvene (10m) was od! dropwise toa solution of 0.005 mo} ofthe comespending amin in Table: Reaction conditions of synthesis and IR data of amides 4 toluene (IO ml). The action mistwe vas sined for 25-3 hat rom temperature, extracted several tines with ilate HCI (0 remove beat ‘le and excess amine) and then with wate. The organic Iyer was died (Godium sulphate Teo! and vapor under rced. pest. The fade product obtsined was rerytlse from ethanol (48 and 4) or hromatogrphed on a preparative TLC plate tmobile phase: chloroform! ‘methanol 191) (4). “Method B: A solution of 2 (0250 g, 0.007 mal) in acti (Smit) wes ‘Met dropwise tot sation of ethanoimine (0.128 f. 00021 mol) cto (1m). Tho escon mature nas sted for 1-3 a oo te erature al evaporsed under reduced pestire. The cae reside ob tuned was washed with water. CC th beanefgetone (1) a he eluent The reaction conditions and analieal dats for compounds are given in Tables 6, Comp ‘Save Tie Yel Mp THB Ys owe tr 4a GSC; toluene: 3 306 119-122 3339, 3034, 2963, 2928, 2870, 1642, 1584, 1537, 1510, 1457, 1416, 1396, 1363, 1253, 1224, 1158, 1130, 1088, 1033, 1016, 937, 858, 807, 733, 693, 587, 513 4b CgEKCHRCH, toluene 3 282 oll 3850, 3027, 2952, 2925, 2857, 1639, 1586, 1530, 1510, 1476, 1455, 1414, 1391, 1356, 1285, 1265, 1226, 1157, 1130, 1041, 1000, 844, 804,748, 700° fe Coty toluene 25 1A BB-9L_——_-3BIT, 3256, 3044, 2972, 2935, 2855, 1632, 1586, 1536, 1SL1, 1475, 1454, 1413, 1394, 1302, 1268, 1218, 1157, 1130, 1094; 1049, 096, 889, 866, 803, 664, 586 4d HOCIDCH; —acetonitle 1567.3. -93-9G 310, 2953, 2924, 2853, 16¥4, I5RS, 1545, 1512, 1482, 1454, 1399, 1365, 1288, 1250, 1227, 1212, 1157, 1133, 1038, 998, 947, 902, 820, 756, 706, 613, 591, 540 Taw 814 Pharmazie $5 (2000) 11ORIGINAL ARTICLES ‘Table 5: "HNMR dat of amides 4 taken in CDCIy* or DMSO-1? solution, 5 (ppm) Ianto tn fe Y0- Cat, briy EHC En cit, a rm . ts du 8-Sn e = = * ina "ata Tasso “ea Tjosan as Lacan ret toot Uses at a soe att acai yoo sana én 1410 ob a rain 964 1H soram Gay as) 6 G3 1 sa eb a oto ‘ood oa os as 63) ma ut ken Gb Go ti oiesan Soc os 3 S09 sai this Moca son Da Daca thle SoH ier train patil 49) 8) (5.4) ar diem 3am 3a 33.11 mau ns pra 241-3. m2 aa v9 stun Liam on a) ii 7at-n24mst nat ea 730-215 am os 1k ‘Table 6: "C NMR data of amides 4 taken in CDCI" or DMSO-d," solution, 5 (ppm) co = = © we a 739 Tras visa 7701 & He tts atte He Ga aa ass ser a6 © be ins mat ros © ast ie ato ae ¢ an on ons ast ¢ sea sea Sor Soa € tao inn tants iam Go roa tia raze toa en rapes iano ran ime ch Tinat re tie Tinos chs rinos nat maa maa ci 133 Bat Ka 15a ets ait aio ie aie ctr al ‘as: ae iis ets hess ssa aa sons es xs Le So ro inks ca tro waka? cH to tas cH tikes iaear a rasan Pharmazie $5 (2000) 11 BisORIGINAL ARTICLES ‘Table 7: Topological and physicochemical descriptors used in QSPR study of compounds 3 and 4 on Foul © ™ % er we Semi Gen Cistx0 08 6262 25032 152.69 4612 0212 Se Cas 37 easi 26634 vik 5106 asi By Chthx0> 1070 7238 837 205 3530 “0501 Es Citin0 133 1338 29239 18228 6.068 “0575 x Coto, 147 8238 30602 19251 659 “0.630 3e Codiuos i623 8738 saps 20274 7126 “0.889 x Ciatli0) 1215 1633 2929 182.27 S43 “0.2 Se Coto 1419 1938 sous 189.00, ean 0575 ri CiHNOs 2071 S353 irrao 20880 $302 0176 4 ChthiNO: 2348 083 $5850 26087 5832 01% « CiHhyNOs i739 9183 3189 20633 37 ° 4a CHO; 1333 7108 29340 18123 2455 0907 fe ChiiaNO; 1233 1197 29242 183.73 2518 ‘nln Sy we pov Se 23, OSPR sy Referees Wicor nunc, W, «tpn index whic sper 0 bea comeneat 1 Muscle, Dered H: DrugActins, Basi sine and Ths Ines of he congue the ok eden nance am agen Aspe p34, Medpim Seem Pls, Stiga tnt dtd che aso ol teenth ance mae Ds OS a 2 Mile, DB Spence. 3D: Cink. Pumacon 34 1551998) LES oy 5 Aber, Fi Appt; Bese, Eno, Ms Ange, Bi whore Ds represents ofigonal elements of, the sum of he fest di lances between the observed verter and all other vertices presenti the eph a single bond is counted one a double ond 35 two, ab pe trond a thre divans (1820), The firs oder valence connestity inde, is defined as v= Eeosar whore AG) and 5G) are weights (valence deta values of veties (atoms) andj making up the Tj edge bond) in a vertexwelghted graph (ht ‘vaio syste) Gy (21-22). Valence dla values are ven by 8) = (2 — MYM —25 1) whore ZY stands forthe numberof valence eletons inthe stom ,Z isis monic number, and H,& the numberof hydrogen atoms ached 10 an dee Waals volume, V, (en mol, was obtained by summing van der Waals group inerements foreach group cootaned in He molecular seve ture [23]. The following ghoup Increments were Used: 13.67 (CH), 2390 (-Coll), MIS (-Culh), 3.12 (-CHICHB), 1023 (CH), 3067 (.C(CH)-), 11.94 [=CH), $01 C2), 805 (CH an) and 5.54 (CR~ a, a), 45.84 (Call), 11.70 (2C0 ap, 152 (-0-CO~ aly a) 804 (OH a, at), 37 (=0~ ab), 32 (-0~ ac}, 678 CH), 47 (CH=), 80s (NH), 1.54 (NH) an S68 (ey Cally A lipophilic pacameter tog P as obtained using hitmphobic fragment, onslansf ekke's constant) [23, 24] It is definod by the fallowing equation ogP = Eas where f represents lipopile contbuton of the structure fregment 1 the Toul lipophcy, and’ ait factor which defines an appsuranos ofeach fragment n chemical stucre "The folowing feonsans Were used: 1431 (CGH, 0702 CCH), 0433. (-O- ee), 0830 (CH), 0200 (C2), ~0.984 (COOH), 1.292 (COO a), 0235 (—CHe}, 0935, (CECH, 271 (CONH. 1885 (GH, L491 (OH a) and =1428 (NH, a). A lipophilic paraeter Ry is expressed as Ry = log (1/R = 1) Juhere Ry isthe tention fator aban by TLE. “The calculated topological deserters snd physicochemical parameters ate sven in Table 7. ‘Acknowledgements: We thank Professir van Botulaforvalable discus: Sons. Genco financial support of the Ministy of Science and Tech nology of the Republic of Croatia is highly apprised (Gat nue 006285), 816 Hisonahl, Dalle, Gy Bur. 2. Cline lavest 28,238 (1998) 4 Matindsle, The Extra Pharmacopeea, 31. Ed, p. 1308, The Pharma ‘tial Press, Lanon 1996 5 Larmelle, C+ Lepant Mo PTC bt. Appl WO 91 07,378, 30 May 1991: CA. 115, 1141668 (1991) {6 Zhong, P: Vin, C: Bejing Shifan Daxwe Xuebso, Zan Kexeban 28, 379 (1902), CA. 120, 2447700 (1994) Peco, Gz Taguni, A; Frate, Ge PTC Int Appl. WO 94 27.918, 08 Dee 1994, C.A. 122, L6027le (1985) Sica L; Holnwstef A US. Pa US 4413011, 01 Nov 1983; CA. 100, 854306 (1984) 9 Hocils, ML: U.S. Pal US 4285 203763) (1981) 10 Wang, H, Ps Lee, Og Fan CT US. Pat, US 5,530,145, 25 Jun 106: CA, 138, 1422770 (1996) 11 De Cock, Bs Van Brussel, W: Mongescows, A: Bur. Pat Appl. EP 515,308, 22 Dee 199% CA. 120, 163704 (1994) 12 Zhong, Z: Yang, QZ: Huatue Shi 18, 253 (1996), CA. 125, 328224 (1996) 19 Chege, P-L; Moench, G. Wi; Nekls, W. As Pre. Roy. Soe. Med 69 appl 2,3 (1976) 14 Cerméede-Pozo, R. A: Pérer-Ginéner, F Galver-Alvave, 1 Sto beet Salvadr, MT; Gace Marl, F-1; Anén-Fes, GML J. Pham Phanmacl. 48, 240 (1998) 15 Salaert Salvador, M, TL: Cero} Pooo, R.A. Rérer-Ginne, F Galvez-Alvare, 1; GaclrMarch, F. Js Antin Fo, @, M; Soler Recs, RM Ars Pharm 33,1086 (1992) 16 Sia. HA Chun. Ber 99, 19271836}, 9, 1320 (1987) 17 Proteik, M, Ws Vela, Vs Buta, L> Croat, Chem, Acta 49, 883 7) 18 Wiener: J. Aim Chem, Soe. 69,7, 2646 (847) 19 Hosays, He: Bll. Chem, Soo. pn. 44, 2332 (1971) 20 Tiinajai, Ni Choma! Grp Theory, 2 El, CRC Press, Hoss Rs von 1982 21 Rand, Ms J. Am. Chem. Sos. 97, 6609 (1975) 22 Koet, LB Hall L. HJ Pharm. Si 68,1806 (1975) 23 Seydel J. K: Scher KJ: Chemische Stuktur und Bologische At vit von Winstofen ~ Methoden der Quantaven StukturWikung- Analyse, Verag Chemie, Weinhcin 17 24 Nys, GG: Rether KF Eat J led. Chem. 9, 361 (1974) 25 Lovick, My Zor B.; Boneschas, B; Bul, 1: It J, Pharm, 200, s0.2000) 1, 28. Aug 1981; CA. 95, Received November 29, 1999 Pf. Ds. Banka Zone ‘Accepted Feb, 2000 Faulty of Pharmacy and Biochemistry A Kova | 100 Zags Coun enka zre@ nana phere Pharmazie 35 (2000) 11