Arch. Pharm. Chem. Life Sci. 2007, 340, 367 – 371 L. Popescu et al. 367

Short Communication

Quinoline-Based Derivatives of Pirinixic Acid as Dual PPAR a/cAgonists

Laura Popescu1, Oliver Rau1, Jark B�ttcher2, Yvonne Syha1, and Manfred Schubert-Zsilavecz1

1 Johann Wolfgang Goethe University Frankfurt, Institute of Pharmaceutical Chemistry/ZAFES, Frankfurt,Germany

2 Philipps-University Marburg, Institute of Pharmaceutical Chemistry, Marburg, Germany

Pirinixic acid is known for its peroxisome proliferator-activated receptor (PPAR) agonistic action.In a recent publication, we have shown that aliphatic a-substitution of pirinixic acid enhancesboth PPARa and PPARc agonism. The goal of this study was to evaluate, whether the PPAR ago-nism of pirinixic acid may be also maintained in quinoline-based derivatives. The present studyrevealed that the mere substitution of the dimethyl aniline moiety of pirinixic acid by quinolineleads to a total loss of PPARa/c agonism, whereas concomitant a-substitution with n-butyl orn-hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARa/c ago-nists. In the following we report the synthesis of quinoline-based derivatives of pirinixic acid,which in a Gal4-based luciferase-reporter gene assay proved to be potent dual PPARa/c agonists.Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that oftesaglitazar.

Keywords: Peroxisome proliferator-activated receptor / Pirinixic acid / PPARa/c dual agonist /

Received: March 1, 2007; accepted: Arpil 27, 2007

DOI 10.1002/ardp.200700042

Introduction

Peroxisome proliferator-activated receptors (PPARs)comprise a three-member subgroup (a, c and b/d) withinthe nuclear hormone receptor family of ligand-activatedtranscription factors that have been the focus of exten-sive research during the past decade [1, 2]. Being acti-vated by the fibrate and glitazone types of drugs, PPARa

and PPARc are among the major targets for the treat-ment of dyslipidemia and type 2 diabetes. Dual PPARa/cagonists are currently under investigation for the com-bined treatment of both diseases, which, furthermore,are frequently associated. In addition, PPAR is gaining

more and more evidence to be an anti-inflammatory tar-get [3–7].

Pirinixic acid (WY-14643), which is a common researchtool for PPARa, was developed in the 1970s as an antihy-percholesterolemic agent [8] and was found to be a perox-isome proliferator [9], whereas the target of pirinixicacid, the peroxisome proliferator activated receptor(PPAR), was discovered in 1990 [10], which led to the dis-covery of the PPARa and the less known PPARc agonismof pirinixic acid [2, 11]. In a recent publication, wereported the structural optimisation of the pirinixic leadby a-alkylation (R1), which enhanced both PPARa andPPARc agonism [Rau, Syha et al. manuscript in revision].In this study, we were interested whether PPAR agonismof pirinixic acid can be enhanced with quinoline basedderivatives. We report the synthesis of quinoline-substi-tuted pirinixic acid derivatives in which the concomitantsubstitution of the a-position with n-butyl or n-hexylgroups leads to potent dual PPARa/c agonists andrestores the PPAR activity, which got totally lost uponquinoline substitution alone.

Correspondence: Prof. Manfred Schubert-Zsilavecz, Johann WolfgangGoethe University Frankfurt, Institute of Pharmaceutical Chemistry/ZAFES, Max-von-Laue Str. 9, 60438 Frankfurt am Main, GermanyE-mail: schubert-zsilavecz@pharmchem.uni-frankfurt.deFax: +49 69 798-29328

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368 L. Popescu et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 367 –371

Results and discussion

We evaluated pirinixic acid in our assay to activate thehuman PPARa and PPARc with EC50 values of 36.3 lM and53.2 lM, while PPARd is merely activated at 100 lM(Table 1). The substitution of the dimethylaniline by 6-aminoquinoline in 1 led to a total loss of both PPARa and

PPARc agonism. The concomitant introduction of an a-methyl group in 2 reconstituted the PPARc agonism.However, only the introduction of larger alkyl chains ofn-butyl or n-hexyl length in 3 and 4 potently enhanceddual PPARa/c agonism compared to pirinixic acid. Substi-tution of the linking nitrogen by an oxygen in 6 and 7 orelongation of the linker by methylene in 5 again led to a

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Table 1. Pharmacological data of synthesised compounds.

EC50 values lSD determined in a luciferase reporter gene assay described earlier [12 –15]. Calculations were done using Sigma-Plot2001, based on the mean values of at least three determinations, each prepared in triplicate wells.Second line, where applicable, gives the relative activation l SD compared to reference compound (WY14,643 for PPARa and piogli-tazone for PPARc).ia: inactive at 100 lM or at the concentration indicated.a: at 50 lM; b: at 30 lM; c: at 10 lM; data for tesaglitazar is cited as given in reference [19].

Arch. Pharm. Chem. Life Sci. 2007, 340, 367 – 371 Derivatives of Pirinixic Acid as Dual PPARa/c Agonists 369

total loss or diminished PPAR activity. The bis-(trifluore-thoxy)-substituted compound 8 on the other handshowed a slightly increased dual PPARa/c agonism. Noneof the compounds did show PPARd agonism.

In summary, the introduction of 6-aminoquinolineinstead of dimethylaniline led to a total loss of PPARactivity. However, in combination with an a-alkyl chaindual PPARa/c activity was restored and at chain lengthsof n-butyl or n-hexyl even enforced compared to pirinixicacid. As can be seen in the table, significant increases inPPAR agonism compared to pirinixic acid were observed.In an assay using transfected Cos7 cells, compounds 3and 4 exhibited a prominent increase in activation ofPPARc and PPARa. Compound 3 strongly activated PPARc

(EC50 = 11.5 lM), but also PPARa (EC50 = 9.2 lM). Replace-ment of the butyl group 3 with hexyl 4 especiallyimproved PPARa activation (EC50 = 2.2 lM). On the otherhand, the introduction of a trifluoro-ethoxy-benzene sub-

stituent 8 did also significantly increase PPARa/c activa-tion compared to pirinixic acid. With our synthesis strat-egy, we were thus able to optimise the pirinixic-acid leadstructure. In addition, we prepared a molecular dockingof compound 4 into the structures of tesaglitazar (Fig. 1)with PPARa (pdb entry 1I7G) (Fig. 2A) and PPARc (1I7I)(Fig. 2B) with FlexX. These dockings suggests a bindingmode for compound 3 resembling to that of the dualPPARa/c agonist tesaglitazar.

We would like to thank Dr. M. Tawab for careful revision of themanuscript.

Experimental

The final compounds 1–8 were evaluated by a reporter geneassay described earlier [12–15]. In brief, we utilised the ligandbinding domain (LBD) of the respective PPAR subtype fused tothe yeast Gal4-DNA binding domain of pFA-CMV (Stratagene), incombination with the Gal4-driven reporter plasmid pFR-Luc(Stratagene) and the control plasmid pRL-SV40 for normalisa-tion, transfected into Cos7 cells with lipofectamine (Invitrogen)according to the manufacturer's protocol. Four hours after trans-fection cells were incubated with appropriate concentrations oftest compounds in Dulbeccos modified Eagle Medium withoutphenolred and fetal calf serum using 0.1% DMSO as control. Fol-lowing overnight incubation, luciferase reporter gene activity

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Figure 1. Chemical structure of Tesaglitazar.

A B

Figure 2. Superposition of the binding mode of compound 4, as suggested by docking, with the crystal structure of tesaglitazar incomplex with PPARa (A) (pdb code:1I7G) and PPARc (B) (pdb code:1I7I), respectively. The crystal structure ligand tesaglitazar iscolour-coded by atom types in yellow, compound 4 in pink. The amino acid residues forming the hydrogen-bond network character-istic for agonists are represented in grey.

370 L. Popescu et al. Arch. Pharm. Chem. Life Sci. 2007, 340, 367 –371

was measured using dual glo Luciferase Assay system (Promega)according to manufacturer's protocol in a GENiosPro Luminom-eter (Tecan). After subtraction of non transfected control, lucifer-ase activity was normalised for transfection efficacy, divided byDMSO control and by maximum activity to gain relative activa-tion. Calculation of EC values was done using SigmaPlot2001(SPSS Inc.)

The general, synthesis of these compounds has been carriedout, adopting a method by d'Atri et al. we started with commer-cially available 2-mercapto-pyrimidine-4,6-diol (2-thiobarbituricacid) [16]. Its sodium salt was alkylated with a-bromo-alkanoicacid ester. The reaction with phosphorus oxychloride gave 2(-alkylthio)-4,6-dichloropyrimidine in quantitative yield. The 4-chloro group was substituted by 6-aminoquinoline, 6-methyla-minoquinoline, 3,5-bis-(2,2,2-trifluoro-ethoxy)-phenylamine or6-hydroxyquinoline in the presence of Na2CO3 or NaOH underreflux in ethylic alcohol. The synthetic route was completedwith the saponification of esters with diluted sodium hydroxide1N in ethanol or isopropanol to obtain compounds 1–8.

Docking analyses were preformed using the FlexX [17] andFlexX-Pharm algorithm [18], as implemented in the softwaremodule FlexX 2.0. The crystal structures of the dual agonist tesa-glitazar binding either to PPARa and PPARc were used as refer-ence in our study (pdb entry 1I7G and 1I7I) [19]. In the crystalstructure (Fig 1) four hydrogen bonds are formed to the acidichead group, accordingly, in the Flexx-Pharm docking runs, onlybinding modes showing at least two of these hydrogen bondswere considered as reasonable docking solutions. The energy-minimized structure of tesaglitazar was docked into PPARa andPPARc in order to evaluate the binding mode generated byFlexX. The top ranked solutions exhibited an RMS deviation of2.34 � and 1.81 � to the crystal structure whereas the lowestRMS values were found on rank 5 with 0.49 � and rank 6 1.09 �,respectively.

[4-Chloro-6-(quinolin-6-ylamino)-pyrimidin-2-ylsulfanyl]acetic acid 11H-NMR (300 MHz, DMSO, 258C): d = 4.02 (s, 2H, S-CH2), 6.63 (s,1H, Pyr), 7.50 (d, 1H, J = 4.20, 5-ArH), 7.54 (dd, 1H, J = 4.17, 7-ArH),7.82 (dd, 1H, 3-ArH), 8.00 (d, 1H, J = 9.03, 4-ArH), 8.38 (d, 1H, J =8.73, 8-ArH), 8.80 (d, 1H, J = 3.12, 2-ArH), 10.32 (brs, 1H, NH), 12.83(brs, 1H, OH). 13C-NMR (300 MHz, DMSO, 258C): d = 170.50 (C-OO),169.887 (Pyr-C),160.52 (Pyr-C), 157.48 (Pyr-C), 148.53 (C2-Quino-line), 143.74 (C-NH-Quinoline), 136.84 (C9-Quinoline), 136.29 (C4-Quinoline), 128.93 (C5-Quinoline), 128.48 (C10-Quinoline), 124.58(C8-Quinoline), 121.80 (C7-Quinoline), 115.83 (C3-Quinoline),101.47 (CH-Pyr), 3.04 (S-CH2); mp: 290-2918C; yield: 46.14%; ESI–MS: m/z = 346.8 [M+H]+; (C15H11ClN4O2S [346.8]) C, H, N: Calcd. [%]:C 51.95, H 3.20, N 16.16; Found. C 51.69, H 3.35, N 15.90.

2-[4-Chloro-6-(quinolin-6-ylamino)-pyrimidin-2-ylsulfanyl]propionic acid 21H-NMR (300 MHz, DMSO, 258C): d = 1.55 (d, 3H, J = 7.32, CH3),4.50 (q, 1H, J = 7.23 S-CH), 6.62 (s, 1H, Pyr), 7.50 (d, 1H, J = 4.14, 5-ArH), 7.80 (dd, 1H, J = 2.28, 7-ArH), 8. 00 (dd, 1H, 3-ArH), 8.32 (d,1H, J = 1.98, 4-ArH), 8.88 (d, 1H, J = 3.8, 8-ArH), 9.05 (d, 1H, J = 3.99,2-ArH), 10.79 (brs, 1H, NH), 12.94 (brs, 1H, OH). 13C-NMR(300 MHz, DMSO, 258C): d = 172.69 (C-OO), 170.12 (Pyr-C),160.59(Pyr-C), 157.52 (Pyr-C), 149.08 (C2-Quinoline), 144.64 (C-NH-Quino-line), 136.54 (C9-Quinoline), 135.40 (C4-Quinoline), 129.58 (C5-Quinoline), 128.36 (C10-Quinoline), 124.31 (C8-Quinoline), 121.85

(C7-Quinoline), 116.03 (C3-Quinoline), 101.48 (CH-Pyr), 42.20 (S-CH2), 17.74 (CH3); mp: 238 –2408C; yield: 53.38%; ESI–MS: m/z =359 (M –1) [M+H]+; (C15H14ClN3O2S [360.82]60.3 H2O60.4 MeOH[379.05]) C, H, N: Calcd. [%]: C 51.97, H 4.04, N 14.78; Found. [%]: C51.96, H 3.62, N 14.41.

2-[4-Chloro-6-(quinolin-6-ylamino)-pyrimidin-2-ylsulfanyl]hexanoic acid 31H-NMR (300 MHz, DMSO, 258C ): d = 0.75 (t, 3H, J = 7.05, CH3-Butyl), 1.18–1.33 (m, 4H, CH2-Butyl), 1.78-1.97 (m, 2H, CH2-Butyl),4.45 (t, 1H, J = 7.05, S-CH), 6.61 (s, 1H, Pyr), 7.50 (d, 1H, J = 4.20, 5-ArH), 7.80 (dd, 1H, J = 2.34, 7-ArH), 7.97 (dd, 1H, 3-ArH), 8.29 (d,1H, J = 7.86, 4-ArH), 8.33 (d, 1H, J = 1.86, 8-ArH), 8.77(d, 1H, J = 1.5,2-Ar), 10.27 (brs, 1H, NH), 12.96 (brs, 1H, OH). 13C-NMR (300 MHz,DMSO, 258C): d = 172.48 (C-OO), 170.07 (Pyrimidine-C), 160.52((Pyrimidine-C), 157.48 (Pyrimidine-C), 149.09 (C2-Quinoline),144.68 (C-NH-Quinoline), 136.43 (C9-Quinoline), 135.2 (C4-Quino-line), 129.53 (C5-Quinoline), 128.28 (C10-Quinoline), 124.36 (C8-Quinoline), 121.75 (C7-Quinoline), 116.24 (C3-Quinoline), 101.43(CH-Pyrimidine), 46.99 (S-CH2), 31.20 (CH2-Butyl), 26.67 (CH2-Butyl), 21.51 (CH2-Butyl), 13.53 (CH3-Butyl); mp: 238-2408C; yield:54.71%; ESI–MS: m/z = 402.9 [M+H]+; C21H23ClN4O2S Calcd. [%]: C:56.64, H: 4.75, N: 13.91 [402.91] Found. [%]: C: 56.67, H: 4.90, N:13.75.

2-[4-Chloro-6-(quinolin-6-ylamino)-pyrimidin-2-ylsulfanyl]octanoic acid 41H-NMR (300 MHz, DMSO, 258C ): d = 1.14–1.35 (m, 8H, CH2-Hexyl), 1.79–1.91 (m, 2H, CH2-Hexyl), 4.47 (t, 1H, J = 6.99, S-CH),6.76 (s, 1H, Pyr), 7.89 (d, 1H, J = 4.65, 5-ArH), 8.10 (dd, 1H, J = 8.94,7-ArH), 8.22 (dd, 1H, 3-ArH), 8.63 (d, 1H, J = 7.86, 4-ArH), 8.83 (d,1H, J = 8.52, 8-ArH), 9.04 (d, 1H, J = 3.90, 2-ArH), 10.82 (brs, 1H,NH), 12.96 (brs, 1H, OH); 13C-NMR (300 MHz, DMSO, 258C): d =172.56 (C-OO), 170.22 (Pyr-C), 160.47 (Pyr-C), 157.64 (Pyr-C),144.54 (C2-Quinoline), 142.268 (C4-Quinoline), 138.73 (C-NH-Qui-noline), 137.22 (C9-Quinoline), 129.23 (C10-Quinoline), 127.61 (C5-Quinoline), 123.87 (C8-Quinoline), 122.19 (C7-Quinoline), 115.60(C3-Quinoline), 102.16 (CH-Pyr), 47.13 (S-CH2), 31.33 (CH2-Butyl),30.85 (CH2-Hexyl), 28.02 (CH2-Hexyl), 26.44 (CH2-Hexyl), 21.84(CH2-Hexyl), 13.76 (CH3-Hexyl); mp: 155-1578C; yield: 28.5%; ESI–MS: m/z = 431.1 [M+H]+; (C21H23ClN4O2S [430.96]) C, H, N: Calcd.[%]: C 58.53, H 5.38, N 13; Found. [%]: C 58.26, H 5.39, N:12.79.

2-{4-Chloro-6-[(quinolin-6-ylmethyl)-amino]-pyrimidin-2-ylsulfanyl}octanoic acid 51H-NMR (300 MHz, DMSO, 258C): d = 0.75 (t, 3H, J = 6.9, CH3-Hexyl), 1.06-1.18 (m, 8H, CH2-Hexyl), 1.55-1.69 (m, 2H, CH2-Hexyl),4.11 (t, 1H, J = 7.0, S-CH), 4.82 (q, 2H, CH2-Hex), 6.42 (s, 1H, Pyrimi-dine), 7.93 (dd, 1H, J = 4.20, 8.31, 5-ArH), 7.99 (dd, 1H, J = 2.63,9.13, 7-ArH), 8.09 (brs, 1H, NH), 8.29 (d, 1H, J = 2.58, 3-ArH), 8.71(d, 1H, J = 9.13, 4-ArH), 8.97 (dd, 1H, J = 7.64, 8-ArH), 9.17 (dd, 1H, J= 4.1, 1.6, 2-ArH), 12.5 (brs, 1H, OH); 13C-NMR (300 MHz, DMSO,258C): d = 172.55 (C-OO), 169.71 (Pyrimidine-C-NH), 162.54 (Pyri-midine-C-S), 156.67 (Pyrimidine-C-Cl), 145.99 (C2-Quinoline),143.23 (C4-Quinoline), 140.16 (C9-Quinoline), 139.62 (C6-Quino-line), 132.72 (C5-Quinoline), 128.31 (C10-Quinoline), 125.66 (C8-Quinoline), 123.12 (C7-Quinoline), 122.03 (C3-Quinoline), 99.75(CH-Pyrimidine), 47.14 (S-CH2), 43.22 (CH2-NH), 31.21 (CH2-Hex),30.80 (CH2-Hex), 27.99 (CH2-Hex), 26.30 (CH2-Hex), 21.79 (CH2-Hex), 13.73 (CH3-Hex + CH3-Ethyl); mp: 160 –1628C; yield: 72.94%;

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Arch. Pharm. Chem. Life Sci. 2007, 340, 367 – 371 Derivatives of Pirinixic Acid as Dual PPARa/c Agonists 371

ESI–MS: m/z = 445 [M+H]+; (C22H25ClN4O2S [444.99]) C, H, N: Calcd.[%]: C 59.38, H 5.66, N 12.59; Found. [%]: C 59.21, H 5.56, N 12.59.

[4-Chloro-6-(quinolin-6-yloxy)-pyrimidin-2-ylsulfanyl]acetic acid 61H-NMR (300 MHz, DMSO, 258C): d = 0.80 (t, 3H, J = 7, CH3-Hexyl),3.75 (s, 2H, S-CH2), 7.15 (s, 1H, Pyr), 7.59 (dd, 1H, J = 4.17, 8.31, 3-ArH), 7.67 (dd, 1H, J = 2.64, 9.15, 7-ArH), 7.86 (d, 1H, J = 2.55, 5-ArH), 8.10 (d, 1H, J = 9.12, 8-ArH), 8.38 (dd, 1H, J = 8.25, 4-ArH),8.92 (dd, 1H, J = 4.17, 1.56, 2-ArH), 12.69 (brs, 1H, OH). 13C-NMR(300 MHz, DMSO, 258C): d = 170.87 (C-OO), 169.15 (Pyr-C), 167.56(Pyr-C), 160.73 (Pyr-C), 150.44 (C2-Quinoline), 149.18 (C-O-Quino-line), 145.75 (C9-Quinoline), 135.82 (C4-Quinoline), 130.80 (C5-Quinoline), 128.33 (C10-Quinoline), 124.54 (C8-Quinoline), 121.54(C7-Quinoline), 118.28 (C3-Quinoline), 103.39 (CH-Pyr), 33.07 (S-CH2); mp: 234-2368C; yield: 74.76%; ESI–MS: m/z = 347.8 [M+H]+;(C15H10ClN3O3S [347.78]) C, H, N: Calcd. [%]: C 51.80, H 2.90, N12.08; Found. [%]: C 51.56, H 2.95, N 11.93.

2-[4-Chloro-6-(quinolin-6-yloxy)-pyrimidin-2-ylsulfanyl]octanoic acid 71H-NMR (300 MHz, DMSO, 258C): d = 0.80 (t, 3H, J = 7, CH3-Hexyl),1.09 –1.18 (m, 8H, CH2-Hexyl), 1.56–1.70 (m, 2H, CH2-Hexyl), 3.96(t, 1H, J = 7.30, S-CH), 7.20 (s, 1H, Pyr), 7.59 (dd, 1H, J = 4.20, 8.31,3-ArH), 7.70 (dd, 1H, J = 2.63, 9.13, 7-ArH), 7.87 (d, 1H, J = 2.58, 5-ArH), 8.09 (d, 1H, J = 9.09, 8-ArH), 8.37 (dd, 1H, J = 7.64, 4-ArH),8.92 (dd, 1H, J = 4.1, 1.59, 2-ArH), 12.92 (brs, 1H, OH); 13C-NMR(300 MHz, DMSO, 258C): d = 171.71 (C-OO), 170.13 (Pyr-C), 169.34(Pyr-C), 160.78 (Pyr-C), 150.48 (C2-Quinoline), 149.34 (C-O-Quino-line), 145.83 (C9-Quinoline), 135.77 (C4-Quinoline), 130.73 (C5-Quinoline), 128.38 (C10-Quinoline), 124.77 (C8-Quinoline), 121.96(C7-Quinoline), 118.44 (C3-Quinoline), 103. 67 (CH-Pyr), 47.70 (S-CH2), 31.59 (CH2-Hex), 30.79 (CH2-Hex), 27.95 (CH2-Hex), 26.29(CH2-Hex), 21.84 (CH2-Hex), 13.82 (CH3-Hex); mp: 157 –1598C;yield: 47.20%; ESI–MS: m/z = 431.8 [M+H]+; (C21H22ClN3O3S [431.9])C, H, N: Calcd. [%]: C 58.39, H 5.13, N 9.73; Found. [%]: C 58.52, H5.07, N 9.45.

2-{5-[3,5-Bis-(2,2,2-trifluoro-ethoxy)-phenylamino]-4-chloro-pyrimidin-2-ylsulfanyl}octanoic acid 81H-NMR (300 MHz, DMSO, 258C): d = 0.81 (t, 3H, J = 6.50, CH3-Hexyl), 1.16 –1.19 (m, 6H, CH2-Hexyl), 1.32-1.35 (m, 2H, CH2-Hexyl), 1.71-1.90 (m, 2H, CH2-Hexyl), 4.38 (t, 1H, J = 7.11, S-CH),4.75 (q, 2H, J = 8.76, O-CH2-CF3), 6.53 (s, 1H, Pyr), 6.59 (d, 1H, J =2.07, Ar), 6.94 (d, 2H, J = 2.0, Ar), 10.01 (brs, 1H, NH), 12.90 (brs,1H, OH); 13C-NMR (300 MHz, DMSO, 258C): d = 172.39 (C-OO),170.03 (Pyr-C), 160.49 (Pyr-C), 158.17 (2C, C-Ar-O), 157.52 (Pyr-C),140.43 (2C-F3), 125.67 (C-Ar-NH), 101.35 (CH-Pyr), 96.93 (CH-Ar),

64.98 (2CH2-CF3), 47.22 (S-CH2), 31.67 (CH2-Hex), 30.85 (CH2-Hex),28.12 (CH2-Hex), 26.24 (CH2-Hex), 21.84 (CH2-Hex), 13.77 (CH3-Hex); mp: 139-1418C; yield: 42.67%; ESI–MS: m/z = 574.1 [M+H]+;(C22H24ClF6N3O4S [575.96]) C, H, N: Calcd. [%]: C 45.88, H 4.20, N7.30; Found. [%]: C 46.05, H 4.39, N 7.27.

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