untitled ISSN 215 Applicat molecul Sankar Ch Cephalon, Inc., 1 * Corresponding Tel.: +1.610.896 COMMUNIC DOI: 10.5155/e Received: 09 No Received in rev Accepted: 13 De Published onlin Printed: 31 Mar KEYWORDS CNS 5‐HT6 Antagonist Benzazepine Furanoquinolin Cyclocondensat 1. Introduct Due to it (CNS) disor emerged as intervention Alzheimer’s depression generation o frequent fea sulfone moi encountered the 5‐HT6 r receptor (h5 Compoun thia‐4,7‐diaz antagonism. to expand th the potent a against h5‐H developing t B/C) was on explore whe this class of c in compoun 53‐2249 (Print) tion of a m lar scaffol hatterjee * 145 Brandywine Pa g author at: 1375 In 69125. E‐mail addre ATION INFOR eurjchem.7.1.135‐1 ovember 2015 vised form: 07 Dece ecember 2015 ne: 31 March 2016 rch 2016 S ne tion tion ts emerging role rders, the 5‐h s a promising for the trea disease and and sleep‐wa of literature rep ature was the iety [5]. While d compound 1, receptor (Ki of ‐HT6R), Figure nd 1 contained za‐spiro[4.4]non Thus a program he scope of the antagonist, com HT6R) [6]. Whi the SAR around ngoing, a para ther the motif i compounds. Ac nd 1 was de E / ISSN 2153‐225 htt Europ multi‐com ld arkway, West Chest ndian Creek Dr., Wy ess: sankar.chatterj MATION 136.1360 ember 2015 e in various cen hydroxytryptam g target for t atment of co schizophrenia ake activity [ orted antagoni presence of e profiling a c a moderately f 5,700 nM ag 1). d a hitherto un nane‐3,6‐dione m was initiated series. This res mpound 2 (Fig le the research d the central [5, llel program a itself was need ccordingly, the s econstructed in uropean Journal Europ 57 (Online)  20 tp://dx.doi.org/ pean Jo Journal web mponent c ter, PA 19380‐4245 Wynnewood, PA 1909 rjee24@gmail.com ABSTRACT A molecular architecture component cy Cite this: Eur. ntral nervous sy mine 6 (5‐HT6 the pharmacol gnitive functio a, anxiety, ob [1‐4]. In the sts of this recep a sulfonamide chemical librar active antagon gainst human nknown motif t e for the rece d around this sc search culmina gure 1, Ki of 2 h program aim ,5]‐spiro motif also was initiat ed for the pote spiro bicyclic sy nto a linear l of Chemistry 7 pean Journal of C 016 Atlanta Pub 10.5155/eurjche ournal bpage: www. cyclocond 5, USA 96‐3321, USA. (S. Chatterjee). scaffold contain for 5‐hydroxytr yclization reactio . J. Chem. 2016, ystem ) has logical on in besity, first ptor, a or a ry we nist of 5‐HT6 the 1‐ eptor’s caffold ated in 26 nM med at (rings ted to ncy of ystem array gen aga anta seri (1) (2016) 135‐ Chemistry lishing House LL em.7.1.135‐136. of Che .eurjchem.co densation ning a furanoqu ryptamine 6 re on. 7(1), 135‐136 nerating the po ainst h5‐HT6R, F N H N O O S 1 A B C D Figure Emergence o agonists inspire ies. ‐136 LC ‐ All rights re .1360 emistry m n to develo uinoline motif t ceptor antagon otent antagonis Figure 1) [7]. O Me H e 1. Structures of co of the above‐ ed us to explor served ‐ Printed y op a bioac that offered a u nism was gener st, compound 3 2 N E E 3 N A D A ompounds 1, 2 and ‐mentioned pa re additional de d in the USA ctive unique molecula rated by a mult 3 (Ki of 10 nM N H N O O S N H Cl Cl Me B C D d 3. air of potent e novo designed ar ti‐ M t d 136 Chatterjee / European Journal of Chemistry 7 (1) (2016) 135‐136 Telescoping features from both compounds 2 and 3, respectively, the structural fragment A was envisioned followed by addition of an element of constrain between the positions as shown, as well as inclusion of a hetero atom near the constrained region (cf. compound 2). This concept gave rise to a furanoquinoline motif as exemplified in compound 4 (Figure 2, X represents varying halogen substituents) that became the scaffold to explore. N N N O H S O Me N N H HMe N H O H H N H Me Cl Cl N NH H Me 2 3 1. Constrain the depicted positions 2. Add a hetero atom (O or N) 4 X X A X: Halogens Figure 2. Evolution of compound 4. 2. Experimental As depicted in Scheme 1, commercially available N‐ protected amine (compound 5), dihydrofuran 6 and various aromatic benzaldehydes (compound 7, X = variable substi‐ tuents), in presence of ceric ammonium nitrate, underwent an one pot‐three components cyclocondensation reaction to generate a mixture of compounds cis‐8 and trans‐8 compounds, respectively [8]. To the best of our knowledge, this was the first example of a Povarov‐type reaction employing a benzazepine nucleus. Each separated individual isomer then underwent following series of transformations. Deprotection of t‐Boc group in acidic medium of compounds cis‐8 and trans‐8 generated compounds cis‐9 and trans‐9, respectively. Subsequent reductive amination of compounds cis‐9 and trans‐9 with paraformaldehyde generated com‐ pounds cis‐4 and trans‐4, respectively. Based on the partial structural feature of the active compound 3 (Figure 2), the pair cis‐10 and trans‐10 (generated utilizing 2,3‐dichlorobenz‐ aldehyde as one of the starting materials) became further focus of the study (vide infra). 3. Results and discussion In 1H NMR spectra of the cis‐adduct, the coupling constant between 2‐H and 3‐H (quinoline numbering, Scheme 1) was 5 Hz due to syn‐orientations of the hydrogens whereas in the trans‐adduct, the corresponding value was 10 Hz due to anti‐ orientation of the hydrogens. Similar trends also were reported in coupling constants between similar hydrogens in a different set of recently disclosed cis‐ and trans‐ adducts [9]. Activity of both compounds cis‐10 and trans‐10 were assessed against recombinant h5‐HT6R following previously disclosed assay procedure [7]. Compound cis‐10 displayed a Ki of 90 nM, while the corresponding trans‐isomer was ca. six‐ fold less active indicating the influence of three‐dimensional structural architecture on activity. The result is the first example of a furanoquinoline‐based active 5‐HT6 receptor antagonist. Reagents and conditions: (a) Ceric ammonium nitrate (CAN), CH3CN, room temp., overnight, 75%; (b) chromatographic separation of the isomers; (c) Individual isomer from above step (b), 4 N HCl in dioxane, room temp., 2 h, quantitative; (d) Individual isomer from above step c, formalin, methanol, catalytic gl. acetic acid, sodium triacetoxyborohydride, 0 °C to room temp., 3 h, 70‐75%. Scheme 1 4. Conclusions Based on the structural information gleaned from previously disclosed potent compounds 2 and 3, a series of compounds represented by compound 4 containing a furanoquinoline motif was conceptualized, synthesized and profiled for h5‐HT6R antagonism. Compound cis‐10 displaying a Ki of 90 nM offered a new platform for further exploration of the series. Acknowledgement Biology team is thanked for providing the assay data. References [1]. Benhamu, B.; Martiin‐Fontecha, M.; Vazquez‐Villa, H.; Pardo, L.; Lopez‐Rodriguez, M. L. J. Med. Chem. 2014, 57, 7160‐7181. [2]. Ramirez, M. J. Alzheimer’s Res. Ther. 2013, 5(15), 1‐8. [3]. Wesolowska, A. Pharmacol. Rep. 2010, 62, 564‐567. [4]. Ly, S.; Pishadari, B.; Lok, L. L.; Hajos, M.; Kocsis, B. ACS Chem. Neurosci. 2013, 4, 191‐199. [5]. Rosse, G.; Schaffhauser, H. Curr. Top. Med. Chem. 2010, 10, 207‐221. [6]. Hostetler, G.; Dunn, D.; McKenna, B. A.; Kopec, K.; Chatterjee, S. Chem. Bio. Drug Des. 2014, 83, 149‐153. [7]. Hostetler, G.; Dunn, D.; McKenna, B. A.; Kopec, K.; Chatterjee, S. Chem. Bio. Drug Des. 2014, 83, 666‐669. [8]. Ravindranath, N.; Ramesh, C.; Reddy, M. R.; Das, B. A. Chem. Lett. 2003, 32, 222‐223. [9]. DaSilva, B. H. S. T.; Martins, L. M.; Silva‐Filho, L. C. Synlett. 2012, 23, 1973‐1977.