ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Synthesis of a Novel Series of Benzocycloalkene Derivatives as Melatonin Receptor Agonists

View Author Information
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan
Cite this: J. Med. Chem. 2002, 45, 19, 4212–4221
Publication Date (Web):August 15, 2002
Copyright © 2002 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan derivatives with the S-configuration at position 1 were the most promising in terms of potency and selectivity for the human melatonin receptor (MT1 site), while compounds with the R-configuration showed little potential. Our next attempt was to investigate the most favorable conformation of the methoxy group, the other important pharmacophore for binding to the MT1 receptor. The introduction of a methyl group at position 5 of the indene ring conserved affinity; however, at position 7, it caused a decrease in affinity. These results suggested that the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation. The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT1 receptor (Ki = 0.041 nM) but no significant affinity for the hamster MT3 receptor (Ki = 3570 nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]alkanamides employing asymmetric hydrogenation with (S)-2,2‘-bis(diphenylphosphino)-1,1‘-binaphthyl−Ru has been established.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.


     To whom correspondence should be addressed. Tel:  +81-6-6300-6546. Fax:  +81-6-6300-6306. E-mail:  [email protected].

    Supporting Information Available

    Jump To

    X-ray crystallographic data of (S)-8o; detailed information on the synthesis and characterization of the target compounds listed in Table 2; a list of receptors and enzymes tested for (S)-8d; the inhibitory effect of (S)-8d on forskolin-induced cAMP production in CHO cells expressing the human MT1 receptor. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 41 publications.

    1. Jianping Yang, Luca Massaro, Suppachai Krajangsri, Thishana Singh, Hao Su, Emanuele Silvi, Sudipta Ponra, Lars Eriksson, Mårten S. G. Ahlquist, Pher G. Andersson. Combined Theoretical and Experimental Studies Unravel Multiple Pathways to Convergent Asymmetric Hydrogenation of Enamides. Journal of the American Chemical Society 2021, 143 (51) , 21594-21603.
    2. Jan B. Metternich, Denis G. Artiukhin, Mareike C. Holland, Maximilian von Bremen-Kühne, Johannes Neugebauer, and Ryan Gilmour . Photocatalytic E → Z Isomerization of Polarized Alkenes Inspired by the Visual Cycle: Mechanistic Dichotomy and Origin of Selectivity. The Journal of Organic Chemistry 2017, 82 (19) , 9955-9977.
    3. Mario de la Fuente Revenga, Nerea Fernández-Sáez, Clara Herrera-Arozamena, José A. Morales-García, Sandra Alonso-Gil, Ana Pérez-Castillo, Daniel-Henri Caignard, Silvia Rivara, and María Isabel Rodríguez-Franco . Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential. Journal of Medicinal Chemistry 2015, 58 (12) , 4998-5014.
    4. Annalida Bedini, Simone Lucarini, Gilberto Spadoni, Giorgio Tarzia, Francesco Scaglione, Silvana Dugnani, Marilou Pannacci, Valeria Lucini, Caterina Carmi, Daniele Pala, Silvia Rivara, and Marco Mor . Toward the Definition of Stereochemical Requirements for MT2-Selective Antagonists and Partial Agonists by Studying 4-Phenyl-2-propionamidotetralin Derivatives. Journal of Medicinal Chemistry 2011, 54 (24) , 8362-8372.
    5. Tatsuki Koike, Yasutaka Hoashi, Takafumi Takai, Masaharu Nakayama, Nobuhito Yukuhiro, Takashi Ishikawa, Keisuke Hirai, and Osamu Uchikawa . 1,6-Dihydro-2H-indeno[5,4-b]furan Derivatives: Design, Synthesis, and Pharmacological Characterization of a Novel Class of Highly Potent MT2-Selective Agonists. Journal of Medicinal Chemistry 2011, 54 (9) , 3436-3444.
    6. Jacob M. Janey,, Charles J. Orella,, Eugenia Njolito,, Jenny M. Baxter,, Jonathan D. Rosen,, Michael Palucki,, Rick R. Sidler,, Wenjie Li,, Jason J. Kowal, and, Ian W. Davies. Raney-Co Mediated Reductive Cyclization of an α,β-Unsaturated Nitrile. The Journal of Organic Chemistry 2008, 73 (8) , 3212-3217.
    7. Nicholas B. Johnson, Ian C. Lennon, Paul H. Moran and James A. Ramsden. Industrial-Scale Synthesis and Applications of Asymmetric Hydrogenation Catalysts. Accounts of Chemical Research 2007, 40 (12) , 1291-1299.
    8. Andrew Tsotinis,, Margarita Vlachou,, Demetris P. Papahatjis,, Theodora Calogeropoulou,, Spyros P. Nikas,, Peter J. Garratt,, Vincent Piccio,, Stefan Vonhoff,, Kathryn Davidson,, Muy-Teck Teh, and, David Sugden. Mapping the Melatonin Receptor. 7. Subtype Selective Ligands Based on β-Substituted N-Acyl-5-methoxytryptamines and β-Substituted N-Acyl-5-methoxy-1-methyltryptamines. Journal of Medicinal Chemistry 2006, 49 (12) , 3509-3519.
    9. Yuxi Gao, Lijuan Gao, Endiao Zhu, Yunhong Yang, Mi Jie, Jiaqian Zhang, Zhiqiang Pan, Chengfeng Xia. Nickel/photoredox dual catalyzed arylalkylation of nonactivated alkenes. Nature Communications 2023, 14 (1)
    10. Anže Meden, Damijan Knez, Xavier Brazzolotto, Florian Nachon, Jose Dias, Jurij Svete, Jure Stojan, Uroš Grošelj, Stanislav Gobec. From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series. European Journal of Medicinal Chemistry 2022, 234 , 114248.
    11. Xumu Zhang, Pan‐Lin Shao. Industrial Applications of Asymmetric (Transfer) Hydrogenation. 2021, 175-219.
    12. Jean A. Boutin, Paula A. Witt‐Enderby, Christoph Sotriffer, Darius P. Zlotos. Melatonin receptor ligands: A pharmaco‐chemical perspective. Journal of Pineal Research 2020, 69 (3)
    13. Andrew Tsotinis, Ioannis P. Papanastasiou. Synthetic Melatonin Receptor Agonists and Antagonists. 2020
    14. Luca Massaro, Jia Zheng, Cristiana Margarita, Pher G. Andersson. Enantioconvergent and enantiodivergent catalytic hydrogenation of isomeric olefins. Chemical Society Reviews 2020, 49 (8) , 2504-2522.
    15. Elvira R. Zaitseva, Alexander Yu. Smirnov, Nadezhda S. Baleeva, Mikhail S. Baranov. Synthesis of spirocyclic pyrrolidines from cyclopentylideneacetic acid derivatives. Chemistry of Heterocyclic Compounds 2019, 55 (7) , 676-678.
    16. Romain Duroux, Marouan Rami, Elodie Landagaray, Mohamed Ettaoussi, Daniel-Henri Caignard, Philippe Delagrange, Patricia Melnyk, Saïd Yous. Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT 1 /MT 2 ) and serotoninergic (5-HT 2C ) dual ligands. European Journal of Medicinal Chemistry 2017, 141 , 552-566.
    17. Maris Vilums, Jules Heuberger, Laura H. Heitman, Adriaan P. IJzerman. Indanes—Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors. Medicinal Research Reviews 2015, 35 (6) , 1097-1126.
    18. Hardeep Singh Tuli, Dharambir Kashyap, Anil K. Sharma, Sardul Singh Sandhu. Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sciences 2015, 135 , 147-157.
    19. Naseem Ahmed, Gulab Khushalrao Pathe, Sohan Jheeta. SnCl 4 or TiCl 4 : highly efficient catalysts for the detetrahydropyranylation and demethoxymethylation of phenolic ethers and sequential one-pot asymmetric synthesis of 3-aryl-2-hydroxy-2,3-dihydroindan-1-ones from chalcone epoxides. RSC Advances 2015, 5 (77) , 63095-63103.
    20. Yuhei Shimizu, Megumi Noshita, Yuri Mukai, Hiroyuki Morimoto, Takashi Ohshima. Cleavage of unactivated amide bonds by ammonium salt-accelerated hydrazinolysis. Chem. Commun. 2014, 50 (84) , 12623-12625.
    21. Martin G. Banwell, Matthew T. Jones, Tristan A. Reekie, Brett D. Schwartz, Shen H. Tan, Lorenzo V. White. RANEY® cobalt – an underutilised reagent for the selective cleavage of C–X and N–O bonds. Org. Biomol. Chem. 2014, 12 (38) , 7433-7444.
    22. Xuan Zhang, Zhilong Wang, Qingqing Huang, Yu Luo, Xin Xie, Wei Lu. Design, synthesis, and biological evaluation of a new class of MT 2 -selective agonists. RSC Adv. 2014, 4 (49) , 25871-25874.
    23. XiaoDan Fu, XingQun Guo, XingWei Li, LiDong He, YuShe Yang, YouXi Chen. Synthesis of the melatonin receptor agonist Ramelteon using a tandem C–H activation–alkylation/Heck reaction and subsequent asymmetric Michael addition. Tetrahedron: Asymmetry 2013, 24 (13-14) , 827-832.
    24. Rajendran Suresh, Shanmugam Muthusubramanian, Muthusamy Boominathan, Govindaswamy Manickam. Acid controlled generation of indanes and oxazolines from β-hydroxyarylethanamide. Tetrahedron Letters 2013, 54 (19) , 2315-2320.
    25. Abha Chaudhary, Pralay Das, Awanish Mishra, Pushpinder Kaur, Bikram Singh, Rajesh K. Goel. Naturally occurring himachalenes to benzocycloheptene amino vinyl bromide derivatives: as antidepressant molecules. Molecular Diversity 2012, 16 (2) , 357-366.
    26. D.J. Ager, J.G. de Vries. 9.4 Industrial Applications of Asymmetric Reduction of C=C Bonds. 2012, 73-82.
    27. Saïd El Kazzouli, Amaury Griffon du Bellay, Sabine Berteina-Raboin, Philippe Delagrange, Daniel-Henry Caignard, Gérald Guillaumet. Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands. European Journal of Medicinal Chemistry 2011, 46 (9) , 4252-4257.
    28. Guo‐Qiang Lin, Xing‐Wen Sun. Chiral Drugs through Asymmetric Synthesis. 2011, 29-76.
    29. Giorgio Giorgi, Francisco J. Arroyo, Pilar López-Alvarado, J. Carlos Menéndez. Two chemodivergent anionic domino processes from cyclic α-nitroketones and aromatic aldehydes. Tetrahedron 2011, 67 (31) , 5582-5589.
    30. Vinayak Hegde, Marc Campitelli, Ronald J. Quinn, David Camp. Synthesis of novel molecular probes inspired by harringtonolide. Organic & Biomolecular Chemistry 2011, 9 (12) , 4570.
    31. Margarita L. Dubocovich, Philippe Delagrange, Diana N. Krause, David Sugden, Daniel P. Cardinali, James Olcese. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors. Pharmacological Reviews 2010, 62 (3) , 343-380.
    32. Hans‐Ulrich Blaser, Garrett Hoge, Benoît Pugin, Felix Spindler. Industrial Applications of Homogeneous Enantioselective Catalysts. 2010, 153-203.
    33. Masayuki Yamashita, Toru Yamano. Synthesis of Melatonin Receptor Agonist Ramelteon via Rh-catalyzed Asymmetric Hydrogenation of an Allylamine. Chemistry Letters 2009, 38 (1) , 100-101.
    34. József Csontos, Péter Kálmán, Gyula Tasi, Miklós Kálmán, Richard F. Murphy, Sándor Lovas. The effect of electron correlation on the conformational space of melatonin. Journal of Computational Chemistry 2008, 29 (9) , 1466-1471.
    35. Hans‐Ulrich Blaser, Felix Spindler, Marc Thommen. Industrial Applications. 2006, 1279-1324.
    36. Gilberto Spadoni, Annalida Bedini, Tomaso Guidi, Giorgio Tarzia, Valeria Lucini, Marilou Pannacci, Franco Fraschini. Towards the Development of Mixed MT 1 ‐Agonist/MT 2 ‐Antagonist Melatonin Receptor Ligands. ChemMedChem 2006, 1 (10) , 1099-1105.
    37. Anton O. Chugunov, Amaury Farce, Philippe Chavatte, Roman G. Efremov. Differences in Binding Sites of Two Melatonin Receptors Help to Explain Their Selectivity to Some Melatonin Analogs: A Molecular Modeling Study. Journal of Biomolecular Structure and Dynamics 2006, 24 (2) , 91-107.
    38. Silvia Rivara, Giuseppe Diamantini, Barbara Di Giacomo, Doriano Lamba, Giuseppe Gatti, Valeria Lucini, Marilou Pannacci, Marco Mor, Gilberto Spadoni, Giorgio Tarzia. Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue. Bioorganic & Medicinal Chemistry 2006, 14 (10) , 3383-3391.
    39. Toru Yamano, Masayuki Yamashita, Mari Adachi, Mitsutaka Tanaka, Kiyoharu Matsumoto, Mitsuru Kawada, Osamu Uchikawa, Kohji Fukatsu, Shigenori Ohkawa. Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation. Tetrahedron: Asymmetry 2006, 17 (2) , 184-190.
    40. József Csontos, Miklós Kálmán, Gyula Tasi. The stereochemistry of the chemical expression of darkness. Journal of Molecular Structure: THEOCHEM 2003, 666-667 , 515-520.
    41. Ronald J. Mattson, John D. Catt, Daniel Keavy, Charles P. Sloan, James Epperson, Qi Gao, Donald B. Hodges, Lawrence Iben, Cathy D. Mahle, Elaine Ryan, Frank D. Yocca. Indanyl piperazines as melatonergic MT2 selective agents. Bioorganic & Medicinal Chemistry Letters 2003, 13 (6) , 1199-1202.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect