Synthesis and SAR of sulfonyl- and phosphoryl amidine compounds as anti-resorptive agents Myung Yun Lee a,d,  , Myung Hee Kim b,  , Jinho Kim c , Seok Hwan Kim c , Bum Tae Kim d , In Howa Jeong a , Sukbok Chang c , Seong Hwan Kim b , Sung-Youn Chang d, * a Department of Chemistry and Medical Chemistry, Yonsei University, Wonju 220-710, Republic of Korea b Laboratory of Chemical Genomics, Pharmacology Research Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Sinseongno19, Yuseong-gu, Daejeon 305-600, Republic of Korea c Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea d Medicinal Chemistry Research Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Sinseongno19, Yuseong-gu, Daejeon 305-600, Republic of Korea article info Article history: Received 23 September 2009 Revised 13 November 2009 Accepted 19 November 2009 Available online 26 November 2009 Keywords: Sulfonyl amidine Phosphoryl amidine Osteoporosis Osteoclast Anti-resorptive agent abstract Sulfonyl amidines (1) and phosphoryl amidines (2), which were efficiently synthesized via a Cu-catalyzed one pot reaction, showed potent anti-bone resorptive activity in vitro. Structure activity relationship studies led to the identification of numerous osteoclast differentiation inhibitors. Ó 2009 Elsevier Ltd. All rights reserved. A practical synthesis of amidines would be very helpful for medicinal chemists because amidines are found in many bioactive natural products 1 and identified as important pharmacophores. 2 Recently, efficient one-pot syntheses of amidines using Cu-cata- lyzed three component coupling reactions have been published. 3,4 The reaction was proposed to proceed via the formation of a kete- nimine intermediate, which is generated in situ by the Cu-cata- lyzed cycloaddition of sulfonyl- or phosphoryl azides with terminal alkynes followed by the ring-cleavage of the resultant tri- azoles. 5 It is believed that the excellent reactivity of the ketenimine intermediate allows for the amazingly diverse reactions with pro- nucleophiles such as amines, alcohols, water, and imidazole. In the present study, we synthesized various sulfonyl- and phosphoryl amidines according to the reported procedure and evaluated their biological activity. Sulfonyl amidines (1) were synthesized from alkyne, amine, and sulfonyl azide in the presence of CuI catalyst at rt in 66–99% yield. 6 In addition, phosphoryl amidines (2) were synthesized from phos- phoryl azide instead of sulfonyl azide in 38–82% yield. 7 N-Dime- thoxy phosphoryl amidine (2k), which had been previously obtained in relatively low yield with Cu-catalyzed one-pot reaction, was synthesized in 88% yield using substitution of the phenoxy group with methoxide. 4 Subsequent hydrolysis of the N-dimethoxy phosphoryl amidine (2k) with TMSCl in the presence of NaI gave the amidine containing phosphonic acid (2l) in 72% yield 8 (Scheme 1). Based on the methodology in Scheme 1, we prepared 64 sulfo- nyl amidine derivatives (1) and screened them in vitro for their anti-cancer, anti-obesity, bone forming, and anti-bone resorptive activities (Data are not shown). From the screening, amidine 1a showed anti-resorptive activity with tartrate-resistant acid phos- phatase (TRAP, a biomarker of osteoclastogenesis; IC 50 value of 16.7 lM in RAW264.7 cells). In contrast, these same derivatives did not exhibit efficient anti-cancer, anti-obesity, and bone form- ing activities at a concentration of 10 lM. 9 These results suggested that amidine derivatives could be developed as selective anti- resorptive osteoporosis drugs. Bone is constantly remodeled through osteoblast-mediated for- mation of bone matrix and osteoclast-mediated bone resorption in order to maintain skeletal strength and integrity. However, an imbalance in bone remodeling caused by increased bone resorp- tion over bone formation leads to the reduction of bone mineral density that is a major cause of several bone disorders such as osteoporosis. 10 Since the loss of bone mass can increase the risk 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.11.104 * Corresponding author. Tel.: +82 42 860 7161; fax: +82 42 861 0307. E-mail address: sychang@krict.re.kr (S.-Y. Chang).   These authors contributed equally to this Letter. Bioorganic & Medicinal Chemistry Letters 20 (2010) 541–545 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl