Efficient Synthesis of N-[4-(4-Chlorophenyl)butyl]-S-(3-piperidinopropyl)isothiourea (OUP-186) and Its Analogues Using 2-Nitrophenylacetyl Isothiocyanate: Application to Novel Histamine H₃R Antagonists

Abstract

A potent histamine H₃ receptor antagonist OUP-186 with an S-alkyl-N-alkylisothiourea structure was synthesized using 3-phenylpropanoyl isothiocyanate (PPI) as an SCN source. The synthetic route was significantly improved by replacing 3-phenylpropanoyl isothiocyanate with 2-nitrophenylacetyl isothiocyanate (NPAI), giving a 74% overall yield in three steps from 4-(4-chlorophenyl)butylamine. In addition, the 2-nitrophenylacetyl isothiocyanate method successfully yielded two fluorine-containing analogues, and a shorter, C₂ homologue of OUP-186.

Key words

S-alkyl-N-alkylisothiourea - histamine H₃ receptor - non-imidazole­ - H₃ antagonist - cancer growth inhibition

• References

• 1 Arrang JM, Garbarg M, Schwartz JC. Nature (London) 1983; 302: 832
• 2 Morisset S, Rouleau A, Ligneau X, Gbahou F, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR, Schwartz JC, Arrang J.-M. Nature (London) 2000; 408: 860
• 3 Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC. Nature (London) 1987; 327: 117
• 4 Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL. Pharmacol. Rev. 1997; 49: 253
• 5 Schlicker E, Fink K, Detzner M, Göthert M. J. Neural Transm.: Gen. Sect. 1993; 93: 1
• 6 Sclicker E, Betz R, Göthert M. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1988; 337: 588
• 7 Bray GA, Tartaglia LA. Nature (London) 2000; 404: 672
• 8 Pillot C, Ortiz J, Heron A, Ridray S, Schwartz JC, Arrang JM. J. Neurosci. 2002; 22: 7272
• 9 Mignot E, Taheri S, Nishino S. Nature Neurosci. 2002; 5: 1071
• 10 Leurs R, Blandina P, Tedford C, Timmerman H. Trends Pharmacol. Sci. 1998; 19: 177
• 11a Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. J. Biol. Chem. 2000; 275: 36781
• 11b Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K. Biochem. Biophys. Res. Commun. 2000; 279: 615
• 11c Hough LB. Mol. Pharmacol. 2001; 59: 415 ; and references therein
• 11d Smits RA, Leurs R, de Esch IJ. P. Drug Discovery Today 2009; 14: 745
• 11e Histamine H₄ Receptor: A Novel Drug Target in Immunoregulation and Inflammation. Stark H. Versita; London: 2013
• 12a Berlin M, Boyce CW, Ruiz M.deL. J. Med. Chem. 2011; 54: 26
• 12b Łażewska D, Kieć-Kononowicz K. Expert Opin. Ther. Pat. 2010; 20: 1147
• 12c Sander K, Kottke T, Stark H. Biol. Pharm. Bull. 2008; 31: 2163
• 13 Stephanos J. J. Inorg. Biochem. 1996; 62: 155
• 14 Chadha HS, Abraham MH, Mitchell RC. Bioorg. Med. Chem. Lett. 1994; 4: 2511
• 15 Schwartz JC. Br. J. Pharmacol. 2011; 163: 713
• 16a Medina V, Croci M, Crescenti E, Mohamad N, Sanchezjimenez F, Massari N, Nunez M, Cricco G, Bergoc R, Rivera E. Cancer Biol. Ther. 2008; 7: 28
• 16b Cowart MD, Altenbach RJ, Liu H, Hsieh GC, Drizin I, Milicic I, Miller TR, Witte DG, Wishart N, Fix-Stenzel SR, McPherson MJ, Adair RM, Wetter JM, Bettencourt BM, Marsh KC, Sullivan JP, Honore P, Esbenshade TA, Brioni JD. J. Med. Chem. 2008; 51: 6547
• 17a Manimala JC, Anslyn EV. Eur. J. Org. Chem. 2002; 3909
• 17b Drouin C, Woo JC. S, MacKay DB, Lavigne RM. A. Tetrahedron Lett. 2004; 45: 7197
• 17c Powell DA, Batey RA. Org. Lett. 2002; 4: 2913
• 18 Comprehensive Heterocyclic Chemistry . Katrizky AR, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996
• 19 Smith MB, March J. March’s Advanced Organic Chemistry . 5th ed. John Wiley & Sons; New York: 2001: 495-496
• 20a Taylor JE, Bull SD, Williams JM. J. Chem. Soc. Rev. 2012; 41: 2109
• 20b Srinivas K, Srinivas P, Prathima PS, Balaswamy K, Sridhar B, Rao MM. Catal. Sci. Technol. 2012; 2: 1180
• 21a Sandler RS, Karo W. Organic Functional Group Preparations . 2nd ed. Academic Press; New York: 1986: 206-210
• 21b Denk MK, Ye X. Tetrahedron Lett. 2005; 46: 7597
• 22a Hasegawa K, Hirooka S, Sasaki T. Bull. Chem. Soc. Jpn. 1975; 48: 2611
• 22b Iwakawa T, Tamura H, Sato T, Hayase Y. Chem. Pharm. Bull. 1988; 36: 4755
• 22c Takagi K. Chem. Lett. 1985; 1307
• 22d Vowinkel E, Claussen G. Chem. Ber. 1974; 107: 898
• 23 Mampuys P, Zhu Y, Vlaar T, Ruijter E, Orru RV. A, Maes BU. W. Angew. Chem. Int. Ed. 2014; 53: 12849
• 24 Harusawa S, Sawada K, Magata T, Yoneyama H, Araki L, Usami Y, Hatano K, Yamamoto K, Yamamoto D, Yamatodani A. Bioorg. Med. Chem. Lett. 2013; 23: 6415
• 25 Yoneyama H, Shimoda A, Araki L, Hatano K, Sakamoto Y, Kurihara T, Yamatodani A, Harusawa S. J. Org. Chem. 2008; 73: 2096
• 26 Acetyl isothiocyanate and 2-(4-chlorophenyl)ethylamine (2c) were purchased from Sigma-Aldrich.
• 27 Smith PA. S, Kan RO. Org. Synth. Coll. Vol. V . John Wiley & Sons; London: 1973
• 28 Neat NPAI decomposed at 90 °C. 1 M NPAI solution in toluene was kept in the refrigerator for 2 months with no signs of degradation.
• 29 Welch JT, Lim DS. Bioorg. Med. Chem. 2007; 15: 6659
• 30a Wolin R, Connolly M, Afonso A, Hey JA, She H, Rivelli MA, Williams SM, West RE. J. Bioorg. Med. Chem. Lett. 1998; 8: 2157
• 30b Yasunaga T, Kimura T, Naito R, Kontani T, Wanibuchi F, Yamashita H, Nomura T, Tsukamoto S, Yamaguchi T, Mase T. J. Med. Chem. 1998; 41: 2765