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

Hiroki Yoneyama; Takuji Magata; Kenji Uemura; Yoshihide Usami; Satoshi Tanaka; Masanori Takaoka; Shinya Harusawa

doi:10.1055/s-0034-1380345

Synthesis, Inhaltsverzeichnis

Synthesis 2015; 47(09): 1291-1302
DOI: 10.1055/s-0034-1380345

paper

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

Hiroki Yoneyama

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Takuji Magata

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Kenji Uemura

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Yoshihide Usami

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Satoshi Tanaka

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Masanori Takaoka

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

,

Shinya Harusawa*

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan eMail: yoneyama@gly.oups.ac.jp

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Abstract

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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

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Referenzen

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