Synthesis and Antiallergic Activity of Dimethyl-2-(phenylcarbamoyl)ethylsulfoniump-Toluenesulfonate Derivatives

Abstract

The derivatives of dimethyl-2-(phenylcarbamoyl)ethylsulfonium p-toluenesulfonates were synthesized and evaluated for antiallergic activity. The 2,3-dihydroxyethoxy group was introduced to the phenyl ring from the standpoint of lipophilicity and electronic effects of substituent. The IgE-induced rat passive cutaneous anaphylaxis (PCA) was inhibited by oral administration of several substituted 2-[(4-propoxyphenyl)carbamoyl]ethyldimethylsulfonium p-toluenesulfonate derivatives. Among them (+/-)-2-[N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]carbamoyl]ethyldimeth ylsulfonium p-toluenesulfonate (1a, IPD-1151T) was found to possess considerable activity in the PCA test, and it was launched as Suplatast tosilate in Japan.

A Correlation between Physicochemical Properties and Acute Toxicity of Sulfonium p-Toluenesulfonates as the Lead Compound of Suplatast Tosilate

“…Consequently, sulfonium p-toluenesulfonates that have hydrophilic substituent and low reactivity of methyl group were desirable for reducing acute toxicity. Suplatast Tosilate, which was launched as an anti-allergic drug in 1995, which has no unsaturated carbon as substituents of sulfur and has OH group [12].…”

“…The H-D exchange rate constants (k obsd/HD ) are shown in Table 1. Methyl groups of sulfonium p-toluenesulfonates (6)(7)(8)(9)(10)(11)13), which have unsaturated carbon adjacent to positive sulfur, exchanged their protons about 13 times more rapidly than did other compounds (1)(2)(3)(4)(5)12). There were not any significant correlations between k obsd/H-D and immunological activity (HPFC).…”

Lead Generation of Anti-allergic Agent ; Suplatast Tosilate

“…1 H NMR spectra were obtained in DMSO-d 6 with Me 4 Si as an internal standard on a JEOL LMN-FX 100 spectrometer. Analytical results for compounds followed by elemental symbols were determined on a Perkin-Elmer Model 240 CHN analyzer.…”

“…Suplatast tosilate (1, IPD-1151T) (Chart1) was launched as an agent for the treatment of bronchial asthma, atopic dermatitis, and allergic rhinitis in 1995 in Japan [1]. This drug decreased the levels of some immune system associated substances such as Interleukin-4 (IL-4), eosinophils, and Immunoglobulin E (IgE) [2].…”

Optimal Lipophilicity of Sulfonium <i>p</i>-Toluenesulfonate as Anti-allergic Drug

“…During the development of Suplatast Tosilate (IPD-1151T) (67) (Chart 1), which is a Th2 cytokine inhibitor and used as anti-allergic drug [3], we have reported some QSAR analysis by using only the calculated values as lipophilic parameter [5][6] [7][8] [9] [10], because the logK values of sulfonium compounds had been previously only rarely measured. We could comprehend the relative lipophilicity of sulfonium compounds in the developmental process (Chart1), but we did not determine a suitable logK value for the anti-allergic activity and toxicity.…”