Phenoxypropylamines: Synthesis and Antiulcer Evaluation

We have synthesized a number of phenoxypropylamines from N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}chloroacetamide (3). All the products have been characterized by elemental analysis, 1H-NMR and MS. The biological activity effects of the title compounds were examined. From the biological activity results, we found that two of them showed significant gastric acid antisecretory activity.


Introduction
The introduction of roxatidine acetate (4) as a H 2 -receptor antagonist for the control of peptic ulcer disease has been responsible for intense synthetic efforts by medicinal chemists in this therapeutic area to prepare highly efficacious drugs with greater potency and lower toxicity [1].

OPEN ACCESS
As part of our effort to explore a new antiulcer agent, this work was initiated with the goal of preparing a new compound which might possess potent gastric acid antisecretory and gastrointestinal protective activities with lower toxicity. In this paper we describe the preparation and antiulcer activity of compounds 6a-6f. Roxatidine acetate (4) was synthesized by a series of reaction including Leukart reductive amination, acylation and substitution [2]. On the basis of the bioisosterism principle phenoxypropylamines were prepared from compound 3 using primary amines [3]. The process is simple and moderate. The desired products were synthesized and identified on the basis of elemental analysis, 1 H-NMR and MS. The title compounds 6a-6f were also been evaluated for gastric acid antisecretory activity and the structure activity relationships of gastric acid antisecretory activity are also discussed.

Results and Discussion
N-{3- phenoxy]propyl}chloroacetamide (3) was synthesized by a three-step reaction from m-hydroxybenzaldehyde. The hydrochloric acid salt of roxatidine acetic ester 4 was prepared in 28.8% yield by the reaction of 3 with AcOK [2]. Six phenoxypropylamine derivatives were then synthesized by the reaction of 3 with primary amines, followed by oxalic acid to obtain their corresponding salts 6. The synthesis route is outlined in Scheme 1.

NaOH, NMF
Biological evaluation [4,5] The effects of the title compounds 6a-6f on gastric acid secretion are shown in Figure 1. The percentages of inhibition of gastric juice, GJ, 98.1%, 91.1%, 47.5%, 60.2%, 88.3% and 61.2%, respectively. As seen in the Figure, compounds 6a and 6f exhibited significant gastric acid antisecretory activity. That this gastric acid antisecretion efficacy was based on H 2 -receptor antagonist properties was confirmed by using the isolated guinea pig right atrial assay [7]. The calculation methods used In Figure 1 were as follows: With regards to possible SAR, our preliminary assumption was to synthesize the compounds 6a and 6b by adding primary amine straight chains in order to enhance the ability of the molecules to inhibit gastric acid. We synthesized compounds 6c and 6d by adding a branched chain primary amine in order to enhance the flexibility of the molecules. The compounds 6e and 6f are the H 2 -receptor antagonists.

Conclusions
In summary, we have developed the method for preparing phenoxypropylamine derivatives of roxatidine acetate from N-{3- [3-(1-piperidinylmethyl)phenoxy]propyl}chloroacetamide. The protocol offers several advantages such as mild reaction conditions, short reaction times, easy isolation and good yields. Also two of them showed some potential effects on the inhibition of gastric juice.