A NOVEL HISTAMINE 2(H-2) RECEPTOR ANTAGONIST WITH GASTROPROTECTIVE ACTIVITY - I - SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF N-PHENOXYPROPYLACETAMIDE DERIVATIVES WITH THIOETHER FUNCTION

In an attempt to develop new types of anti-ulcer agents, a series of N -(phenoxypropyl)acetamide derivatives with a thioether moiety and thei r sulfur-oxidized analogues were synthesized and evaluated for histami ne H-2-receptor antagonistic activity, Ca antagonistic activity and ga stric anti-secretory activity in the lumen-perfuseed rat. Selected com pounds were also tested for gastroprotective activity, which was expec ted to be based on Ca antagonistic activity, Structure-activity relati onships are discussed, hs a thioether moiety, -CH2S(O)p-CH2-Ar (Ar; ph enyl or furyl) was found to be optimal for the above activities. Espec ially, N'-[3-[(3-(piperidinomethyl) phenoxy]propyl]acetamide with a be nzyl sulfinyl, benzylsulfonyl, furfurylsulfinyl or furfurylsulfonyl gr oup showed potent gastroprotective activity upon oral administration i n a rat model. These compounds are candidates for novel anti-ulcer dru gs with gastric anti-secretory and gastroprotective activities. l-N-[3 -[(piperidinomethyl)phenoxy]propyl]acetamide was the most potent among the compounds tested and was given the code designation FRG-8701.