Pyrrolidonecarboxylic acid derivatives as anti-ulcer agents

#This invention relates to new and useful N-substituted pyrrolidonecarboxylic acid compounds of principal interest to those in the field of chemotherapy. More particularly, it is concerned with certain novel N-(p-benzamido)-2-pyrrolidone-4-carboxylic acid compounds, which are of especial value in view of their unique anti-ulcer properties.

#In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and useful anti-ulcer agents. For the most part, these efforts have involved the synthesis and testing of various new and heretofore unavailable organic compounds, particularly in the area of organic heterocyclic bases. For instance, C. A. Lipinski in U.S. Pat. No. 3,862,190 discloses various 4-amino-5-phenoxypyrimidine compounds useful for these purposes. However, in the search for still new and better or more improved anti-ulcer agents, little is known about the effect of acidic functional groups on compounds of this type and particularly, a carboxylic acid group attached to a heterocyclic ring moiety.

#In accordance with the present invention, it has now been rather unexpectedly found that certain novel N-substituted pyrrolidonecarboxylic acid compounds are extremely useful when employed in therapy as anti-ulcer agents. More specifically, the novel compounds of this invention are all selected from the group consisting of N-(p-benzamido)-2-pyrrolidone-4-carboxylic acids of the formula: ##STR1## and the lower alkyl esters and unsubstituted amide derivatives thereof, and the base salts of said acids with pharmacologically acceptable cations, wherein R is a member selected from the group consisting of alkyl having from seven to eighteen carbon atoms arranged in a straight chain, benzyl, .beta.-phenylethyl and 2-pyridyl. These novel compounds all possess anti-ulcer activity to a significantly high degree and are therefore useful in the treatment of peptic ulcers.

#An intimate mixture of 22.0 g. (0.795 mole) of p-amino-N-(n-decyl)benzamide and 10.34 g. (0.0795 mole) of itaconic acid was prepared by combining said materials together in a suitable round-bottomed flask with the aid of a magnetic stirring apparatus. The mixture was then heated via an oil bath to a temperature of ca. 130.degree. C., while being maintained in a nitrogen atmosphere with continued stirring. At this point, the contents of the flask had completely turned to a liquid. After maintaining the bath temperature at 135.degree. C. for a period of 0.6 hours, the material started to solidify again and was completely solid after an additional one-half hour at this same temperature. The sample was then cooled to room temperature (.about.25.degree. C.) and dissolved in 250 ml. of cold 0.5 N aqueous sodium hydroxide solution, followed by filtration to remove any insoluble material present. The resulting filtrate was then adjusted to pH 3.0 with 6 N hydrochloric acid, while being maintained at 0.degree. C. throughout this step by means of immersion in an ice bath. The precipitate which soon formed was filtered and thereafter washed with cold water and air-dried. Recrystallization of the crude material from absolute ethanol then gave 20.18 g. (67%) of pure N-[N'-(n-decyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p. 174.degree.-177.degree. C.

#Anal. Calcd. for C.sub.22 H.sub.32 N.sub.2 O.sub.4 : C, 68.01; H, 8.30; N, 7.21. Found: C, 68.14; H, 8.46; N, 7.40.

#The procedure described in Example I was repeated except that p-amino-N-(n-octyl)benzamide was the starting material employed in place of p-amino-N-(n-decyl)benzamide, using the same molar proportions as before. In this particular case, the corresponding final product obtained was N-[N'-(n-octyl)-4'-benzamido]-2-pyrrolidone-4-carboxylic acid, m.p. 175.degree.-177.degree. C.