A compound having the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein A is N--Ac--Sar, pGlu, or homo-pGlu-; B is an aryl group, a heteroaryl group, a cycloalkyl group, an aralkyl group, a heteroalkyl group, a heteroaralkyl group, a benzoyl group, an alkyl group, an acetyl group, or a substituted aryl group wherein the substituent is halogen, hydroxy, alkoxy, nitro, cyano, or hydroxyalkyl; E is H or an alkyl group; B and E being separate substituents or, together with C.sub.1 and the nitrogen atom to which B is attached, forming a 5,6, or 7-membered ring; m is an integer between 0 and 4; either F is ##STR2## wherein R is an alkoxy group or an aralkoxy group; or F is ##STR3## and is capable of forming a 6-membered ring with the nitrogen atom of A, provided that F can only be ##STR4## forming a ring with A when A is pGlu or homo-pGlu.

cl BACKGROUND OF THE INVENTION 
This invention relates to antiulcer compounds. 
SUMMARY OF THE INVENTION 
In general, the invention features compounds having the formula 
##STR5## 
or a pharmaceutically acceptable salt thereof, where A is N--Ac--Sar, 
pGlu, or homo-pGlu; B is an aryl group having between 6 and 12, inclusive, 
carbon atoms (e.g., phenyl), a heteroaryl group having between 3 and 12, 
inclusive, carbon atoms (e.g., imidazolyl), a substituted aryl group where 
the substituent is halogen, hydroxy, alkoxy having 1 to 3, inclusive, 
carbon atoms, nitro, cyano, or hydroxyalkyl having 1 to 3, inclusive, 
carbon atoms, a cycloalkyl group having between 3 and 7, inclusive, carbon 
atoms (e.g., cyclohexyl), an aralkyl group having between 7 and 17, 
inclusive, carbon atoms (e.g., benzyl), a heteroalkyl group having between 
1 and 5, inclusive, carbon atoms (e.g., thioalkyl), a heteroaralkyl group 
(e.g., 4-imidazole ethyl), a benzoyl group, an alkyl group having between 
1 and 5, inclusive, carbon atoms (e.g., methyl or ethyl), or an acetyl 
group; E is H or an alkyl group having between 1 and 5, inclusive, carbon 
atoms; B and E either being separate substituents or, together with 
C.sub.1 and the nitrogen atom to which B is attached, forming a 5,6, or 
7-membered ring; m is an integer between 0 and 4, inclusive; and either F 
is 
##STR6## 
where R is a hydroxy group, an aralkoxy group having between 7 and 17, 
inclusive, carbon atoms (e.g., benzyloxy), or an alkoxy group having 
between 1 and 3, inclusive, carbon atoms; or F is 
##STR7## 
and can form a 6-membered ring with the nitrogen atom of A, provided that 
F can only be 
##STR8## 
forming a ring with A when A is pGlu or homo-pGlu. (When no isomer 
designation is given with reference to an amino acid, the L-isomer is 
intended.) 
In other preferred embodiments, B is phenyl, benzyl, or benzoyl; E is H, 
methyl, or ethyl; and B and E, together with C.sub.1 and the nitrogen atom 
to which B is attached, form a 5,6, or 7-membered ring having the formula 
##STR9## 
where W is nothing, --CH.sub.2 --, or 
##STR10## 
and Z is nothing, --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --. 
In other preferred embodiments, B is ethyl, thiomethyl, acetyl, or E is 
methyl, ethyl, or propyl; and B and E, together with C.sub.1 and the 
nitrogen atom to which B is attached, form a 5,6, or 7-membered ring 
having the formula 
##STR11## 
where X and Y, together, are --CH.sub.2 CH.sub.2 --, --CH.sub.2 S--, 
##STR12## 
and p is an integer from 1 to 3, inclusive. 
Preferred compounds of the invention include 
N-(pyroglutamyl)-N-benzylglycine; N-(pyroglutamyl)-N-benzylglycine 
ethylester; N-(N'-acetylsarcosyl)-N-benzylglycine; 
N-(N'-acetylsarcosyl)-N-benzylglycine ethylester; 
.beta.-[N-(pyroglutamyl)-N-benzyl]aminopropionic acid; 
ethyl-.beta.-[N-(pyroglutamyl)-N-benzyl]aminopropionate; 
.beta.-[N-(N'-acetylsarcosyl)-N-benzyl]aminopropionic acid; 
ethyl-.beta.-[N-(N'-acetylsarcosyl)-N-benzyl]aminopropionate; 
1-benzylpyrrolo(1,5-c)-piperazine-3,6,9-trione; N-(N.sup.1 
-acetylsarcosyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic ethyl ester; 
and N-(N.sup.1 
-acetylsarcosyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; or 
pharmaceutically acceptable salts thereof. 
In other preferred embodiments, a therapeutically effective amount of the 
therapeutic compound and a pharmaceutically acceptable carrier substance, 
e.g., magnesium carbonate or lactose, form a therapeutic composition, 
e.g., a pill, tablet, capsule, or liquid for oral administration to a 
patient; a liquid capable of being administered nasally to a patient; or a 
liquid capable of being administered intravenously, parenterally, 
subcutaneously, or intraperitoneally. 
The compounds of the invention are effective in treating gastric, peptic, 
or duodenal ulcers. They are stable, inexpensive, non-toxic, and 
non-mutagenic. 
Other features and advantages of the invention will be apparent from the 
following description of the preferred embodiments thereof, and from the 
claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
We now describe the structure, synthesis, and use of preferred embodiments 
of the invention. 
Structure 
The compounds of the invention have the general formula recited in the 
Summary of the Invention above. Examples of preferred compounds within 
this formula are those referred to as preferred embodiments above. 
The compounds of the invention are N-disubstituted glycine or 
N-disubstituted B-aminopropionic acid derivatives; the tertiary amines 
thus created confer stability to the compounds. The N-substituents include 
an L- or D-amino acid (pGlu, homo-pGlu, or N-AcSar) and an aryl, 
heteroaryl, benzoyl, aralkyl, heteroalkyl, cycloalkyl, alkyl, 
heteroaralkyl, or acetyl group; these groups can be substituted or 
unsubstituted. 
When the compound is an N-disubstituted glycine in which one of the 
substituents is pGlu or homo-pGlu, a 6 membered ring can form between the 
nitrogen atom of the pGlu or homo-pGlu group and the carbonyl of the 
glycine group. Cyclization reactions to form 4, 5, 6, or 7 membered rings 
between the nitrogen and C.sub.1 atoms of the glycine or B-amino propionic 
acid groups is also possible. 
The compounds can also be provided in the form of pharmaceutically 
acceptable salts. Examples of suitable salts include those formed with 
hydrochloric, hydrobromic, sulfuric, maleic, or fumaric acid; potassium, 
sodium, or aluminum hydroxide; or dicyclohexylamine. 
Synthesis 
The aabove compounds can be synthesized as follows. First, a compound of 
formula (2), (3), or (4); 
##STR13## 
where X represents a hydroxyl or carboxylic acid activating group, e.g., a 
halogen such as chlorine, is condensed with a secondary amino-ester of 
formula (5) 
##STR14## 
where R is lower (between one and three, inclusive, carbon atoms) alkoxy 
or aralkoxy and m is between 0 and 4, inclusive. 
The corresponding acids are then prepared from these compounds by 
hydrolyzing the esters with aqueous base. When compounds (2) or (3) are 
condensed with compound (5) in which m=0, intramolecular cyclization via 
nucleophilic displacement of R by the nitrogen of compounds (2) or (3) can 
take place, resulting in the formation of a 6-membered ring. 
Compounds within formulae (2), (3), (4), and (5) are commercially 
available; alternatively they can be synthesized according to standard 
methods, e.g., as described in Greenstein et al. Chemistry of the Amino 
Acids, Vols. 1-3, J. Wiley, New York (1961); and J.Pharm.Sci., 51, 1058 
(1962). 
The condensation reactions are preferably carried out in an inert polar 
organic solvent, e.g., dimethylformamide, tetrahydrofuran, acetonitrile, 
or dichloromethane, using a suitable mild condensing agent, e.g., 
dicyclohexylcarbodiimide (DCC), and, optionally, a catalyst, e.g., 
1-hydroxybenzotriazole. The reaction temperature is maintained below room 
temperature (-15.degree. C. to room temperature) in order to minimize side 
reactions. Typical suitable condensation procedures are described in 
Schroeder et al., The Peptides, Vols. 1-2 (1965, 1966) and Gross et al., 
The Peptides, Vols. 1-3 (1979, 1980, 1981). 
The intermediate and final products are isolated and purified by standard 
methods, e.g., column chromatography or crystallization. Purity is 
determined using chromatographic, spectroscopic, and chemical analysis. 
Specific compounds are made as follows. 
N-(pyroglutamyl)-N-benzylglycine ethylester 
A cold solution of 2.48 g DCC in 10 ml dimethylformamide is added to a 
stirred ice-cooled solution of 1.5 g pyroglutamic acid, 2.18 g 
N-benzylglycine ethylester, and 3.13 g 1-hydroxybenzotriazole in 20 ml dry 
dimethylformamide, and the resulting solution is stirred at 0.degree. C. 
for 1 hr and then at room temperature overnight. It is then filtered and 
the solvent evaporated in vacuo to dryness. The residue is dissolved in 
150 ml chloroform, washed with 5% aq NaHCO.sub.3 and water, and dried over 
anhydrous MgSO.sub.4. Following evaporation of solvent, the residue is 
chromatographed on silica gel (55 g) using chloroform followed by 
chloroform/methanol (20:1). Appropriate fractions are pooled and the 
solvent removed in vacuo to yield 2.6 g of the product as an oil. 
TLC: (silica gel; CHCl.sub.3 /MeOH=9:1) R.sub.f =0.45. 
N-(pyroglutamyl)-N-benzylglycine and 1-benzylpyrrolo[1, 
5-c]-piperazine-3,6,9-trione 
1.25 g N-(pyroglutamyl)-N-benzylglycine ethylester is dissolved in 5 ml 
methanol, treated with 3 ml 2N NaOH, and stirred for 5 min., after which 
the solution is concentrated to a small volume by removal of solvents. The 
residue is then dissolved in 10 ml H.sub.2 O, acidified to pH2, extracted 
several times with ethyl acetate, and dried over anhydrous MgSO.sub.4. 
Following evaporation of solvent, the residue is chromatographed on silica 
gel (55 g) using chloroform/methanol/acetic acid (4:1:0.1). The first 
fractions give 0.36 g N-(pyroglutamyl)-N-benzylglycine as a white solid. 
TLC: (silica gel; CHCl.sub.3 /MeOH/HOAC=4:1:0.1) R.sub.f =0.6, Mass: 276 
(molecular ion). 
Later fractions afford 0.18 g 
1-benzylpyrrolo[1,5-c]-piperazine-3,6,9-trione, the result of 
intramolecular cyclization, as a foamy solid. 
TLC: (silica gel; CHCl.sub.3 /MeOH/HOAC=4:1:0.1) R.sub.f =0.2. Mass: 258 
(molecular ion). 
Ethyl-.beta.-[N-(pyroglutamyl)-N-benzyl]aminopropionate and 
.beta.-[N-(pyroglutamyl)-N-benzyl]aminopropionic acid are prepared in 
analogous fashion by substituting ethyl-.beta.-[N-benzyl]-aminopropionate 
for N-benzylglycine ethylester. 
N-(N'-acetylsarcosyl)-N-benzylglycine ethylester 
A cold solution of 1.65 g DCC in 3 ml dimethylformamide is added to a 
stirred ice-cooled solution of 1.0 g N-acetylsarcosine and 1.4 g 
N-benzylglycine ethylester in 9 ml dry dimethylformamide, and the 
resulting solution is stirred at 0.degree. C. for 1 hour and then at room 
temperature for 2 hours. It is then filtered and the precipitate is washed 
with dimethylformamide. The filtrate and washings are combined and the 
solvent is evaporated to dryness in vacuo to yield a residue which is then 
dissolved in 30 ml chloroform, washed with 5% aq. NaHCO.sub.3 and water, 
and dried over anhydrous MgSO.sub.4. Evaporation of solvent produces the 
desired ester which is either isolated (m.p. 98.degree.-101.degree. C.) or 
hydrolyzed directly to form the corresponding acid, 
N-(N'-acetylsarcosyl)-N-benzylglycine. 
N-(N'-acetylsarcosyl)-N-benzylglycine 
Crude N-(N'-acetylsarcosyl)-N-benzylglycine ethylester from the above 
preparation is dissolved in 8 ml ethanol, treated with 10.8 ml 1N NaOH, 
and stirred for 10 min, after which the solution is diluted with 30 ml 
water and extracted several times wih ether. The aqueous layer is then 
adjusted to pH1, extracted several times with ethyl acetate, and dried 
over anhydrous MgSO.sub.4. Following evaporation of solvent, the residue 
is recrystallized from methanol-ether to yield 1.16 g of the desired acid 
(m.p. 135.degree.-136.degree. C.). 
TLC: (silica gel; CHCl.sub.3 /MeOH/HOAC=6:2:0.5) R.sub.f =0.58. 
Anal. calc'd. for C.sub.14 H.sub.18 N.sub.2 O.sub.4 : C, 60.41; H, 6.51; N, 
10.06. Found: C, 60.16; H, 6.43; N, 10.08. 
Ethyl-.beta.-[N-(N'-acetylsarcosyl)-N-benzyl]aminopropionate and 
.beta.-[N-(N'-acetylsarcosyl)-N-benzyl]aminopropionic acid are prepared in 
analogous fashion by substituting ethyl-.beta.-[N-benzyl]aminopropionate 
for N-benzylglycine ethylester. 
Benzyl-.beta.-[N-(pyroglutamyl)-N-(4-ethylimidazolyl)]aminopropionate and 
Benzyl-.beta.-[N-(N'-acetylsarcosyl)-N-(4-ethylimidazolyl)]aminopropionate 
These compounds can be prepared by condensing 
benzyl-.beta.-[N-(4-ethylimidazolyl)]aminopropionate, formed from the 
reaction of histamine with benzylacrylate, with either pyroglutamic acid 
or N-acetylsarcosine according to the above-described methods; the 
corresponding acids can be prepared via catalytic hydrogenation of the 
product esters using Lindlar's catalyst. 
N-(N.sup.1 -acetylsarcosyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic 
ethyl ester 
This compound can be prepared by condensing 
1,2,3,4-tetrahydroisoquinoline-3-carboxylic ethyl ester with 
N-acetylsarcosine according to the above-described methods; the 
corresponding acid can be prepared via catalytic hydrogenation of the 
product ester using Lindlar's catalyst or via base hydrolysis. 
USE 
When administered to a patient (e.g., orally, intravenously, parenterally, 
nasally, or by suppository), the compounds are effective in the treatment 
of gastric, peptic, and duodenal ulcers, especially those induced by 
dimaprit, indomethacin, and aspirin. 
The compounds can be administered to a human patient in a dosage of 5-500 
mg/kg/day, preferably 25 mg/kg/day. 
Other embodiments are within the following claims.