COMPOSITIONS COMPRISING PEPSTATIN AND AN HISTAMINE H2-RECEPTOR ANTAGONIST HAVING AN ENHANCED ANTIULCER ACTIVITY

Abstract: Enhanced antiulcer activity is obtained in warm-blooded animals by the concomitant administration of the pepsin complexing agent, pepstatin, and an histamine H₂-receptor antagonist of the formula wherein A, m, Z, n, R¹ and R² are as defined herein. Concomitant administration of the two entities reduces the amount of histamine H₂-receptor antagonist necessary for treatment, thereby decreasing its side-effect liability.

Description: In the treatment of peptic ulcers in warm-blooded animals, the concomitant administration of the pepsin-complexing agent, pepstatin, and a histamin H2-receptor antagonist of the formula I: EMI1.1 wherein A, m, Z, n, RÚ and Rê are as defined below, provides enhanced antiulcer activity, reduces the amount of the compound of Formula I necessary for effective treatment and thereby reduces the side effect liability of the compound of Formula I. This invention relates to pharmaceutical compositions containing pepstatin and at least one compound of Formula I for treating peptic ulcers in warm-blooded animals. The precise cause of peptic ulceration in man is unknown although gastric acid is considered to be one of the essential factors in the etiology of this disease. It recently was discovered that gastric acid secretion is mediated, at least in part, by histamin H2-receptors located on pa rietal cells in the gastric mucosa and the gastric acid output induced by all secretagogues could be antagonized by specific antagonists of these receptors [Black, J. W. et al., Nature, 236, 385-390 (1972); Brimblecombe, R. Wet et al., J. Int. Ned. Res., 3, 86-92 (1975)]. The first successful commercial histamine H2-receptor antagonist, cimetidine (II), EMI2.1 is now in widespread use as. an antiulcer agent. A more recently introduced histamine H2-receptor antagonist, ranitidine (III), EMI2.2 is now being sold and used in several countries of the world. The role of the proteolytic enzyme, pepsin, in the etiology of ulceration is not completely understood. Pepsin has been shown to play a major role in the development of experimentally induced ulcers in animals, but this may be due to lesion enlargement by means of pepsin digestion of necrotic tissue rather than by causing the initial damage. It is also possible that pepsin is entirely responsible for the erosions and that the acid produces pain and retards healing. 1) Umezawa, H. et al., in J. Antibiotics, 23, 259-262 (1970), disclose the pentapeptide, pepstatin, which has the structure EMI3.1 and which is a specific complexing agent for the enzyme pepsin. Pepstatin was found to prevent the formation of stomach ulcers in the pylorus ligated (Shay) rat. 2) Miyawaki,- et al., in Nagano-ken Noygo Sogo Shikenjo Chikusan Shikenjo Kenkyu Hokoku, 14, 14-25 (1977) las reported in Chemical Abstracts, 90, 34373X (1979)] report that the addition of pepstatin to the feed at > 50 ppm inhibited pepsin activity in the gastric juice of swine and prevented the occurrence of ulcers. 3) Bonnevie, O. et- al., in Gut, 20, 624-628 (1979), report the results of a double-blind randomized clinical trial of pepstatin versus placebo in patients having duodenal ulcers. Pepstatin was administered in 100 mg doses, given seven. times a day, this dosage being sufficient to inhibit the peptic activity of gastric juice for 18 hours a day. They found no significant difference between pepstatin and placebo in the healing or symptomatology of duodenal ulcer. 4) Svendsen, L. Bet et al., inscand. J. Gastroent., 14, 929-932 (1979), report the results of a double-blind randomized clinical trial of pepstatin versus placebo in patients having gastric ulcer. Pepstatin was administered in 100 mg doses seven times a day. They were not able to detect any influence of pepstatin either on the healing or on the symptomatology of gastric ulcer. 5) Strauss, R. J. et al., in Surg. Forum, 28, 361-363 (1977), disclose that, in stress ulceration tests in rats, two or more days of pretreatment with either cimetidine or carbenoxolone significantly decreased ulcer formation. When the two agents were given together, significant ulcer reduction was found after only one-half day of predosing. Carbenoxolone is not an antisecretory or anti-pepsin agent, but acts by stimulating gastric mucus synthesis. 6) Dajani, E. Z. et al., in J. Pharmacol. Exp. Ther., 210, 373-377 (1979), disclose that, in stress ulceration tests in rats, a combination of cimetidine and propantheline bromide produced synergistic antiulcer activity and that a combination of cimetidine and thiopropazate hydrochloride produced additive antiulcer activity. Propantheline bromide (an anticholinergic agent) and thiopropazate hydrochloride (a tranquilizer) each act by inhibiting gastric secretion. 7) British Medical Journal, 95-96 (1980) reviews the results obtained in a large number of studies with various new antiulcer agents. With regard to pepsin antagonists, it states: "The results of using pepsin antagonists have been uniformly disappointing. Amylopectin showed no significant benefit in patients with duodenal ulcer, and sucralfate showed none in those with gastric ulcer. Even pepstatin, the most potent in vitro and in-vivo pepsin antagonist, was ineffective in a formal controlled trial in healing duodenal ulcer and in preventing recurrent bleeding in patients admitted with haematemesis and melaena. n 8) U.S. 4,101,650 discloses long-acting pepstatin floating minicapsules comprising center particles of sodium bicarbonate coated with a water-soluble film-coating agent, which are further coated with pepstatin and a water-soluble film coating agent. Because of the release of carbon dioxide in gastric juice, these minicapsules float in the stomach and provide pepsin suppression for 3-5 hours as compared with about 1 hour for plain pepstatin. 9) U.S. Patent 4,062,863 discloses histamine H2-receptor antagonists of the formula EMI5.1 wherein R is hydrogen, (lower)alkyl or (CH2)2 Z'CH2-HET' ; Z and Z' each are sulfur or methylene; and HET and HET' each are an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring, and pharmaceutically acceptable acid addition salts thereof. U.S. Patents 4,120,968, 4,120,973 and 4,166,857 are divisionals thereof which have substantially the same disclosure. 10) Published European Patent Application No. 30,092 dis closes histamine h -antagonists of the formula EMI5.2 in which R1 and R2 are hydrogen or optionally halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl, provided that at least one of R1 and Rz is halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl; X is a phenyl ring with 1 or 2 optional substituents or a 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, the heterocyclic ring, where possible, having 1 optional substituent, which optional substituents are halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy and amino; Y is 0, S, a direct bond, methylene, cis or trans vinylene, sulfinyl or NR4 in which R4 is H or alkyl; m is 0 to 4 and n is 1 to 5; R3 is inter alia AB in which A is inter alia a 3,4-dioxocyclo buten-l,2-diyl radical and B is inter alia the radical NR7R8 in which R7 and R8 are inter alia hydrogen, alkyl, haloalkyl, alkoxycarbonyl, alkenyl, alkynyl, (primary hydroxy)alkyl or (primary amino)alkyl, or R and R9., together with the nitrogen atom to which they are attached, may be a 5- or 6-membered ring which optionally contains O or NR9 in which R9 is H or alkyl. The patents listed under items 9) and 10) above are cited as illustrative of those disclosing histamine H2-receptor antagonists containing a 1,2-di (optionally substituted)amino- cyclobutene-3,4-dione nucleus. Other such patents exist, but none discloses that their compounds provide enhanced antiulcer activity when administered with pepstatin, and none discloses the compounds of Formula I utilized herein. This invention relates to a pharmaceutical composition comprising a mixture of the pepsin-inhibiting agent, pepstatin, and at least one histamine H2-receptor antagonist of the formula EMI6.1 wherein R1 and R2 each are independently hydrogen or (lower)alkyl, and, when R1 is hydrogen, R2 also may be allyl, propargyl, cyclo (lower) alkyl (lower) alkyl, cyclo (lower) alkyl, cyano (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, hydroxy, 2,3dihydroxypropyl, EMI6.2 in which p is an integer of from 1 to 6 inclusive, q is an integer of from 1 to 6 inclusive, R3 and R4 each are independently hydrogen, (lower)alkyl, hydroxy, (lower)alkoxy or halogen, and, when R3 is hydrogen, R4 also may be trifluoromethyl, or R3 and R4, taken together, may be methylenedioxy, R5 is hydrogen, (lower)alkyl, (lower)alkoxy, hydroxy, amino or halogen; ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; and A is EMI7.1 in which R6 is hydrogen, (lower)alkyl, (lower)alkoxy or halogen; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen, (lower)alkyl, allyl, propargyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo(lower)alkyl, or phenyl(lower)alkyl, provided that R8 and R9 may not both be cyclo(lower)alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2)- nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. The method of treating peptic ulcers in a warm-blooded animal in need of such treatment , > comprises concomitantly administering to said animal a peptic activity-inhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. The improvement in the treatment of peptic ulcers in a warm-blooded animal by the administration to said animal of an effective antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof comprises reducing the amount of the compound of Formula I necessary for effective treatment by concomitantly administering to said animal a peptic activity-inhibiting amount of pepstatin. The compounds of Formula I are not themselves our invention, but are the invention of our colleagues, Aldo A. Algieri and Ronnie R. Crenshaw. The compounds of Formula I are relatively nontoxic substances, as demonstrated by pharmacological studies in animals of some of the compounds. These studies showed a toxicity profile substantially the same as that of the commercial B2- antagonist cimetidine. Although widespread human usage!of cimetidine has demonstrated it to be a relatively safe drug with a low incidence of side-effects, it would, of course, be desirable to even further reduce the side-effect liability of such a drug. The compounds of Formula I have been shown by various animal studies to be from about equipotent to about 150 times as potent as cimetidine as inhibitors of gastric acid secretion, depending on the animal model and route of administration, with the preferred compounds of Examples 1 and 9 being about 20-25 times more potent than cimetidine by the oral route. Based on this potency difference, the oral dosage of the compounds of Examples 1 and 9 would be about 1/20 to 1/25 that of cimetidine, thus reducing the expected incidence of side effects. The usual oral dosage of cimetidine is 300 mg, given four times a day, while the usual dosage of the compounds of Examples 1 and 9 is about 12-15 mg, given four times a day. It was an object of this invention to further reduce the necessary dosage of the compounds of Formula I by the concomitant administration of a peptic activityinhibitory amount of pepstatin. As will be shown below, such concomitant administration provides about a three-fold increase in potency compared with the administration of an equal amount of the compound of Formula 1 alone, thus permitting a further three-fold reduction in the dosage of the compound of Formula I. Pepstatin has also been shown by pharmacological studies in animals to be a relatively nontoxic substance; its exceeded 3000 mg/kg in all animal species studied tSvendsen, L. B. et al., Scand. J. Gastroent., 11, 459-463 (1976)). It is essentially unabsorbed upon oral administration; no side effects were observed in human patients with ulcer dyspepsia receiving daily oral doses of 700 mg of pepstatin for up to three months [Svendsen, L. B. et al. (1976) supra]. Pepstatin does not inhibit the production of pepsin but inhibits peptic activity by forming a 1:1 pepsin-pepstatin complex which is devoid of proteolytic activity. In patients with ulcer dyspepsia, it has been demonstrated that pepstatin inhibits gastric peptic activity, but has no effect on the gastric acidity [Svendsen, L. B. et al., Scan. J. Gastroent., 11, 459-463 (1976)). In contrast, the histamine H2-receptor antagonist cimetidine has been shown to antagonize both basal and stimulated gastric acid secretion in normal volunteers [Burland, W. L. et al., Brit. J. Clin. Pharmacol., 2, 481-486 (1975)] and in patients with duodenal ulcer [Longstreth, G. F. et al., New England J. Med., 294, 801-804 (1976)), but its effect on pepsin secretion is less marked [Binder, H. J. and Donaldson Jr., R. M., Gastroenterology, 74, 371-375 (1978)1. The results of those studies indicate that pepstatin and cimetidine act by different mechanisms. The inhibitory effect of the compounds of Formula I on gastric acid secretion is also significantly greater than on pepsin activity, and in this respect its pharmacological profile is similar to that of cimetidine. In the tests described below, gastric erosions produced in rats by the oral instillation of 1.D mL of 0,75N HCl were compared with those in rats which had been pretreated with the most preferred compound of Formula I (of Example 1) or with that compound and pepstatin. Comparison tests utilizing pretreatment with the newer commercial product,¯ ranitidine, and with ranitidine and pepstatin, are also shown. Ranitidine is about 4 and 6 times as potent as cimetidine as an inhibitor of gastric acid secretion by the oral route in the rat and dog, respectively. Experimental Methods A modification of the method of Robert et al., [Gastroenterology, 77, 433-443 (1979)) was employed to produce gastric erosions. Adult male, Long Evans rats weighing 280-300 g (Blue Spruce Farms, Alton, New York) were used. The animals were individually caged and food and water were removed 24 and 18 hours, respectively, prior to testing. On the following day, the test compound was administered orally to the animals 30 minutes before 1.0 m's of 0.75N HC1 was instilled into the stomach by gavage. Animals treated with the combination of the test compound and pepstatin received the test compound 30 minutes before, and a fixed amount of pepstatin (20 mg/kg po) 10 minutes before, the hydrochloric acid was administered. Previous studies in our laboratories had shown that this dose of pepstatin (20 mg/kg po) completely inhibited pepsin activity and antagonized ulcer formation in the 18 hour pylorus ligated rat*. One hour after receiving the HC1 solution, the animals were sacrificed with an intraperitoneal injection of 0.2 mL of T-61GD, a euthanasia solution (National Laboratories Corp.). The stomachs were removed from the animals, cut along the greater curvature, opened, rinsed with saline and pinned out flat in a standard position for macroscopic examination and scoring of erosions. The stomachs were photographed with a Polaroi 9 Close Up camera (Polaroid Corporation) and scoring was determined from the photographs. For scoring purposes, only those erosions with a minimum length of 1 mm were considered. The severity of gastric ulceration was defined for each animal as the sum of the maximum continuous lengths (in mm) of the erosions satisfying the above criteria. Percent inhibition of lesion formation was defined as (mm erosion, vehicle control) - (mm erosion, test agent) X 100. (mm erosion, vehicle control) Data were analyzed using the t-test for unpaired data and ED50 values were calculated from the dose response data using probit analysis [Finney, Probit Analysis, 3rd ed., University Press, Cambridge, England (1971)). The compound of Example 1 and ranitidine (synthesized by the Medicinal Chemistry Research Department of 3ristol laboratories, Division of Bristol-Myers Company) were dissolved in one equivalent of EC1 and the pH adjusted to 5.5 with NaOH. A suspension of pepstatin (Banyu Pharmaceutical Co. Ltd.) in water was made by homogenizing the compound with a few drops of Tween-8 w (Atlas Chemical Industries). Each of these compounds were administered orally by gavage in a volume of 2 mL/kg. Test Results The instillation of HC1 to untreated rats caused extensive gastric erosions consisting of elongated bands 1-10 mm long by 1-3 mm wide. These erosions were located primarily in the corpus (portion of the stomach which secretes acid and pepsin), while the antrum was not as severely affected and no lesions were observed in the forestomach (the non-secretory portion). These findings are similar to those reported by Robert et al., in their initial description of this procedure. Pretreatment of the rats with a 25, 50 or 75 mg/kg dose of the compound of Example 1 prior to instillation of the HC1 decreased the formation of gastric erosions in a dose-related manner Pretreatment of the rats with the compound of Example 1 plus 20 mg/kg of pepstatin significantly enhanced the inhibitory effect or the compound of Example 1 at doses of 50 and 75 mg/kg. An enhancement was also seen at 25 mg/kg, but the difference was not statistically significant (.05 < p < -.10). Figure 1 shows, in graphic form, the percent of reduction in gastric erosions over that of the control rats (no pretreatment), which was obtained at each of the dosage levels of the compound of Example 1 alone and the compound of Example 1 plus pepstatin. When the data shown in Figure 1 were analyzed by probit analysis according to Finney,-it was shown that the response to the compound of Example 1 was linear with respect to the log dose, and that the addition of pepstatin shifted the dose response to the left in a parallel manner. These data are shown in Figure 2. It may be seen from Figure 2 that the ED50 values for the compound of Example 1 alone and the compound of Example 1 plus pepstatin combination were found to be 115 and 33 mg/kg, respectively, thus showing that the combination had more than three times the potency of the compound of Example 1 alone. Pretreatment of rats with a 25, 50, 75 or 100 mg/kg dose of ranitidine prior to instillation of the HC1 similarly decreased the formation of gastric erosions in a dose-related manner. No enhancement of the inhibitory effect over that of ranitidine alone occurred when pepstatin was given along with ranitidine. Figure 3 shows, in graphic form, the percent reduction in gastric erosions over that of the control rats (no pretreatment), which was obtained at each of the dosage levels of ranitidine alone and ranitidine plus pepstatin. When the data shown in Figure 3 were analyzed by probit analysis according to Finney, it was shown that the response to ranitidine was linear with respect to the log dose of the compound and that the addition of pepstatin shifted the dose response to the left in a parallel manner. These data are shown in Figure 4. It may be seen from Figure 4 that the End 50 values for ranitidine alone and the ranitidine-pepstatin combination were found to be 123 and 104 mg/kg, respectively. The ratio of potencies of the combination to ranitidine alone was 1.18, which was not statistically different from unity. The data from these tests are summarized in Table 1. It may be seen that the EDSO's for the compound of Example 1 and ranitidine, given alone, were substantially the same. However, when each of these compounds were administered with pepstatin, the compound of Example 1 showed an enhancement of protection against ulcer formation (by a factor of 3.5) while ranitidine showed no significant enhancement of protection. Thus, the potency of the compound of Example 1 plus pepstatin was approximately three times that of ranitidine plus pepstatin. Table 1 Comparison of the Compound of Example 1 and Ranitidine in Inhibiting HCl-Induced Formation of Gastric Lesions, Alone or in Combina tion with Pepstatin EMI13.1 <tb> <SEP> FED50 <SEP> (mg/kg) <SEP> for <SEP> Inhibition <SEP> of <SEP> Ulcer <SEP> Formation <tb> Compound <SEP> Alone <SEP> with <SEP> Pepstatin <SEP> Potency <SEP> Ratioa <tb> Compound <SEP> of <SEP> Example <SEP> 1 <SEP> 115 <SEP> 33 <SEP> 3.5 <tb> Ranitidine <SEP> 123 <SEP> 104 <SEP> 1.18 <tb> aRatio of potency (cpd. alone) to potency of combination (cpd. plus pepstatin). Antagonism of H2-receptors and the subsequent antisecretory effect probably is not the mechanism of the antiulcer effect in this test, since exogenous HC1 is being supplied. Pepstatin is only poorly absorbed following oral administration as animal studies have shown that more than 90 percent of the compound is excreted in the feces within 72 hours. Therefore, the inhibition of proteolytic activity following oral administration of pepstatin is due primarily to a local effect of this compound. In order to obtain the maximum benefit of the present invention, it is desirable that the dosage of pepstatin be such that there is substantially complete inhibition of gastric pepsin activity for as long a period of the day as practical. When pepstatin was administered to ulcer patients in 100 mg doses seven times a day (with meals, two hours after meals and at bedtime), pepsin activity was inhibited for 18 hours a day. In one preferred embodiment of this invention, pepstatin is administered in dosages of about 100 mg seven times a day. In another preferred embodiment of this invention, pepstatin is administered in dosages of about 175 mg four times a day. In a more preferred embodiment of this invention the pepstatin is administered in the form of floating minicapsules as described in U.S. Patent 4,101,650. The pepstatin floating minicapsules provide pepsin suppression for about 3-5 times as long as plain pepstatin and, in this form, may be administered, for example, four times a day in a dosage of floating minicapsules containing about 100 mg of pepstatin. The dosage of the compounds of Formula I to be adminis terd concomitantly with pepstatin will depend not only on such factors as the weight of the patient, but also on the degree of gastric acid inhibition desired and the potency of the particular compound being utilized. The decision as to the particular dosage to be employed is within the discretion of the physician. In the Heidenhain Pouch Dog test described below, cimetidine has an oral ED50 of approximately 3.3 pmoles/kg. The usual human adult oral dose of cimetidine is 300 mg, given four times a day. The usual human adult starting oral dosages of the compounds of Formula I (without pepstatin) are readily determined from their oral ED50 in this same test. Thus, if the oral ED50 of a particular compound of Formula I is 0.33 moles/kg, the usual starting dosage (without pepstatin) would be approximately 30 mg, given four times a day, etc. VMen administered concomitantly with pepstatin, the usual starting dose would be approximately 15 mg, given four times a day. Similar calculations may be made for parenteral dosages. These starting dosages (and the number of times administered per day) may, of course, be varied by titration of the dosage to the particular circumstances of the specific patient. It will be appreciated by those skilled in the art that, to obtain the benefits of the present invention, it is not neces sÅary to physically combine the compound of 'Formula I and pepstatin in.'a a single unitary dosage form. Not only may the two active ingredients be taken separately, but they may even be given by different routes of administration. Lthough pepstatin provides its effects by local action in the stomach and must be given orally, the compound of Formula I may be given orally or parenterally. For convenience, however, it usually is preferred to administer it orally. The treat- ment of peptic ulcers in a warm-blooded animal in need of such treatment comprises concomitantly administering to said animal a peptic activity-inhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. In man, the usual dosage of the preferred compounds of Formula I is from about 2 to about 100 mg (and most preferably from about 4 to about 50 mg), given three or four times (and most preferably four times) a day. With the most preferred compound of Formula I (the compound of Example 1), the usual dosage is from about 2 to about 15 mg, and preferably from about 4 to about 10 mg. The preferred dosage of pepstatin in man is from about 100 mg when administered about seven times a day, to about 175 mg when administered about four times a day. However, in a more preferred embodiment of this invention, when the pepstatin is in the form of pepstatin floating minicapsules, the preferred dosage is that amount of minicapsules containing about 100 mg of pepstatin, administered about four times a day. The improvement in the treatment of peptic ulcers in a warm-blooded animal by administering to said animal an effective antiulcerogenic amount of at least one compound of Formula I or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof -¯- comprises reducing the amount of the compound of Formula I necessary for effective treatment by concomitantly administering a peptic activity-inhibiting amount of pepstatin. The preferred dosage of pepstatin and of pepstatin floating minicapsules in man is as described in the preceding paragraph. There is provided by the present invention a pharmaceutical composition useful in the treatment of peptic ulcers which comprises a peptic activityinhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. In a preferred embodiment the composition contains from about 2 to about 100 mg (and most preferably from about 4 to about 50 mg) of one of the preferred compounds of Formula I and from about 100 to about 175 mg of pepstatLn. In the most preferred embodiment, the composition contains from about 2 to about 15 (and most preferably from about 4 to about 10) mg of the compound of Example 1, plus from about 100 to about 175 mg of pepstatin. Preferably the compositions according to the invention are in unitary dosage form. As used herein, reference to a pharmaceutically acceptable acid addition salt of a compound of Formula I means the monoor di-salt with a nontoxic pharmaceutically acceptable organic or inorganic acid. Such acids are well known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, berizenesulfonic, acetic, propionic, tartaric, citric, camphorsulfonic, levulinic and the like. The salts are made by methods known in the art. In practicing the present invention, a wide variety of pharmaceutical forms may be employed for the administration of the compound of Formula I and pepstatin, or the pharmaceutical composition containing both entities. Thus, if a solid carrier is used, the preparations maybe tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is used, the prepara tions may be in the form of a soft gelatin capsule, syrup, emulsion, aqueous or non-aqueous suspension or, in the case of the compounds of Formula I, a sterile solution or suspension for injection. These pharmaceutical dosage forms are prepared by conventional techniques. Preparation of Compounds of Formula I The compounds of Formula I may be prepared by various alternative procedures, utilizing as a starting material a compound of the formula EMI17.1 in which 212 is a good leaving group such as halogen, phenoxy, substituted phenoxy, alkoxy or the like. Suitable leaving groups are well-known to those skilled in the art. Preferably, R12 is (lower) alkoxy, and especially methoxy and ethoxy. The compounds of Formula I may be prepared from a compound of Formula IV by various alternative reaction schemes, as shown below in Reaction Schemes 1 and 2. Reaction Scheme 1 EMI18.1 The reactions are conducted in an inert organic solvent; methanol is a convenient and readily available solvent. The reaction temperature is not critical. Most starting materials are quite reactive and the reaction preferably is conducted at a temperature below room temperature, e.g. 0-100C. With some less reactive compounds it is convenient to conduct the reaction at room temperature. Sometimes it is desirable to subsequently raise the temperature of the reaction mixture (e.g. to 50-60 C) to complete the reaction. Reaction Scheme 2 EMI19.1 In Reaction Scheme 2, X is a conventional leaving group 13 @ 13 such as fluoro, chloro, bromo, iodo, -O3SR in which R is (lower)alkyl [e.g. methanesulfonate], aryl or substituted aryl [e.g. benzenesulfonate, p-bromobenzenesulfonate or p-toluene sulfonate], -O3SF, acetoxy or 2,4-dinitrophenoxy. For convenience and economy we prefer to utilize a compound in which X is chloro. The reaction conditions for the preparation of the compounds of Formula VI, VII and VIII are as described for Reaction Scheme 1. The reaction of the compound of Formula VIII with A(CH2)mX may be conducted in any inert organic solvent such as alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or the like. Preferably, the reaction is conducted in an alkanol such as methanol, ethanol or isopropanol. The reaction temperature is not critical; the reaction may be conducted at temperatures of from about 0 to about 2000C. At low temperatures the reaction is slow, while high temperatures normally lead to less pure products due to decomposition and the formation of side-products. Preferably, the reaction is conducted at room temperature. The reaction of the.compound of Formula VIII with A(CH2)mX to produce the compound of Formula I preferably is conducted in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases include, for example, NaOH, ROH, LiOH, triethylamine, dimethylaniline, sodium ethoxide and the like. In a preferred embodiment, the compounds of Formula I have the structure EMI20.1 wherein Rê is hydrogen, (lower) alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and and R9 each are independently hydrogen or (lower)alkyl, or R8 and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3, 6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]- nonane; or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. In another preferred embodiment, the compounds of Formula I have the structure EMI21.1 wherein R2 is hydrogen, (lower)alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl-3-pyridylmethyl; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and 8 and 9 R and R each are independently hydrogen or (lower) - alkyl1 or R and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]- nonane; or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof, In another preferred embodiment, the compounds of Formula I have the structure EMI22.1 wherein R2 is hydrogen or (lower)alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl- 3 -pyridylmethyl; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; ; r is an integer of from 1 to 4 inclusive ; and R8 and R9 each are independently hydrogen or (lower)alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclot3 2.23- nonane; or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. In another preferred embodiment, the compounds of Formula I have the structure EMI23.1 wherein R2 is hydrogen or (lower)alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl-3-pyridylmethyl; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and 9 R8 and R each are independently hydrogen or (lower) - alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3, 6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2]- nonane; or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. As presently envisaged, the particularly preferred compounds of Formula I are a) l-Amino-2- [3- (3-piperidinomethylphenoxy)propylamino)- cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. b) l-Amino-2- [3- (3-piperidinomethylphenoxy ) propylamino) - cyclobutene-3,4-dione hydrochloride. c) l-Amino-2-{2-[ (5-dimethylaminomethyl-2-furyl)- methylthio]ethylamino}cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. d) 1-Amino-2-{2-[(5-dimethylaminomethyl-3-thienyl) methylthio]ethylamino}cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt-, hydrate or solvate thereof. e) 1-Amino-2-(2-I-( 5-piperidinomethyl-3-thienyl )methyl- thio) ethylamino )cyclobutene-3 , 4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. f) l-Amino-2-t3-(3-dimethylaminomethylphenoxy)propyl- amino)cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. g) l-Amino-2-13-(3-pyrrolidinomethylphenoxy)propyl- amino) cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. h) l-Amino-2-{3-t3-(3-methylpyrrolidino)methylphenoxy3- propylamino)cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. i) 1-Methylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. j) 2-[3-(3-Piperidinomethylphenoxy)propylamino3-1-(2- propynylamino)cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. k) 2-[3-(3-Piperidinomethylphenoxy)propylamino]-1-(3pyridyl)methylaminocyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. l) 1-Amino-2-[3-(3-hexamethyleneiminomethylphenoxy) propylaminozcyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. m) l-Amino-2-[3-(3-piperidinomelhylthiophenoxy)propyl- amino) cyclobutene-3 , -dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. n) l-Amino-2-13-(3-heptamethyleneiminomethylphenoxy)- propylamino]cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. o) l-Amino-2-I3-(3-octamethyleneiminomethylphenoxy)- propylamino)cyclobutene-3,4-dione, or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof. The starting materials of Formula II used in the preparation of the compounds of this invention are either known or are prepared by methods known in the art. See, for example, the extensive review article by A. H. Schmidt in Synthesis, Pages 961-994 (December 1980) and references cited therein. Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals, including man, Brimblecombe et al., J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H2-receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, 1, 8001 (1977). Two of the standard animal models for determining gastric antisecretory activity of histamine H2-antagonists are the Gastric Fistula Rat and the Heidenhain Pouch Dog. The EDsots for some of the compounds of Formula I in these two animal models are given in Tables 2 and 3, below. Determination of Gastric Antisecretory Activity in the Gastric Fistula Rat Male Long Evans rats weighing about 240-260 grams at the time of cannula implantation are used. The design and implantation of the stainless steel cannula into the anterior wall of the fore-stomach are carried out essentially as described by Pare et al. ILaboratory Animal Science, 27, 244 (1977)) The fistula components are designed and the operative procedure is carried out exactly as described in the above preference. Post operatively the animals are individually housed in solid bottom cages with sawdust and are allowed food and water ad libitum throughout the entire recovery period. Animals are not used for test purposes for at least 15 days after the operative procedure. The animals are fasted but allowed water ad libitum for 20 hours before the testing procedure is to begin. Immediately prior to collection, the cannula is opened and the stomach washed gently with 30-40 mL of warm saline or distilled water to remove any residual contents. The catheter is then screwed into the cannula in place of the plugging screw and the rat is placed in a clear plastic rectangular cage measuring 40 cm long, 15 cm wide and 13 cm thigh. The bottom of the cage has a slit approximately 1.5 cm wide and 25 cm long running down the center to accommodate the catheter which hangs through it. In this way the rat is not restricted and can move freely about the cage during collection periods. The remainder of the assay is carried out as described by Ridley et al. [Research Comm. Chem. Path. Pharm., 17, 365 (1977)). Gastric secretions collected during the first hour after washing the stomach are discarded as they may be contaminated. For oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 m1/kg) is administered orally via gastric intubation and the animal is returned to the cage for 45 minutes. After this time the plugging screw is removed and replaced with a catheter to which a small plastic vial has been attached to collect the gastric secretions. A two hour sample is collected (this represents the control secretion), the catheter removed and replaced with the plugging screw. The test drug is now administered orally in a volume of 2 mL/kg via gastric intubation. Forty-five minutes later the plugging screw is again removed, replaced with the catheter attached to a small plastic vial and another 2 hour sample is collected. The secretions in the second sample are compared to those of the contrbl sample in order to determine the effects of the test drug. When test compounds are to be evaluated parenterally, the animal is injected ip or sc with the test compound vehicle in a volume of 2 mL/kg immediately after discarding the initial 60 minute collection. A two hour sample is collected (control secretion) and the animals are injected either ip or sc with the test compound in a volume of 2 mL/kg. An additional two hour sample is collected and its secretions are compared to those of the control period to determing drug effects. The samples are centrifuged in a graduated tube for volume determination. Titratable acidity is measured by titrating a one mt sample to pH 7.0 with 0..02N NaOR, using an Autoburet and an electrometric pH meter (Radiometer). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter. Results are expressed as percent inhibition relative to control readings. Dose response curves are constructed and ED50 values are calculated by regression analyses. At least three rats are used at each dosage level and a minimum of three dosage levels are utilized for determination of a dose response curve. Determination of Gastric Antisecretory Actitity in the Heidenhain Pouch Dog Prior to surgery, hematology and blood chemistry profiles are obtained and an assessment made as to the general health of selected female dogs. Dogs are vaccinated with Tissue Vax 5 (DHLP - Pitman-Moore) and housed in general animal quarters for four weeks' observation so incipient diseases may become apparent. Dogs are fasted with water ad libitum 24 hours prior to surgery. Anesthesia is induced with Sodium Pentothal (Abbott) 25-30 mg/kg iv. Subsequent anesthesia is maintained with methoxyflurane (Pitman-Moore). A mid-line linea alba incision from xiphoid to umbilicus provides good exposure and ease of closure. The stomach is pulled up into the operative field, the greater curvature stretched out at multiple points and clamps placed along the selected line of incision. The pouch is made from the corpus of the stomach so that true parietal cell juice is obtained. About 30% of the corpus volume is resected. The cannula is made of light-weight, biologically-inert material such as nylon or Delrin with dimensions and attachments after DeVito and Harkins [J. Appl. Physiol., 14, 138 (1959)). Post operatively, dogs are medicated with antibiotics and an analgesic. They are allowed 2-3 months for recovery. Experiments are carried out in the following way: Dogs are fasted overnight (X18 hours) with water ad libitum prior to each experiment. The dogs are placed in a sling and a saphenous vein cannulated for drug administration. Histamine as the base (100 pg/kg/hr) and chlorpheniramine maleate (0.25 mg/kg/hr) are infused continuously (in a volume of 6 mL/hr) with a Harvard infusion pump. Ninety minutes' infusion are allowed for the dogs to reach a steady state of acid output. At this time the drug or normal saline (control) is administered concomitantly with the secretagogue in a volume of 0.5 mL/kg over a 30 second period. When oral studies are to be carried out, the drug is administered via gastric gavage in a volume of 5 mL/kg. Infusion of the secretagogue is continued and 15 minute samples of the gastric juice are taken for 4.5 hours. Each sample is measured to the nearest 0.5 mL and titratable acidity is determined by titrating a 1 mL sample to pH 7.0 with 0.2N NaOH, using an Autoburet and an electrometric pH meter '(Radiometer). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter. Results are expressed as percent inhibition relative to control readings. Dose response curves are constructed and ED values are calculated by regression analyses. From 3 to S dogs are used at each dose level and a minimum of three dosage levels are utilized for determination of a dose response curve. Table 2 Gastric Antisecretory Activity of Compounds of Formula I in the Gastric Fistula Rat EMI29.1 <tb> <SEP> ED50 <SEP> sc <SEP> Potency <SEP> Ratio <tb> <SEP> Compound <SEP> [ moles/kg] <SEP> [cimetidine <SEP> = <SEP> 1.0 <SEP> <tb> Cimetidine <SEP> 3.8 <SEP> 1.0 <tb> <SEP> (2.3-5.5)* <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 1 <SEP> 0.023 <SEP> 162 <tb> <SEP> (0.011-0.037) <SEP> (77-328)* <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 2 <SEP> < 1 <SEP> > 4 <tb> Compound <SEP> of <SEP> Example <SEP> 3 <SEP> ¯4 <SEP> 1 <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 9 <SEP> 0.055 <SEP> 61 <tb> <SEP> (0.016-0.14) <SEP> (20-204) <tb> Compound <SEP> of <SEP> Example <SEP> <RTI ID=29.7> 10i <SEP> 0.08 <SEP> 48 <tb> <SEP> (0.04-0.16) <SEP> (21-97) <tb> Compound <SEP> of <SEP> Example <SEP> 10j <SEP> 0.044 <SEP> 88 <tb> <SEP> (0.019-0.09) <SEP> (36-211) <tb> Compound <SEP> of <SEP> Example <SEP> 10m <SEP> 0.7 <SEP> 5.4 <tb> <SEP> (0.36-1.4) <SEP> (2.1-12) <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 11 <SEP> 0.067 <SEP> 50 <tb> <SEP> (0.02-0.18) <SEP> (15-169) <tb> Compound <SEP> of <SEP> Example <SEP> 12 <SEP> 0.094 <SEP> 44 <tb> <SEP> (0.046-0.17) <SEP> (22-90) <tb> Compound <SEP> of <SEP> Example <SEP> 14d <SEP> 0.031 <SEP> 124 <tb> <SEP> (0.016-0.056) <SEP> (62-243) <tb> *numbers in parentheses are 95% confidence limits Table 3 Gastric Antisecretory Activity of Compounds of Formula I in the Heidenhain Pouch Dog EMI30.1 <tb> <SEP> ED50 <SEP> Potency <SEP> Ratio <tb> Compound <SEP> Tumoles/kgl <SEP> [gimetidine <SEP> = <SEP> 1 <SEP> 0] <tb> <SEP> Compound <SEP> [ moles/kg] <SEP> [cimetidine <SEP> = <SEP> 1.0] <SEP> <tb> <SEP> (INTRAVENOUS) <tb> Cimetidine <SEP> 2.18 <SEP> 1.0 <tb> <SEP> (1.48-2.95)* <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 1 <SEP> 0.024 <SEP> 87 <tb> <SEP> (0.019-0.029) <SEP> (62-117)*. <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 2 <SEP> ¯20 <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 9 <SEP> ¯40 <SEP> <tb> Compound <SEP> of <SEP> Example <SEP> 10i <SEP> > 40 <tb> <SEP> (ORAL) <tb> Cimetidine <SEP> 3.29 <SEP> 1.0 <tb> <SEP> (1.05-5.19) <tb> <SEP> Compound <SEP> of <SEP> Example <SEP> 1 <SEP> 0.16 <SEP> 25 <tb> <SEP> (0.10-0.22) <SEP> (14-40) <tb> <SEP> Compound <SEP> of <SEP> Example <SEP> 9 <SEP> 20 <SEP> <tb> *numbers in parentheses are 95% confidence limits As used herein and in the claims, the terms "(lower)- alkyl" and "(lower)alkoxy" mean straight or branched chain alkyl or alkoxy groups containing from 1 to 6 carbon atoms. Preferably these groups contain from 1 to 4 carbon atoms and, most preferably, they contain 1 or 2 carbon atoms. The term "cyclo (lower)alkyl", as used herein and in the claims, means a cycloalkyl ring containing from 3 to 7 carbon atoms and preferably from 3 to 6 carbon atoms. Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth. In the following examples, all temperatures are given in degrees Centigrade. Example' 1 1-Amino-2-[3-(3-piperidinomethylphenoxy) propylamino]cyclobutene3,4-dione A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 4.46 g; 13.9 mmoles) [prepared according to published U.K. Patent Application 2,023,133] in 40 mL of methanol was added all at once to a solution of 1,2-dimethoxycyclobutene-3,4-dione (1.97 g; 13.9 mmoles) in 40 mL of methanol that had been cooled to 50 in an ice-water bath. After 2 hours at ambient temperature, the solution was cooled to SC and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then filtered to give 4.35 g of product. The product (4.20 g; 12.2 mmoles) was suspended in 40 mL of 95% aqueous ethanol and 6.11 mL (12.2 mmoles) of aqueous 2.ON HC1 was added with stirring. The solution was filtered through Celite, cooled at 0 for 17 hours, and then filtered to give 4.33 g of the title compound as its hydrochloride salt, mp 254-257 . Anal. Calc'd. for C,9H26C1N303: C, 60.08; H, 6.90; N, 11.06; C1, 9.33. Found (corr. for 0.28% H2O) : C, 59.73; H, 6.97; N, 11.14; Cl, 9.36. Example 2 l-Amino-2-{2-l(5-dlmethylamlnomethyl-2-furyl)methylthio]eth amino )cyclobutene-3 , 4-dione A solution of 2-[(5-dimethylaminomethyl-2-furyl) methylthio]ethylamine (2.89 g; 13.5 mmoles) [prepared according to the procedure described in Belgian Patent 857,3883 in 30 mL of methanol was added dropwise over a period of 30 minutes to a cold (50) stirred solution of 1,2-dimethoxycyclobutene-3,4-dione (1.92 g; 13.5 mmoles) in 50 mL of methanol. After 3 hours at ambient temperature, the solution was cooled to Sc and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then filtered to give 2.48 g of the title compound, mp 227-230 (dec.). An analytical sample was prepared by recrystallization from 95% aqueous ethanol and then from methanol, and was dried in vacuo over P205 for 18 hours to give the title compound as a non-friable sticky solid; the NMR spectrum (100 MHz) in d6 dimethylsulfoxide showed the presence of approximately 0.2 moles of methanol. Anal. Calc'd. for C14HlgN303S-0.2 CH4O: C, 54.01; H, 6.32; N, 13.31; S, 10.15. Found (corr. for 0.54% H2O): C, 53.72; H, 6.07; N, 14.01; S, 10.51. Example 3 1-Amino-2-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino )cyclobutene-3, 4-dione A solution of 2-l(5-dimethylaminomethyl-2-thienyl)- methylthio)ethylamine (2.06 g; 8.94 mmoles) prepared according to the procedure described in Belgian Patent 867,105) in 20 mL of methanol was added all at once to a cold (50) solution of 1,2-dimethoxycyclobutene-3,4-dione (1.27 g; 8.94 mmoles) in 20 mL of methanol. After 3.5 hours at ambient temperature, the solution was cooled to 50 and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred for 18 hours at ambient temperature and then filtered to give 2.66 g of product. Recrystallization from 95% aqueous ethanol yielded the title compound, mp 240-243 (dec.). Anal. Calc'd for C14H19N3O2 S2: C, 51.67; H, 5.88; N, 12.91; S, 19.70. Found: C, 51.60; H, 5.76; N, 12.97; S, 19.69. Example 4 2-{2-[t5-Dimethylaminomethyl-2-furyl)methylthioZethylamino}-l- methylaminocyclobutene-3,4-dione A solution of 2-[(5-dimethylaminomethyl-2-furyl)methyl- thio)ethylamine (2.89 g; 13.5 mmoles) in 30 mL of methanol was added all at once to a cold (50) solution of 1,2-dimethoxycyclobutene-3,4-dione (1.92 g; 13.5 mmoles) in 50 mL of methanol. After 3 hours at ambient temperature, the solution was cooled to 50 and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 18 hours at ambient temperature, evaporated under reduced pressure and then triturated with acetonitrile and filtered to give 2.9 g of crude product. The product was placed on 40 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-acetonitrile. The appropriate fractions were evaporated, then combined in methanol, treated with charcoal, filtered and evaporated to near dryness. The solid was triturated with acetonitrile and filtered to give the title compound, mp 176-177.5 . Anal. Calc'd for C15H21N303S: C, 55.71; H, 6.54; N, 12.99; S, 9.91. Found (corr. for 1.868 H2O): C, 55.46; H, 6.39; N, 13.14; S, 10.30. Example 5 2-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-1methylaminocyclobutene-3,4-dione A solution of 2-[(5-dimethylaminomethyl-2-thienyl)- methylthio3ethylamine (1.32 g; 5.73 mmoles) in 20 mL of methanol was added to a cold (5 ) solution of 1,2-dimethoxycyclobutene3,4-dione (814 mg; 5.73 mmoles) in 15 mL of methanol. After 3.5 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 70 hours at ambient temperature and then filtered to give 1.38 g of product. Recrystallization from ethanol yielded the title compound, mp 185-187 . Anal. Calc'd. for Cl5H21N302S2: C, 53.07; H, 6.23; N, 12.38; S, 18.89. Found: C, 53.18; H, 6.21; N, 12.25; S, 18.94. Example 6 1-Amino-2-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}cyclobutene-3,4-dione A mixture of 2-[(5-dimethylaminomethyl-4-methyl-2thienyl)methylthio]ethylamine (3.0 g; 12.3 mmoles) [prepared according to the procedure described in published United Kingdom Patent Application 2,063,875) and l-amino-2-methoxycyclobutene3,4-dione (1.56 g; 12.3 mmoles) in 50 rat of methanol was stirred at ambient temperature for 18 hours and then filtered to give 3.72 g of product. Recrystallization from 95% aqueous ethanol gave 3.1 g of the title compound. The product (3.1 g; 9.13 mmoles) was suspended in 40 mL of methanol and 1.52 mL of aqueous 6.ON HC1 was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous methanol to give the title compound as its hydrochloride salt, mp 202-205 . Anal. Calc'd. for C15H21N3O2S2HC1: C, 47.93; H, 5.90; N, 11.18; S, 17.06; C1, 9.43. Found (corr. for 0.38% H2O) : C, 47.74; H, 5.79; N, 11.41; S, 17.21; C1, 9.42. Example 7 l-Amino-2-{2- [ (5-piperidinomethyi-4-methvl-2-thienyl )-methylthioj - ethylamino)cyclobutene-3,4-dione The general procedure of Example 6 was repeated except that the 2- [ (5-dimethylaminomethyl-4-methyl-2 -thi enyl ) methyl- thiofethylamine utilized therein was replaced by an equimolar amount of 2-! (5-piperidinomethyl-4-methyl-2 -thienyl ) methylthio) - ethylamine prepared according to the procedure described in published United Kingdom Patent Application 2,063,875). The product (3.64 g; 9.6 mmoles) was suspended in 50 mL of ethanol and 4.8 mL of aqueous 2.ON HC1 was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous ethanol to give the title compound as its hydrochloride salt, mp 150-157 . Anal. Calc'd. for C18H25N303S2HCl: C, 51.97; H, 6.30; N, 10.10; S, 15.41; Cl, 8.52. Found (corr. for 1.58% H2O) : C, 52.05; H, 6.33; N, 10.37; S, 15.24; C1, 8.16. Example 8 l-Amino-2-[3-(3-piperidinomethylphenoxy)propylaminolcyclobutene- 3,4-dione A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 43.37 g; 0.135 moles) in 250 mL of methanol was added to a suspension of l-amino-2-methoxycyclobutene-3,4-dione (17.16 g; 0.135 moles) in 350 mL of methanol and stirred at ambient temperature. After 22 hours, the mixture was filtered to give 38.0 g of product. The product (38.0 g; 0.111 moles) was suspended in 375 mL of aqueous 95% ethanol and 55.3 mL of aqueous 2.ON HC1 was added with stirring. The mixture was filtered to give 40.5 g of the title compound as its hydrochloride salt, which is identical to the product prepared in Example 1. The e product was further purified by dissolving in 30% aqueous ethanol then filtered through a pad of silica gel and carbon, evaporated and the solid recrystallized from aqueous ethanol to yield a colorless hydrochloride salt of the title compound, mp 257-259 . Anal. Calc'd. for C19H25N303HC1: C, 60.08; H, 6.90; N, 11.06; Cl, 9.33. Found: C, 59.82; H, 7.10; N, 10.87; Cl, 9.47. Example 9 1-Amino-2-[3-(3-dimethylaminomethylphenoxy) propylamino]cyclobutene-3, 4-dione A mixture of 3-(3-dimethylaminomethylphenoxy)propyl- amine (1.41 g; 6.77 mmoles) prepared according to the procedure described in Belgian Patent 867,1063 and l-amino-2-methoxycyclobutene-3,4-dione (0.86 g; 6.77 mmoles) in 40 mL of methanol was stirred at ambient temperature for 20 hours and then filtered to give 1.95 g of the title compound. The product (1.95 g; 6.43 mmoles) was suspended in 35 mL of ethanol and 3.21 mL of 2.ON aqueous HCl was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, mp 205-207 . Anal. Calc'd. for C16H21N303HC1: C, 56.55; H, 6.52; N, 12.37; C1, 10.43. Found: C, 56.25; H, 6.56; N, 12.36; C1, 10.27. Example 10 The general procedure of Example 9 is repeated, except that the 3-(3-dimethylaminomethylphenoxy)propylamine utilized therein is replaced by an equimolar amount of (a) 3-(3-pyrrolidinomethylphenoxy)propylamine, (b) 3-l3-(2-methylpyrrolidino)methylphenoxyzpropylamine, (c) 3-[3-(3-methylpyrrolidino)methylphenoxy]propylamine, (d) 3-[3-(4-methylpiperidino)methylphenoxy]propylamine, (e) 3- (3-morpholinomethylphenoxy)propylamine, (f) 3 - 13- (4 -hydroxypiperidino )methylphenoxyf propylamine, (g) 3-[3-(N-methylpiperazino)methylphenoxy]propylamine, (h) 3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propylamine, (i) 3 - (3 -hexamethyleneiminomethylphenoxy) propylamine, (j) 3-(3-heptamethyleneiminomethylphenoxy)propylamine, (k) 4-(3-piperidinomethylphenoxy)butylamine, (1) 5- (3-piperidinomethylphenoxy)pentylamine, (m) 3-(3-octamethyleneiminomethylphenoxy)propylamine, (n) 3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamine and (o) 3-[3-(3-pyrrolino)methylphenoxy)propylamine, respectively, and there is thereby produced (a) l-amino-2- [3- (3-pyrrolidinomethylphenoxy)propylamino) cyclo- butene-3,4-dione as its hydrochloride salt, mp l92.5l950. Anal. Calc'd. for C18H23N3O3HC1: C, 59.10; H, 6.61; N, 11.49; Cl, 9.69. Found (corr. for 0.55% H2O) : C, 58.92; H, 6.73; N, 11.61; C1, 9.41. (b) l-amino-2-3- [3- (2-methylpyrrolidino) methylphenoxy) propyl- aminocyclobutene-3,4-dione as its hydrochloride salt, mp 210-212 . Anal. Calc'd. for C19H25N303HCl: C, 60.08; H, 6.90; N, 11.06; Cl, 9.33. Found: C, 59.97; H, 6.92; N, 10.88; Cl, 9.46. (c) 1-amino-2-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino} cyclobutene-3,4-dione as its hydrochloride salt, mp 184.5 1870. Anal. Calc'd. for C19H25N3O3HCl : C, 60.08; H, 6.90; N, 11.06; Cl, 9.33. Found (corr. for 0.26% H2O) : C, 60.43; H, 7.02; N, 11.03; Cl, 9.31. (d) 1-amino-2-{3-[3-(4-methylpiperidino)methylphenoxy]propyl amino}cyclobutene-3,4-dione, (e) 1-amino-2-[3-(3-morpholinomethylphenoxy)propylamino]cyclo butene-3,4-dione, (f) l-amino-2-{3-[3-(4-hydroxypiperidino)methylphenoxyZpropyl- amino}cyclobutene-3,4-dione, (g) l-amino-2-l3-[3-(N-methylpiperazino)methylphenoxy]propyl- amino}cyclobutene-3,4-dione, (h) 1-amino-2-{3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy] propylamino}cyclobutene-3,4-dione, mp 213-215 (dec.), (i) l-amino-2-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]- cyclobutene-3,4-dione as its hydrochloride salt, mp 200-202 . Anal. Calc'd. for C20E27N303HC1: C, 60.98; H, 7.16; N, 10.67; Cl, 9.00. Found (corr. for 0.28% H2O) : C, 61.25 ; H, 7.14 ; N, 10.55 ; Cl, 8.61. (j) l-amino-2-[3-(3-heptamethyleneiminomethylphenoxy)propylamino] cyclobutene-3,4-dione, mp undefined, gradual decomposition ¯200-240 . Anal. Calctd. for C21H29N303: C, 67.90; H, 7.87; N, 11.31. Found: C, 66.44; H, 7.74; N, 11.33. (k) 1-amino-2-[4-(3-piperidinomethylphenoxy)butylamino]cyclo butene-3,4-dione, (l) 1-amino-2-[5-(3-piperidinomethylphenoxy)pentylamino]cyclo butene-3,4-dione, (m) l-amino-2- 13- (3-octamethyleneiminomethylphenoxy)propylamino) - cyclobutene-3,4-dione, mp undefined. Anal. Calc'd. for C22H31N3O3 : C, 68.54 ; H, 8.11 ; N, 10.90. Found : C, 68.42 ; H, 8.42 ; N, 11.10. (n) 1-amino-2-{3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy] propylamino)cyclobutene-3,4-dione as its hydrochloride salt, mp 162-164 and (o) l-amino-2-{ 3-13- (3-pyrrolino)methylphenoxy] propylamino)cyclo- butene-3,4-dione, respectively. Example 11 1-Methylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3 ,4-dione A solution of 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride, 3.21 g; 10.0 mmoles) in 40 mL of methanol was added to a solution of 1,2-dimethoxycyclobutene3,4-dione (1.42 g; 10.0 mmoles) in 40 mL of methanol. After 1 hour at 100 and 30 minutes at ambient temperature, the solution was cooled to 5D and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 17 hours at ambient temperature and then filtered to give 2.77 g of product. The product (2.77 g) was suspended in 40 mL of ethanol and 4.07 mL (8.1 mmoles) of aqueous 2N HC1 was added with stirring to yield the hydrochloride salt of the title compound, mp 194-198 . Anal. Calc'd. for C20H27N3O3,HCl: C, 60.99; H, 7.16; N, 10.67. Found (corr. for 1.35% H2O) : C, 60.63; H, 6.96; N, 10.71. Example 12 2-[3-(3-Piperidinomethylphenoxy)propylamino]-1-(3-pyridyl)methyl aminocyclobutene-3, 4-dione The general procedure of Example 11 was repeated, except that the methylamine utilized therein was replaced by 1.08 g (10.0 mmoles) of 3-aminomethylpyridine. The crude product was placed on 65 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanolmethylene chloride containing 1% NH4 OH. The appropriate fractions were combined, evaporated and' the solid residue recrystallized from methanol to give the title compound, mp 2:74- 178.50. Anal. Calc'd. for C25H30N403: C, 69.10; H, 6.96; N, 12.89. Found (corr. for 0.52% H2O) : C, 68.80; H, 7.03, N, 12.74. Example 13 2-[3-(3-Piperidinomethylphenoxy)propylamino]-1-propylaminocyclo butene-3 , 4-dione' The general procedure of Example 11 was repeated, except that the methylamine utilized therein was replaced by 4.0 mL (48.7 mmoles) of propylamine. The crude product was placed on 60 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions were combined and the solid residue recrystallized from methanol to yield the title compound, mp 158-1600. Anal. Calc'd. for C22H31N3O3 : C, 68.54 ; H, 8.11 ; N, 10.90. Found : c, 68.11 ; H, 8.25 ; N, 11.21. Example 14 The general procedure of Example 12 is repeated, except that the 3-aminomethylpyridine utilized therein is replaced by an excess molar amount of (a) ethylamine, (b) n-butylamine, (c) allylamine, (d) propargylamine, (e) benzylamine and (f) 6-methyl-3-aminomethylpyridine, respectively, and there is thereby produced (a) l-ethylamino-2-[3-(3-piperidinomethylphenoxy)propylamino3- cyclobutene-3 , 4-dione, (b) -butylamino-2-[3-(3-piperidinomethylphenoxy)propylamino] cyclobutene-3,4-dione, (c) l-allylamino-2-[3-(3-piperidinomethylphenoxy)propylamino]- cyclobutene-3,4-dione, mp 158-159.5 . Anal. Calc'd. for C22H29N3O3 : C, 68.90 ; H, 7.62 ; N, 10.96. Found : C, 68.81 ; H, 7.70 ; N, 10.72. (d) 2-13- (3-piperidinomethylphenoxy)propylamino] -1- (2-propynyl- amino)cyclobutene-3,4-dione, mp 158-160 . Anal. Calc'd. for C227N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C, 69.26; H, 7.25; N, 10.78. (e) l-benzylamino-2-[3-(3-piperidinomethylphenoxy)propylamino3- cyclobutene-3,4-dione hydrochloride, mp 136-140 . Anal. Calc'd. for C26H31N303HC1: C, 66.44; H, 6.86; N, 8.94; Cl, 7.54. round: C, 65.41; H, 7.08; N, 8.83; Cl, 7.67. and (f) 1- (6-methyl-3-pyridyl )methylamino-2- [3- (3-piperidinomethyl- phenoxy)propylamino]cyclobutene-3,4-dione, respectively. Example 15 1-Amino-2-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]cyclobutene-3 , 4-dione A. 2-Chloro-6-piperidinomethylpyridine To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinimide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 100 and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCl (65 mL) and 3N HCl (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 418 of the title compound as a colorless oil, bp 101-103 /0.45 mm Hg. Anal. Calc'd. for C11H15C1N2: C, 62.71; H, 7.18; 13.29; C1, 16.82. Found: C, 61.71; H, 7.31; 13.63; Cl, 17.20. B. N-[3-(6-Piperidinomethyl-2-pyridyloxy)propyl]formamide 3-Aminopropanol (12.84 g, 0.171 mole) was added to a suspension of 50% sodium hydride in mineral oil (7.96 g, 0.166 mole) in 180 mL of dry DMF and the mixture was warmed to 80-83 . A solution of 2-chloro-6-piperidinomethylpyridine (34.0 g, 0.161 mole) [prepared in Step A] in 180 mL of dry DMF was then added dropwise and when complete, the temperature was raised to 125-128 for 3 hours followed by 17 hours at ambient temperature. The precipitated salts were removed by filtration and the solvent stripped under vacuum. The oily residue was dissolved in methylene chloride, washed with water, dried and the solvent evaporated. This residue was redissolved in acetonitrile and extracted with skelly B. After removing the solvent the crude oil was purified by flash chromatography on 270 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride and evaporated to give the title product as a yellow oil, 21.63 g (48.4%). C. 3-(6-Piperidinomethyl-2-pyridyloxy)propylamine N- 13- (6-Piperidinomethyl-2-pyridyloxy)propyl) formamide (19.6 g, 70.7 mmoles) Iprepared in Step B3 was added to a solution of 85% potassium hydroxide pellets (18.63 g, 0.332 mole) dissolved in 180 mL of methanol and the solution was heated at gentle reflux for 20 hours. The solvent was stripped in vacuum and the residue partially purified by redissolving in about 180 mL of 20% methanol-methylene chloride and passing through a pad of 38 g of silica gel. The silica was washed with an additional 120 mL of eluant and the combined filtrates were evaporated to an amber oil. Final purification was effected by flash chromatography on 120 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride containing 0.58 NH4OH. The title compound was obtained as a yellow oil in 63% yield. D. l-Amino-2- 13- (6-piperidinomethyl-2-pyridyloxy) propylamino) - cyclobutene-3,4-dione A mixture of 3-(6-piperidinomethyl-2-pyridyloxy)- propylamine (2.5 g, 10 mmoles) prepared in Step C) and l-amino2-methoxycyclobutene-3,4-dione (1.27 g, 10 mmoles) in 35 ml: of methanol was stirred at ambient temperature for 18 hours and filtered to give 2.71 g of product. The product (2.71 g, 7.87 mmoles) was suspended in 35 mL of absolute ethanol and 7.87 mt of aqueous 6.ON HCl was added with stirring. After 64 hours at 0 the salt was collected by filtration and recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, mp 255-258 . Anal. Calc'd. for C18H24N4O3HCl : C, 56.77; H, 6.61; N, 14.71; Cl, 9.31. Found: C, 56.71; H, 6.80; N, 14.41; Cl, 9.98. Example 16 l-Amino-2- 13- (6-dimethylaminomethyl-2-pyridyloxy) propylamino) - .yclobutene-3 , 4-dione The general procedure of Example 15 was repeated, except that the piperidine utilized in Step A was replaced with an excess of anhydrous dimethylamine. The product (2.26 g, 7.43 mmoles) was suspended in 40 mL of 95% ethanol and 7.43 mL of aqueous 2.0N EC1 was added with stirring. After evaporating most of the solvent, the residue was triturated under isopropyl alcohol and recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, mp 230-234 (dec.). Anal. Calc'd. for C15H20N4O3'HCl: C, 52.87; H, 6.21; N, 16.44; C1, 10.40. Found: C, 51.52; H, 5.98 ; N, 16.64; Cl, 10.88. Example 17 l-Amino-2-[2-(3-piperidinomethylthiophenoxytethylamino] butene-3,4-dione A. m-Dithiobenzoyl chloride A mixture of m-dithiobenzoic acid (20.8 g, 67.9 mmoles) prepared according to the procedure described in J. Chem. Soc., London, 119, 1792 (1921)] and thionyl chloride (200 mL) was refluxed for four hours, filtered and the excess SOCl2 removed in vacuum. B. Dithio bis-3,3'-N,N-di(piperidino)benzenecarboxamide The crude product from Step A, dissolved in 100 mL of tetrahydrofuran, was added dropwise at 30 to a solution of piperidine (25.1 g, 0.29 mole) in 500 mL of tetrahydrofuran. The mixture was stirred at ambient temperature for 76 hours and poured into 1500 mL of dilute HC1 (ca. 2N). After one hour the product was extracted into ether and washed sequentially with water, aqueous 1N NaOH and water. The solvent was evaporated to leave 26.4 g of the title compound. C. 3-(Piperidinomethyl)thiophenol To a suspension of lithium aluminum hydride (45.3 g, 1.19 moles) in 2200 mL of ether was added, dropwise under nitrogen, a solution of dithio bis-3,3'-N,N-di(piperidino)- benzenecarboxamide (141.5 g, 0.32 mole) [prepared in Step B) in 2200 mL of ether and the mixture was stirred at ambient temperature for 20 hours. The mixture was decomposed by the addition of saturated sodium sulfate solution and filtered. The filter cake was stirred with 3000 mL of water and a solution of citric acid monohydrate (550 g, 2.62 moles) in 550 mIl of water was added. The pH of the solution was adjusted to about 2 with 12N HC1 and then to pH 8 with concentrated ammonium hydroxide. The solution was exhaustively extracted with ether to yield 120 g of product. An aliquot of the title compound was recrystallized from isopropyl alcohol, mp 121-1230: Mass spectrum 206 (M+). Anal. Calc'd. for C12Hl7NS: C, 69.56; H, 8.21; N, 6.76; S, 15.46. Found: C, 69.02; H, 8.03; N, 6.67; S, 15.06. D. N-{2-E3-(Piperidinomethyl)thiophenoxytethylwphthaldmide A mixture of 3-(piperidinomethyl)thiophenol (2.07 g, 10 mmoles) (prepared in Step C] and N-(2-bromoethyl)phthalimide (2.41 g, 9.5 mmoles) in 10 mli of dry DMF was stirred at ambient temperature for 84 hours. The solvent was evaporated under reduced pressure and the crude oil flask chromatographed on 100 g of silica gel (230-400 mesh) using 2.5% methanol in methylene chloride with 0.2% NE40H as the eluant. The appropriate fractions were combined and evaporated to give an oil that crystallized under ether. Recrystallization from acetonitrile yielded 1.2 g of the hydrobromide salt of the title compound, mp 180-181.5 . Anal. Calc'd. for C22H24N2O2SHBr: C, 57.26; H, 5.46; N, 6.07; Br, 17.32; S, 6.95. Found: C, 56.98; H, 5.43; N, 6.30; Br, 17.51; S, 7.10. E. 2-(3-Piperidinomethylthiophenoxy)ethylamine Anhydrous hydrazine (1.79 g, 56.0 mmoles) was added to a suspension of N-{2-[3-(piperidinomethyl)thiophenoxy]ethyl}- phthalimide hydrobromide (5.17 g, 11.2 mmoles) prepared in Step D] in 200 mL of 95% ethanol, stirred at ambient temperature for 18 hours and filtered. The filtrate was stripped and the semi-solid residue was stirred with several portions of ether. Evaporation of the solvent gave 2.8 g of title compound as a yellow oil. F. 1-Amino-2-[2-(3-piperidinomethylthiophenoxy)ethylamino] cyclobutene-3,4-dione The crude amine prepared in Step E (1.4 g, 4.05 mmoles) in 40 mL of methanol was added to a suspension of l-amino-2methoxycyclobutene-3,4-dione (0.515 g, 4.05 mmoles) in 100 mL of methanol. The mixture was stirred for 20 hours at ambient temperature and then filtered to give 0.8136 g of product. A second crop was obtained from the concentrated mother liquor and the combined lots were recrystallized from methanol to yield 0.786 g (56%) of the title compound, mp 228-230 (dec.). Anal. Calc'd. for C18H23N3O25: C, 62.58; H, 6.71; N, 12.16; S, 9.28. Found: C, 62.17; H, 6.36; N, 12.59; S, 9.60. Example 18 1-Amino-2-[3-(3-piperidinomethylthiophenoxy)propylamino]cyclobutene-3,4-dione A. N-{3-[3-(Piperidinomethyl)thiophenoxy]propyl}phthalimide The general procedure of Example 17, Step D, was repeated, except the N-(2-bromoethyl)phthalimide utilized therein was replaced with an equimolar amount of N- (3-bromopropyl)- phthalimide. The chromatographed product was recrystallized from isopropyl alcohol to give the title compound as its hydrobromide salt, mp 188-192". Anal. Calc'd. for C23H26N202SHBr: C, 58.10; H, 5.72; N, 5.89; Br, 16.81. Found: C, 57.79; H, 5.41; N1 5.73; Br, 16.80. B. 3-(3-Piperidinomethylthiophenoxy)propylamine To a solution of N-{3-[3-(piperidinomethyl)thiophenoxy]- propyl)phthalimide hydrobromide (58.0 g, 0.12 mole) prepared in Step A] in 1650 mL of 95% ethanol was added hydrazine hydrate (26.9 g, 0.54 mole) and the reaction mixture was heated at 450 for 4.5 hours. The mixture was diluted with 500 mL of ether, filtered and the filtrate evaporated to dryness to give the title compound as an amber oil (14.1 g). An aliquot was distilled to a colorless oil, bp 154-155e/0.15 xnm Hg. Anal. Calc'd. for C15H24N2S: C, 68.13; H, 9.15; N, 10.59. Found: C, 67.37; H, 9.07; N, 10.94. C. l-Amino-2-[3-(3-piperidinomethylthiophenoxy)PropylaminOt- cyclobutene-3 , 4-dione l-Amino-2-methoxycyclobutene-3 , 4-dione (1.20 g, 9.5 mmoles) was added to a solution of the crude amine prepared in Step B (2.50 g, 9.5 mmoles) in 75 mL of methanol and the mixture was stirred at ambient temperature for 16 hours. The precipitate was filtered to give 2.82 g of crude product. The crude solid (2.82 g, 7.84 mmoles) was suspended in 30 mL of 95% ethanol and 4.0 mL of aqueous 2.ON HC1 was added with stirring. After ca. 15 minutes 40 mL of acetone was added and the mixture stored at ambient temperature for 16 hours. The precipitate was recrystallized from aqueous ethanol to yield 1.64 g of the hydrochloride salt of the title compound, mp 236 237,50. Anal. Calc'd. for ClgH25N303SsHCl: C, 57.64; H, 6.62; N, 10.61; S, 8.10; C1, 8.95. Found: C, 57.72; H, 6.56; N, 10.66; S, *8.49; C1, 8.88. Example 19 1-Amino-2-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino)cyclobutene-3 , 4-dione A mixture of 2-[(5-dimethylaminomethyl-3-thienyl)methyl- thio)ethylamine (2.11 g, 8.68 mmoles) [prepared according to the procedure described in published European Patent Application 27,744] and l-amino-2-methoxycyclobutene-3,4-dione (1.10 g, 8.68 mmoles) in methanol was stirred at ambient temperature for 18 hours and filtered. The crude product was recrystallized from 2-methoxyethanol to yield 1.30 g of the title compound as a colorless solid, mp 234-236 . Anal. Calc'd. for C14H19N3O252: C, 51.66; H, 5.88; N, 12.91; S, 19.71. Found: C, 51.53; H, 5.64; N, 12.62; S, 19.91. Example 20 1-Amino-2-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}cyclobutene-3,4-dione The general procedure of Example 19 was repeated except that the 2-ls5-dimethylaminomethyl-3-thienyl)methylthiozethyl- amine utilized therein was replaced by an equimolar amount of 2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamine [prepared according to the procedure described in published European Patent Application 27,744). The crude solid was recrystallized from 2-methoxyethanol to give the title compound (1.27 g), mp 236-238 . Anal. Calc'd. for C17H23N3O2S2 : C, 55.86 ; H, 6.34 ; N, 11.50 ; S, 17.54. Found: C, 55.59; H, 6.23; N, 11.75; s, 17.62. Example 21 1-Amino-2-[3-(5-dimethylaminomethyl-3-thienyloxy)propylamino] cyclobutene-3 , 4-dione An equimolar mixture of 4-13-(amino)propoxy)-N,N- dimethyl-2-thiophenemethanamine prepared according to the procedure described in published European Patent Application 27,7443 and 1-amino-2-methoxycyclobutene-3,4-dione is reacted according to the general procedure of Example 19 to yield the title compound.

Claims: C 1 a i m 5: 1. A pharmaceutical composition useful in the treatment of peptic ulcers which comprises a peptic activityinhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one compound of the formula I: EMI50.1 wherein R1 and R2 each are independently hydrogen or (lower) alkyl, and, when R1 is hydrogen, R2 also may be allyl, propargyl, cyclo (lower)alkyl(lower)alkyl, cyclo(lower)alkyl, cyano (lower) alkyl, 2-f luoroethyl, 2,2, 2-trifluoroethyl, hydroxy, 2,3-dihydroxypropyl, EMI50.2 in which p is an integer of from 1 to 6 inclusive; q is an integer of from 1 to 6 inclusive; R3 and R4 each are independently hydrogen, (lower)alkyl, hydroxy, (lower)alkoxy or halogen, and, when R3 is hydrogen, R4 also may be trifluoromethyl, or 23 and R4, taken together, may be methylenedioxy, R5 is hydrogen, m is an integer of from 0 to 2 inclusive; - n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; and A is EMI51.1 in which R6 is hydrogen, (lower)alkyl, (lower)alkoxy or halogen; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen, (lower) alkyl, allyl, propargyl, (lower)alkoxy (lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo(lower)alkyl, or phenyl(lower)alkyl, provided that R8 and R9 may not both be cyclo(lower)alkyl, or. 8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo13.2.23nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 2. A composition of Claim 1 wherein R1 and R2 each are independently hydrogen or (lower)alkyl, and, when R1 is hydrogen, R2 also may be allyl, propargyl, cyclo(lower)alkyi(lower)alkyl, EMI52.1 in which p and q each are independently an integer of from 1 to 6 inclusive and R3 and R5 each are hydrogen, (lower)alkyl or (lower) alkoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; and A is EMI52.2 in which R6 is hydrogen, (lower)alkyl or (lower)alkoxy; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen or (lower)alkyl, or, g8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo13,2,2]- nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 3. A composition of Claim 1 wherein the compound of Formula I has the structure EMI53.1 wherein R2 is hydrogen, (lower)alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyi-3-pyridylmethy 1; m is an integer of from 0 to 2 inclusive; n is an integer-of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and 9 RS and R9 each are independently hydrogen or (lower) - alkyl, or R8 and 29, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3, 6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclot3.2.2]- nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 4.. A composition of Claim 1. wherein the compound of Formula I has the structure EMI53.2 wherein R2 is hydrogen, (lower)alkyl, allyl, propargyl, 3 pyridylmethyl or 6-methyl-3-pyridylmethyl; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen or (lower)alkyl, or R8 and , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]- nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a phammaceutically acceptable carrier. 5. A composition of Claim 1 wherein the compound of Formula I has the structure EMI54.1 wherein R2 is hydrogen or (lower)alkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl-3-pyridylmethyl; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen or (lower)alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]- nonane, or a nontoxic, pharmaceutically acceptable acid addition st, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 6. A composition of Claim 1. wherein the compound of Formula I has the structure EMI55.1 wherein Rê is hydrogen or (lower)a-lkyl, allyl, propargyl, 3pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene; R6 is hydrogen or (lower)alkyl; iis an integer of from 1 to 4 inclusive; and B and R and R9 each are independently hydrogen or (lower) - alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo[3.2.2]- nonane, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 7. A composition of Claim 5 wherein R2 is hydrogen. A A composition of any one of Claims .1-7- wherein the dosage of pepstatin is from about ioo to about 175 mg and the dosage of the compound of Formula I is from about 2 to about 100 mg. 9. A composition of claim 8 wherein the dosage of the compound of Formula I is from about 4 to about 50 mg. 10. A pharmaceutical composition of claim 8 which comprises from about 100 to about 175 mg of pepstatin and from about 2 to about 15 mg of 1-amino-2-[3-(3piperidinomethylphenoxy)propylamino]-cyclobutene-3,4-dione or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition of claim 8 which comprises from about 100 to about 175 mg of pepstatin and from about 2 to about 15 mg of 1-amino-2-[3-(3-dimethyl amirzomethylphenoxy)-propylamino]cyclobutene-3,4-dione, or a nontoxic, pharmaceutically acceptable acid addition salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier. 12. A composition of claims 8 - 11 in which the pepstatin is in the form of pepstatin floating minicapsules. 13. A composition of anyone of claims 1 - 12 in unit dosage form. 14. Use of at least one compound of the formula I of anyone of claims 1-7 in combination with pepstatin for the treatment of peptic ulcers.

Inventors: BUYNISKI, JOSEPH P., CAVANAGH, ROBERT L., GORDON, MAXWELL
Applicants: BRISTOL-MYERS COMPANY
Application year: 1983
Main classification: A61K37
IPC codes: C07D333, A61K31, C07D213, A61P1, C07D295, C07K7, C07D211, A61K45, A61K38, C07C225, C07D207, C07C213, C07C67, C07D307, A61P43, C07D209