GB2117769A - Substituted diamino-thiadiazoles - Google Patents

Abstract

Histamine H2-receptor antagonists of the formula <IMAGE> wherein A, m, Z, n and R<1> are as defined herein, and their nontoxic pharmaceutically acceptable salts, hydrates and solvates are novel anti-ulcer agents which are prepared by ring closure of a substituted ethanediimidamide of the formula <IMAGE>

Description

SPECIFICATION Substituted diamino-thiadiazoles Summary of the invention Certain 3-(amino or substituted amino)-4-(substituted amino)-1 ,2,5-thiadiazoles having the formula

wherein A, m, Z, n and R1 are as defined below, and their nontoxic pharmaceutically acceptable salts, hydrates and solvates, are potent histamine H2-receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other pathological hypersecretory conditions.The compounds are prepared by ring closure of the correspondingly substituted ethanediimidamide of the formula

Background and prior art Our published United Kingdom Patent Application No. 2,067,987 discloses 3,4-disubstituted-1,2,5thiadiazole 1-oxides and 1,1-dioxides having the formula

and processes for their preparation, wherein the variables A, m, Z, n and R1 are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein are 1-oxides or 1,1-dioxides (p is 1 or 2), and the compounds of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds.

Published European Patent Application No. 40,696 discloses inter alia 3,4-disu bstituted-1 ,2,5-thiadiazole 1-oxides and 1,1-dioxides having the formula

and processes for their preparation, wherein the variables R, &commat; , n, X, m, R1 and R2 are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein also are 1 -oxides or 1,1-dioxides (p is 1 or 2) and the compounds of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds.

In the two publications cited above, each of the processes described for preparation of the prior art compounds involves the use (as a starting material or intermediate) of a 1,2,5-thiadiazole 1-oxide or 1,1-dioxide having either amino groups or suitable "leaving groups" own the 3- and 4-positions. The desired substituents on the 3- and 4-positions are then obtained by substitution on the amino groups or by replacement of the "leaving groups". We have made extensive attempts to prepare the compounds of the present invention by similar procedures, i.e. by utilizing 1,2,5-thiadiazole having amino groups or suitable "leaving groups" on the 3- and 4-positions as starting materials or intermediates. Although numerous variations were tried, along with varying reaction conditions, we were not able to isolate the compounds of this invention by that route.

We have now found that the compounds of the present invention may be prepared by ring closure of the correspondingly substituted ethanediimidamide of the formula

Intermediate II, itself, may be prepared by various procedures.

Complete description This invention relates to histamine H2-receptor antagonists of the formula

wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifiuoroethyl, allyl, propargyl,

in which p is 1 or 2, R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen, R3 also may be trifluoromethyl, or R2 and R3, taken together, may be methylenedioxy, and R4 is 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 oxygen, sulfur or methylene; and Ais

in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and Re and R7 each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when Re is hydrogen, R7 also may be cyclo(lower)alkyl, or Re and R7, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-piperidino, dimethylpiperidino, N-methylpiperazino, 1 ,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; and nontoxic, pharmaceutically acceptable salts, hydrates and solvates thereof.

This invention also relates to processes for the preparation of the compounds of Formula I and to the intermediate compounds of Formula II.

The present invention includes within its scope all possible tautomeric forms, diastereoisomeric forms and optically active isomers of the compounds of Formula I as well as mixtures thereof. As used herein and in the claims, the term "(lower)-alkyl" means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms. The term "(lower)alkoxy" means a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms. "Cyclo(lower)alkoxy" means a cycloalkyl group containing from 3 to 6 carbon atoms. The term "nontoxic pharmaceutically acceptable salts" means acid addition salts formed with acids such as hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, tartaric, citric levulinic, benzoic, succinic and the like.

In the compounds of Formula I, R1 preferably is hydrogen or (lower)alkyl, more preferably is hydrogen or methyl and most preferably is hydrogen. Substituent A preferably is the substituted phenyl moiety, substituted furyl moiety or substituted thienyl moiety shown above, and most preferably is the substituted phenyl moiety. Substituent Z preferably is sulfur or oxygen and, when A is the substituted phenyl moiety, Z preferably is oxygen. It is preferred that m is zero or 1 and n is 2 or 3, and that, when A is the substituted phenyl moiety, m is zero and n is 3. R5 preferably is hydrogen or methyl and most preferably is hydrogen. It is preferred that q is 1. R6 and R7 preferably are (lower)alkyl or, taken together with the nitrogen atom to which they are attached, are pyrrolidino or piperidino.

The compounds of Formula I may be prepared by reaction of a compound of Formula II with sulfur monochloride (S2Cl2), sulfur dichloride (SCI2) or chemical equivalents thereof, as follows:

wherein A, m , Z, n and R1 are as defined above. At least about 1 mole of S2C12 or SCI2 should be used per mole of Compound ll; it is preferred to use an excess of S2Cl2, e.g. from about 2 to about 3 moles of S2C12 per mole of Compound II. It has been found that SCI2 often gives a cruder product and lower yield of purified product, and we usually prefer to use S2C12 for the reaction. The reaction temperature is not critical; we prefer to conduct the reation at a temperature of from about 0 C to about 50"C, and it is most convenient to conduct the reaction at ambient temperature. The reaction time is not critical and is dependent on temperature. We normally utilize a reaction time of from about 30 minutes to about 6 hours. At ambient temperature, reaction times of from about 1 1/2 to 4 hours usually are peferred. The reaction may be conducted in an inert organic solvent, preferably a mixture of an inert organic solvent and dimethylformamide. Most preferably the reaction is conducted in dimethylformamide.

In a preferred embodiment of the invention, the compounds of Formula I have the structure

wherein R1 is hydrogen or (lower)alkyl, m is O or 1, n is 2 or 3, Z is oxygen or sulfur and A is

in which R5 is hydrogen or methyl, and Re and R7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In a more preferred embodiment, the compounds of Formula I have the structure

wherein R1 is hydrogen or methyl, and Re and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another more preferred embodiment, the compounds of Formula I have the structure

wherein R1 and R5 each are independently hydrogen or methyl, and Re and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another more preferred embodiment, the compounds of Formula I have the structure

wherein R1 and R5 each are independently hydrogen or methyl, and Re and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. In another more preferred embodiment, the compounds of-Formula I have the structure

wherein R1 and R5 each are independently hydrogen or methyl, and Re and R7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, R6 and R7 represent piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

As presently envisaged, the most preferred compounds of Formula I are 1) 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, 2) 3-am ino-4-(2-[(5-dimethylam inomethyl-Bfuryl )-methylthio]ethylamino)-l ,2,5-thiadiazole; 3) 3-amino-4-{2-(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1 ,2,5-thiadiazole, 4) 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole, 5) 3-methylamino-4-[3-(3-piperidinomethylphenoxy)-propylaminoj-1 ,2,5-thiadiazole, 6) 3-benzylamino-4-[3-(3-piperidinomethyl phenoxy)-propylamino]-1 ,2,5-thiadiazole, 7) 3-amino-4-(2-[(5-dimethyla minomethyl-3-thienyl)-methylthio]elhylam no)-l ,2,5-thiadiazole, 8) 3-amino-4-}2-[(5-piperidinomethyl-3-thienyl)-methylthio]ethylamino}-1,2,5-thiadiazole, 9) 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)-propylam ino]-1 ,2,5-thiadiazole and 10) 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)-propylamino]-1 ,2,5-thiadiazole; and their nontoxic, pharmaceutically acceptable salts, hydrates and solvates.

The intermediates of Formula II used in the preparation of the compounds of Formula I may themselves be prepared by various procedures. In one procedure, the corresponding 3-(amino or substituted amino)-4 (substituted amino)-1 ,2,5-thiadiazole 1 -oxide of Formula Ill is treated with a strong mineral acid (preferably HCI) to produce the compound of Formula II.

The reaction may be conducted in an inert solvent and preferably is conducted in methanol. Reaction temperature is not critical; it most conveniently is conducted at room temperature. The compounds of Formula Ill are known or may readily be prepared by the procedures described in our published United Kingdom Patent Application No. 2,067,987.

In an alternate procedure, the compounds of Formula II may be prepared by the following reaction scheme. The

reaction may be conducted in an inert solvent and preferably is conducted in methanol. The starting materials of Formula IV are known or may be readily prepared by known procedures, e.g. as by procedures described in our published United Kingdom Patent Application No. 2,067,987.

In another aspect, this invention relates to novel intermediates of the formula

wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

in which p is 1 or 2, R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen, R3 also may be trifluoromethyl, or R2 and R3, taken together, may be methylenedioxy, and R4 is hydrogen, (lower)alkyl or (lower)alkoxy; mis an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and Ais

in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and Re and R7 each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when Re is hydrogen, R7 also may be cyclo(lower)alkyl, or Re and R7, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1 ,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2.]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof.

In a preferred embodiment, the intermediates of Formula II have the structure

wherein R1 is hydrogen or (lower)alkyl, m is O or 1, n is 2 or 3, Z is oxygen or sulfur and A is

in which R5 is hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure

wherein R' is hydrogen or methyl, and Re and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure

wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure

wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure

wherein R1 and R5 each are independently hydrogen or methyl, and Re and R7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, Re and R7 represent piperidino; or a salt, hydrate or solvate thereof.

As presently envisaged, the most preferred intermediates of Formula II are 1) N-[3-(3-piperidinomethylphenoxy)prnpyl]ethane-diimidamide, 2) N-I2-[(5-dimethylaminomethyl-2-f uryl )methylthio]-ethyl)ethanediimidamide, 3) N-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl )-methylthio]ethyl}ethanediimidam ide, 4) N-[3-(3-pyrrnlidinomethylphenoxy)prnpyliethane-diimidamide, 5) N-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]-ethyl}ethanediimidamide, 6) N-(2-[)5-piperidinomethyl-3-thienyl )methylthio]-ethyl)ethanediimidamide, 7) N-[3-(6-piperidinomethyl-2-pyridyloxy)propyl]-ethanediimidamide and 8) N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-ethanediimidamide;; or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in its basic form or in the form of a nontoxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier.

The pharmaceutical compositions may be administered orally, parenterally or by rectal suppository. A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation may be 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 employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or non-aqueous liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.

The dosage of the compounds of this invention 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 (and the number of times to be administered per day) is within'the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of the specific patient. With the preferred compounds of this invention, each oral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 mg. The active ingredient will preferably be administered in equal doses from one to four times a day.

Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and man, Brimblecombe etna/., 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, (1977). Some of the preferred compounds of this invention have been compared with cimetidine in various tests and have been found to be more potent than cimetidine both as an histamine H2-receptor antagonist in isolated guinea pig right atria and as an inhibitor of gastric acid secretion in rats and dogs.

Determination ofgastric 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 ofthefore-stomach are carried out essentially as described by Pare etna/. [Laboratory Animal Science, 27, 244 (1977)]. The fistula components are designed and the operative procedure is carried out exactly as described in the above reference. Post operatively the animals arre individually housed in solid bottom cages with sawdust and are allowed food and water adlibitum 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 adlibitum 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 high. 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., 17365(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 mUkg) is administered orally via gastric intubation and the animai 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 is 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 control sample in order to determine the effects of the test drug.

When test compound are to be evaluated parenterally, the animal is injected ip or cc 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 determine drug effects.

The samples are centrifuged and placed in a graduated centrifuge tube for volume determination.

Titratable acidity is measured by titrating a one-mL sample to pH 7.0 with 0.02N NaOH, using an Autoburet and an electrometric pH meter (Radiometer). Titratable acid output is calculated in micro-equivalents 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.

TABLE 1 Gastric an tisecre tory activity in the gastric fistula rat ED50 sc Potency Ratio Compound limoles/kg (cimetidine = 1.0) cimetidine 3.48 1.0 (1 .68.5.75)* Example 1 0.094 37 0.043-0.20) Example 2 0.77 4.5 (0.45-1.4) Example 3 --0.5 7 Example4 0.18 20 (0.10-0.36) *95% confidence limits Histamine H2-receptor antagonism-isolated guinea pig atria assay Histamine produces concentration-related increases in the contractile rate of isolated, spontaneously beating guinea pig right atria.Black etna/., Nature, 236,385(1972), described the receptors involved in this effect of histamine as histamine H2-receptors when they reported the properties of burimamide, a competitive antagonist of these receptors. Subsequent investigations by Hughes and Coret, Proc. Soc. Exp.

Biol. Med., 142, 127 (1975) and Verma and McNeill, J. Pharmacol. Exp. Ther., 200,352 (1977) support the conclusion of Black and coworkers that the positive chronotropic effect of histamine in isolated guinea pig right atria is mediated via histamine H2-receptors. Black petal., Agents and Actions, 3, 133 (1973) and Brimblecombe etna/., Fed. Proc., 35, (1976) have a utilized isolated guinea pig right atria as a means for comparing the activities of histamine H2-receptor antagonists. The present comparative studies were carried out using a modification of the procedure reported by Reinhardt et al., Agents and Actions, 4217(1974).

Male Hartley strain guinea pigs (350-450 gm) were sacrificed by a blow on the head. The heart was excised and placed in a Petri dish of oxygenated (95% 02, 5% CO2) modified Krebs solution (niter: NaCI 6.6, KCI 0.35, MgSO4.7H2O 0.295, KH2PO4 0.162, CaCI2 0.238, NaHCO3 2.1 and dextrose 2.09). The spontaneously beating right atrium was dissected free from other tissues and a silk thread (4-0) attached to each end The atrium was suspended in a 20 ml muscle chamber containing oxygenated modified Krebs solution maintained at 32"C. Atrial contractions were recorded isometrically by means of a Grass FT 0.03 force displacement transducer and recordings of contractile force and rate were made with a Beckman RP Dynograph.

A resting tension of 1 g was applied to the atrium and it was allowed to equilibrate for 1 hour. At the end of the equilibration period a submaximal concentration of histamine dihydrochloride (3 x 10-6M) was added to the bath and washed out to prime the tissue. Histamine was then added to the bath in a cumulative fashion using 1/2 log 10 intervalsto give final molar bath concentrations of 1 x 107to3 x 10~5.The histamine-induced increase in atrial rate was allowed to plateau before the next successive concentration was added. The maximal response invariably occurred at the 3 x 10-sM concentration. The histamine was washed out several times and the atrium allowed to return to control rate.The test compound was then added at appropriate molar concentrations and, after a 3D-minute incubation, the histamine dose response was repeated adding higher concentrations as needed.

The dissociation constants (KB) were derived from Schild plots by the method of Arunlakshana, 0. and Schild, H. O. [Br. J. Pharmacol. 14,48(1959)] using at least three dose levels. Parallel shifts in dose-response curves were obtained without depressing the maximal response at the antagonist concentrations utilized, and the results are shown in Table 2.

TABLE 2 Activity in isolated guinea pig right atria Potency Ratio Compound N K5 (moles) (cimetidine=1.0) cimetidine 20 0.41 (.21-.64)* 1.0 Example 1 12 0.003 (.001-.004) 137 Example4 11 0.004(.001-.010) 102 *95% confidence limits As described in U.S. Patent Application Serial No, (Sy-1751), filed (concurrently) by our colleague Thomas A. Montzka, the compounds of Formula I also may be prepared by ring closure of a compound of Formula II with N,N'-thiobisphthalimide having the formula

The use of N,N'-thiobisphthalimide instead of S2C12 or SCI2 for the ring closure reaction results in both purer and higher crude yields of the compounds of Formula I.The crude products of Formula I thereby produced normally are pure enough to form crystalline salts directly without prior chromatographic purification.

In this process, the starting diimidamide of Formula II is reacted with about an equimolar amount of N,N'-thiobisphthalimide in an inert organic solvent such as CH2Cl2. Preferably the starting diimidamide is used in the form of its trihydrochloride salt, in which case three molar equivalents of an amine, such as triethylamine, are added to the reaction mixture to neutralize the trihydrochloride salt. The reaction may be conducted by stirring at room temperature for about an hour to insure completeness of the reaction. The phthalimide which precipitates from the reaction mixture is then extracted with a strong base (e.g. 10-20% aqueous KOH), and the organic solvent layer is dried, filtered and concentrated to yield the crude compound of Formula I.The N,N'-thiobisphthalimide used in the reaction is a known compound which may be prepared as described in the Canadian Journal of Chemistry, 44,2111-2113(1966), or as described below in Preparation No. 1.

PREPARATION NO. 1 N,N'-Thiobisphthalimide A cooled (0 C) solution of phthalimide (14.7 g 0.1 mole) in 80 ml of dimethylformamide (DMF) was treated dropwise with sulfur dichloride (5.15 g, 0.05 mole). After the addition, the mixture was allowed to warm to 20"C with stirring over four hours. The solid was collected and dried to give 12.5 g of the title compound as a DMF solvate, mp 301-315"C. Both ir and nmr spectra are consistant for structure.

Anal. Calc'd. for C16H8N204S'C3H7NO : C, 57.42; H, 3.80; N, 10.57; S, 8.07 Found: C,57.50; H, 3.80; N, 10.29; S, 8.57 The DMF solvate can be removed by recrystallization of the above material from chloroform; mp of the DMF-free product was 320-325"C. The nmr spectrum shows that the DMF has been removed.

Anal. Calc'd. for C16HsN204S C, 59.25; H, 2.49; N, 8.64S,9.89 Found: C, 59.21; H, 2.21; N, 8.91; S, 10.14 EXAMPLE 1 3-Amino-4-[3-/3-piperidinometh ylphenoxylpropylaminol- 1,2,5-thiadiazole A. N- f3- (3-Pip eridinometh ylphen ox y)prop yljethanediimidamide trihydrochloride A suspension of 3-amino-4-[3-(3-piperidinomethyl-phenoxy)prnpylamino]1 ,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmoles) [prepared according to published United Kingdom Patent Application No.2,067,987] in 450 mL of methanol was treated with 38 mL of concentrated HCI. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals.These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.6%) of the title compound, m.p. 205-222"C (dec.). Recrystallization from 50% methanol-ethyl acetate gave an analytical sample, m.p. 206-216"C (dec.).

Anal. Calc'd for C17H27N5O.3HCl : C, 47,84; H, 7.08; N, 16.41 Found: C, 47.56; H, 7.18; N, 16.75 B. 3-A mino-4-J3-(3-piperidinomethylphenoxy)prop ylamin j- 1,2,5-thiadiazole A stirred suspension of N-[3-(3-piperidinomethyl-phenoxy)propyl]ethanediimidamide trihydrochloride (2.13 g, 5.0 mmoles) [prepared in Step A] in 20 mL of dimethylformamide (DMF) was treated with sulfur monochloride (2.02 g, 15.0 mmoles) and stirred for 4 hours.The resultant mixture was poured cautiously into 200 mL of water and made basic with K2C02. This was extracted with 3 x 50 mL portions of methylene chloride and, after drying over MgSO4 and concentration, 2.1 g of a dark gum containing the product was obtained. The product was purified by preparative high pressure liquid chromatography on silica using CH2Cl2 (100) :2-propanol(1 0): NH4OH(0.5) as the mobile phase. The appropriate fractions yielded 0.89 g of the title compound which gave, with fumaric acid in n-propanol, 0.76 g (21.4%) of the title compound as a crystalline fumarate salt, m.p. 187-187.5"C. HPLC indicated a purity of > 99%.

Anal. Calc'd for (C17H25N5OS)2.C4H4O4 : C, 56.27; H, 6.71; N, 17.27; S, 7.90 Found: C, 56.09; H, 6.36; N, 16.98; S, 8.08 A portion of the fumarate was suspended in water, neutralized with K2CO3 and extracted with CH2C12. The CH2C12 was concentrated and the free base of the title compound crystallized cut; m.p. 43-47'C. A portion of the free base was converted to the hydrochoride salt, m.p. 138-140"C.

Anal. Calc'd. for C17H25N5OS.HCl C, 53.18; H, 6.83; N, 18.24; S, 8.35 Found: C, 53.14; H, 6.88; N, 18.49; S, 8.74 EXAMPLE 2 3-A mino-4-{2-[(5-dimethylaminomethyl-2-furyl)meth ylthioj-ethylamino}- 1,2,5-thiadiazole A. N-{2-[2-(5-Dimethylaminomethyl-2-furyl)methylthio,ethyl}-ethanediimidamide trih ydrochloride hydrate A suspension of 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1 ,2,5-thiadiazole 1-oxide (6.59 g; 20.0 mmoles) [prepared according to published United Kingdom Patent Application No.

2,067,987] in 200 mL of methanol was warmed slightly to achieve complete solution, then treated with 13.3 mL of concentrated HCI. After stirring at ambient temperature for 2.5 hours, the solution was concentrated and the residue was triturated with 70 mL of absolute ethanol. The crystals were collected by filtration and dried under vacuum to give 4.3 g (52%) of the title compound, m.p. 166-169"C (dec.).

Anal. Calc'd for C12H21N5OS.3HCl.H 20 C, 35.08; H, 6.38; N, 17.05; S, 7.80 Found: C, 34.85; H, 6.24; N, 17.45; S, 7.97 B. 3-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]-ethylamino}- 1,2,5-thiadiazole.

To a stirred suspension of N-{2-[(5-dimethylamino-methyl-2-furyl)methylthio]ethyl)ethanediimidamide trihydrochloride hydrate (12.3 g; 30.0 mmoles) [prepared in Step A] in 150 mL of DMF was added 7.2 mL of sulfur monochloride (12. 1g; 90 mmoles). After stirring for 4 hours at ambient temperature, approximately half of the DMF was removed at reduced pressure. The remaining black solution was poured into 1 liter of water, made basic with K2CO3 and extracted first with ethyl acetate and then with chloroform. After drying over MgSo4, filtration and concentration, 9.0 g of a black gum containing the product was obtained. This was purified by preparative high pressure liquid chromatography on silica using ethyl acetate (100):2 propanol(1 0): NH2OH(0.5) as the mobile phase.The appropriate fractions yielded 1.24 g of the title compound as a gum.

Treatment of part of this product with an equivalent amount of 2N HCI in methanol yielded the hydrochloride salt of the title compound.

Anal. Calc'd for Cq2H19N5S2O-HCi : C, 41.13; H, 5.76; N, 20.02; S,18.33 Found (corr. for 1.65% H2O) : C, 40.54; H, 5.70; N, 19.39; S,18.44 Treatment of the product with an equivalent amount of cyclohexylsulfamic acid in actone yielded the cyclohexylsulfamate salt of the title compond, m.p.93-95 C.

Anal. Calc'd for C12HagN5S2O-C6Ha3NO3S : C, 43.88; H, 6.55; N, 17.06; S, 19.53 Found: C, 43.77; H, 6.17; N, 17.21; S, 19.58 EXAMPLE 3 3-A mino-4-(2-f(5-dimethylaminomethyl-4-methyl-2-thien yl)-methylthiojeth ylamino}- 1,2,5-thiadiazole A. N-{2-[(5-Dimethylaminomethyl-4-methyl-2-thienyl)methylthiol-ethyllethanediimidamide trih ydroch chloride A stirred solution of 3-amino-4-{2-[(5-dimethylamino-methyl-4-methyl-2-thienyl)methylthio]ethylamino}- 1,2,5-thiadiazole 1-oxide (17.9 g, 50.0 mmoles) [prepared according to the general procedure described in published United Kingdom Patent Application No. 2,067,987] in 500 mL of methanol was treated with 33.3 mL of concentrated HCI.After stirring for 3 hours, the reaction mixture was concentrated and excess water was removed by azeotropic concentration with absolute ethanol to give an almost colorless crystalline residue. The residue was triturated with 200 mL of absolute ethanol at 0 C, filtered and dried to give 16.9 g (80%) of the title compound, m.p.206-220 C (dec.). Recrystallization from 50% methanolethyl acetate gave a product having m.p. 210-221C (dec.).

Anal. Calc'd for C13H23N5S2.3HCl C, 36.92; H, 6.20; N, 16.56; S,15.17 Found: C, 36.76; H, 6.33; N, 16.97; S,15.54 B. 3-A min o-4-(2-J(5-dimeth ylaminometh yl-4-m eth yl-2-thien yl)-meth ylthio]eth ylamin o}- 1,2, 5-thia diazole To a stirred suspension of N-(2-[(5-dimethylaminomethyl-4-methyl-2- thienyl)methylthio]ethyl}ethanediimidamide trihydrochloride (6.34 g; 15.0 mmoles) [prepared in Step A] in 60 mL of DMFwas added 6.1 g (45.0 mmoles) of sulfur monochloride. After stirring for 4 hours at ambient temperature, the reaction mixture was poured into 800 mL of water, made basic with K2CO3, and extracted several times with 100 mL-portions of methylene chloride. The extracts were dried over MgSO4, filtered, and concentrated to give 3.4 g of a black gum containing the product. The product was purified by preparative high pressure liquid chromatography on silica using CH2Cl2 (100): 2-propanol(10) :NH40H(0.5) as the mobile phase. Further purification was achieved by an additional preparative high pressure liquid chromatography on silica using CH2Cl2(1 00): CH30H(2.5):NH40H(0.5) as the mobile phase. The appropriate fractions yielded the title compound (purity 98%). Treatment of the product with an equivalent amount of 2N HCI gave the hydrochloride salt of the title compound.

Anal. Calc'd for C13H21 N5S3.HCl . C, 41.09; H, 5.84; N, 18.43; S, 25.32 Found (corr. for 0.51% H2O) C, 40.78; H, 5.63; N, 18.31; S, 25.44 EXAMPLE 4 3-Amino-4-[3-(3-pyrrolldinomethylphenoxy)propylamino] 1,2,5-thiadiazole A. N- [3- (3-Pyrrolldinometh ylphenoxy)propyl]ethanedllmidamide trih ydrochloride A suspension of 3-amino-4-[3-(3-pyrrolidinomethyl-phenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (13.4 g; 38.3 mmoles) [prepared according to published United Kingdom Patent Application No.2,067,987] in 350 mL of methanol was treated with 25.5 of concentrated HCI. The resultant solution was stirred for 3 hours at ambient temperature.Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195-203"C (dec.).

Anal. Calc'd for Ca6H25N5O.3HCI : 46.55; H, 6.84; N, 16.97 Found: C, 46.55; H, 6.93; N, 16.93 B. 3-Amino-4-[3-{3-pyrrolidinomethylphenoxy)propylaminol- 1,2,5-thiadiazole A stirred suspension of N-[3-(3-pyrrolidinomethyl-phenoxy)propyl]ethanediimidamide trihydrochloride (8.25 g; 20.0 mmoles) [prepared in Step A] in 80 mL of DMF was treated with sulfur monochloride (5.4 g; 40.0 mmoles) and stirred under a nitrogen atmosphere for 3 hours. Concentration of the reaction mixture gave a dark gum which was suspended in 500 mL of water, made basic with K2CO3 and extracted with 3 x 100 mL of methylene chloride. The extracts were dried over MgS04, filtered and concentrated to give 7.5 g of a dark gum containing the product.The product was purified by preparative high pressure liquid chromatography on silica using CH2C12 (100) :2-propanol(S): NH40H(0.5) as the mobile phase. Fractions containing the desired product were combined and concentrated to give 1.64 g (24.6%) of the purified title product. Treatment of the product in absolute ethanol with an equivalent amount of 2N HCI gave the hydrochloride salt of the title compound (1.139); m.p. 138-140"C.

Anal. Calc'd for C16H23N50S.HCI : C,51.95; H, 6.54; N, 18.93; S, 8.67 Found: C, 51.97; H, 6.36; N, 18.63; S, 8.76 EXAMPLE 5 The general procedure of Example 1, Steps A and B, is repeated except that the 3-amino-4-[3-(3 piperidinomethyl-phenoxy)propylamino]-1,2,5-thiadiazole 1-oxide utilized therein is replaced by an equimolar amount of (a) 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (c) 3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy]-propylamino}-1,2,5-thiadiazole 1-oxide, (d) 3-amino-4-{-[3-(3-methylpyrrolidino)methylphenoxy]-propylamino}-1 ,2,5-thiadiazole 1-oxide, (e) 3-aminoA43-[3-(4-methyl piperidino)methylphenoxy]-propylamino}-1 ,2,5-thiadiazole 1-oxide, (f) 3-amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (g) 3-amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]-propylamino-1,2,5-thiadiazole 1-oxide, (h) 3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1 2,5-thiadiazole l-oxide, (i) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (j) 3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propyl-amino]-1 ,2,5-thiadiazole 1-oxide, (k) 3-amino-43-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]-prnpylamino}-1 ,2,5-thiadiazole 1-oxide and (I) 3-amino-4-{3-[3-(3-pyrrol ino)methyl phenoxy]propylam ino}- 1 ,2,5-thiadiazole 1-oxide, respectively, and there is thereby produced (a) 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1 ,2,5-thiadiazole, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1 ,2,5-thiadiazole, (c) 3-amino-4-(3-[3-(2-methyl pyrrolidino)methylphenoxyl-propylamino)- 2,5-thiadiazole, (d) 3-amino-4-{3-[3-(3-methylpyrrolidino)methylphenoxy]-propylamino}-1 ,2,5-thiadiazole, (e) 3-amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]-propylamino}-1,2,5-thiadiazole, (f) 3-amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (g) 3-amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]-propylamino)-1 ,2,5-thiadiazole, (h) 3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole, (i) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole, (j) 3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-1,2,5-thiadiazole, (k) 3-amino-4-{3-[3-(3-azabicyclo[3.2.2.]non-3-yl)methylphenoxy]-propylamino}-1 ,2,5-thiadiazole and (I) 3-amino-4-(3-[3-(3-pyrrolino)methyl phenoxy] propylamino)-l ,2,5-thiadiazole, respectively.

EXAMPLE 6 3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]- 1,2,5-thiadiazole This is a variation of Example 1, Step B, utilizing less sulfur monochloride and a shorter reaction time.

To a stirred suspension of N-[3-(3-piperidinomethyl-phenoxy)propyljethanediimidamide trihydrochloride (12.08 g; 28.3 mmoles) in 120 mL of DMF was added sulfur monochloride (7.64 g; 56.6 mmoles) and the mixture was stirred under an N2 atmosphere for 3 hours. The DMF was removed at reduced pressure to leave a black gum which was suspended in water, made basic with K2CO3 and extracted with 3 x 100 mL portions of CH2C12. The combined extracts were dried over MgSO4, filtered and concentrated to a black gum.

This gum was purified by preparative high pressure liquid chromatography on silica using CH2Cl2 (1 00):2-propanol(5): NH4OH(0.5) as the mobile phase. The appropriate fractions yielded 3.1 g of the title product as a dark oil which gave, with fumaric acid in n-propanol, 2.66 g (23.2%) of the title compound as a crystalline fumarate salt, m.p. 186-186.5"C. HPLC indicated a purity of 99%.

Anal. Calc'd, for (C7H25N5OS)2-C4H404 : C, 56.27; H, 6.71; N, 17.27; S, 7.90 Found: C, 56.27; H, 6.96; N, 17-.31; S, 7.98 EXAMPLE 7 3-A mino-4-J3-(3-piperidinometh ylphen oxy)prop ylamino]- 1,2, 5-thia diazole This is a variation of Example 1, Step B, utilizing sulfur dichloride instead of sulfur monochloride.

To a stirred suspension of N-[3-(3-piperidinomethyl-phenoxy)propyl]ethanediimidamide trihydrochloride (854 mg; 2 mmoles) in 6 mL of DMF under N2 in an ice bath was added SCRIP (206 mg; 2 mmoles) in 2 mL of DMF. The reaction mixture was stirred at ambient temperature and the title compound was produced.

EXAMPLE 8 3-Methylamino-4-[3-3-piperidinomethylphenoxyJpropylaminol- 1,2,5-thiadiazole A. N-Methyl-N'-[3-r3-piperidinomethylphenoxyJpropyllethane-diimidamide trihydrochloride A suspension of 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1 -oxide (4.13 g; 10.9 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 95 ml of methanol was treated with 7.2 ml of concentrated HCI. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to give 4.35 g (90.4%) of product.A sample was recrystallized from aqueous isopropyl alcohol to give the title compound, mp 207-225"C (dec.).

Anal. Calc'd. for C18H29NeO.3HCl C, 49.03; H, 7.33; N, 15.89 Found (corr. for 0.94% H20) C, 49.37; H, 7.35; N, 15.71 B. 3-Methylamino-4-[3-83-piperidinomethylphenoxyJpropylaminol- 1,2,5-thiadiazole A mixture of N-methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochioride (3.74 g; 8.47 mmoles) [prepared in Step A], 34 ml of CH2CI2 and 3.5 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (3.36 g; 8.46 mmoles) and stirred for one hour. The mixture was washed with 30 ml of 10% % KOH, dried (MgSO4), filtered, diluted with toluene and concentrated to give 3.6 9 of the product.The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95: 5) as the eluentto give 1.9 g (62%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCI in 1-propanol gave the hydrochloride salt of the title compound, mp 163.5-164.5"C.

Anal. Calc'd. for C18H27N5OS-HCI : C, 54.32; H, 7.04; N, 17.60; S, 8.06; Cl, 8.91 Found: C, 54.35; H, 7.07; N, 17.64; S, 8.36; Cl, 8.86 EXAMPLE 9 3-BenzZlamino-4-[3-{3-piperidinomethy/phenoxyJpropylaminol- 1,2,5-thiadiazole A. N-Benzyl-N'-[3-63-piperidinomethylphenoxyJpropyllethane-diimidamide trShydrochloride A suspension of 3-benzylamino-4-[3-(3-piperidinomethyiphenoxy)propylamino]-1,2,5-thiadiazole 1 -oxide (5.14 g; 11.3 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 100 ml of methanol was treated with 7.55 ml of concentrated HCI.After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to give 5.16 g (88%) of the title compound, mp 1 87-205"C (dec.).

Anal. Calc'd. for C24H33N5O.3HCl : C, 55.75; H, 7.03; N, 13.55; Cl, 20.57 Found: C, 54.88; H, 6.75; N, 13.33; Cl, 20.20 B. 3-Benzylamin o-4-[3-/3-piperidinometh ylph enoxy)prop ylamino]- 1,2, 5-thiadiazole A mixture of N-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml of CH2CI2 and 3.8 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmoles) and stirred for one hour. The mixture was washed with 44 ml of 10% KOH, dried (MgSO4), filtered, diluted with toluene and concentrated.The residue was chromatographed by flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCI in 2-propanol gave the hydrochloride salt of the title compound, mp 138-141"C.

Anal. Calc'd for C24H31N5OS.HC1 C, 60.80; H, 6.80; N, 14.77; S, 6.76; Cl, 7.48 Found: C, 60.53; H, 6.64; N, 14.99; S, 6.91; CI, 7.47 EXAMPLE 10 3-Amino-4-[3-(3-piperidinom ethylphen oxy)prop ylamino]- 1,2,5-thiadiazole This is a variation of Example 1, Step B, utilizing N,N'-thiobisphthalimide instead of sulfur monochloride.

A mixture of N-[3-(3-piperidinomethylphenoxy)propyl]-ethanediimidamide trihydrochloride (27.3 g; 64.0 mmoles) [prepared in Example 1, Step A], 250 ml of CH2CI2 and 26.6 ml (192.0 mmoles) of triethylamine was treated portionwisewith N,N'4hiobisphthalimide (DMF solvate) (25.4g; 64.0 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 120 ml of 20% KOH, dried (MgS04), filtered and concentrated, then taken up in 150 ml of toluene and reconcentrated. The product was taken up in 250 ml of 1 -propanol and 10.7 ml of 6N HCI, treated with decolorizing carbon and filtered through Celite.This solution was concentrated to 100 ml volume, diluted with 175 ml of dry 1-propanol and stored at 0 Cto give 20.2 g (82.1%) of crystalline hydrochloride salt of the title compound, mp 137-138"C.

Anal. Calc'dforC17H25N5OSHCl C, 53.18; H, 6.83; N, 18.24; S, 8.35 Found: C, 52.78; H, 6.74; N, 18.52; S, 8.66 EXAMPLE 11 3-Amino-4-[3-(3-p yrrolidin ometh ylphen oxy)prop ylaminoj- 1,2,5-thiadiazole This is a variation of Example 4, Step B, utilizing N,N'-thiobisphthalimide instead of sulfur monochloride.

A mixture of N-[3-(3-pyrrolidinomethylphenoxy)propyl]-ethanediimidamide trihydrochloride (22.0 g; 53.0 mmoles) [prepared in Example 4, Step A], 200 ml of CH2C12 and 22 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (21.2 g; 53.0 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 100 ml of 20% KOH, dried (MgS04), filtered, diluted with 100 ml of toluene and concentrated. The product was treated with one equivalent of aqueous HCI in 1-propanol to give 13.2 g (67%) of the hydrochloride salt of the title compound, mp 135-137 C.

Anal. Calc'd for C16H23N5OS.HCl C, 51.95; H, 6.54; N, 18.93; S, 8.67 Found: C,51.92; H, 6.55; N, 19.30; S, 9.06 EXAMPLE 12 3-Amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthioj-ethylamino}- 1,2,5-thiadiazole A. N-{2-[(5-dimeth ylaminometh yl-34hienyl)meth ylthiojethyl }-ethanediimidamide trihydrochloride A suspension of 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1 ,2,5- thiadiazole 1-oxide (7.8 g; 22.6 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 150 ml of methanol was treated with 15.0 ml of concentrated HCI.After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 190-205 C (dec.).

Anal. Calc'dforC12N21N5S2HCl C, 35.25; H, 5.92; N, 17.13 Found: C, 35.03; H, 5.93; N, 17.39 B. 3-Amino-4-{2-[(5-dimethylaminomethyl-3-thienylymethylthio]-ethylamino}- 1,2,5-thiadiazole A mixture of N-f2-[(5-dimethylaminomethyl-3-thienyl)-methylthio]ethyl}ethanediimidamide trihydrochloride (6.13 g; 15.0 mmoles) [prepared in Step A], 60 ml of CH2C12 and 6.3 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.96 g; 15.0 mmoles) and stirred for one hour. The mixture was washed with 100 ml of 10% KOH, dried (MgSO4), filtered, diluted with toluene and concentrated to give 5.1 g of product.Treatment of the product with 0.5 molar equivalent of fumaric acid in 1-propanol gave the fumaric acid salt of the compound, mp 141-143"C. The nmr spectrum in DMSO-d6 shows the presence of approximately 0.12 moles of 1-propanol.

Anal. Calc'd. for (C12H19N5S3)2C4H4O40.12C3H5O : C,43.68; H, 5.61; N, 17.75; S, 24.38 Found: C, 43.41; H, 5.53; N, 17.54; S, 24.24 EXAMPLE 13 3-Amino-4-f2-[(5-pip eridinometh yl-3-thien yl)methylthiojethylamin o}- 1,2,5-thia diazole A. N-{2-[(5-piperidinomethyl-3-thien yl)meth ylthiojethyl }ethanediimidamide trih ydrochloride A suspension of 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylaminoj-1 ,2,5-thiadiazole 1 oxide (6.1 g; 15.8 mmoles) [prepared according to published United Kingdom Patent Application No.

2,067,987] in 80 ml of methanol was treated with 10.5 ml of concentrated HCI. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 50 ml of 1-propanol, filtered and dried to give 5.86 g (83%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 201-214"C (dec.).

Anal. Calc'd.forC15H25N5S2-3HCI C, 40.13; H, 6.29; N, 15.60; S, 14.29 Found: C, 39.97; H, 6.47; N, 15.28; S, 14.63 B. 3-A mino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthioj-eth ylamino}- 1,2, 5-thia diazole A mixture of N-{2-[(5-piperidinomethyl-3-thienyl)-methylthio]ethyl}ethanediimidamide trihydrochloride (5.17 g; 11.5 mmoles) [prepared in Step A], 48 ml of CH2C12 and 4.8 ml of triethylamine was treated with N,N'4hiobisphthalimide (DMF solvate) (4.57 g; 11.5 mmoles) and stirred for one hour. The mixture was washed with 90 ml of 10% KOH, dried (MgS04), filtered, diluted with toluene and concentrated to give 4.5 g of product.Treatment of the product with one equivalent of cyclohexyl sulfamic acid in methanol gave the cyclohexyl sulfamate salt of the title compound, mp 142-143 C.

Anal. Calc'd. for C15H23N5S3-C6H13NO3S C, 45.96; H, 6.61; N, 15.31; S, 23.38 Found: C, 45.61; H, 6.41; N, 15.46; S. 23.48 EXAMPLE 14 The general procedures of Example 1, Step A, and then either Example 1, Step B, or Example 10 is repeated except that the 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1 -oxide utilized therein is replaced by an equimolar amount of (a) 3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide, (b) 3-allylamino-4-[3-(3-piperidi nomethyl phenoxy) ,2,5-thiadiazole 1-oxide, (c) 3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino)-1,2,5-thiadiazole 1-oxide, (d) 3-(3-pyridylmethylamino)-4-[3-(3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole 1-oxide, (e) 3-(6-methyl-3-pyridyl)methylamino-4-[3-(3-piperidinomethyl-phenoxy)propylamino]-1,2,5- thiadiazole 1-oxide and (f) 3-(3,4-methyienedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide, respectively, and there is thereby produced (a) 3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (b) 3-allylamino-4-[3-3-piperidinomethyl phenoxy)propylamino]-1 ,2,5-thiadiazole, (c) 3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (d) 3-(3-pyridyl methylamino)-4-[3-(3-piperidinomethyl phenoxy)-propylamino]-1 ,2,5-thiadiazole, (e) 3-(6-methyl-3-pyridyl)methylamino-4-[3-(3-piperidinomethyl-phenoxy)propylamino]-1 ,2,5- thiadiazole and (f) 3-(3,4-methylenedioxybenzylamino)-4-[3-(3-piperidinomethyl-phenoxy)propylamino]-1,2,5- thiadiazole, respectively.

EXAMPLE 15 3-Amino -4-[3-(6-pip eridin om eth yl-2-p yridyloxy)prop ylamin ol- 1,2,5-thiadiazole A. 3-Am in o-4-[3- (6-pip eridin om eth yl-2-p yridyloxy)prop ylamin ol- 1,2,5-thiadiazole 1-oxide A solution of 3-(6-piperidinomethyl-2-pyridyloxy)-propylamine (4.65 g; 18.6 mmoles) [prepared according to published United Kingdom Patent Application No.2,098,988] in 50 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.74 g; 18.6 mmoles) according to the general procedure described in United Kingdom Patent Application No. 2,067,987 to give a solution containing 3-amino-4-[3-(6 piperidinomethyl-2-pyridyloxy)propylamino]-1 ,2,5-thiadiazole 1-oxide.A purified sample melted at 145 1470C.

B. N-[3-{6-Piperidinomethyl-2-pyridyloxy)propylyethanediimidamide trShydrochloride A methanolic solution of the product prepared in Step A was diluted to 100 ml and 12.4 ml of concentrated HCI was added. The solution was stirred at ambient temperature for 18 hours, concentrated, and the residue was dissolved in 80 ml of water and extracted twice with CH2C12. The aqueous layer was concentrated, treated with n-propanol and concentrated under high vacuum to give the title compound as a foam.

C. 3-A mino-4-[3-/6-piperidinomefhyl-2-p yridyloxylprop ylamino]- 1,2,5-thia diazole A mixture of the crude product prepared in Step B in 80 ml of CH2C12 and containing 7.69 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (7.35 g; 18.5 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCI solution, dried (Na2So4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 100 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as the eluent to give 3.63 g of the title compound as a viscous oil.Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, mp 125.5-131"C.

Anal. Caic'd. for C16H24NSOS C6H13NO3S : C, 50.07; H, 7.07; N, 18.58; S, 12.15 Found; C, 50.02; H, 7.03; N, 18.54; S, 12.14 EXAMPLE 16 3-Amino-4-[3-(6-dimethylaminometh yl-2-p yridyloxy)prop ylaminoj- 1,2, 5-thiadiazole When a methanolic solution of 3-(6-dimethylaminomethyl-2-pyridyloxy)propylamine [prepared according to published United Kingdom Patent Application No.2,098,988] is reacted with 3-amino-4-methoxy-1,2,5thiadiazole 1-oxide according to the general procedure described in United Kingdom Patent Application No.

2,067,987 and the resulting 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1 ,2,5-thiadiazole 1 -oxide is successively reacted by the general procedure described in Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

EXAMPLE 17 3-Amino-4-{2-[{6-dimethylaminomethyl-2-pyridyl)methylthiol-ethylamino}- 1,2,5-thiadiazole When a suspension of 3-amino-4-}2-[6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1 .2,5- thiadiazole 1- oxide [prepared according to published United Kingdom Patent Application No.2,067,987] is successively reacted according to the procedures of Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

EXAMPLE 18 3-A mino-4-(2-[(6-piperidinometh yl-2-p yridyl)meth ylthiojeth yl-amino}- 1,25-thia diazole When a suspension of 3-amino-4-{2-[(6-piperidino-methyl-2-pyridyl)methylthio]ethylamino}-1 ,2,5- thiadiazole 1-oxide [prepared according to published United Kingdom Patent Application No.2,067,987] is successively reacted according to the procedures of Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

EXAMPLE 19 The general procedure of Example 1, Step A, and then either Example 1, Step B, or Example 10 is repeated except that the 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1 ,2,5-thiadiazole 1 -oxide utilized therein is replaced by an equimolar amount of (a) 3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (b) 3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1 ,2,5-thiadiazole 1-oxide, (c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole 1-oxide, (d) 3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)-propylamino]-1 ,2,5-thiadiazole 1-oxide, (e) 3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propyl-amino]-1 ,2,5-thiadiazole 1-oxide, (f) 3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole 1-oxide, (g) 3-amino-4-f2-[(4-dimethylam inomethyl-2-pyridyl)methylthio]-ethylamino-1 ,2,5-thiadiazole 1 -oxide and (h) 3-amino-4-{2-[(4-piperidinomethyl-2-pyridyl)methylthio]-ethylamino}-1 2,5-thiadiazole 1-oxide, respectively, and there is thereby produced (a) 3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1 ,2,5-thiadiazole, (b) 3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1 2,5-thiadiazole, (c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole, (d) 3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)-propylamino]-1 ,2,5-thiadiazole, (e) 3-amino-4-[3-(5-dimethyla minomethyl-3-thienyloxy)propyla ,2,5-thiadiazole, (f) 3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propylamino]-1 ,2,5-thiadiazole, (g) 3-am ino-4-(2-[(4-dimethylam inomethyl-2-pyridyl )methylth io]-ethylamino)-l ,2,S4hiadiazole and (h) 3-amino-4-{2-[(4-piperidinomethyl-2-pyridyl)methylthio]-ethylamino}-1,2,5-thiadiazole, respectively.

The above starting materials are prepared according to the general procedures described in published U.K. Patent Application No.2,067,987. The precursors of the starting materials are prepared by the procedures and analogous general procedures described in U.K. Patent Application Nos. 2,067,987, 2,098,988, 2,063,875 and published European Patent Application No. 49,173.

EXAMPLE 20 3-Amino-4-[3-r4-piperidinomethyl-2-pyridyloxy)propylaminol- 1,Z5-thiadiazole A. 3-r4Piperidinomethyl-2-pyridyloxy)propylamine When the general procedure for the preparation of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine described in U.K. Patent Application No. 2,098,988 was followed except that the 2-chloro-6-methylpyridine utilized therein was replaced by 2-bromo-4-methylpyridine, then the title compound was produced as an oil.

Anal. Calc'd. for C,4H23N3O C, 67.44; H, 9.30; N, 16.85 Found: C, 67.54; H, 8.98; N, 16.55 B. 3-A mino-4-[3-(4-piperidinomethyl-2-p yridyloxy)prop y!amino]- 1,2, 5-thiadiazole 1-oxide A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.K. Patent Application 2,067,987 to give 6.33 g of product. Recrystallization from methanol-acetonitrile yielded the title compound, mp 154-1 58"C.

Anal. Calc'd. for C16H24NsOS : C, 52.73; H, 6.64; N, 23.06; S, 8.80 Found: C, 52.72; H, 6.30; N, 23.32; S, 8.74 C. N-[3-b4Piperidinomethyl-2-pyridyloxy)propyllethanediimidamide trihydrochloride The product of Step B (5.0 g; 13.7 mmoles) was dissolved in 80 ml of methanol and treated with 9.1 ml of concentrated HCI. After stirring at ambient temperature for 4.5 hours, the solution was evaporated to dryness under reduced pressure to give the title compound.

D. 3-Amino-4-[3-64-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole A mixture of the product prepared in Step C in 50 ml of CH2C12 and 5.7 ml of triethylamine was treated with N, N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 40 ml of 4N NaOH, water, saturated aqueous NaCI solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (96:4) as the eluent to give 3.44 g of the title compound as a viscous oil.Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate of the title compound, mp 124.5-126"C.

Anal. Calc'd for C6H24N6OS-C6H3NO3S : C, 50.07; H, 7.07; N, 18.58; S,12.15 Found: C, 50.47; H, 7.12; N, 18.33; S,11.87 EXAMPLE 21 3-A mino-4-{3-[3-(1,2,3, 6-tetrah ydro- 1-p yridyl)methylphenoxy]-propylamino}- 1,25-thiadiazole The general procedure of Example 15 was repeated, except that the 3-(6-piperidinomethyl-2pyridyloxy)propylamine utilized therein was replaced by an equivalent amount of 3-[3-(1 ,2,3,6-tetrahydro-1 pyridyl)methylphenoxy]propylamine, to give 2.31 g of product. Crystallization from toluene yielded the title compound, mp 99.5-104"C.

Anal. Calc'd. for C,7N23N5OS : C, 59.10; H, 6.71; N, 20.27; S, 9.28 Found (corr. for 2.19% H2O) : C, 58.78; H, 6.71; N, 19.90; S, 9.26

Claims (1)

1. Acompound oftheformula

wherein R' is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

in which p is 1 or 2, R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen, R3 also may be trifluoromethyl, or R2 and R3, taken together, may be methylenedioxy, and R4 is 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 oxygen, sulfur or methylene; and Ais

in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R6 and R7 each are independently (lower)alkyl, (lower)alkoxy)lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when R6 is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolindino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1 ,2,3,64etrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino;; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

2. A compound of Claim 1 having the formula

wherein R1 is hydrogen or (lower)alkyl, m is0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is

in which R5 is hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

3. A compound of Claim 1 havingtheformula

wherein R1 is hydrogen or methyl, and R6 and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolindino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

4. A compound of Claim 1 having the formula

wherein R1 and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

5. A compound of Claim 1 having the formula

wherein R1 and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

6. A compound of Claim 1 having the formula

wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, Re and R7 represent piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

7. The compound of Claim 1 which is 3-amino-4-[3-(3-piperidinomethyl phenoxy)propylamino]-1 ,2,5- thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The compound of Claim 1 which is 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1 .2,5- thiadiazole hydrochloride.

9. The compound of Claim 1 which is 3-amino-4-{2-[(5-dimethylaminomethyl-2- furyl)methylth io]ethylamino)-l ,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

10. The compound of Claim 1 which is 3-amino-4-f2-[(5-dimethylaminomethyl-4-methyl-2- thienyl)methylthio]ethylamino)-l ,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

11. The compound of Claim 1 which is 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylaminoj-1 ,2,5- thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

12. The compound of Claim 1 which is 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]- 1,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

13. The compound of Claim 1 which is 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]- 1,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

14. The compound of Claim 1 which is 3-amino-4-{2-[(5-dimethylaminomethyl-3 thienyl)methylthio]ethylamino}-1,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

15. The compound of Claim 1 which is 3-amino-4-(2-[(5-piperidinomethyl-3- thienyl)methylthio]ethylamino)-l ,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

16. The compound of Claim 1 which is 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]- 1,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

17. The compound of Claim 1 which is 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]- 1 ,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

18. The compound of Claim 1 which is 3-amino-4-C3-[3-(1 ,2,3,6-tetrahydro-l - pyridyl)methyl phenoxy)propylam ino)-l ,2,5-thiadiazole, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

19. Acompound oftheformula

wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

in which p is 1 or 2, R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen, R3 also may be trifluoromethyl, or R2 and R3, taken together, may be methylenedioxy, and R4 is 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 oxygen, sulfur or methylene; and Ais

in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R6 and R7 each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when R6 is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetra hydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof.

20. A compound of Claim 19 having the formula

wherein R1 is hydrogen or (lower)alkyl, m is0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is

in which R5 is hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

21. A compound of Claim 19 having the formula

wherein R' is hydrogen or methyl, and Re and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R6 and r7 represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

22. AcompoundofClaim 19 having the formula

wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

23. A compound of Claim 19 having the formula

wherein R' and R5 each are independently hydrogen or methyl, and Re and R7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

24. A compound of Claim 19 having the formula

wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, R6 and R7 represent piperidino; or a salt, hydrate or solvate thereof.

25. The compound of Claim 19 which is N-[3-(3-piperidino-methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

26. The compound of Claim 19 which is N-{2-[(5-dimethyl-aminomethyl-2-furyl)methylthio]- ethyllethanediimidamide, or a salt, hydrate or solvate thereof.

27. The compound of Claim 19 which is N{2-[(5-dimethyl-aminomethyl-4-methyl-24hienyl)- methylthio]ethyl)ethanediimidamide, or a salt, hydrate or solvate thereof.

28. The compound of Claim 19 which is N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

30. The compound of Claim 19 which is N-{2-[(5-piperidinomethyl-3-thienyl)methylthio]- ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

31. The compound of Claim 19 which is N-[3-(6-piperidinomethyl-2-pyridyloxy)propyl] ethanediimidamide, or a salt, hydrate or solvate thereof.

32. The compound of Claim 19 which is N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]- ethanediimidamide, or a salt, hydrate or solvate thereof.

33. The compound of Claim 19 which is N-{3-[3-(1 ,2,3,6-tetrahydro-1 -pyridyl)methylphenoxy]- propyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

34. A compound as claimed in claim 1, prepared by a procedure substantially as described in any of the foregoing Examples 1 to 7.

35. A composition comprising a compound as claimed in any of claims 1 to 18, or claim 34, in association with a pharmaceutically acceptable carrier.

36. Process for preparing a compound of formula I, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1, comprising reacting, preferably at a temperature of from about 0 C to about 50"C and preferably in a reaction inert organic solvent, a compound of the formula

with at least a molar equivalent, preferably a molar excess, more preferably a molar excess of 2-3 moles, of sulfur monochloride, sulfur dichloride or a chemical equivalent thereof, preferably sulfur monochloride, to produce said compound of Formula I.

37. Process for preparing a compound of the formula Il according to claim 19, comprising reacting preferably in an inert solvent and at room temperature, a compound of formula

with a strong mineral acid, preferably hydrochloric acid, or reacting a compound of formula A-(CH2)mZ(CH2)nNH2 IV with a compound of formula

to produce a compound of formula

then reacting said compound of formula VI with a compound of formula R1NH2.