CA1253144A - Substituted 3,4-diamino-1,2,5-thiadiazoles having histamine h.sub.2-receptor antagonist activity - Google Patents

Abstract

Abstract of the isclosure Substituted ethanediimidamide compounds of the formula II
wherein A, m, Z, n and R1 are as defined herein. The compounds of formula II are useful in the preparation of histamine H2-receptor antagonists of the formula

Description

1.25~

SY-l7o6A

SUBSTIII~TE~3 3, 4-DIAMIN~-1, 2, 5-THIADIAZOLES
HAVING HISTAMINE H;~-RECFPTOR ANTAGONIST ACTIVITY

Summa~y of the Invention Certain 3-(ami~o or substituted amino)-4-(su~sti~ute amino~-1,2,5-thiadiazoles having the formula A-(CH2)mZ~CH2)nNH~ NHR

~Ç/ \~!1 ~S~

wherein ~, m, Z, n and Rl are as defined below, and the~r non.oxic pharmaceutically acceptable salts, hydrates and solva.es, zre potent histamine H2-receptor antagonists.
which inhibit gastric acid secretion and are use-ul in the treatment of peptic ulcers and other pathological hypersecre.ory conditions. The compounds are prepared by ring closure o~
the correspondingly substituted ethanediimidamide of the formula A-(CH2)~Z(CH2)nNH~ ~ NHRl . lI

Back~round and ~rior Art Our published ~nited Xinqdo~ Patent Application No.

2,067,987 discloses 3,4-disubstituted-1,2,5-~hiadiazole 1-oxides and l,l-dioxides having the formula A-(C~2)mZ(CH2)~NH ~ 1 // \\
~S
(O) p and processes for their preparation, wherein the ~ariables ~, m, Z, n and Rl are s~milar to the corres~onding substituents of the compounds disclosed and clai~ned herein. However, the compounds disclosed therein are l-oxides or l,l-dioxides (p is 1 or 2), and the compounds of the present inYention cannot be prepared by any of the processes described therein f~r the prepz_a~ion of the prior art compounds .
~ ub1ished ~uropean Pa tent Application No. 40,696 discloses inter alia 3,4-disubstituted-1,2,5-thiadiaæole 1-oxices and 1,1-dioxides having the formula ~1 R- ~ - (CH2)n-x-(cH2)mN~ ~ \ R2 N ~ ~
(~)p and processes for their preparation, wherein the variab~es ~, , n, X, m, Rl and R2 are similar to the corresponding su~stituents of the compounds disclosed znd claimed herein.
~owe~er, the compounds disclosed therein also are l-oxides or l,l-dioxides (p is 1 or 2) and the compounds of the present invention cannot be prepared by any of the processes described therein for ~he preparation of the prior art compoundsO

~i3~

In the two publications cited above, e~ch 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 l~oxide or l,l-dioxide having either amino groups or suitable "lea~ing groups" on the 3- and 4~positions.
The desired substituents on the 3- and 4-positions are hen 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 pres~nt invention by similar procedures, i.e. by utilizing 1,2,5-thiadiazole having amir.o groups or suitable "leaving sroups" on the 3- and 4-positions as starting ~aterials or int~rmediates. Although numerous vasiations were tried, along with ~arying reaction conditions, we were not able to isolate the compounds of this invention ~y thzt route.

We have no~ found that the compounds of.the present invention may be prepared by ring closure of the co~respondingly substituted ethanediimidamide of the formula A-(CH2)mZ(CH2)nNH/I ~\ II
HN HN

Intermediate II, itself, may ~e prepared by various procedures.

Complete Description This invention relates to histamine H2-receptor antagonists of the formula .- (CH2)mZ (CH2)nNH~NH}~,l // \\ I

wherein Rl is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, ~3~

R3 ~ (C~2 ) p~ or R4--~ (C~2 ) p~

in which p is 1 or 2, R2 and R3 each are independently hydrogen , (lower) alkyl, (lower) alkoxy or halogen, ~nd, when R2 is hydrogen, R3 also may be trifluoro~ethyl, or R2 and R , t~.ken together, may be methylenedioxy, and R4 is hydrogen, (lower)alkyl or (lower) alkoxy;
m is an integer o~ from O to 2 inclusive;
n is an integer of from 2 to 5 inclusive;
~ is oxygen, sulfur or methylene; and A is ~(C~)q~ / (CH

/N (CH2 ) q ~ or 6/ (C112)q ~

in which R5 is ~ydrogen, tlower)alkyl or (lower)alkoxy, q is an integer ~f from 1 to 4 inclusive and R6 and R7 each are independently tlower)alkyl, (lower)alkoxy(lowcr)al~yl in which ~ the (lower)alkoxy moiety is at least two carbon atoms re~oved from the nitrogen atom, or phenyl(lower)alkyl, and, when R
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 pyrro:Lidino, ~ethylpyrrolidino, ~methyl-pyrrolidino t morpholino, thiomorpholino, piperidino, methyl-piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa methyleneLmino, 3-azabicyclot3.2.2~non-3-yl or 3-pyirolino;
and nontoxic, pharmaceutically acceptable s~lts, hydrat~s and solv2tes thereof.

:~253~

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 thereo~. ~s used herein and in the claims, th~ term ~(lower)-alkyl~ means a straight or branched chain alkyl sroup conta~ning from 1 to 6 carbon atoms. The tenm ~(lower)alkoxy~ me~ns a skraight or branched chain alkoxy group containing from 1 to 4 carbon atomsO ~Cyclo(lower)al~oxy" me ns a cycloalkyl group containing from 3 to ~ carbon atoms. The term "nontoxic pharma-ceutically acceptable salts~ means acid addition salts formed with a~ids such as hydrochloric, hydrobromic, nitric, sulfuric, acetic, pr~pionic, fumaric, methanesulfonic, maleic, tartaric, citric, levulinic, benzoic, succinic and the like.

In the compounds of Fo~mula I, Rl preferably is hydrogen or (lower)alkyl, more preferably is hydrogen or methyl and most preferably is hydrogen. Substituent A pre erably 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 sul.ur 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, a~d that, when A is the substituted phenyl moiety, m is zero and n is 3. R5 pre.erably is hydrogen or methyl and most preferably is hydrogen. It is preferred that q is 1. R6 and R7 preferably are (lower)alXyl or, taken together with the nitrogen atom to which they are attached, are pyrrolidino o~ piperidino.

The compounds of Formula I may be prepared by reaction of a compound of Formula II with sulfur monochlorid~
~52C123, sulfur dichloride 5SCl~) or chemical equivalents thereof, as follows:

A-(cH2)mz(cH2)nN~ C~NHR II
HN }I

¦ 52C12 V

A_(C~2)mZ(CH2)nN ~ N~Rl ~t ~ I
~S~

wherein ~, m, Z, n and Rl are as defined above. At least about 1 mole of 52C12 or SC12 should be used per mole of Compound II;
it is preferred to use an excess of S2C12 or SC12, e.g. from about 2 to about 3 moles of S2C12 or SC12 per mole of Compound II. It has been found that SC12 often give~ a cruder product and lower yiel~ of purified product, and we usually prefer to use S2C12 for the reaction. The reaction tempe_ature is not critical; we prefer to conduct the reaction at a temperature of 'rom about 0C to about 50C, 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 preferred. The reaction may be conducted in an inert organic solvent, preferably a mixture of an inert organic solvænt and dimethylformamide. Most preerably the reaction is conducted in dimethylformamide.

~L2~

Ln a preferred embodlment of the invention, the compounds of Formula I have khe structure A (CH2)mZ(c 2)n NHRl I
?~
~S~

wherein Rl is hydrogen or (lower)alkyl, ~ is O or 1, n is 2 or

3, ~. is oxygen or sulfur and A is '2 ~_ ' 6~NC1:

6~ 2 ~ ~ NC~ ~

in which R5 is hydrogen or methyl, and R6 and R7 each are i~dependently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and ~7 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 R \ ~
/~CH2 ~ I Ia R6 ~ CH2CH2 2 ~t~ Rl // \\ .
~ S

-wherein Rl is hydrogen or methyl, and R~ and R7 each are methyl or/ when taken together with the nitrogen atom to which they are at~ached, R6 and R7 represent a pyrrolidino or piperidino riny; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereoC

In another more preferred embodiment, the compounds of Formula I have the structure NCH,,~CX25CH2CH2 ~HRl Ib N ~ ~

wherein Rl and R5 each are in~ependently hydrogen or methyl, nd R6 and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically ac~eptable salt, hydrate or sol~ate khereof.

In another more preferred embodiment, the compounds of Formula I have the structure R6/ ~ ~2scll2c~2N~ ~ N~Rl Ic wherein Rl and RS each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a nontoxic pharmaceutically accepta~le salt, hydrate or solvate thereof.

In another more preferred embodiment, 'he compounds of Formula I have the structure ~L2~3~

R6/ ~ CH2c~2c 2 ~ NHRl Id N
~S~

wherein Rl 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 nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.
As presently envisaged, the most preferred compounds of Formula I are 1) 3-~mino-4-130(~-piperidinomethylphenoxy)propyl-æmino~-l,2,5-thiadiazole;
2) ~-amino-4-~2-1(5-dimethylaminomethyl-2-~uryl)-methyl~hio]ethylamino~l,2,5-thiadi2zole;
33 3-~mino-4-{2-1(5-dimethylaminome~hyl-4-methyl-2-thi~nyl)methylthio~ethylamino}-l,2,5-~hiadiazole,

4) 3-~mino-4-13-(3-pyrrolidinomethylphenoxy~-propylamino~-~,2,5~thiadiazole,

5) 3-methylamino-4-13-(3-piperidinomethylphenoxy)-propylamino~-l,2,5-thiadiazole,

6) 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)-propylamino~-l,2,5-thiadia~ole,

7) 3-amino-4-~2-1~5-dimethylaminomethyl-3-thienyl)-methylthio~ethylamino}-l,2,5-thiadiazole,

8) 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)-methyl~hiolethylamino}-l,2,~-thiadiazole,

9) 3 ~mino-4-[3-~6-piperidi~o~ethyl-2-pyridyloxy)-propyl~mino~-l,2,5-thiadiazole ~nd

10) 3-amino-~4-~3-~4-piperidinomethyl-2-pyridyloxy)-propyli~minol-l,2,5-thiadiazole; i~nd their nontoxic, pharma-ceutically accepti~ble salts, hydrates and solvatesL

The intenmediates of Formula II used in the prepara-tio~ o~ ~he compounds of Formula I may themselves be prepared hy various procedures. In one procedure, ~he corresponding ~3~

3-(amino or substituted amino)~4-(substituted am~no)-1,2,5-thiadiazole l-oxide of Formula III is treated with a strong mineral acid (preferably HCl) to produce ~he compound of Formula II.

A- (CH2 ) mZ (CH2) nNH NHRl III

~ HCl A-(CR2~mZ(c~2)nNH ~ NHRl II

The reaction m~y be conducted in an ~nert solvent ~nd preferably is conducted in methanol. Reaction temperature is not critic~l;
it most conveniently is conducted at room temperatureO The com-pounds of Formula III ~re known or may read~ly be prepared by the procedures described in our published United Xing~om Patent Application No. 2,067,987.

In an alternate procedure, the compounds of Formula II may be prepared by the following reaction scheme. The CH30 \ / OCH3 A-(cH2)mz(c~2)nN~2 /C - ~
~f ~H
I~7 V

~.%~

A-~C~2)mZ(c~2)n \ OCH3 VI
C --~/

¦~R1N~2 A-(CH2)~Z(CH2)nNH \JNHRl III

reaction may be conducted in an inert sol~ent and preferably is conducted in methanol~ The start mg matexials of Formula TY
are kn~wn or may be seadily prepared by ~nown procedures, e.g.
as by procedures described in our publlshed Uni~ed Kingdom Paten~ ~pplication No. 2,067,987.

In another aspect, ~hls invention relates to novel intermediates of the formula A-(C~2)mZ(cH2)nMH ~ ~Rl H~/ ~H II

wherein Rl is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-tri~luoroethyl, allyl, propargyl, ~3 ~ (CN2)p- or R ~ ~ r ~CH2)p-in which p is 1 or 2, R2 and R3 ea~h are independently hydrogen, (lower)alkyl, tlower~al~oxy or halogen, and, when ;

~Z~3~

R2 is hydrogen, R3 also may be trifluoro~ethyl, or R~ 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 incl~sive;
Z is oxygen, sulfur or methylene; and A is N~C}12)q~ /n(C~2)q~

/~C~2)q ~ or N(Cl~2)q ~

in which R 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)al~yl, ~lower)alkoxy~lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms re~oved ~rom the nitrosen atom, or phenyl~lower)alkyl, and, when R6 is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7, ta~en 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, octa-methyleneimino, 3-azabicyclol~02.2)non-3-y~ or 3-pyrrolino;
or a s~lt, hydrat~ or solvate thereo~.

I~ a preferred embodiment, the intermediates of Formula I~ have ~he structure ~-(CH~1mZ(CH2)nNH ~NHR
~ II
HN NH

~.25;~

wherein Rl is hydrogen or (lower)alkyl, ~ is O or 1, ~ is 2 or 3, Z is oxygen or sulfur and A is 6~ 2 ~ , 6/NCH

/N~2 ~ ~ or 6/ NC~2 ~

in which R5 is hydroqen or methyl, and R6 and R7 ea~h are ndependently methyl or ethyl, or when take~ together with the nit_oqen to which they are ~ttached, R6 and R7 represent a pyrrolidino ~r piperidino ring; or a nontoxic pharmaceutically acce?table salt, hydrate or sol~ate thereof.

In another preferred embodiment, the intermediates of Formula I~ have the structure 2 ~ C~2CH2CI~2 }~N NH

wherein Rl is hydrogen or methyl, and R6 and R7 each are methyl or, when taken together with the nitrogen ~tom to which they are attached, R6 and R7 .re~resent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure ~3~

NCH2- ~ H2scH2c~2NH ~ ~Rl IIb ~N N~

wherein Rl and R5 each are independ~ntly 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 ~he structure NC82 ~ ~ ~2sCrl2c 2 ~ ~HRl IIc XN NH

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

~ n another preferred embodiment, the intermediates of Formula II have the structure - /NCH~ OCH2C~2 2 ~ HRl IId NH

wherein Rl and R5 each are independently hydrogen or me~hyl, and R6 and R7 each are independently methyl or ethyl, or, when taken tosether with the nitrogen to which they are at~ached, ~ and R
represent pi~eridino; or a salt, hydrate or solvate thereof.

~253~

As presently envisaged, ~he most pre rerred intermediates of Formula II are 1) N-~3-(3-piperidinomethylphenoxy)propyl~ethane-diimidamide, 2) N-{2-~(5-dimethylaminomethyl-2-furyl)methylthio]-ethyl}ethanedii~idamide, 3) N-{2-~(5-dime~hylami~omethyl-4-methyl-2-thienyl)-methylthio)ethyl~ethanediimidamide, 4) N-~3-(3-pyrrolidinome~hylphenoxy)propyl]ethane-di~midamide~
5) N-{2-l(5-dimethyl~minomethyl-3-thienyl)~ethylthio]-ethyl}e~hanediimidamide, 6) N~12-l(5-piperidinom~thyl-3-thienyl)methylthio]-P~hyl}ethanediimidamide, 7) N-~3-(6-piperidinomethyl-2-pyridyloxy)propyl~-ethanediimidamide and 8) N-~3-t4-piperidinomethyl-2-pyridyloxy~propyl~
ethanediimidamide;
or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologlcally active compounds of ~ormula I will normally be administered as a pharmaceutical composition comprising as the ~or an) esse2,ial acti~e ingredient at least one such compound in its basic form or in the for~ of a nontoxic pharmaceutically acceptable acid addition salt, in association with a phanmaceutically acceptable carrier.

The pharmaceutical compositions may be administered or211y, pare~terally 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 ~f a syrup, ~mulsion, soft gelatin capsule, sterile solution for ~njection, or an aqueous or non-aqueous liquld suspension. The pharmaceutical compositions are prepared by ~onventional techniques appropriate to ~he desired preparation.

The dosage of ~he compounds of thi in~ention will depend not only on such factors as the weight of the patient;
but also on the degree of gastri~ 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 admLnistered per day) is within the discretion of the physician, and may be varied by titration of the dosage t~ the particular circumstances of the specific patient. ~ith the preferred compounds of this in~ention, each oral dosage unit will contain the ~ctive ingredient in an amount of from about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 my. The active ingredient will preferably be administered in equal doses from one to four times a day.

Histamine H2-receptor antagonists have ~e~n shown t~
be effective inhibitors of gastric secretion in animals ~nd ~an, Brimblecombe et al., J. Int. Med. ~es., 3, 86 (1975)~ Clinical evaluation of the histamine H2-receptor antag~nist cimetidine has shown it to be an effecti~e therapeutic agent in the treatment of peptic ulcer disease, G~ay et al , ~ancet, 1, ROOl (1977).
Some of the preferred compounds of this invention hav~ be~n compared with cimetidine in various tests and ha~e b2en found to be more potent than cimetidine both as an histamine H2-receptor antagonist in isolated guinea pig right atria and as an inhibitor o gastric acid secretion in rats and doss.

Determination of Gastric Antisecretory Activlty_in the Gastric ~istula Rat Male Long Evans rats weighing about 240~260 grams ak the time of cannula implantation are use~. The design and implantation of the stainless s~eel cannula into ~he anterior wall of the fore-stomach are carried out essentially as described by Pare et al. ~Labor~tory ~nimal Science, 27, 244 (1977)~. The fistula components a_~ designed and the operative procedure is carried out exactly as described in the above refere~ce. Post operati~ely the an~mals 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 allowe~ water ad libitum for 20 hours before the testing procedure is to begin. Immed-iately ~rior to collection, the cannula is opened and the stomach washed gently with 30-40 mL of w~rm saline or distilled wa~er to remove any residual contents. m e catheter is then scre~ed into the cannula in place of ~he plugging screw and the rat is pla~ed in a clear plastic rectangular cage measuring 40 cm long, lS cm wide and 13 ~m high. The bottom of ~he cage has a slit approximately 1.5 ~ wide and 25 cm long runnins down the center to ac~ommodate the catheter which hangs ~hrough it. In this way the rat is not restricted and can move freely about the cage during collectio~ periods. The remainder of the assay is car~ied out as des~ribed 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 contam-inated. Por oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 mL/
kg) is administered orally via gastric intubation and ~he animal is returned to the cage for 45 minutes. A~ter this time the plugging screw is removed and replaced with a catheter to which a small plasti~ vial has been attached to collect ~he 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 zttached to a small plastic ~ial and another 2-hour sample is collected. The secretions in the second sample are compared to ~hose of ~he con~rol sample in order to determine the effects of the test dru~.

~53~

l~en 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 af ter discarding the initial 60-minute collection. A two-hour sample is collected (eontrol secretion) and the animals are injected either ip or sc with the test compound in a volume of 2 mL/kg. ~n zdditional two-hour sample is collected and its secretions are compared to those of the control period to determine drug ef f ects .

The ~amples are centrifuged and placed in a graduated centrifuge tube for volume deter~inatlon. Titratable aci~ity is measured by titrating a one~mL sample to pH 7.0 wi~h 0.02N
NaOH, using an AutoburPt and a~ electrometric pH meter ~Radiometer). Ti~ratahle acid output is calculated in micro~
equivalents by multiplying the ~olume in milliliters by ~he acid concentration in milliequivalents per liter.

Results are expressed as percent i~hibition relati~e to control readings. Dose response curves are constructed a~d ED50 values are calculated ~y regressio~ analyses, At least ~hree rats are used at each dosage leve~ and a minimum of three dosage levels are utilized for determination of a dose response cur~e.

- ` ~%53~

Table 1 _ _ Gastric Antis~cretory Activity in the Gastric Fistula Rat ._ ~
ED50 sc Potency Ratio Compound ~moles/kg (cimetidine = 1.0) _ _ _ _ . _ cimetidine 3.48 1.0 (1.68-5.70 *
__ , _ __ _ ___ Example 1 0.094 37 (0.043~0.20) I ._ . _ __ _ _ . ,.
Example 2 O.77 4.5 (0.45-1~4) . _ . _ Example 3 ~0~5 ~7 _ _ _ _ __ _ _ _ _ _ Example 4 0.18 20 (0.10-0.36) _ i . _ *95% confidence limits ~istamine H -Receptor Antagonism-Isolated _ 2 Guinea Pig Atria Assay Histamine produces co~centration-related increases in the contractile rate of isolated, spontaneo~sly beating guinea pi$ right atriaO Black et al-, Nature, 236, 385 (1972), described the receptors involved in this effect of histamine as histamine H2-r2ceptors when they reported the properties o~
burimamide, a eompetit.ive antayonist of these receptors. Subse~
quent inves~igatior.s by Hughes and Coret, Proc. Soc. Exp. Biol.
Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol.
Exp. Ther., 200, 352 ~1977) support the conclusion of Bla~k and coworkers ~ha~ the positive chrono~ropic effect of histamine ~n isolated guinea pig right atria is mediated via histamine ~2-receptors. Black et al., Agents and Actions, 3, 133 (19~3) and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) have~_.
utilized isolated guinea pig right atria as a means or compar-ing the activities of histamine Y.2-receptor antagonists. The present comparative studies were carried out using a modifi cation of the procedure reported by Reinhardt et al., Agents and Actions, 4, 217 (1974).

~ ale Hartley stra m guinea pigs (350-450 gml wese sacrificed ~y a ~low on the head~ The heart was excised and placed in a Petri dish of oxygenated (95% 2~ 5% C02) modified Krebs solution (g/liter: NaCl 6.6, XCl 0.35, MsS~4-7~20 0.295, ~X2P04 0.162, CaC12 0.238, NaHCO3 2.1 and dextrose ~.99). The spontaneously beating right atrium was dissected free from other tissues and a silk t~read (4-0) attached to each end.
The atrium was suspended in a 20 ml muscle chamber containing o~ygenated modified Krebs solution maintained at 32C. Atrial contractions were recorded isometrically by means of a Grass FT 0.03 force displacement transducer and rec~rdings of contractile force and rate were made with a ~eckman RP
D~nosraph .

A res~ing tension o~ 1 g was applied to the atrium and it was allowed to equilibrate for 1 hour. At the end of the equilibration period a su~maximal concentrationrof histamine dihydrochloride (3 x 10 6M) was added to the bath and washed out to prLme the tissue. Histamine was then added to the bath in a cumulative ~ashion using 1/2 log 10 intervals to give final molar bath concentrations of 1 x 10 7 to 3 x 10 5. The histamine-induced increase in atrial rate was allowed to plateau befo~e the next successi~e concen ration was added. The maximal response invaria~ly occurred at the 3 x 10 ~M concen-tration. 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 30-minute incubation, the histamine dose response was repeated -21- ~ 2 adding higher concentratibns as needed~

The dissocia~ion consta~t~ ~X~) were derived from Schild plots by the method of ~runlakshana, O. and Schild, H. O~
lBr. J Pharmacol. 14, 48 (l9591~ using at least three dose levels. Parallel shifts in dose-response curves were obtained without depressing the maximal response at the antagonis~
concen~rations utilized, and the results are shown in Table 2.

Table 2 A tivit in Isolated Guinea Pi Ri ht Atria c y g g _ _ Potency Ratio Compound N KB (~moles) (cimetidine=l.0) _ _ _ cimetidine 20 O.41 ~.21-.64)* l.0 Example 1 12 0.003 ~.OOl-.004) 137 Exampl 4 ll 0.004 ~.OOl-.OlO) 102 *95% confidence limits The compounds ~f Formula ~ als~ ma~
be prepared by ring closure of a compound of Formula II with N~N'-thiobisphthalimide having the formula O ~
~;tS

The use of N,N'-thiobisphthalimide ~nstead of S2C12or SCl~ 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 chromato~raphic purifi-cation. - ~

In this process, the starting diimidamide of ~ormula II
is reacted with about an equimolar amount of N,N'-thiobis-phthalimide in an inert organic solvent such as CH2C12. Prefer-ably the starting diimidamide is used in the form of its tri-hydrochloride salt, in which case three molar equivalents of an amine, such as trlethyl~mine, are added to the reaction mix-ture ~o neutral~ze the trihydrochloride salt. The reaction may be conducted by stirring at room temperature for about an hour to insure completene~s of the reaction. ~he phthalimide which precipitates rom the reaction mixture i5 then extracted with a strong base (e.g. 10-20~ aqueous XOH), and the organic solvent layer is dried, filtered and concentrated to yield the csude compound of Formula I. The N,N'-thiGbisphthalimide 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.
~9~
N,N'-Thiobisphthali _de A cooled (0C) solution of phthalimide (14.7 g, 0.1 mole) in 80 ml of dimethylformamide (DMF) was treated dropwise with sul~ur dichloride (5.15 g, 0.05 mole). After the addition, the mixture was allowed to warm to 20C with stirring over four hours. ~he solid was collected and dried to give 12.5 g of the title compound as a DMF solvate, mp 301-315C. Both ir and nmr spectra are consistant or structure.

Anal. Calc d. for Cl~jH8N2O~S-C3H7NO: C, 57.42; H, 3.80; N, 10.57;
$, ~.07 Found: C, 57.50; H, 3.80; N, 10.29;
S, 8.57 ~2~3~
-~3-The DME solvate can be removed by recrystallization of the above material from chloroform; mp of the DMF-free produck was 320-325C. The ~mr spectrum shows that the D~ has been removed. r Anal. Calc'd. for C16H~N204S: C, 59.25; H, 2.49; N, 8.64; S, 9.89 Found: C, ~9.~ , 2.21; N, 8.91; S, 10.14 3~

~xa~ple 1 thiadiazole A. N-[3-(3-Piperidinomethylphenoxy)pro~yl~ethanediimidamide trihvdrochloride A suspension of 3-amino-4-[3-(3-piperidinomethyl-phenoxy)propyl~m mo]-1,2,5-thiadiazole l-oxide (17.1 g; 47.0 mmoles) ~prepared accordi~g to published ~nited Xingdom Patent Application No. 2,067,9873 ln ~50 mL of methanol was treated with 38 mL o ~oncentrated ~Cl. The resultant solution was stirred f~r 3 hours at ambient t~mperaturer Concentration of the solution followed by a2eotropi~ remo~al of water with absolute ethanol gave colorless ~rystals. ~he~e were suspended i~ ~00 ~ of absolute ethanol, filtered and dried und~r ~2cuum to give 16.6 g (82~6~) v~ the title compound, m.p. 205-222C (dec.). Recrystallization from 50~ methanol-e~hyl acetate ga~e an analytical sample, m.p. 206-216DC (dec.) J

Anal- Cal~d for Cl7H27~so-3~cl: C, 47-84; H~ 7-08; N~ 16-41 Found: C, 47.56; ~, 7.18; N, 16.75 B. 3-Amino-4-~3-(3-piperidinometh~lp_enoxy)pro~yl2m~no~-1,2,5-thiadiazole -A s~irred suspension of M-[3-(3-piperidinome.thyl-phenoxy)propyl~ethanediimidamide trihydrochloride (2.13 g, ,.
5.0 mmoles) [prepared in Step A~ in 20 m~ o dimethylformamide (DME) 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 ~CO3.
Tnis was extracte~ with 3 x 50 mL portions of methylene chloride and, after drying over .~gSO4 ~nd concentration, 2 .1 g of a dar~ gum containing the product was obtained. The product was purified by pxepa~ative high press~re liq~id chromatography ~i3~4~

on silica using CH2C12tlOO):2-propanol(lO):NH40H(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 ~umarate salt, m.p. 187-187.5C. ~PLC indicated a purity of ~99~.

Anal. Calc'd for (Cl7~25N50s~2 C4H404~ C~
N, i7.27; S, 7.90 Found: C, 56.09; ~, 6.36;
N, 16.98; 5, 8.08 A portion o~ the fumarate was suspended in water, neutralized with X2C03 and extracted wi~h CH2Cl~. The CH2C12 was con~entrated and the free base of the title compound crystallized out; m.p. 43-47~C. A por~ion of the free base was converted to the hydrochloride salt, m,p. ~38-140JC.

A~al calc~d fr Cl7H25Nsos-~cl: C~ 53-18; H~ 6-83; N~ 18-2~;
S, 8.35 Found: C, 53.14; H, 6.88; N, 18.49;
S, 8.74 Ex æ le 2 3-Ammo-4-{2- ~ t5-dimethYlaminomethx~-2-furyl)rnethylthio] =
ethylamino}-1,2,5-thiadiazole A. N-~2-~(5-Dimethylæminome yl-2-furyl)methylthio]ethyl}-ethanediimidamide trihydrochloride hYdrate A suspension o~ 3-amino-4-{2-l(5-d~methylamino~ethyl-2-fusyl)methylthiolethylamino}-1,2,5-thiadiazole l-oxide (6.59 g; 20~0 mmoles) lprepared according to published United Ringdom Patent Application No. 2,067,987] in 200 mL o methanol was warmed slightly to achieve complete solution, then treated with 13.3 mL o~ concentrated HCl. After ~tirring at ambient temperature ~or 2.5 hours, the solution ~as concen-~L2~3~

trated 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 compoun~, m.~.
166-169C (dec.).

Anal. Calc'd for Cl2H21N5S-3HCl H2O
N, 17.05; S, 7.80 Found: C, 34.8~; ~, 6.24;
N, 17.45; S, 7.97 B. 3 Amino 4-{2-[(5-dimethylæm1nomethyl-2-furyl)methylthio~_ ethylamino~-1,2,5-thiadiazo~e To a stirred suspension of N-{2-l(5-dimethylamino-methyl-2-furyl)~e~hylthio]ethyl~ethanediimidamide trihydro-chloride hydrat~ ~12.3 g; 30.0 rnmoles) Iprepared in Step A]
in 150 mI. of DMF was added 7 . 2 mL of sulfur monochloside (12.1 y; 90 mmoles~. After stirring for 4 hours at ambient t~mperature, approximately half of the DMF was r2moved at reduced pressure. The ~emai~ing blac~ 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 MgS04, filtration and concen~ration, 9.0 g of a black gum oontaining the product was obtained. This was purified by preparative high pressu~ liquid chromatography on silica using ethyl acetate(lO0~:2-propa~ol(lO):NH4OH(0.5) as the mobile phase. The appropriate fractions yielded 1.~4 g of the title compound as a gum.

Treatment ~f part of ~his product with an e~uivalent a~ount of 2N HCl in methanol yielded the hydrochloride salt of the title compound.

Anal. Calc d for Cl~HlgN552O-HCl: C, 41.18; Ho 5.76; N, 20.02;
S, 18.33 Found (corr. for 1.65~ H2O): C, 40.54; H, 5.7~; N, 19.3~;
5, 18,44 Treatment of the product with an equivalent amount of cyclohexylsulfamic acid in acetone yielded the cyclohexyl--sulfamate salt of the title compound, m.p. 93-95C.

Anal. CalC'd for C12HlgN552 C6H13 3 N, 17.06; S, 19.53 Found: C, 43.77; H, 6~17;
N, 17.21; S, 19.58 ~x~mple 3 3-.~mino-4-{2~ d~meth~laminometh~ 4-methyl-2-thienyl)-methylthio?ethylamino-}-1,2,5-thiadiazole A. N-{2-[(5-Dimethylaminomethyl-4-methyl-2-th enyl?methy_thio~-ethy~}ethanediimidamide trihydsochloride A stirred solution o~ 3-amino-4-i2-l(5~dimethylamino-methyl-4-methyl~2-thienyl)methylthio~ethylamino3-1,2,5-thiadiazole l-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 concent~ated HCl. 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 0C, filtered and dried to give 16.9 g ~80~) of the title compound, m.p. 206-220C (dec.). Recrystallization from 50% methanol-~thyl acPtate gave a product having m.p. 210-2~1C (dec.).

Anal- ealc d ~or Cl3~23M5s2~3Hcl C, 36 g2; H~ 6-20; N~ 16-56;

Found: C, 36.76; H, 6.33; N, 16.97;
S, 15.54 3~

3. 3-Amino-4 ~2-[(S-dlmethylaminomethv methYl~hio]eth~lamino}-1,2,5- h _diazole To a stirred suspension of N- { 2- [ ( 5-dimethylamino-methyl-4-methyl-2-thienyl)methylthio~ethyl}ethanediimidamide trihydrochloride (6.34 g; 15.0 mmoles) ~prepared in Step A]
in 60 mL of DMF was added 6.1 g (45.0 mmoles) of sulfur mono-chloride. After stirring for 4 hours at ambient temperature, the reaction mixture was poured into 800 mL of water, made basic with ~C03, and extracted seYeral tLmes with 100 ~L-portions o~ methylene chloride. The extracts were dried over MsS04, filtered, a~d concentrated to give 3.4 g o~ a black gum containing the product. The product was p~rified by preparative high pressure liquid chromatography on silica using CH2Cl~(100):
2-propanol510):NB~OH(0.5) as the mobile phase. ~urther purification was achieved by an additional preparative high pre sure li~uid chromatography on silica usins CH2cl2tloo):
C~.30~(2.5):NH40H(005) as the mobile phase. The appropriate fractions yielded the title co~pound (purity ~98~). Treatment of the product with an equivalent amount of 2N HCl gave the hydro~hloride salt of the title compound.

C lc~d ~r C ~21N553 HCl: C~ 41-09; ~ 5-S, Z5.32 Found (corr. for 0.51% H20): C, 40078; ~, 5.63; ~, 18.31;
S, 25.44 Exampl e 4 3-Amino-4-[3-~3-pyrrolidinome~hyl~henoxy~propylamino~-1,2,5-~hiadiazole A. N-~3-(3-Pyrrolidinomethyl~henoxy)pro~yl]ethanedii~idamide rihydrochlor~de A suspension of 3-amino~4-[3-(3-pyrrolidinomethyl-phenoxy)propyl~nino~-1,2,5-thiadiazole l-oxide (13.~ g; 38~3 ~moles) ~prepared accordins to puhlished United ~ingdom Patent Application No. 2,067,987] in 350 mL of methanol was treated with 25.5 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ,~mbient temperature. Concentration of the solution ~ollowed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered ,~nd dried to g ~e 10.8 g of the title compound, m.p. 195-203C (dec.).

Anal calc~d for C16~25N5o~3~cl: C, 46.55; H, 6-84; N~
Found: C, 46.55; B, Ç.93; N, 16093 B, 3-Amino-4-~3-~3-pyrrol~dinomethylphenoxy)propylamino]-1,2,5-thiadiazole A s'irred suspension of N-~3~(3-pyrrolidinomethyl phenoxy)propyl~ethanediimidamide trihydrochloride (8.25 g: 20.0 ~moles) [prepared ~n 5tep A~ in 80 mL of DMF was treated wi~h sulfur monochloride (5.4 g; 40.0 mmoles) and stirred under a nitrogen a~mosphere for 3 hours. Concentration o~ the reaction mixture gave a dark sum which was suspended in 500 ml of water, made basic with X~C03 and extracted with 3 x 100 mL of methylene chloride. The extracts were dried over MgS0~, filtered and concentrated to giv~ 7.5 g of a dark gum containing the product.
The product wa~ purified by preparative high pressure liquid chromatography on silica using CH2C12(100):2-propanol~5):
NH40H(0.5) as the mobile phase. Fractions containing the desired product were combined and concentrated to give 1~64 g (~4.6%) of the purified title product. Treatment of the product in absolute ethanol with an equivalent a~ount of 2N ~Cl g2ve the hydrochloride salt o~ ~he title compound (1.13 g);
m.p. 138-140C.

Anal, Calc~d ~or Cl6H23N5os-Hcl: C, 51-95; H~ 6-54; N~ 18-93;
S, 8.67 Found: C, 51.97; H, 6~36; N! 18.63;
5, 8.76 Example 5 The general procedure of Example 1, S~eps A and~B, is repeated except that ~he 3-amino-4-[3-~3-piperidinomethyl~
phenoxy)propylami~o]-1,2,5-thiadiazole l-oxide u~ilized ~herein is replaced by an equimolar amount of ~a) 3--amino-4-~3-(3-dimethylaminomethylphenoxy)propylamino~-1,2,5-~hiadiazole l-oxide, (b) 3-amino-4-l3-(3-diethylaminomethylphenoxy)propylamino~-1,2,5-thiadiazole l-oxide, (c) 3-amino~4-~3 ~3-~2-methylpyrrolidino)me~hylphenoxy]-propylamino~-1,2,5-thiadiazole ~-~xide, (d) 3-amino-4-{3-l3-(3-methylpyrrolidino)methylphenoxy~-propylamino} 1,2,5-thiadiazole l-oxide, (e) 3-amino-4-{3~3-(4-methylpiperidilo)methylphenoxy]~
propylamino~-1,2,5-thiadiazole l-oxid~, (f) 3-amino-4-~3-( 3-morpholinomethylphenoxy) propylamino)-1,2,~
~hiadiazole l-oxide, (g) 3-amino-4-{3-l3~ methylpiperazino)methy~pheno~y~-propylamino}-1,2,5-thiadiaz~le l-oxide, (h) 3-amino-4-13-(3-diallylaminomethylphenoxy)propylamino~-1,2,5-thiadiazole l-oxide, (i) 3-~mino-4-[3-(3-hexamethyle~eiminomethylphenoxy)propylamino)-1,2,5-thiadiazole 1-oxide, (j) 3-amino-4-l3-(3~heptamethyleneiminomethylphenoxy)~ropyl-amino~-1,2,5-~hiadiazole l-oxide, (k) 3-amino-4-{3-L3-(3-azabicyclo~3.2.2lnon-3-yl)methylph~oxy~-propylamino} 1,2,5-thiadiazole l-oxide and (1) 3-amino-4-;3~3-(3-pyrrolino)methylphenoxy]propyl~mino~-1,2,5-thiadiazole l-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-methylpyrrolidino)methylphenoxy~-propylamino~-1,2,5-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-4-13-(3-mor~holinome~hylphenoxy)propylamino~-1,2,5-thiadiazole, (g) 3-amino-4-{3-~3-(N-methylpiperazino)methylphenoxy) propylamino)-1,2,5-~hiadiazole, (h) 3-amino-4-13-(3-diallylaminomethylPh~oXy)prOpylamino]-1~2,5-thiadiazole, (i) 3-amino-4-13-~3-hexamethyleneiminomethylphenoxy)propyl~mino~
1,~,S-thiadiazole, (j) 3 amino-4-~3-~3-heptamethyleneiminDmethylphenoxy)propylamino]-1,2,5-thiadiazole, (k) 3-amino-4-{3-[3-(3-azabicyclo[3.2.2.)non-3-yl)methylphenoxy]-propylzmino}-1,2,5-thiadiazole and (1) 3-amino-4-{3-[3-~3-pyrrolino)methylphenoxy~propylami~o~-1,2,5-thiadiazole, respectively.

Exam~le 6 3-Amino-4-[3-(3-Piperidino ethyl~henoxy)propylamino]-l~2 thiadiazole This is a variation of Example 1, Step B, utilizing le~s sulfur monochloride and a shorter reaction tlme.
To a stirred suspension of N-~3-(3-piperidino~ethyl- J
phenoxy)propyl~ethanediimidamide 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 DM~ was removed at reduced ~L~253~

pressure to leave a black gum which was suspended in water, made basic with K2C03 and extracted with 3 x 100 mL portions of CH2C12. The combined extracts were dried o~e- MgS04, .
f iltexed and concentrated to a blacX gum. This gum was purified by prepara~ive high pressure liquid chromatography on silica using CH2C12(100):2-propanol(5):1~H40H(O~S) as the mobile phase~ The appropriate fractions yielded 3.1 g o' the title product as a dark oil which gav~, with fumaric acid in n-propanol, 2.66 g (23.2~) of the title compound as a cry~tal-~ine fumarate sal , m.p. 186-1~6.5C. HPLC indicated a purity of 99%.

Anal. Calc'd. for (C17H25~50S)2 C4 4 4 N, 17,27; S, 7.90 Found: C, 56.27; H, 6.96;
N, 17.31; S, 7.98 Example 7 3-Amino-4-~3-(3-piperid~no~ethylphenoxy~pro-pylamino~ 2!5 thiadi2zol~

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-pheno~y)propyl~ethanediimidamide trihydrochloride (854 mg; 2 mmoles) in 6 mL of D~ under N2 in an ice bath was added SC12 (206 ~g; 2 mmoles) in 2 mL o. DMF. The reaction mixture was stirred at ambient temperature and the title compound was produced.

3-Methylam~no-4-~3-~ piperidinomet~phenoxy)~ropylamino]-1,2,~-thiadiazole A. ~ _ ~253~4L~

di~midamide trih drochloride . Y

A suspensio~ of 3~methylamino-4-I3-13-piperidinomethyl-phenoxy)propylamino]-1,2,5-thiadiazole l-oxide (4.13 g; 10.9 mmoles) Iprepared according to published United Ringdom Patent Application No. 2,067,987] in 9S ml of methanol was treated with 7~2 ml of concentrated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to gi~e 4.35 g (90.4%) of product. A sample was recrystallized from aqueous i opropyl alcohol to give the title compound, mp 207-225C (dec.).

Anal. Calcld. for Cl H29N5O-3HCl: C, 49.03; B, 7.33; N, 15.89 Found (corr. for 0-94% ~2) C, 49.37; ~, 7.35; N, 15.71 B. 3-Methyla_ino-4-~3-~3 ~iperidinometh~lpheno~y)propylamino]-1,2,5-thiadiazole A mixt~re of ~-methyl-N'-~3-(3-piperidinomethyl-phenoxy)propyllethanedilmidamide trihydrochloride (3.74 g; 8.47 ~moles) [prepared in Step A~, 34 ml of C~2C12 and 3.5 ml of triethylamine was treated with N,N'-thiobisph~halimide (D~
solvate) (3.36 g; 8.46 mmoles) and stirred for one hour. The mixture was washed with 30 ml o 10% KOH, dried (MsSO4), filtered, diluted with toluene and ooncentrated to give 3.6 g 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 eluent to give 1.9 g (62~) of the title compound. Treatment o~ the product with an equivalent amnunt o~ aqueous HCl in l-propanol gave the hydrochloride salt of the title compound, mp 163.5-164.5C.

Anal. Calc'd. for C18H27N5OS~HCl: C, 54.32; H, 7.04, ~, 17.60;
S, 8.06; Cl, 8.91 Found: C, S4.35; H, 7.07; N, 17.64;
S, 8.3~; Cl, ~.8~

~ ~ 3*~
-3~-Example 9 3-Benzylamino-4~[3-(3-piperidinometh~lphenox~)proEy~mino]
1,2,5-thiadiazole _ . N-Benzyl-N'-I3-(3-piperidinometh~l~henoxy)~op~l~ethane-diimidamide trihydrochlorlde A suspension of 3-benzylæmino-4-[3-(3-piperidinomethyl-phenoxy)propylamino]-~,2,5-thiadiazole l-oxide ~.14 g; 11.3 mmoles) [prepared according to publi~hed United Kingdom Pa~ent Application No. 2,067,987~ in 100 ml of methanol was treated with 7O55 ml of concentratea HCl A~ter stirring at ambient temperature for 3 hours, ~he solution was concentrated and ~he residue was triturated with acetone, filtered and dried to give 5.16 g (88%) of the title compound, mp 187-205~C (dec.)~

Anal Calc'd for C24~33N50-3HCl: C, ~5.75; H, 7.03; N, 3.55;
-Cl, 20.57 Found: C, 54.88; ~1, 6.75; N, 13.33;
C~, 20.20 B. 3-Benzylamino-4-~3-(3-~iperidinomethylphenoxy)propylamino~-1,2,5-thiadiazole A mixture of N-benzyl-N'-13-(3-piperidinomethylphenoxy) propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles) [prepared in Step A], 45 ml of CH2C12 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~ ROH, dried (~gSO4), filtered, diluted with toluene and concentrated. The residue wa~ chromatographed by flash chromatography o~ 110 g of silica gel (230-400 mesh) using ethyl acetate as ~he eluènt to give 3~1 g ~77~) of the ti~le compourld. Treatment: of the product with an equivalent amount of aqueous HCl in 2-propanol gave the hydrochloride salt of the title compound, mp 138-141C.

~;3~

nal. Calc'dO for C24H31N5OS~HCl: C, 60.80; H, 6.80; N, 14.77;
S, 6.76; Cl, 7.48 Found: C, 60.53; H, ~.64; N, 14~99;
S, 6.91; Cl, 7.~7 Exam~le 10 3-Amino-4-¦3-(3-piperidinometh ~ e oxy)propylamino~-1,2,5-~hiadiazole This is a variation of Example 1, s~ep B, u~ilizing N,NI-thio~isphthalimide instead of sulfur monochloride .

A mixture of N- E3- (3-piperidinomethylphenoxy)propyl]-ethanediimidamide trihydroohloride (27.3 g; 64.0 mmoles) ~prepared in Example 1, Step A), 250 ml of CH2C12 nd 26.6 ml (192.0 mmoles) of triethylamine was treated portionwise with N,N'-thiobisphthalimide (DMF solvate) S25.4 g; 6400 mmoles).
After tirring at ambient temperature for one hour, the mixture was wa~hed with 120 ml of 20~ KOH, dried (~gSO4~, filtered and concentrated, then taken up ~n 150 ml of toluene and reconcen-traked. The product was taken up in 250 ml of l-propanol and 10.7 ml of 6N HCl, treated with decoloriziny carbon and ~iltered through Celite* This solution was concentrated to 10a ml volume, diluted with 175 ml of dry l-propanol and stored at 0C to give 20.2 g (82.1%) of crystalline hydrochloride salt of the title compound, mp 137-138C.
nal. Calc d. ~ox C17H25N5O5 HCl: C, 53-18; H, 6-83 N~ 18-24;
S, 8.35 Found: C, 52.78; H, 6.74; N, 18.52;
S, 8.~6 Example 11 3-Amino-4-l3-(3-~yrrolidinomethylphenox~)pro~ mino]-1,2,5-thiadiazole This is a variation of Example 4, Step B, utilizing N,N'-thiobisphthalimide instead of sul.ur monochlorideO

*T~ade Mark 3~

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 CH2Cl~ and 22 ~1 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 m~xture was washed with 100 ml of 20~ KOH, dried (MgSO4), filtered, diluted with 100 ml of toluene and concentrated. The product was treated with one equivalent of aqueous HCl in l-propanol to give 13.2 g (67%) of the hydro-chloride salt of the title compour.d, mp 135-137C.

Anal. Calc'd. for C16H23N5OS~HCl: C, 51.95; H, 6.54; N, 18~93;
S, B.67 ~und: C, 51.92; H, 6.55; N, 19.30;
S, 9.06 3-.~mino-4-{2-[~5-dimethylaminomethyl-3-thie~yl)methvlthio]-ethylamino}-1,2,5-thiadiazole A. N-{2-~(5-dimeth~laminomethyl-3-thien~l)methylthioJethyl}-ethanediimidamide trihydrochloride A suspension of 3-amino-4-{2-[15-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole l-oxide (7.8 g;
22.6 mmoles) [prepared according to published ~nited Xingdom Patent Application No. 2,067,987] in 150 ml of methanol was treated with 15.0 ml of concer.trated HCl. After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with l-propanol, filtered and dried to give 7.38 g t80~) of product. A sample was recrystallized from methanol acetone to give the title compound, mp 190-205~C (dec.~.

Anal. Calc~d- or C12N21N5S2~3Hcl C, 35.25; H, 5-92; N~ 17-13 Found: C, 35.03; H, 5.g3; N, 17.39 B. 3-Amino-4-{2-~(5-dimethylaminomethyl-3-thienyl~meth~lthio~-ethylamino~l,2,5-thiadiazole A mixture of N-{2-[(5-dimethylaminomethyl-3-thienyl)-methylthio]ethyl}ethanediimidamid0 trihydrochlor~de ~6.i~ g;
15.0 mmoles~ [prepared in Step A~, 60 ml of CH2C12 and 6.3 ml of triethylamine was trea~ed with N,N'-thiobisphthalimide ~DMP
solvate) (5.96 g; 15.0 mmol~s) and stirred ~or one hour. Th~
mixture was washed with 100 ml of 10~ XOH, dried (MgSO4), filtered, diluted with toluene and concentrated to give S.l g of product. Treatme~t of the product with 0.5 molar equivalent o fumaric acid in l-propanol ga-~e the fumaric acid salt of ~he compound, mp 141-143C. The nmr spectrum in D~SO-d6 shows the presence of approximately 0~12 moles of l-propanol.
nal~ Calc~d. f~r (Cl2~lgNss3)2-c4H4O4Dool2c3~8o 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 {2-[(5-2~peridinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole A. N-{2-[(5-piperidinomethyl-3-thi~nyl)methylthio]ethyl}ethane-diimidamide trih~drochloride A suspension of 3-amino-4-{2-[(5-piperidinomethyl 3-~hienyl)methylthio~ethylamino}-1,2,5-thiadiazole l-oxide (6.1 g;
15.8 mmoles) IprPpared according to published United ~ingdom Patent Application No. 2,067,987~ in 80 m' of methanol was treated with 10.5 ml of concer.trated HC1. After stirring at ambient tempera~ure for 3 hours, the solution was concentrated 5 ~ LLi~
~38-and the residue triturated with 50 ml of l-propanol, filtered and dried to give 5.86 g (83%) o~ product. A cample was recrystal-lized from methanol-acetone to give the title compound, mp 201-214C (dec.).

Anal. Calc'd. for C15H25N5S2-~HCl: C, 40,13; H, 6.29; N, 15.60;
~, 14.29 Found: C, 39.97; H, 6.47; N, 15.28;
S, 14.63 B. 3-Rmino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthiol-eth lamino}-1,2,5-thiadiazole .
~ mixture of N-{2-t(5-piperidinomethyl-3-thienyl)-methylthio]ethyl}ethanediimidamide trihydrochloride (5.17 g;

11.5 mmoles) Iprepared in Step A], 48 ml of CH2C12 and 4.8 ml of triethylamine was treated with N,N'-thiobisphthalimide ~DMP
solvate) (4.57 g; 11.5 mmoles) and stirred for one hour. The mixture was washed with 90 ml of 10% ~OH, dried (MgSO4), filtered, diluted with toluene and concentrated to give 4.5 g of product.
Treatment of the product with one equivalent of cyclohexyl slllfamic acid in methanol gave the cyclohexyl sulamate salt of the title compound, mp 142-143C.

Anal Calc'd- for C15H23~5S3 C6H13 3 N, 15.31; S, 23.38 Found: C, 45.61, H, 6.41;
N, 15.46; S, 23.48 Example 14 The gene~al 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)propylaminol-1,2,5-thiadiazole l-oxide utilized the_ein is repla~ed by a~ equimolar amount of (a~ 3-ethylamino-4-13-t3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole l--oxide, ~ l ~ 2~ 3 (b) 3-allylamino-4-i3-(3-piperid momethylphenoxy)propylamlno]-1,2,5-thladiazole l-oxide, (c) 3-(2-p~opynyl)-4-~3-(3-piperidinomethylphenoxy)propyla~ino3-1,2,5-thiadiazole 1-oxide, (d) 3-(3-pyridylmethylamino)-4-l3-t3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole l-oxide, (e) 3-(6-methyl-3-pyridyl)methylamino-4-l3-(3-piperidinomethyl-phenoxy)propylamino]-1,2,5-thiadiazole l-oxide and (f) 3-(3,4-methylenedioxybenzylamino)-4-~3-~3-piperidinomethyl~
phenoxy)propylamino]-1,2,5-thiadiazole l-oxide, respectively, and there is therPby produced (a) 3-e.thylamino-4-[3 (3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (b) 3-allylamino-4-[3-(3-pip2ridinomethylphenoxy)propylamino]-1,2,5-thia~iazole, (c) 3 (2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (d) 3-(3-pyridylmethylamino~-4-[3-(3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole, (e) 3-(6-methyl-3-pyridyl)~ethylamino-4-~3-(3-piperidinomethyl-phenoxy3propylamino]-1,2,5-thiadiazole and (f) 3-(3,4-methylenedioxybenzylamino)-4-~3-(3-piperidinomethyl-phenoxy)propylamino]-1,2,5-thiadia~ole, respectively.

Exam~le 15 -3-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propyl~m~
1,2,5-thiadiazole A. 3-~mino-4-~3-(6-piperidinomethyl-2-pyridyloxy)propylamino~-1,2,5-thiadiazole l-oxide A solution of 3-(6-piperidinomethyl-2-pyridyloxy)-propylamine (4.6S g; 18.6 n~oles) [prepared according to published United Ki~gdom Patent Application No. 2,098,988~ in 50 ml of methanol was reacted wi~h 3-amino-4-methoxy-1,2,5-~253~

~40-thiadiazole l-oxide (2.74 gi 18.6 mmoles) according to the general procedure described in United Xingdom Patent Applica~ion 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 145-147C.

B. N
trih drochloride Y

A methanolic solution of the product prepared in Step A was diluted to 100 ml and 12.4 ml of co~centrated HCl was added. The ~olution was stirred at ambien~ temperature 'or 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-Amino 4-~3 _6-piperidmomethyl-2-~yridylo ~ ropylamino~-1,2,5-thiadiazole A mixture of the crude product prepared in Step B in 80 ml of CH~C12 and containing 7.69 ml of triethylamine was ~rea~ed with N,N'-thiobisphthalimide tDMF solvate) (7.35 g; 18.5 mmoles)~
After stirring at ambient temperature for one hour, the mixture was washed ~ith 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SO4), flltered and evaporated under reduced pressure to give ~he crude product. The product was purified by ~lash chromatography on 100 g of silica gel (230-400 mesh~ using ethyl acetate-methanol (95:5) as the eluent to give 3.63 9 of the title compo-md as a viscous oil. Treatment of the product with one e~uivalent o~ cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, mp 125.5-131C.

Anal. Calc'd. for C16H~4N60S C6H13N03S: C, 50.07; H, 7.07;
N, 18.58; S, 12.~5 Found: C, 50.02; H, 7.03;
~, 18.54; S, 12.14 ~253~

Example 16 3-Amino-4-[3-(6-dimet~laminomethyl-2-pyridyloxy)propylamino]-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 rPacted with 3-amino-4-methoxy-1,2,5-~hiadiazole l-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 l-oxlde is succes-sively reacted by ~he general procedure described in Example 1, Step A, and then by either Example 1, Step B, or Example 10 r the title compound is thereby produced.

Example 17 3-Amino-4-{2-[(6-dimethylaminomethyl-2-pyriZ~l)methylthio~
ethylam~no}-1,2,5-thiadiazole When a suspension of 3-amino-4-~2-[~6-dimethylamino-methyl-2-pyridyl)methylthio~ethylamino}-1,2,5-thiadiazole 1-oxide [prepared according to published United Kingdom Patent Application No. 2,067,987] is succes~ively reacted according to the procedures of Example 1, Step A, ~nd then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

3-Amino-4-{2- [ (6-piperidinomethyl-2-pyrid~l)methylthio~ eth amino}-1,2,5-thiadiazole 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 ~nited gingdom Patent Application No. 2,067,9871 is successively reacted according to the procedures of ExamplP 1, Step A, and then by either Example 1, ~253~l4~

Step B, or Example 10, the title compound is thereby produced.

Example 19 The genexal procedure of Example 1, Step Ar and then either Example 1, Step B, or Example 10 is repeated except that the 3-amino-4-13-(3-piperidinomethylphenoxy)propylamino]~ ,5-thiadiazole l-oxide utilized therein is replaced by an equimolar amount of (a) 3-amino-4-13-(3-piperidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole l-oxide, ~b) 3-amino-4-13-(3-dimethylaminomethylthiophenoxy)pxopylamino]-1,2,5-thiadiazole l-oxide, (c) 3-amino-4-13-(3-pyrrolidinomethylthiophenoxy)propylamino~_ 1,2,5-thiadiazole l-oxide, (d) 3-amino-4-[3-~4-dimethylaminomethyl~2-pyridyloxy)-propylam~no]-1,2,5-thiadiazole l-oxide, (e) 3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propyl-amino]-1,2,5-~hiadiazole l-oxide, (f) 3-amino-4-~3-(5-piperidinomethyl-3-thienyloxy)propylamino~-1,2,5-thiadiazole l-oxide, (g) 3-amino-4-{2-1(4-dimethylaminomethyl-2-pyridyl)methylthio]-ethylamino}-1,2,5-thiadiazole l-oxide and (h) 3-amino-4-{2-~(4-piperidinomethyl-2-pyridyl)methylthio~-ethylamino}-1,2,5-thiadiazole l-oxide, respectively, and therP is thereby produced (a) 3-amino-4-13-(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-pyrrolidinomethylthiophenoY.y)propylamino~-1,2,5-thiadiazole, (d) 3-amino-4-~3-(4-dimethylaminomethyl-2-pyriGyloxy)-propylamino]-1,2,5-thiadiazole, ~e) 3-amino-4-13-(5-dimethylaminomethyl-3-thienyloxy)propyl-amino]~l,2,5-thiadiazole, , :~ ;

_43- ~.253~4~

(f) 3-amino-4-~3~(5-piperidinomethyl- -thienyloxy)propylamino~-1,2,5-thiadiazole, (g) 3-amino-4-{2-[(4-dimethylaminomethyl 2-pyridyl)methylthio~-ethylamino}-1,2,5-thiadiazole and (h1 3-amino-4-{2-1(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. ~,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-[3-54-piperidinometh~1-2-pyridyloxy)propylamino]-1,2,5-thiadiazole A. 3-(4-Piperidinomethyl-2-pyridyloxy)propylamine When the general procedure for the preparation of 3~~6-piperidinomethyl-~-pyridyloxy)propylamine described in U.K.
Patent Application NoO 2,098,988 was followed except that the 2-chloro-6-methylpyridine utilized therein was replaced by ~-bromo-4-methylpyridine, then the title compound was produced as an oil.

Anal. Calc'd. for C H N30: C, 67.44; El, 9.30; N, 16.85 Found: C, 67.54; H, 8.98; N, 16.55 B. 3-Amino-4-[3-(4-~iperidinomethy1 2-pyridyloxy)propylamino]-1,2,5-thiadiazole l-oxide A solution o the product of Step A (6.5 g; 2~.0 mmoles~
in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole l-oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.K. P~tent Application 2,067,987 to give 6.33 g of product. Recrystallization from methanol-acetonitrile yielded the title compound, ~p 154-158C.
Anal. Calc d. for C16H24N6OS: 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 ~2~3~

~44 C. N-[3-(4-Piperidinomethyl-2-~yridyloxy)~ropvl~ethanediimid~ide trihydroohloride 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 HCl.
After stirring at ambient t~mperature for 4.5 hours, the solution was evaporated to dryness under reduced pressure to give the title compound.

D. 3-Amino-4-[3-~4-pi~eridinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole A mixture o~ the product prepared in Step C in 50 ml of CH2C12 and 5.7 ml of triethylamine was treated with N,N'-thio-bisphthallmide (DMF solvate) (5.44 g; 13.7 mmoles). After stir-ring at ambient temperature for one hour, the mixture was washed with 40 ml of 4N NaO~, water, saturated aqueous NaCl solution, dried tNa2so4)~ filtered and evaporated under redu~ed 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 o~ the title compound, mp 124.5-126C.

AnalO Calc'd. for C16H2~N6OS-C6H13NO35: C, 50.07; H, 7.07;
N, 18.58; S, 12.15 Fvund: C, 50.47; H, 7.12;
N~ 18.33; S, 11.87 Exam~le 21 3_~mino-4-{3-t3-(1,2,3,6-tetrah~dro-1-pyridyl)methvlpnenoxy~=
ro~vlamino}-1,2,5-thiadiazole The general procedure of Example 15 was repeated, except th~t the 3-(6-piperidinomethyl-2-pyridyloxy)propylamine utilized th~rein was replaGed by an equivalent amount of 3-l3-(1,2,3,6 ~S ! i '~

~253~L~4 tetrahydro-l-pyridyl)methylphenoxy~propylamine, to give 2.31 g of product. Crystallization from toluene yielded the title com-pound, mp 99.5-104C. ~_, Anal. Calc'd. for C17N23N50S: C, 59-10; H, 6-71; N~ 20-27; S~ 9-2 Found (corr. for 2.19~ H2O): C, 58.78; ~, 6.71; N, 19.90; S, 9.26

Claims (45)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS.

1. A process for preparing a compound of the Formula II

II

wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, or 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 A is or 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, methyl-piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof, which process comprises a) reacting in an inert solvent and at room temperature, a compound of Formula III
III
wherein R1, m, n, Z and A are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Formula II to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IV

A-(CH2)mZ(CH2)nNH2 IV
wherein m, n, Z and A are as defined above, with a compound of Formula V

V
to produce a compound of Formula VI
then reacting said compound of Formula VI with a compound of Formula R1NH2, and, if desired, converting the resultant compound of Formula II to a suitable salt, hydrate or solvate.

2. A process for preparing a compound of the Formula II

wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is or 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, which process comprises a) reacting in an inert solvent and at room temperature, a compound of Formula III
III
wherein R1, m, n, Z and A are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Formula II to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IV
A-(CH2)mz(CH2)nNH2 IV

wherein m, n, Z and A ara as defined above, with a compound of Formula V
V
to produce a compound of Formula VI
the reacting said compound of Formula VI with a compound of Formula R1NH2, and, if desired, converting the resultant compound of Formula II to a suitable salt, hydrate or solvate.

3. A Process for preparing a compound of the Formula IIa IIa 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 pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof, which process comprises a) reacting, in an inert solvent and at room temperature, a compound of Formula IIIa IIIa wherein R1, R6 and R7 are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Formula IIa to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IVa IVa wherein R6 and R7 are as defined above, with a compound of Formula V

V
to produce a compound of Formula VIa VIa wherein R6 and R7 are as defined above, then reacting said compound of Formula VIa with a compound of Formula R1NH2 and, if desired, converting the resultant compound of Formula IIa to a suitable salt, hydrate or solvate.

4. A process for preparing a compound of the Formula IIb IIb wherein R1 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, which process comprises a) reacting in an inert solvent and at room temperature, a compound of Formula IIIb IIIb wherein R1, R5 R6 and R7 are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Formula IIb to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IVb IVb wherein R5, R6 and R7 are as defined above, with a compound of Formula V

V

to produce a compound of Formula VIb VIb wherein R5, R6 and R7 are as defined above, then reacting said compound of Formula VIb with a compound of Formula R1NH2 and, if desired, converting the resultant compound of Formula IIb to a suitable salt, hydrate or solvate.

5. A process for preparing a compound of the Formula IIc IIc wherein R1 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, which process comprises a) reacting in an inert solvent and at room temperature, a compound of Formula IIIc wherein R1, R5, R6 and R7 are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Forumula IIc to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IVc IVC
wherein R5, R6 and R7 are as defined above, with a compound of Formula V
V

to produce a compound of Formula VIc VIc wherein R5, R6 and R7 are as defined above, then reacting said compound of Formula VIc with a compound of Formula R1NH2 and, if desired, converting the resultant compound of Formula IIc to a suitable salt, hydrate or solvate.

6. A process for preparing a compound of the Formula IId wherein R1 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, which process comprises a) reacting in an inert solvent and at room temperature, a compound of Formula IIId IIId wherein R1, R5, R6 and R7 are as defined above, with a strong mineral acid and, if desired, converting the resultant compound of Formula IId to a suitable salt, hydrate or solvate; or b) reacting a compound of Formula IVd IVd wherein R5, R6 and R7 are as defined above, with a compound of Formula V

V

to produce a compound of Formula VId VId wherein R5, R6 and R7 are as defined above, then reacting said compound of Formula VId with a compound of Formula R1NH2 and, if desired, converting the resultant compound of Formula IId to a suitahle salt, hydrate or solvate.

7. The process of claim 3 wherein R1 is hydrogen, and R6 and R7 taken together is piperidino.

8. The process of claim 4 wherein R1 and R5 are both hydrogen and R6 and R7 are both methyl.

9. The process of claim 5 wherein R1 is hydrogen and R5, R6 and R7 are each methyl.

10. The process of claim 3, wherein R1 is hydrogen, and R6 and R7 taken together is pyrrolidino.

11. The process of claim 5 wherein R1 and R5 are both hydrogen and R6 and R7 are both methyl.

12. The process of claim 5 wherein R1 is hydrogen, R5 is methyl and R6 and R7 taken together is piperidino.

13. The process of claim 6 wherein R1 is hydrogen, R5 is methyl, and R6 and R7 taken together is piperidino.

14. The process of claim 6 wherein R1 is hydrogen, R5 is methyl, and R6 and R7 taken together is piperidino.

15. The process of claim 3 wherein R1 is hydrogen and R6 and R7 taken together is 3-(1,2,3,6-tetrahydro-1-pyridyl).

16. A compound of the formula II

wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, or in which p is 1 or 2, R2 and R3 each are independtly 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, sulfer or methylene; and A is or 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 indepently (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, methyl-piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

17. A compound of claim 16 having the formula II

wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is or 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, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

18. A compound of claim 16 having the formula IIa 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 pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

19. A compound of claim 16 having the formula IIb wherein R1 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, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

20. A compound of claim 16 having the formula IId wherein R1 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. whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

21. A compound of claim 16 having the formula IId wherein R1 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, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

22. The compound N-[3-(3-piperidino-methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

23. The compound N-[2-[(5-dimethyl-aminomethyl-2-furyl)methylthio]ethyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

24. The compound N-[2-[(5-dimethyl-aminomethyl-4-methyl-2-thienyl)methylthio]ethyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

25. The compound N-[3-(3-pyrrolidino-methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

26. The compound N-[2-[5-dimethyl-aminomethyl-3-thienyl)methylthio]ethyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

27. The compound N-[2-[(5-piperidino-methyl-3-thienyl)methylthio]ethyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

28. The compound N-[3-(6-piperidino-methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

29. The compound N-[3-(4-piperidino-methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

30. The compound N-[3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propyl]ethanediiimidamide, or a salt, hydrate or solvate thereof, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

31. A compound of the formula II
wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, or in which p is 1 or 2, R2 and R3 each are independtly 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, sulfer or methylene; and A is or 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 indepently (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, methyl-piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof.

32. A compound of claim 31 having the formula II

wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is or 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.

33. A compound of claim 31 having the formula IIa 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 pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

34. A compound of claim 31 having the formula IIb wherein R1 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.

35. A compound of claim 31 having the formula IIc wherein R1 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.

36. A compound of claim 31 having the formula IId wherein R1 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.

37. The compound N-[3-(3-piperidino-methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

38. The compound N-[2-[(5-dimethyl-aminomethyl-2-furyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

39. The compound N-[2-[(5-dimethyl-aminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

40. The compound N-[3-(3-pyrrolidino-methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

41. The compound N-[2-[5-dimethyl-aminomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

42. The compound N-[2-[(5-piperidino-methyl-3-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof-

43. The compound N-[3-(6-piperidino-methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

44. The compound N-[3-(4-piperidino-methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

45. The compound N-[3-[3-(1,2,3,6-tetrahydro-1-pyridyl)methylphenoxy]propyl}ethanediimidamide, or a salt, hydrate or solvate thereof.