LU84716A1 - 3,4-DIAMINO-1,2,5-THIADIAZOLES SUBSTITUTED HAVING HISTAMINE H2 RECEPTOR ANTAGONIST ACTIVITY - Google Patents

Description

* "

3/4-DIAMIN0-1 / 2/5-TH1'ADIAZ0LES SUBSTITUTED WITH ANTAGONIST ACTIVITY OF THE HISTAMINE H2 RECEPTOR

Cross reference to a related request 5 This request is a continuation in part of our previous request in process n ° 363.207, filed on March 29, 1982.

Summary of the invention

Certain 3- (amino or amino-substituted) -4- (amino-substituted) -1,2,5-thiadiazoles having the formula: 10 _ / nhr1 ΪΛ 15 in which: A, m, z, n and R1 are such as defined below, and their pharmaceutically acceptable non-toxic hydrate and solvate salts are potent histamine H2 receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of disgestive ulcers and other pathological conditions of hyper-secretion.

The compounds are prepared by ring closure of the correspondingly substituted ethanediimi-damide of formula:

25 Α- (0Η2) ΛΖ (CH2) nNH-C CrNHR. XI

p. HN NH

2

Background and prior art

Our British patent application No. 2,067,987 describes 3,4- * disubstituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxides having the formula:

5 A- (cVmZ (CH2) nNH. _V

/ ΓΛ

N N

(°) p 10 and processes for their preparation, in which the variables: A, ni, Z, n and R1 are similar to the corresponding substituents of the compounds described and claimed here.

However, the compounds described in this British application 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 methods described in said application for the preparation of the compounds of the prior art.

The published European patent application No. 40.696 describes, inter alia,; 20,4-disubstituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxides having the formula: Z * 1 R - @ - (CH2) n-X- (CH2) mNHx_ "

25 XR

25 N ^

K

and processes for their preparation, in which the variables: R, Α, η, X, m, R1 and R2 are similar to the corresponding substituents of the compounds described and claimed here.

-g · However, the compounds described in said application are also 1-oxides or 1,1-dioxides (p is equal to 1 or 2) and the compounds of t the present invention cannot be prepared by any of the methods described in said application for the preparation of the compounds of the prior art.

In the two publications cited above, each of the processes described for the preparation of the compounds of the prior art involves the use (as starting material or as intermediate) of a 1,2,5-thiadiazole 1-oxide or a 1,1-dioxide having either amino groups * or suitable "leaving groups" in positions 3- and 4-,

The desired substituents in positions 3- and 4- are then obtained by substitution on the amino groups or by replacement of the "leaving groups".

: We have made numerous attempts to prepare the compounds of the present invention by similar methods, that is to say using a 1,2,5-thiadiazole having amino groups or suitable "outgoing groups" on the positions 3- and 4- as starting material or as intermediate. Although numerous variants have been tried, at the same time as the reaction conditions have been varied, it has not been possible to isolate the compounds according to the invention by this route. now found that the compounds according to the present invention can be prepared by ring closure of Vethanediimidamide subs-, correspondingly titrated with the formula:

A- (CH0) Z (CH,) NH-C-C.-NHR1. II

zm 2 η λ \\

HN HN

Intermediate II, itself, can be prepared by various methods.

20 Full description

The present invention relates to histamine H2-receptor antagonists, of formula: »A- (CH2) mZ (CH2) nNIL _ NHR1

25 / T \ I

V in which: R1 represents hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, 5 r2 \ / - \

Vn, V "3B Κ3-Λ = / 4 in which: p is equal to 1 or 2; R2 and R3, independently, each represents hydrogen, lower alkyl, lower alkoxy or halogen; and when R2 is hydrogen, R3 can also be trifluoromethyl, or R2 and R3 taken together, can be methylenedioxy; and R4 represents hydrogen, lower alkyl or lower alkoxy; m is an integer from 0 to 2 inclusive; 10 n is an integer from 2 to 5 inclusive; Z is oxygen sulfur or methylene; and A represents! Sa:, s.

o s - R5 ώ7 „5

2 ° rJ V

\ w, ru. _ ^ I or N (Cil,) —i.

6 / '2} q S 2q ^ T

R ^ N

in which: R5 represents hydrogen, lower alkyl or lower alkoxy; q is an integer from 1 to 4 inclusive; and R6 and R7 each independently represent lower alkyl, lower alkoxy lower alkyl, wherein the lower alkoxy part is at least 2 carbon atoms from the nitrogen atom, or phenyl lower alkyl and, when i · R6 is hydrogen, R7 can also be lower cycloalkyl, or R and R taken together with the hydrogen atom ^ to which they are attached can be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino , dimethylpi peridino, N-methyl-piperazino, 1,2,3,6-tetrahydropyridyle, homopiperidino, hepta-methyleneimino, octamethyleneimino, 3-azabicyclo {3,2,2} non 3-yl or 3-pyrrolino; and their pharmaceutically acceptable non-toxic hydrated and solvated salts.

The invention also relates to methods of preparing the compounds of formula I and the intermediate compounds of formula II.

Included within the scope of the present invention are all possible tautomeric forms, diastereoisomeric forms, and optically active isomers of the compounds of formula I as well as mixtures thereof. Used in the description 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. The term "lower cycloalkoxy" means a cycloalkyl group containing 3 to 6 carbon atoms. The term "non-toxic pharmaceutically acceptable salts" means addition salts of acids formed with acids such as hydrochloric, brohidric, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, tartaric acid, citric, levulinic, benzoic, succinic and the like.

In the compounds of formula I, R1 preferably represents hydrogen or lower alkyl or more preferably hydrogen or methyl, or more preferably hydrogen. The substituent A is preferably the substituted phenyl, substituted furyl or substituted thienyl radical represented above, and above all it represents the substituted phenyl group.

The substituent Z is preferably sulfur or oxygen and, when A is the substituted phenyl radical, Z preferably represents oxygen. It is preferred that m is equal to 0 or 1, and n to 2 or 3 and that, when A represents the substituted phenyl radical, m is equal to 0 and n to 3. R5 preferably represents a hydrogen or a methyl, but above all hydrogen. It is preferred that q is equal to 1. R6 and R7 are preferably lower alkyl or, taken at the same time as the nitrogen atom to which they are attached, 30 which represent a pyrrolidino or piperidino group.

The compounds of formula.I can be prepared by reacting a compound of formula II with sulfur monochloride, sulfur dichloride or chemicals equivalent to them such as the following:

Gold 6

. A- (CH2) niZ (CH2) nlla-C — C-NHR1 H

HN NH

* '5 S2C12 or SC12

10 V

A- (CH2) mZ (CH2) nNH v _v-NHR1 15 XS / in which: A, m, Z, n and R1 are as defined above.

At least one mole of S2Cl2 or SCI2 should be used per mole of compound II; it is preferred to use an excess of S2Cl2 or SCl2, for example, from 2 to about 3 molecules of S2Cl2 or SCl2 per molecule of compound II.

It has been found that SCI s often gives a coarser product and a lower yield of purified product and it is usually preferred to use S2CI2 to carry out the reaction. The reaction temperature is not critical; it is preferred to carry out the reaction at a temperature of from about 0 ° C to about 50 ° C and it is extremely convenient to carry out the reaction at room temperature. The reaction time is not critical and it depends on the temperature. Normally a reaction time of about 30 min to about 6 hours is used. At room temperature, it is usually preferred to use reaction times of about 11/2 to 4 hours. The reaction can be carried out in an inert organic solvent, preferably a mixture of an inert organic solvent and dimethylformamide. It is especially preferred to conduct the reaction in dimethylformamide.

In a preferred embodiment of the invention, the compounds of formula I have the structure A- (CH2) mZ (CH2) ηΝΗ ^ NHR1 ri 7 in which: R1 is hydrogen or lower alkyl, m is equal to 0 or 1; , n is 2 or 3; Z is oxygen or sulfur; and A is f * ’Γ-Κ"> “= - T $ r - 15 5 R5 R7 \ CH J_ A or,> CH2-- -h

R

In which: R5 represents hydrogen or methyl; and R6 and R7 independently each represents methyl or ethyl, and when taken together with the nitrogen to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a non-toxic pharmaceutically acceptable salt, hydrate or solvate of these compounds. In the most preferred embodiment, the compounds of formula I have the structure: “30 R \

6 / ch2 — dd- I

R \ s ^ Î) CH2CH2CIÎ2NH ^ _ / NHR1 s „yt 8 wherein: R1 is hydrogen or methyl; and 'R6 and R7 each represent a methyl or when taken at the same time as the hydrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a non-toxic pharmaceutically acceptable salt, hydrate or solvate of these compounds. In another more preferred embodiment, the compounds of formula I have the structure: 10, R5 NCH, —lj- ^ ^ X-CH, SCH, CH, NIU NHR1

^ H

in which: R1 and R5 each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl; or a pharmaceutically acceptable non-toxic hydrated or solvated salt of these compounds.

In another preferred embodiment, the compounds of formula I have the structure: * 5 25 ^ nch2- ^ lL ^ -ch2scii2ch2nh nhr1 le r6 s * 30 in which: R1 and R5 each independently represent hydrogen or methyl ; and 'R6 and R7 each independently represent methyl or ethyl; or a non-toxic, pharmaceutically acceptable hydrated or solvated salt of these compounds.

In another preferred embodiment, the compounds of formula I

have the structure: 9 R5 NCh2 --- f-OCH2CH2CH2NH NHR1 Ia ^ yi, N N NS / in which: R1 and R5 each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl; or when taken at the same time as the nitrogen atom to which they are attached, R6 and R7 represent a pi peri-w dino group, or a non-toxic hydrate or solvate pharmaceutically acceptable salt of these compounds.

^ 15 As currently contemplated, the most preferred compounds of formula I are: 1) 3-amino-4- {3- (3-piperidinomethylphenoxy) propyl-amino} -1,2,5-thiadiazole ; 2) 3-amino-4- {2 - {(5-diniethylaminomethyl-2-furyl) -methylthio} ethylamino-1.2.5-thiadiazole; 3) 3-amino-4- {2 - {(5-dimethylaminomethyT4-methyl-2-thienyl) methylthio} ethylamino} -1,2,5-thiadiazole; 4) 3-anrino-4- {3- (3-pyrrilidinomethylphenoxy) -propylamino} -1,2,5-thiadiazole; 5) 3-methylamino-4- {3- (3-piperidinomethylphenoxy) -propylamino} -1,2,5-thiadiazole; 6) 3-Benzylamino-4- {3- (3-piperidinomethylphenoxy) -propylamino} -1,2,5-thiadiazole; 7) 3-amino-4- {2 - {(5-dimethylaminomethyT3-thienyl) -methylthio} ethylamino} - 1.2.5-thidiazole; 8) 3-friend no-4- {2 - {(5-pi peri-nomethy1-3-thi enyl) -methy1thi o) ethy1 friend no) - 1,2,5-thiadiazole; 9) 3-amino-4- {3- (6-piperidinomethyT2-pyridyloxy) -propylamino} -1, 2,5-? thiadiazole; and 10) 3-amino-4 ~ {3- (4-piperidinomethy1-2-pyridyloxy) -propylamino) -1, 2,5- ^ thiadiazole; 35 and their pharmaceutically acceptable non-toxic hydrated and solvated salts.

The intermediates of formula II, used in the preparation of the compounds of formula I, can even be prepared by various methods.

In one method, 3- (amino or substituted amino) -4- (substituted amino) -40 1.2.5-thiadiazole 1-oxvde corresDondant dp formula III is treated with j ".

10 a strong mineral acid (preferably HCl) to give the compound of formula II: 5 _xnhr1 ΙΓΛ \ s ü 10 HCl

V

15 A- (CH2) mZ (CH2) nNH ^ _yNHR1 „

HN NH

20

The reaction can be carried out in an inert solvent and is preferably carried out in methanol. The reaction temperature is not critical; it is most conveniently brought to room temperature. The compounds of formula III are known or can be easily prepared by the methods described in our published British patent application No. 2,067,987.

According to another method, the compounds of formula II can be prepared according to the following reaction scheme: "30 CH3 ° \ / OCH3

A- (CH2) mZ (CH2) nNH2. + -CX

HN '^ NH

IV V

V

35 11

A- (CH2) nZ (CH2) ηΝΗχ _ / OCH3 VI

J S.

R1NH2 10 N / A- (CH2V (CH2) nNHx / HR1 m

3 PM ^ TîH

the reaction can be carried out in an inert solvent and is preferably carried out in methanol. The starting materials, of formula IV, are known or can be easily prepared by known methods, for example, by methods described in our published British patent application No. 2,067,987.

The invention also relates to new intermediates of the formula: η • A- (CH2) (CH2) nUH -_ NUR1 * Ti "in which:. R1 represents hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, jK = J p or R4H ^ -tj- <CB2> p- 12 in which: p represents 1 or 2, * R2 and R2 independently each represent hydrogen, lower alkyl, lower alkoxy or halogen, and when R2 represents hydrogen, R3 may also be trifluoromethyl, or R2 and R3, taken together, may be methylenedioxy; and R1 * represents hydrogen, lower alkyl or lower alkoxy; m is an integer from 0 to 2 inclusive; n is an integer from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A represents 15 \ (CH2) g-ÄV. ^ N <CH2> q - # ^ T,

R ^ cr R S

R

in which: R5 represents hydrogen, lower alkyl or lower alkoxy, q is an integer from 1 to 4 inclusive; and

Re and R7 each independently represent lower alkyl, lower alkoxy lower alkyl, in which the lower alkoxy radical is at least 2 carbon atoms away from the nitrogen atom, or phenyl lower alkyl and, when R6 represents a hydrogen, R7 may also be a lower cycloalkyl, or R6 and R7 taken together with the nitrogen atom to which they are attached, may be pyrrolididino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino groups , methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopi-peridino, heptamethyleneimino, octamethylenimino, 3-azabicyclo {3,2,2} non-3-yl, or 3-pyrrolino; or a hydrated or solvated salt 40 thereof.

In a preferred embodiment, the intermediaries of formula II have the structure: 13 (CH,) NH, νηη1 5 y ~ \\ '“

HN NH

wherein: R1 is hydrogen or lower alkyl; 10 m is 0 or 1; n represents 2 or 3; Z is oxygen or sulfur; and ς A is 15 r5 p5

R7 R7 J

/ Tl \\ ^ rjrr Λ "-'j y 2 <st · 20 <Λ" in which: rb represents hydrogen or methyl; and R6 and R7 independently represent each methyl or ethyl and, when taken together with the nitrogen to which they are attached, R6 and R7 represent a ring; pyrrolidino or piperidino; or a non-toxic pharmaceutically acceptable hydrated or solvated salt thereof.

In another preferred embodiment, the intermediates of formula II, have the structure: "Λ R \ IIa

- 5 6 / NCH2-if- I

R \ ^ ÔCH2CH2CI! 2NH n_ / NHR1 yt m nh 10 wherein: R1 is hydrogen or methyl; and R6 and R7 each represents 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 hydrated or solvated salt thereof this.

In another preferred embodiment, the intermediates of formula II have the structure: "Wwws." R6 Nr / ri hn m 25 in which:

R1 and R5 each independently represent hydrogen or methyl; and Rs and R-7 each independently represent methyl or ethyl, or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of · - Formula II have the structure: '' <rÙ 'NCH- -U- -A_ch2scii2ch2nh NHR1 Ile - 3S "f / X; yi

HN NH

in which: R1 and R5 each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl, or a salt, hydrate or solvate thereof.

* In another preferred embodiment, the intermediates of formula II have the structure: 5 R5 R \ _r * ^ L_ y * CH2 --- H— OCH2CH2CH2NH ^ _ ^ HÏT Ild * 6 / fl

HN NH

Wherein: R1 and Rs each independently represent hydrogen or methyl; and ^ R6 and R7 each independently represent methyl or ethyl, or when taken together with the nitrogen atom to which they are attached, Re and R7 represent a peridino group; or a salt, hydrate or solvate thereof.

As is currently contemplated, the preferred intermediates of formula II are: s 1) N- {3- (3-piperidinomethylphenoxy) propyl} ethane-diimidamide; 2) N- {2 - {(5-dimethylaminomethyl-2-furyl) methylthio} -ethylthethanediimidamide; 3) N- {2 - {(5-dimethylaminomethyl-4-methyl-2-thienyl) -methylthio} ethyl} etha-nediiamidamide; 4) N- {3- (3-pyrrodi1i di nométhylphénoxy) propyl} éthanedi imi dami de; 5) N- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} -ethyllethanediimi-25 dami de; 6) N- {2 - {(5-piperidinomethyl-3-thienyl-methylthiol-ethyllethanediimidamide; 7) N- {3- (6-pipéri di nométhyl-2-pyri dyloxy) propyl} -éthanedi imi dami de; and 8) N- {3- (4-piperi dinomethyl-2-pyri dyloxy) propyl} -ethanedi imi dami; or a salt, hydrate, solvate thereof.

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

The pharmaceutical compositions can be administered orally, parenterally or using a suppository rectally.

A wide variety of pharmaceutical forms can be used. Thus, if a solid vector is used, the preparation can be in the form of tablets, placed in a hard gelatin capsule in the form of a powder or granule, or in the form of a dragee or lozenge.

16 *

If a liquid carrier is used, the preparation may take the form of a syrup, an emulsion, a soft gelatin capsule, a sterile solution for injection or an aqueous or non-aqueous liquid suspension. The pharmaceutical compositions are prepared by corventional techniques appropriate to the desired preparation.

The dosage of the compounds according to the invention will depend not only on factors such as the weight of the patient, but also on the degree of inhibition of gastric acid desired and on the potency of the particular compound which is used. The decision as to the particular dosage to be used (and the number of times it should be administered per day) is at the discretion of the doctor - and may vary depending on the extent of the effects of the dosage corresponding to the particular circumstances a specific patient. With the preferred compounds of the invention, each oral dosage unit will contain the active ingredient in an amount from 2 mg to about 300 mg and preferably from about 4 mg to about 100 mg. The active ingredient will preferably be administered in equal doses from 1 to 4 times a day.

Histamine H2 receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and humans, see Brimblecombe et al., J. Int. Med. Res., 3 86 (1975). The clinical evaluation of cimetidine, a histamine H2 receptor antagonist, has shown that it is an effective therapeutic agent in the treatment of digestive ulcers, see Gray et al., Lancet, 1, 8001 (1977) . Some of the preferred compounds according to the invention have been compared with cimetidine in various tests and have been found to be more potent than cimetidine both as histamine H2 receptor antagonists in the body. isolated guinea pig atrium and as inhibitors of gastric acid secretion in rats and dogs.

Determination of gastric anti-secretion activity in rats carrying a gastric fistula * Male Long Evans rats weighing approximately 240 to 260 g are used at the time of implantation of a cannula. The design and implantation of the stainless steel cannula in the anterior wall of the stomach, near the heart, is presented substantially as described by Pare et al. (Laboratory Animal Science, 27, 244 (1977)). The components of the fistula are designed, and the procedure is implemented exactly as described in the above reference. After the operation, the animals are housed individually in flat-bottomed cages covered with sawdust and are given, as they wish, food and water during the entire recovery period. The animals are not used for testing purposes for at least 15 days after the operation has been carried out.

5 The animals are made to fast, but are allowed to take unlimited water for 20 hours before the testing procedure begins. Immediately before collection, the cannula is opened and the stomach is gently washed with 30 to 40 ml of warm salt or distilled water to remove anything that may remain. The catheter is then screwed into [10 the cannula instead of the obturation screw and the rat is placed in a cage! plastic, rectangular, clear, 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slit of approximately - 1.5 cm wide and 25 cm long coming from the center to receive the catheter which hangs through the cage. Therefore, the movements of the rat in the cage are not restricted during the collection periods. The rest of the test is carried out as described by Ridley et al. (Research Comm. Chem. Path. Pharm., 17, 365 (1977)).

Gastric secretions collected during the first hour after washing the stomach are rejected because they can be polluted. 20 For an oral evaluation, the catheter is then removed from the cannula and replaced by the obturation screw. Water (2 ml / kg) is administered orally using gastric intubation and the animal is returned to its cage for 45 minutes. After this time, the closure screw is removed and replaced by a catheter to which a small plastic vial was attached only to collect the gastric secretions. A 2 hour sample is collected (this represents the control secretion), the catheter is removed and replaced by the obturation screw. The drug to be tested is then administered orally in a volume of 2 ml / kg by gastric intubation. 45 min later, the plug is removed again, replaced with the catheter attached to a small plastic vial and another 2 hour sample is collected. The secretions from the second sample are compared to those from the control sample to determine the effects of the drug to be tested.

When the compounds to be tested have to be evaluated by the parenteral route, the animal is injected, intraperitoneally or intraperricardially or subcutaneously, with the vehicle of the compound to be tested in a volume of 2 ml / kg immediately after discarding the initial 60-minute collection. A 2 hour sample is collected (control secretion) and Ton 18 injects the animals, intraperineally or subcutaneously, with the compound to be tested in a volume of 2 ml / kg. An additional 2 hour sample is collected and its secretions are compared with those from the control period to determine the effects of the drug. The samples are centrifuged and placed in a graduated centrifuge tube for volume determination. The titratable acidity is measured by titrating a 1 ml sample at pH 7.0 with 0.02N NaOH using an automatic burette and an electrometric pH meter (radiometer). The production of titratable acid is calculated in micro-equivalents by multiplying the volume in ml by the acid concentration in milli-equivalents per liter.

The results are expressed in percent inhibition relative to the control readings. The dose response curves are established and ED values are calculated by regression analysis. At least three rats are used at each dosage level and a minimum of three dosage calves is used to determine a response curve at a given dose.

TABLE 1

Anti-secretion activity of gastric juice in rats carrying a gastric fistula 20 _______ “EDso sc coniposed power ratio pmoles / kg (cimetidine = 1.0) cimetidine 3.48 1” 0 (1.68-5.75 ) 1 25_______ example 1 0.094 37 (0.043-0.20) example 2 0.77 4.5: - 3o t0 · 45-1 »4 '__' example 3 ^ 0.5 ^ 7 example 4 0.18 20 35 (0.10-0.36) 95% confidence limit.

19

Test on the guinea pig atrium isolated from histamine H2 receptor antagonism Histamine produces increases related to the concentration of the contraction rate of the right atria of isolated guinea pigs 5 and beating spontaneously. Black et al., Nature, 236, 385 (1972), described the receptors involved in this effect of histamine as the H2 receptor for histamine, indicating the properties of burimamide, a competing antagonist of these receptors. Subsequently, investigations by Hughes and Coret, Proc. Soc. Exp. Biol. Med., 148, 127 (1975) and Verma 10 and Mac Nei11, J. Pharmacol. Exp. Ther., 200, 352 (1977) confirm the conclusion of Black et al. That the chronotropic effect posi-; of histamine in the right atria of transi- isolated guinea pigs; attempted by histamine H2-receptors. Black et al., Agents and Actions,; 3, 133 (1973) and Brimblecombe et al., Efd. Proc., 35, 1931 (1976) used isolated right guinea pig atria as a means of comparing the activities of histamine H2 receptor antagonists. Current comparative studies have been performed using a modification i of the method described by Reinhardt et al., Agents et Actions, 4, 217 (1974).

20 Male Hartley guinea pigs (350 to 450 g) are sacrificed by a blow on the head. The heart is excised and placed in a Petri dish containing a modified oxygenated Krebs solution (95¾ of 02, 5¾! Of CO2), (g / 1 = NaCl 6.6; KC1 0.35; MgS0 * .7Ha0 0.295; ΚΗ2Ρ0 * 0.162;

0.238 CaCl2; NaHC03 2.1 and dextrose 2.09). The right atrium flapping 25 spontaneously is stripped of foreign tissue and a silk thread (4-0) is attached to each end. The atrium is suspended in a 20 ml muscle chamber containing an oxygenated Krebs solution maintained at 32 ° C. Ear contractions are recorded isometrically using a force displacement transmitter of 30 Grass FT 0.03 and force and contraction rate recordings are performed with a Beckman RP Dynograph.

A resting tension of 1 g is applied to the headset and allowed to come to equilibrium in one hour. At the end of the equilibration period, a submaximal concentration of histamine dichlorhy-35 drate (3 x 10-6M) is added to the bottom and extracted by washing to prime the tissue. Histamine is then added to the bath cumulatively using 1/2 log intervals of 10, to give a final molar concentration of the bath from 1 x 10-7 to 3 x 10-s. The increased histamine-induced atrial level is allowed to plateau before the following successive concentrations are added. The maximum response invariably occurs at a concentration of 3 x 10_5M. The histamine is removed by washing several times and the headset is allowed to return to the control rate. The compound to be tested is then added at appropriate molar concentrations and, after 30 min of incubation, the response to the dose of histamine is repeated by adding higher concentrations than those necessary.

The dissociation constants (Kg) are deduced from the 10 Schild points by the method of Arunlakshana, 0 and Schild, H.O. (Br. J. Pharmacol. 14, 48 (1959)), using at least three dose levels. Parallel deviations in the dose response curves are obtained without reducing the maximum response to the concentrations of antagonists used, and the results are shown in Table 2.

15 TABLE 2

Activity in the right atria of isolated guinea pigs _ - mv / __ compound power ratio N Kß (pmoles) (cimetidine = 1.0) 20 ---; - cimetidine 20 0.41 (0.21-Oj54) 1.0 example 1 12 0.003 (fl, 001 * 0.004) 137; example 4 11 0.004 (Ο, ΟΟΤαΟΙΟ) 102 25 ---- • jç 95% confidence limits.

As described in United States patent application No. SY-1751), filed (concurrently) by our colleague Thomas A.

Montzka, the compounds of formula I can also be prepared by ring closure of a compound of formula II with an N, N'-thiobisphthalimide having the formula: îs fk â '^: vv> 21 The use of N, N1-thiobisphthalimide instead of S2C12 or SCI2 for carrying out the ring-closing reaction results in giving, at the same time purer products and higher yields, in compounds of formula I. The crude products of formula I thus produced are normally pure enough to form crystalline salts directly without the need for prior chromatographic purification.

In this process, the starting diimidamide of formula II is reacted with an approximately equimolecular amount of N, N'-thiobisphthalimide 10 in an inert organic solvent such as CH2Cl2. Preferably, the starting diimidamide is used in its tri hydrochloride form, in which case three molar equivalents of an amine such as triethyl amine are added, as a reaction mixture, to neutralize the tri hydrochloride. The reaction can be carried out with stirring at room temperature for about 1 hour to assure completion of the reaction. The phthalimide which precipitates from the reaction mixture is then extracted with a strong base (for example, aqueous KOH 10 to 20%) and the layer of organic solvent is dried, filtered and concentrated to give the crude compound of formula I. La N, N * -thiobisphthalimide used in the reaction is a compound; 20 known which can be prepared as described in the Canadian Journal of Chemistry, 44, 2111-2113 (1966), or as described below in Preparation # 1.

Preparation No. 1 N, N'-thiobisphthalimide 25 A cooled solution (0 ° C.) of phthalimide (14.7 g, 0.1 mole) in 80 ml of dimethylformamide (DMF) is treated dropwise with di - sulfur chloride (5.15 g, 0.05 mole). After the addition, the mixture is allowed to warm to 20 ° C while stirring for 4 hours. The solid is collected and dried to give 12.5 g of the title compound in the form of DMF solvate, melting point 301-315 ° C. The infrared and NMR spectra are both consistent with the structure. r 'Upon analysis, it can be seen that the product obtained has the formula:

Ci6H8N20itS.C3H7N0, and we obtain the following values:

C H N S

35 - calculated 57.42 3.80 10.57 8.07 - found 57.50 3.80 10.29 8.57

The DMF solvate can be removed by recrystallization from chloroform of the above material; the melting point of the DMF-free product Γ 22 is 320-325 ° C. The NMR spectrum shows that the DMF has been eliminated.

Upon analysis, it is found that the product obtained has the formula: C-teHeNaOitS, and the following values are obtained:

C H N S

5 - calculated 59.25 2.49 8.64 9.89 - found 59.21 2.21 8.91 10.14 The invention will be better understood using the following examples. EXAMPLE 1 3-amino-4 ~ {3- (3-piperidinométhy Lphenoxy) propylamino} -l / .2 / 5-thiadiazole 10 A.- Tri hydrochloride of N- {3- (3-piperidinomethylphenoxy) propyl} ethane-ai imidamide

A suspension of 3-amino-4- {3- (3-piperidinomethyl-phenoxy) propylamino} -1,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmol) {prepared and according to the request for published British Patent No. 2,067,987} in 15,450 ml of methanol is treated with 38 ml of concentrated HCl. The resulting solution is stirred for 3 hours at room temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gives colorless crystals.

These crystals are suspended in 200 ml of absolute ethanol, filtered and dried under vacuum, which gives 16.6 g (82.6%) of the title compound, melting point 205-222 ° C (dec. ). Recrystallization from a methanol / ethyl acetate mixture gives an analytical sample, melting point 206-216 ° C (dec.).

On analysis, it is found that the product obtained has the formula: 25 C17H27N50.3CH1, and the following values are obtained:

C H N

- calculated 47.84 7.08 16.41 - found 47.56 7.18 16.75 'B.- 3-aminoT4- {3- (3-piperidinomethyLphenoxy) propyLamino} -1 / 2r5 “thiadiazole 30 A stirred suspension of tri N- {3- (3-piperidinomethylphenoxy) propyl} ethanediimidamide hydrochloride (2.13 g, 5.0 mmol) {prepared in step A.-} in 20 ml of dimethylformamide (DMF) is treated with sulfur monochloride (2.02 g, 15.0 mmol) and stirred for 4 hours. The resulting mixture is carefully poured into 200 ml of water and made basic with K2CO3. Extraction is carried out with 3 portions of 50 ml of methylene chloride, and after drying over MgSO *, and concentration, 2.1 g of a dark gum containing the product is obtained. The 23 product is purified by preparative high pressure chromatography in liquid phase on silica using CH2Cl2 (100): propanol-2 (10) iNFUOH (0.5) as mobile phase. The appropriate fractions give 0.89 g of the title compound, which gives, with fumaric acid in N-propanol, 0.76 g (21.4%) of the title compound as crystalline fumarate; melting point 187-187.5 ° C. An HPLC indicates a purity of> 99%.

Upon analysis, it is found that the product obtained has the formula: (CivhUsNsOS ^ .CitHitOit, and the following values are obtained:

C H N S

10 - calculated 56.27 6.71 17.27 7.90 - found 56.09 6.36 16.98 8.08

Part of the fumarate is suspended in water, neutralized with K2C03 and extracted with HC2C12. The CH2Cl2 is concentrated and the free base of the title compound is extracted by crystallization; melting point 15 43-47 ° C. A portion of the free base is transformed into its hydrochloride; melting point 138-142 ° C.

On analysis, it is found that the product obtained has the formula: C17H25N50S.HC1, and the following values are obtained:

C H N S

20 - calculated 53.18 6.83 18.24 8.35 - found 53.14 6.88 18.49 8.74 EXAMPLE 2 3-amino-4- {2- {(5-dimethylLaminomethyL-2-furyl) niethyLthio} -ethy Laroino} “1,2,5-thiadiazole 25 A.- Chtorhydrate.de hydrate.de N- {2 - {(5-dimethyLamino-inethyL-2-furyL) methylthio} ethyl} -ethanediimidamide

A suspension of 3-amino-4- {2 - {(5-dimethylaminomethyl-2-furyl) methylthio} ethylamino} -1,2,5-thiadiazole 1-oxide (6.59 g, 20.0 mmol) {prepared according to published British patent application No. 2,067,987} 30 in 200 ml of methanol is slightly heated to obtain complete dissolution. Then treated with 13.3 ml of concentrated HCl. After stirring at room temperature for 2.5 hours, the solution is concentrated and the residue is triturated with 70 ml of absolute ethanol. The crystals are collected by filtration and dried under vacuum, which gives 3.4 g (52%) of the title compound, melting point 166-169 ° C (dec.).

On analysis, it is found that the product obtained has the formula: Ci2H21N50S.3HC1.H20, and the following values are obtained: 24

C H N S

- calculated 35.08 6.38 17.05 7.80 - found 34.85 6.24 17.45 7.97 B.- 3-am · ΐηο-4- {2- {C5-dimethy Laminométhy L-2 -furyl-methyl Lthio} -ethy Lamino} ~ 5 1,2,5-thiadiazole To a stirred solution of N- {2 - {(5-diniathylamino-methyl-2-furyl) methylthio} ethyl hydrochloride trihydrate } ethanediimidamide (12.3 g; 30.0 mmol) {prepared in step A.-} in 150 ml of DMF, 7.2 ml of sulfur monochloride (12.1 g; 90 mmol) are added. After stirring after 4 hours at room temperature, approximately half of the DMF is removed under reduced pressure. The remaining black solution is poured into 1 liter of water, it is made basic with K2CO3 and it is extracted first with ethyl acetate and then with chloroform. After drying over MgSO 4, filtration and concentration, 9.0 g of a black gum containing the product is obtained. This is purified by preparative high pressure chromatography in liquid phase on silica using ethyl acetate (100): propanol-2 (10): NH * 0H (0.5) as mobile phase.

The appropriate fractions give 1.24 g of the title compound as a gum.

The treatment of a part of this product with an equivalent amount; Slow HC12N in methanol gives the hydrochloride of the title compound.

Upon analysis, it can be seen that the product obtained has the formula:! C12BbN5S20.HC1, and the following values are obtained:

! C H N S

25 - calculated 41.18 5.76 20.02 18.33 - found (for 1.65% H2O) 40.54 5.70 19.39 18.44

Treatment of this product with an equivalent amount of cyclohexylsulfarnic acid in acetone gives the title compound cyclohexylsulfamate, melting point 93-95 ° C.

On analysis, it is found that the product obtained has the formula: C12H19N5S20.C6H13N03S, the following values are obtained:

T C H N S

- calculated 43.88 6.55 17.06 19.53 - - found 43.77 6.17 17.21 19.58 25 EXAMPLE 3 3-amino-4- {2 - {(5-d-imethylaminomethyl-4 -methyl-2-tnnényl) -méthy lthio} 'éthylamino} -1,2, .5-thiadiazole A. - Tri hydrochloride of N- {2 - {(5-dimethyLaminométhyL-4-methyl-2-thienyl) 5 méthyLthio} -éthy1} éthanedi imidamide

A stirred solution of 3-amino-4- {2 - {(5-dimethylamino-methyl-4-methyl -2-thi enyl) methy1thi o} éthy1 ami no} -1,2,5-thi adiazole 1-oxide ( 17.9 g, 50.0 mmol) (prepared according to the general method described in published British patent application No. 2,067,987) in 500 ml of methanol is treated with 33.3 ml of concentrated HCl. After stirring for 3 hours, the reaction mixture is concentrated and the excess water is removed by azeotropic concentration with absolute ethanol to give an almost colorless crystalline residue. The residue is triturated with 200 ml of absolute ethanol at 0 ° C, filtered and dried to give 16.9 g (80%) of the title compound, melting point 206-220 ° C (dec.). Recrystallization from a mixture of 50% methanol / ethyl acetate gives a product having a melting point of 210 at 221 ° C (dec.).

On analysis, it is noted that the product obtained has the formula: Ci3H23N5S2.3HCl, and the following values are obtained:

20 - C H N S

- calculated 36.92 6.20 16.56 15.17 - found 36.76 6.33 16.97 15.54 B. - 3-amino-4- {2 - {(5-dimethylaminomethyl-4-methyl- 2-thienyl) -methylthio} ethylamino} -1y2 / .5-thiadiazole To a stirred suspension of N- {2 - {(5-dimethylamino-methyl-4-methyl-2-thi enyl) methylthi o} hydrochloride ethyl} ethanedi imi damide (6.34 g, 15.0 mmol) {prepared in step A.-} in 60 ml of DMF, 6.1 g (45.0 mmol) of sulfur monochloride are added. After stirring for 4 hours at room temperature, the reaction mixture is poured into 800 ml of water, it is made basic with KaCO3, it is extracted several times with 100 ml portions of methylene chloride. The extracts are dried over MgSO 4, filtered and concentrated to give 3.4 g of a black gum containing the product. The product is purified by preparative high pressure chromatography in liquid phase on silica using CH2Cl2 (100): propanol-2 (10): NH40H (0.5) as mobile phase. Additional purification is carried out by preparative high pressure chromatography in additional liquid phase on silica using CH2Cl2 (100): CH30H (2.5): NHi * 0H (0.5) as mobile phase. The appropriate fractions give the title compound 26 (purity 98 98%). Treatment of the product with an equivalent amount of 2N HCl gives the hydrochloride of the title compound.

• Upon analysis, it is found that the product obtained has the formula: C13H21N5S3.HCI, and the following values are obtained:

5 C H N S

- calculated 41.09 5.84 18.43 25.32 - found (for 0.51% H2O) 40.78 5.63 18.31 25.44 EXAMPLE 4 3-amino-4- {3-C3-pyrroLidinoroethy Lphenoxy) propy Lamino} -1, 2,5-thiadiazoLe 10 A.- N- {3- (3 - pyrroLidinomethylphenoxy) propyL} ethane- di imidainide hydrochloride

A suspension of 3-amino-4- {3- (3-pyrrolidinomethyl-phenoxy) pro-pylamino) -1,2,5-thiadiazole 1-oxide (13.4 g, 38.3 mmol) {prepared according to the request for published British Patent No. 2,067,987) in 350 ml of methanol is treated with 25.5 ml of concentrated HCl. The resulting solution is stirred for 3 hours at room temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gives the product. The crystalline residue is triturated with 150 ml of absolute ethanol, filtered and dried to give 10.8 g of the title compound, melting point 195-203 ° C (dec.).

On analysis, it is found that the product obtained has the formula: C16H25N50.3HC1, and the following values are obtained:

C H N

- calculated 46.55 6.84 16.97 25 - found 46.55 6.93 16.93 B.- 3-amino-4- {3- (3-pyrroLidinomethylphenoxy) propylamino) -1,2,5-thiadiazoLe A stirred suspension of N- {3- (3-pyrrolidinomë-thylphenoxy) propyl) ethanediimidamide hydrochloride (8.25 g, 20.0 mmol) prepared in step A.- in 80 ml of DMF is treated with monochloride of sulfur 30 (5.4 g; 40.0 mmol) and stirred under a nitrogen atmosphere for 3 hours.

Concentration of the reaction mixture gives a dark gum which is suspended in 500 ml of water, made basic with K2CO3 and extracted with 3 times 100 ml of methylene chloride. The extracts are dried over MgSO, filtered and concentrated to give 7.5 g of a dark gum containing the product. The product is purified by preparative high pressure chromatography in liquid phase on silica using CH2Cl2 (100): propanol-2 (5): NH40H (0.5) as mobile phase. The fractions containing the desired product 27 are combined and concentrated to give 1.64 g (24.6%) of the purified title compound. Treatment of the product in absolute ethanol with an equivalent amount of 2N HCl gives the hydrochloride of the title compound (1.13 g); melting point 138-140 ° C.

5 Upon analysis, it can be seen that the product obtained has the formula:

CteHaaNsOS.HCl, and we get the following values:

C H N S

- calculated 51.95 6.54 18.93 8.67 - found 51.97 6.36 18.63 8.76 10 EXAMPLE 5

The general procedure of Example 1, steps A.- and B. is repeated, except that 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1, 2,5-1 - thiadiazole 1- the oxide used here is replaced by an equimolar amount of: (a) 3-amino-4- {3- (3-dimethylaminomethylphenoxy) propylamino} -1,2,5-thidiazole 1-oxide; (b) 3-friend no-4- {3- (3- diy1 friend methylphenoxy) propylami no) -1,2,5-thi a-diazole 1-oxide; (c) 3-friend no-4- (3- {3- (2-methylpyrroli di no) methyl 1 phenoxy} -propylami no} - 1,2,5-thiadiazole 1-oxide; (d) 3-amino-4 - (3- {3- (3-methylpyrrilidino) methylphenoxy} -propylami no} - 1.2.5- thiadiazole 1-oxide; (e) 3-amino-4- (3- (3- (4-methylpiperidino-methylphenoxy}) -propylami no} - 1.2.5- thiadiazole 1-oxide; 25 (f) 3-amino-4- {3- (3-morpholinomethylphenyl propylene)} -1,2,5-thiadia-sole 1-oxide; (g ) 3-friend no-4- {3- {3- (N-methylpi perazi no) methylphenoxy} -propylami no} - 1.2.5- thiadiazole 1-oxide; (h) 3-amino-4- {3- ( 3-diallylanrinomethylphenoxy) propylamino} -1,2,5-thia-diazole 1-oxide; (i) 3-friend no-4- {3- (3-hexamethyTeneiminomethy1phenoxy) propylami no} -1,2,5- " - thiadiazole 1-oxide; (j) 3-amino-4- (3- (3-heptamethyleneiminomethylphenoxy) propyl-amino} - 1.2.5- thiadiazole 1-oxide; 35 (k) 3-friend no-4- (3 - {3- (3-azabi cyclo (3,2,2} non-3-y1) methylphenoxy} -propyl-amino} -1,2,5-thiadiazole 1-oxide; and (1) 3-amino-4 - (3- {3- (3-pyrrolino) methylphenoxy} propylamino} -1,2,5-thiadiazole 1-oxide, respectively, 28 and thus produced: (a) 3-amino-4- {3- (3-dimethylaminomethylphenoxy) propylami no} -1,2,5-thiadiazole; (b) 3-amino-4- (3- (3-diethylaminomethylphenoxy) propylamino} -1,2,5-thiadia-sole; (c) 3-friend no-4- {3- {3- (2- methylpyrri1i dino) methylyphenoxy] -propylami no} - 1.2.5- thiadiazole; (d) 3-friend no-4- (3- {3- (3-methylethylpyrroli di no) methy1 phenoxy} -propylami no} - 1.2.5 - thiadiazole; 10 (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-methyl pi perazino) methyl phenoxy} -propyl amino} - 1.2.5- thiadiazole; 15 (h) 3-friend no-4- {3- (3-diallyl friend nomethylphenoxy) propylami no} -1,2,5-thi adiazole; (i) 3-amino-4- {3- (3 -hexamethyleneiminomethylphenoxy) propylamino} -1,2,5-thiadiazole; (j) 3-friend no-4- {3- (3-heptamethyleneiminomethylphenoxy) propylami no} -1,2,5-20 thiadiazole; (k) 3- ami no-4- {3- {3- (3-azabi cyclo {3,2,2} non-3-yl) methylphenoxy} -propyl -amino} -1, 2,5-thiadiazole; and (1) 3 -amino-4- (3- {3- (3-pyrrolino) methylphenoxy} propylamino} -1,2,5-thiadiazole, respectively .

EXAMPLE 6 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole The present example is a variation of EXAMPLE 1, step B.-, that is, say that you use less sulfur monochloride and a shorter reaction time.

To a stirred suspension of N- {3- (3-piperidino-methylphenoxy) propyl} ethanediimidamide tri hydrochloride (12.08 g, 28.3 mmol) in 120 ml - of DMF, sulfur monochloride (7, 64 g; 56.6 mmol) and the mixture is stirred under an N2 atmosphere for 3 hours. The DMF is removed under reduced pressure to leave a black gum which is suspended in water, made basic with K2CO3 and extracted with 3 portions of 100 ml of CH2Cl2. The combined extracts are dried over MgSO **, filtered and concentrated in a black gum. This gum is purified by preparative high pressure chromatography in liquid phase on silica 29 using CH2Cl2 (100): propanol-2 (5): NH ^ OH (0.5) as mobile phase.

The appropriate fractions give 3.1 g of the title product in the form of a dark oil which gives, with fumaric acid in N-propanol, 2.66 g (23.2%) of the title compound in the form of crystalline fumarate ; melting point 186-186.5 ° C. An HPLC indicates a purity of 99%.

On analysis, we note that the product obtained has the formula: (017Η25Ν50 $) 2. ^ Η4θ ^, and we obtain the following values:

C H N S

- calculated 56.27 6.71 17.27 7.90 10 - found 56.27 6.96 17.31 7.98 EXAMPLE 7 3-amino-4- {3- (3-piperidinomethytphenoxy) propyLamino} -1, 2,5-thiadiazoLe 'The present example is a variation of example 1, stage B.-, that is to say that sulfur dichloride is used instead of sulfur mono-chloride.

To a stirred suspension of N- {3- (3-piperidino-methylphenoxy) propyl} ethanediimidamide tri hydrochloride (854 mg; 2 mmol) in 6 ml of DMF under N2 in an ice bath, SCI2 (206 mg; 2 mmol) in 2 ml of DMF. The reaction mixture is stirred at room temperature and the title compound is produced.

EXAMPLE 8 3-tnethyLamino-4- {3- (3-piperidi nomethylphenoxy) propy Lamino) -1,2,, 5-thiadia-zole 25 A.- Tri hydrochloride of N-methyL-Nl- {3- (3- pip ^ ridinomethylphenoxy) propyL} ethanedi imidamide

A suspension of 3-methylamino ~ 4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole 1-oxide (4.13 g; 10.9 mmol) {prepared according to the published British patent application No. 2,067,987} in 95 ml of methanol is treated with 7.2 ml of concentrated HCl. After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with acetone, filtered and dried to give 4.35 g (90.4%) of the product. A sample is recrystallized from aqueous isopropyl alcohol to give the title compound; melting point 207-225 ° C 35 (dec.).

On analysis, it is found that the product obtained has the formula: Ci8H29N50.3HC1, and the following values are obtained:

C H N

- calculated 49.03 7.33 15.89 5 - found (for 0.94% H2O) 49.37 7.35 15.71 B.- 3-methylamino-4- (5- (3-piperidinomethylphenoxy) propylamino} -1,2,, 5-thiadiazole

A mixture of N-methyl-N '- {3- (3-piperidino-methylphenoxy) propyl} ethanediimidamide hydrochloride (3.74 g; 8.47 mmol) {prepared in step A}, 34 ml of CH2Cl2 and 3.5 ml of triethylamide is treated with Ν, Ν'-thiobisphthalimide (DMF solvate) (3.36 g; 8.46 mmol) is stirred for 1 hour. The mixture is washed with 30 ml of 10% Κ0Η, dried (MgSOi *), filtered, diluted with toluene and concentrated, which gives 3.6 g of the product. The product is purified by flash chromatography on 90 g of silica gel (230-400 mesh) using an ethyl acetate / methanol mixture (95/5) as eluent, which gives 1.9 g (62%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCl in propanol-1 gives the hydrochloride of the title compound, mp 163.5-164.5 ° C.

On analysis, it is found that the product obtained has the formula: C18H27N50S.HC1, and the following values are obtained: CHNS Cl - calculated 54.32 7.04 17.60 8.06 8.91 - found 54, 35 7.07 17.64 8.36 8.86 25 EXAMPLE 9 3-benzylamino-4- {3- (5-piperidinomethylphenoxy) propyLamino} -1,2,5-thiadiazole A. “N-Benzyl-Nl trichlorhydrate - {3- (3-piperidinoniethytphenoxy) propyL} ethanedi imidamide

A suspension of 3-benzylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole .1-oxide (5.14 g; 11.3 mmol) (prepared according to the patent application British published No. 2,067,987} in 100 ml of methanol is treated with 7.55 ml of concentrated HCl After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with acetone, filtered and dried, giving 5.16 g (88%) of the title compound; melting point 187-205 ° C (dec.).

31 On analysis, it can be seen that the product obtained has the formula: C2 * H33N50.3HC1, and the following values are obtained: CHN Cl - calculated 55.75 7.03 13.55 20.57 5 - found 54, 88 6.75 13.33 20.20 B.- 3-benzyLannno-4- (3- (3-piperidinomethylphenoxy) propylannno} -1,2,5-thiadiazole

A mixture of tri-N-benzyl-N '- (3- (3-piperidinomethyl-phenoxy) propyl} ethanediimidamide hydrochloride (4.73 g; 9.16 mmol) (prepared in step 10 A.-} , 45 ml of CH2Cl2 and 3.8 ml of triethylamine is treated with Ν, Ν'-thiobisphthalimide (DMF solvate) (3.64 g; 9.16 mmol) is stirred for 1 hour. The mixture is washed with 44 ml of 10% Κ0Η, dried (MgSO4), filtered, diluted with toluene and concentrated The residue is treated by flash chromatography on 110 g of silica gel (200-400 mesh) using 15 acetate ethyl as eluent, which gives 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCl in propanol-2 gives the hydrochloride of the title compound, melting point 138-141 ° C.

Upon analysis, it is found that the product obtained has the formula: 20 C2 £ tH3-iN50S.HCl, and the following values are obtained: CHNS Cl - calculated 60.80 6.80 14.77 6.76 7.48 - found 60.53 6.64 14.99 6.91 7.47 EXAMPLE 10 25 3-amino-4- (3- (3-piperidinoniethylphenoxy) propylaim'no) -1,, 2,5-thiadiazole

The present example is a variant of EXAMPLE 1, step B.-, that is to say that Ν, Ν'-thiobisphthalimide is used instead of sulfur monochloride.

A mixture of N- (3- (3-piperidinomethylphenoxy) propyl} -ethanediimidamide hydrochloride (27.3 g; 64.0 mmol) (prepared in EXAMPLE 1, step A.-}, 250 ml of CH2Cl2 and 26.6 ml (192.0 mmol) of triethylamine ~ is treated in portions with Ν, Ν'-thiobisphthalimide (DMF solvate) (25.4 g, 64.0 mmol). After stirring at room temperature for 1 hour, the mixture is washed with 120 ml of 20% Κ0Η, dried (MgSOi *), fi 1 -35 very concentrated and then taken up in 150 ml of toluene and reconcentrated. The product is taken up in 250 ml of propanol-1 and 10.7 ml of 6N HCl, treated with charcoal for discoloration and filtered through celite. This solution is concentrated to a volume of 100 ml, diluted with 175 ml of dry propanol-1 and stored at 0 ° C. which gives 20.2 g (82.1%) of crystalline hydrochloride of the title compound, melting point 137-138 ° C.

On analysis, it is found that the product obtained has the formula: 5 C17H25N50S.HC1, and the following values are obtained:

C H N S

- calculated 53.18 6.83 18.24 8.35 - found 52.78 6.74 18.52 8.66 EXAMPLE 11 10 5-amino-4- {5- (5-pyrrolidinomethylphenoxy) propyLamino} -1, 2,5-thiadiazole The present example is a variant of example 4, step B.-, that is to say that Ν, Ν'-thiobisphthalimide is used instead of • sulfur monochloride.

A mixture of N- 3- (3-pyrrolidinomethylphenoxy) ^ propyl ethanediimidamide tri hydrochloride (22.0 g; 53.0 mmol) prepared in Example 4, step A.-, 200 ml of CH Cl and 22 ml of triethylamine is treated with Ν, Ν'-thiobisphthalimide (DMF solvate) (21.2 g; 53.0 mmol). After stirring at room temperature for 1 hour, the mixture is washed with 100 ml of 20% Κ0Η, dried (MgSO 4), filtered, diluted with 100 ml of to-20 luene and concentrated. The product is treated with an equivalent of aqueous HCl in propanol-1, which gives 13.2 g (67%) of the hydrochloride of the title compound; melting point 135-137 ° C.

On analysis, it is found that the product obtained has the formula: C16H23Ns0S.HCl, and the following values are obtained:

25 C H N S

- calculated 51.95 6.54 18.93 8.67 - found 51.92 6.55 19.30 9.06 EXAMPLE 12 5-amino-4- {2 - {(5-dimethylaminomethyL-5-thienyL) methylthio } -ethylainino} -30 1, .2, .5-thiadiazoLe t * A.- Tri N- {2- {(5-dimethylLannnomethyL-3-thienyL) methylthio} ethyl) -ethanediimidamide hydrochloride

A suspension of 3-amino-4- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} ethyl ami no} -1,2,5-thiadiazole 1-oxide (7.8 g; 22.6 mmol) 35 {prepared according to published British patent application No. 2,067,987} in 150 ml of methanol is treated with 15.0 ml of concentrated HCl. After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with propanol-1, filtered and dried, which gives 7.38 g (80%) of the product. A sample is recrystallized from a methanol-acetone mixture to give the title compound, melting point 190-205 ° C (dec.).

On analysis, it is found that the product obtained has the formula: 5 C12N21N5S2.3HC1, and the following values are obtained:

C H N

- calculated 35.25 5.92 17.13 - found 35.03 5.93 17.39 B.- 3-amino-4- {2 - {(5-dimethyLatninoinethyL-3 — thienyUroethyltlvio} -ethylamino} -10 1 , 2, .5-thiadiazole

A mixture of tri N- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} ethyl} ethanediimidamide hydrochloride (6.13 g; 15.0 mmol) {prepared in step A.-}, 60 ml of CH2Cl2 and 6.3 ml of triethylamine is treated with N, Nr-thiobisphthalimide (DMF solvate) (5.96 g; 15.0 mmol) is stirred for one hour. The mixture is washed with 100 ml of 10% Κ0Η, dried (MgSOzt), filtered, diluted with toluene and concentrated to give 5.1 g of the product. Treatment of the product with 0.5 molar equivalent of fumaric acid in propanol-1 gives the fumaric acid salt of the compound, melting point 141-143 ° C. The NMR spectrum in DMS0-d indicates the presence of approximately 0.12 moles of propanol-1.

On analysis, it is found that the product obtained has the formula:; (C ^ H ^ NsSaJg.UHifO ^ .O. ^ CaHeO, and we obtain the following values:

C H N S

- calculated 43.68 5.61 17.75 24.38 25 - found 43.41 5.53 17.54 24.24 EXAMPLE 13 3-amino-4- {2 - {(5-piperidinomethyl-3-thienyl) roethylthio} ethylamino} -1,2,5-thiadiazole 30 A.- N ~ {2 - {(5-piperidinon) ethyl-3-thienyDroethylthio} ethyl} ethanediimidamide t hydrochloride A suspension of 3-amino-4- {2 - {(5-pipèridinomethyl-3-thienyl) methyl- * thio} ethylamino} -1,2,5-thiadiazole 1-oxide (6.1 g; 15.8 mmol) (prepared according to the published British patent application 2,067,987} in 80 ml of methanol is treated with 10.5 ml of concentrated HCl After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with 50 ml of propanol-1 , filtered and dried to give 5.86 g (83%) of the product A sample is recrystallized from a methanol-acetone mixture 34, to give the title compound, melting point 201-214 ° C (dec.) · A analysis, it is found that the product obtained has the formula: C15H25N5S2.3HCI, and the following values are obtained:

5 C H N S

- calculated 40.13 6.29 15.60 14.29 - found 39.97 6.47 15.28 14.63 B.- 3-amino-4- (2- {(5-piperidinon) ethy L-3 -thienyl) methyLthio} -ethyLanrino} - 1.2.5— thiadiazole 10 A mixture of tri N- {2 - {(5-piperidinomethyl-3-thienyl) - methylthio} thyl} ëthanediimidamide hydrochloride (5.17 g; 11, 5 mmol) (prepared in step A.-J, 48 ml of CH2C1z and 4.8 ml of triethylamine is treated with N, N1thiobisphthalimide (DMF solvate) (4.57 g; 11.5 mmol) is stirred for an hour. The mixture is washed with 90 ml of 10% Κ0Η, dried (MgSO / *), filtered, diluted with toluene and concentrated, which gives 4.5 g of the product. Treatment of the product with an equivalent of cyclohexylsulfamic acid in methanol gives the title compound cyclohexylsulfamate, melting point 142-143 ° C.

On analysis, it is found that the product obtained has the formula: C15H23N5S3.C6H13N03S, and the following values are obtained:

C H N S

- calculated 45.96 6.61 15.31 23.38 - found 45.61 6.41 15.46 23.48 EXAMPLE 14 25 We take again the general ways of process of EXAMPLE 1, stage A.-, and then either of EXAMPLE 1, step B.-, or of EXAMPLE 10, except that 3-amino-4- {3- (3-piperidinomethylphenyl) propylamino} -1,2,5-thiadiazole 1- oxide used here is replaced by an equimolar equivalent, of: 30 (a) 3-ethylamino-4- {3- (3-pipéridi nométhylphënoxy) propylami no} -1,2,5-thiadiazole 1-oxide; (b) 3-allylami no-4- {3- (3-pi peri-nomethylphenoxy) propylami no} -1,2,5-thiadiazole 1-oxide; (c) 3- (2-propynyl) -4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-35 thiadiazole 1-oxide; (d) 3- (3-pyri dy1methyl friend no) -4- {3-pi peri-nomethylphenoxy) -propy1 friend no} - 1.2.5- thiadiazole 1-oxide; 35 (e) 3- (6-methyl-3-pyridyl) methylamino-4- {3- (3-piperidinomethyl-phenoxy) propylamino} -1,2,5-thiadiazole 1-oxide, and (f) 3- ( 3,4-methylenedi oxybenzylami no) -4- {3- (3-pipéri dinomethyl-phenoxy) propylamino} - !, 2,5-thiadiazole 1-oxide, respectively, 5 and the following is produced: (a) 3 -ethylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole; (b) 3-allylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole; (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-pyri dyl) methylami no-4- {3- (3-pi peri-nomethylphenoxy) 5 15 propylamino} -1,2,5-thiadiazole, and (f) 3- (3,4-methylenedi oxybenzylami no) -4- {3- (3-pi peri nomethylphenoxy) propylamino} -1,2,5-thiadiazole, respectively.

EXAMPLE 15 3-amino-4- {3- (6-piperidinomethyL-2-pyridyLoxy) propyLamino} -1 / .2y5-thiadiazote A. - 3-amino-4- {3- (6-piperidinomethyl-2-pyridyLoxy ) propylamino} -1,2,5- thiadiazole 1-oxide

A solution of 3- (6-piperidinomethyl-2-pyridyloxy) -propylamine; (4.65 g; 18.6 mmol) {prepared according to British patent application published No. 2,098,988} in 50 ml of methanol is reacted with 3-amino-4-methoxy-1,2, 5-thiadiazole 1-oxide (2.74 g; 18.6 mmol) according to the general procedure described in British patent application No. 2,067,987 to give a solution containing 3-amino-4- {3- (6-piperi-dinomethyl-2-pyridyloxy) propylamino} -1,2,5-thiadiazole 1-oxide. A ëchan-.

. 30 purified tillon melts at 145-147 ° C.

B. - N- {5- (6.-piperidinomethyl-2-pyridyLoxy) propyl} v ethanedi imidamide i hydrochloride. A methanolic solution of the product prepared in stage A.- is; diluted to 100 ml and 12.4 ml of concentrated HCl are added. The solution is stirred at room temperature for 18 hours, concentrated and the residue is dissolved in 80 ml of water and extracted twice with H2Cl2. The aqueous layer is concentrated, treated with n-propanol and concentrated in high vacuum to give the title compound as a foam.

i 36 C-- 3-amino-4- (3- (6-pipendinomethyT2-pyridyloxy) propylannno} -1,2,5-thiadiazole

A mixture of the crude product prepared in step B., in 80 ml of CH2Cl2 and containing 7.69 ml of triethylamine is treated with 5 Ν, Ν'-thiobisphthalimide (DMF solvate) (7.35 g ; 18.5 mmol). After stirring at ambient temperature for 1 hour, the mixture is washed with 50 ml of NaOH4N, water, a saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product. The product is purified by flash chromatography on 100 g of silica gel (230-400 mesh), using an ethyl acetate / methanol mixture (95/5), as eluent to give 3.63 g of the title compound in the form of a viscous oil. Treatment of the product with an equivalent of cyclohexylsuifamic acid in acetone gives the title compound cyclohexylsulfamate, mp 125-131 ° C.

On analysis, it is found that the product obtained has the formula:

Ci6H2 * Ne0S.C6Hi3N03S, and we obtain the following values:

C * H N S

- calculated 50.07 7.07 18.58 12.15 - found 50.02 7.03 18.54 12.14 t 20 EXAMPLE 16 5-atnino-4- (3- (6-dimethyLannnométhyL-2-pyridyLoxy) propyLaiinno} -1,2,5-thia-diazoLe

When a methanolic solution of 3- {6-dimethyl-aminomethyT2-pyridyloxy) propylamine (prepared according to published British Patent Application No. 2,098,988} is reacted with 3-amino-4-methoxy-1,2, 5-thiadia-zole 1-oxide according to the general procedure described in British patent application No. 2,067,987 and that the 3-amino-4- 3- (6-piperidinomethyT2-pyridyloxy) propylamino is reacted - 1,2,5-thiadiazole 1-oxide which results therefrom according to the general method described in exampleI, step A.-, and then either by example 1, step B.-, or EXAMPLE 10, the compound is thus produced of the title.

IV EXAMPLE 17 5-amino-4- (2- {(6-diniethyLaminomethyL-2-pyridyL) methyLthio) -ethy Lamino) - 1,2,5-thiadiazole When a suspension of 3-amino- is reacted successively 4- {2 - {(6-dimethylaminomethyl-2-pyridyl) methylthio} ethylamino} -1,2,5-thiadiazole 1-oxide (prepared according to published British patent application No. 2,067,987} according to the procedures to be followed of EXAMPLE 1, step A.-, and then either according to T EXAMPLE 1, step B.-, or T EXAMPLE 10, the title compound is thus produced.

"EXAMPLE 18 3- amino-4- {2- {C6-piperidinon) ethyL-2-pyridyL) methylthio} ethylamino} -5 1,2,5-thiadiazole

When a suspension of 3-amino- 4- {2 - {(6-piperidinomethyl-2-pyridyl) methylthio} ethylamino] -1,2,5-thiadia-zole 1-oxide {prepared according to published British patent application No. 2,067,987} according to the methods of EXAMPLE 1, step A.-, and then, either according to EXAMPLE 1, step B.-, or either according to EXAMPLE 10 , the title compound is thus produced.

* EXAMPLE 19

The general procedure is repeated from EXAMPLE 1, step A.-, and then either from EXAMPLE 1, step b.-, or from EXAMPLE 10, except that 3-amino-4- { 3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole 1-oxide used here, is replaced by an equimole-circular amount of: (a) 3-amino-4- {3- (3-piperidinomethylthiophenoxy) propylamino} -1,2,5-thiadiazole 1-oxide; (B) 3-friend no-4- {3- (3-dimethylami nomethylthi ophenoxy) propylami no} -1,2,5-: thiadiazole 1-oxide; (c) 3-friend no-4- {3- (3-pyrroli di nomethylthiophenoxy) propylami no} -1,2,5-thiadiazole 1-oxide; (d) 3-amino-4- {3- (4-dimethylaminomethyl-2-pyridyloxy) propylamino} -1,2,5-25 thiadiazole 1-oxide; (e) 3-amino-4- {3- (5-dimethylaminomethyl-3-thienyloxy) propylamino} -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- (2 - {(4-dimethylaminomethyl-2-pyridyl) methylthio} -ethyl-amino} -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 the following is produced: 35 (a) S-amino-A -të-ÎS-pipeVidinométhylthiophénoxyJpropylamino} -1,2,5-thiadiazole; (b) 3-ami no-4- {3- (3-dimethylami nométhylthi ophenoxy) propylami no} -1,2,5-thiadiazole; 38 ( c) 3-amino-4- {3- (3-pyrrolidinomethylthiophenoxy) propylamino} -1,2,5-thiadiazole; (d) 3-friend no-4- {3- (4-dimethylaminomethyl-2-pyridyloxy) propylaniino } -1,2,5-thiadiazole; 5 (e) 3-amino-4- {3- (5-dimethylaminomethyl-3-thienyloxy) propylamino} -1,2,5-thiadiazole; (f) 3-amino- 4- (3- (5-piperidinomethyl-3-thienyloxy) propylamino) -1,2,5-thiadiazole; (g) 3-amino-4- {2 - {(4-dimethylaminomethyl-2-pyridyl) methylthi 0} -ethyl-10 amino} -1,2,5-thiadiazole; and (h) 3-friend no-4- {2- £ (4-pi peri-nomethyl-2-pyri dylJmëthylthi o} -ethylamino} - 1, 2,5-thiadiazole, respectively.

The above starting materials are prepared according to the general procedures described in British patent application No. 2 · .067,987. The precursors of the starting materials are prepared by the procedures and analogous general procedures described in the British patent applications No. 2,067,987, 2,098,988, 2,063,875 and the published European patent application No. 49,173 .

EXAMPLE 20 20 3-amino-4- {3- (4-piperidinomethyL-2-pyridyloxy) propyLamino} -1,2 / 5-thiadia-zole A. - 3- (4 ~ piperidinomethyl-2-pyridyLoxy) propyLamine

When following, for the preparation of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine, the general procedure described in British patent application No. 2,098,988, except that 2-chloro- 6-methyl-pyridine used here is replaced by 2-bromo-4-methylpyridine, then the title compound is produced as an oil.

On analysis, it can be seen that the product obtained has the formula: Cii * H23N30, and the following values are obtained:

* 30 C H N

- calculated 67.44 9.30 16.85 - found 67.54 8.98 16.55 B. - 3-amino-4- {3-C4-piperidinomethyl-2-pyridy [oxy) propyLamino} -1.2 , 5-thiadiazole 1-oxide 35 A solution of the product of step A.- (6.5 g; 26.0 mmol) in 90 ml of methanol is reacted with 3-amino-4-methoxy-1, 2,5-thia-diazole 1-oxide (3.84 g; 26.0 mmol) according to the general procedures described in British patent application No. 2,067,987, which gives 6.33 g of the product. Recrystallization from a methanol-acetonitrile mixture gives the title compound; melting point 154-158 ° C.

On analysis, it is found that the product obtained has the formula: 5 C-ie ^ NeOS, and the following values are obtained:

C H N S

- calculated 52.73 6.64 23.06 8.80 - found 52.72 6.30 23.32 8.74 C.- N-Trichlorohydrate {3- (4-piperidinomethyL-2-pyridyloxy) propyL) _ 10 ethanedi imidamide

The product from step B.-, (5.0 g; 13.7 mmol) is dissolved in! 80 ml of methanol and treated with 9.1 ml of concentrated HCl. After stirring at room temperature for 4.5 hours, the solution is | evaporated to dryness under reduced pressure to give the title compound.

'15 D.- 3-annno-4- {3- (4-pipéridinométhyL-2-pyridyLoxy) propyLamino} -1,2,5- thiadiazoLe

A mixture of the product prepared in step C., in 50 ml of -CH2Cl2 and 5.7 ml of triethylamine is treated with N, N'-thiobisphta-limid (DMF solvate) (5.44 g; 13.7 mmol). After stirring at room temperature for one hour, the mixture is washed with 40 ml of NaOH4N, water, saturated aqueous NaCl solution, dried (Na2S0, *) filtered and evaporated under reduced pressure to give the crude product . The product is purified by flash chromatography on 90 g of silica gel (230-400 mesh) using an ethyl acetate / methanol mixture (96/4) as eluent to give 3.44 g of the title compound in the form viscous oil. Treatment of the product with an equivalent of cyclohexylsulfamic acid in acetone gives the title compound cyclohexylsulfamate, mp 124.5-126 ° C.

On analysis, it is found that the product obtained has the formula: C16H24N60S.C6H13N03S, and the following values are obtained:

C H N S

- calculated 50.07 7.07 18.58 12.15, vr - found 50.47 7.12 18.33 11.87 EXAMPLE 21 35 3-aniino-4- {3- {5- (1,2, 3,6-tetrahydro-1-pyridyl) methyLphenoxy} -propylanrino} -1,2,5-thiadiazol.e

The general procedure of Example 15 is repeated, except that the 3- (6-piperidinomethyl-2-pyridyloxy) propylamine used here is replaced by an equivalent amount of 3- 3- (1,2,3,6 -tetrahydro-1-pyridyl) methylphenoxy propylamine, which gives 2.31 g of product. Crystallization from toluene gives the title compound, melting point 99.5-5 104 ° C.

Upon analysis, it is found that the product obtained has the formula: C17N23N5OS, and the following values are obtained:

C H N S

- calculated 59.10 6.71 20.27 9.28 10 - found (for 2.19¾ H20) 58.78 6771 19.90 9.26

Claims (41)

41 1.- Compound of formula: A- (CH,) „Z (CH,)„ NH ^ ^ NHR1 / ΓΛ S / in which: R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoro -10 ethyl, allyl, propargyl, - "'O- ;, wherein: p is 1 or 2; R2 and R3 independently, each represents hydrogen, lower alkyl, lower alkoxy or halogen, or j ! 20 when R2 is hydrogen, R3 can also be trifluoromethyl, or R2 and R3 taken together can be methylene = dioxy; and! R4 is hydrogen, lower alkyl or lower alkoxy; im is an integer from 0 to 2 inclusive; 25. is an integer from 2 to 5 inclusive;: Z is oxygen, sulfur or methylene; and; A is 7 R5 7 R5 6 / (CH2'q- ^ T '. I · 42 in which: R5 is hydrogen, lower alkyl or lower alkoxy; q is an integer from 1 to 4 inclusive; and n 1 R6 and R7 each independently represents lower alkyl, lower alkoxy lower alkyl in which the lower alkoxy radical is at least two carbon atoms distant from the nitrogen atom, or a lower phenylalkyl, and when R6 is hydrogen, R7 can also be a lower cycloalkyl or, R6 and R7 taken at the same time as the hydrogen atom to which they are attached, can be groups pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpipe'ridino, dimethyl-piperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyle, homo-1 -, piperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo {3, 2,2} non-3-yl or 3-pyrrolino; or a hydrate salt or Pharmaceutically acceptable non-toxic solvate * thereof. 2.- A compound according to claim 1, having the formula: A_ (CH2) mz (ch2 1 n "H \ yNHR1: Yi 20 wherein: R1 is hydrogen, or lower alkyl; m is 0 or 1 ; 25. is 2 or 3; Z is oxygen or sulfur; and A is 7 r5 S; "'v R \ R \> Η2—4- or 6 / ^ 2— H ~ 35 v 43 in which : R5 is hydrogen or methyl, and ^ R6 and R7 independently are each ethyl or methyl, or when taken at the same time as the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a pharmacologically acceptable non-toxic hydrated or solvated salt thereof. 3.- Compound according to claim 1, having the formula: 6 / ca2 ~ ll · Ί R \ ^ SbCH2CH2CH2NHN ^ NHR1 Iri 15 N \ s / H in which: k; R5 is hydrogen or methyl; and j! R6 and R7 are each methyl, or when taken at the same time 2. as the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a hydrated or solvated salt | non-toxic pharmaceutically acceptable thereof. 4. A compound according to claim 1, having the formula: s5 r7 *, / NCH2 "7T JJHR1 n> * V ri N \ s / * - 30 in which:> R1 and R5 each independently represent hydrogen or methyl, and R6 and R7 each independently represents methyl or ethyl; or a non-toxic pharmaceutically acceptable hydrate or solvate salt thereof. 5, - Compound according to claim 1, having the formula: r5 7 R '__ NCH, - ^' - À — CH-SCH-CH-NH NKR1 le s, "/ yi in which: R1 and R5 each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl; or a pharmaceutically acceptable non-toxic hydrated and solvated salt thereof. 6. A compound according to claim 1, having the formula: NCH, - I 0CHoCHoCH-NH NHR1 Yi ’20 N N in which: R1 and R5 each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl; or, when taken at the same time as the nitrogen atom to which they are attached, R6 and R7 represent a group pi peridino; or a pharmaceutically acceptable non-toxic hydrated and solvated salt thereof. 7. The compound of claim 1 which is 3-amino-4- {3- (3-pipe'ridinomethylphenoxy) propylamino} -1,2,5-thiadiazole or a pharmaceutically non-toxic hydrated or solvated salt acceptable of it. 8.- The compound according to claim 1, which is 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole hydrochloride. 9. The compound according to claim 1 which is 3-amino-4- {2- {£ -dimethylaminomethyl-2-furyl) methylthio} ethylamino] -1,2,5-thiadiazole or a hydrated or solvated salt non-toxic pharmaceutically acceptable thereof. 45 10.- Compound according to claim 1, which is 3-amino-4- {2 - {(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio} ethylamino) -. 1,2,5-thiadiazole, or a pharmacologically acceptable non-toxic hydrated or solvated salt thereof. 11. The compound of claim 1 which is 3-amino-4- {3- (3-pyrrilidinomethylphenoxy) propylamino} -1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrated or solvated salt thereof . 12. A compound according to claim 1 which is 3-methylamino-, 4- 4- {3— (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole, or a non-toxic pharmaceutically acceptable hydrate or solvate salt thereof. -this. 13. The compound of claim 1 which is 3-benzylamino- 4- {3- (3-piperidinomethylphenoxy) propylamino -1,2,5-thiadiazole, or a non-toxic pharmaceutically acceptable hydrate or solvate salt thereof. this. 14. The compound of claim 1 which is 3-amino-4- | {2 - {(5-dimethylami nomethyl-3-thienyl) methylthio} ethylami no) -1,2,5-thi diazole, or a pharmaceutically acceptable non-toxic hydrated or solvated salt thereof. 15. A compound according to claim 1, which is 3-amino-4- {2 - {(5-piperidinomethyl-3-thienyl) methylthio} ethylamino} -1,2,5-thiadiazole, or a non hydrated or solvated salt pharmaceutically acceptable toxic thereof. 16. The compound of claim 1 which is 3-amino-4- {3— (6-piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-thiadiazole, or a non-toxic hydrated or solvated salt pharmaceutically acceptable thereof. 17. The compound according to claim 1, which is 3-amino-4-30 {3— (4-piperidinomethyl-2-pyridyloxy) propylamino} -1, 2,5-thiadiazole, or a non-toxic hydrated or solvated salt. pharmaceutically acceptable thereof. 18. The compound of claim 1 which is 3-amino-4- (3- {3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy) propylamino) -1,2,5-35 thiadiazole, or a pharmaceutically acceptable non-toxic hydrated or solvated salt thereof. 19.- Compound of formula: 5 46 A- (CH2) mZ (CH2) nNH-v S ** 1 „in which: R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-tri- fluoroethyl, allyl, propargyl, 10 r2n5— \ 7 k in which: 15. is equal to 1 or 2, R2 and R3 each independently represent hydrogen, lower alkyl, lower alkoxy or halogen, and, when R2 is hydrogen , R3 can also be trifluoromethyl, or R2 and R3 taken together can be methylenedioxy; and R ^ is hydrogen, lower alkyl or lower alkoxy; m is an integer from 0 to 2 inclusive; n is an integer from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A is 25 R \ ή ~ Λ <Γ + Λ y -y ' 30. S i :, s R 47 in which: R5 is hydrogen, lower alkyl or lower alkoxy; % q is an integer from 1 to 4 inclusive; and "R6 and R7 are each independently lower alkyl, lower alkoxy lower alkyl in which the lower alkoxy radical of two carbon atoms distant from the nitrogen atom, or phenyl-lower alkyl, and, when R6 is a hydrogen, R7 can also be a lower cycloalkyl or R6 and R7 taken at the same time as the nitrogen atom to which they are attached, can be a group of pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino,> ./ heptamethylëneimino, octamëthylèneimino, 3-azabicyclo {3,2,2} non * 3-yl or 3-pyrrolino; or a hydrated or solvated salt thereof. 20.- A compound according to claim 19, having the formula: A * (CH2> mZ (CH2> nNH \ / l "®1) ri KN NH I 20: wherein: | R is hydrogen or lower alkyl; im is 0 or 1; n is 2 or 3; 2. Z is oxygen or sulfur; and: A represents R5 5 R \ r-jU JL. V - # - '4- \ ch —ÛJA 3. K6 "2 ~ x 'y 2 χ. Y' * S w ~ t - v y 35 R5 -7 R \ R \ f ^ N ‘NC« -LL · OU ^ NCH, --- f- 2 yy ί ......... 48 in which: R5 is hydrogen or methyl; and 'R6 and R7 each independently represent a methyl or an ethyl, or when taken at the same time as the nitrogen atom 5. to which they are attached, R6 and R7 represent a pyrrolidino or pi peri no ring; or a hydrated or solvated salt thereof. 21. A compound according to claim 19, having the formula: 10 R \ 6 / ch2r-rf- \ R \ i ^ ÔCH2CH2CH2NHNHR1 IIa Iri HN NH 15 in which: J R1 is hydrogen or methyl, and R6 and R7 each represent methyl or, when taken together time that the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or pi peridino cycle; or a hydrated or solvated salt thereof. 22. A compound according to claim 19, having the formula: 25 7 R # I \ c h2 H2 sch2c K2 ΝΠ. _NHR1 Nr / ΓΛ HN Nh, 30 î in which: * R1 and R5 each independently represent hydrogen or methyl; , and - R6 and R7 each independently represent methyl or ethyl; 35 or a hydrated or solvated salt thereof. 49 23. Compound according to claim 19 having the formula: * 7 r5 s. · / 2t, T) ri m nh in which: R1 and Rs each independently represent hydrogen or methyl; and Re and R7 each independently represent methyl or ethyl; or a hydrated or solvated salt thereof. 24. A compound according to claim 19, having the formula: ## STR2 ## MCH2CH2CH2NH J1HR1 jTfl "" M HN NH in which: R1 and Rs each independently represent hydrogen or methyl; and R6 and R7 each independently represent methyl or ethyl; or when taken at the same time as the nitrogen to which they are attached, R6 and R7 represent a group pi peridino; or a hydrated or solvated salt thereof. 25. The compound of claim 19 which is N- {3- (3-pipe- rid ridinomethylphenoxy) propyl} ethanediimidamide, or a hydrated or solvated salt thereof. 26. The compound according to claim 19 which is N- {2 - {(5-di-methylaminoethyl-2-furyl) methylethyl} ethyl} ethanediimidamide, or a hydrated or solvated salt thereof. 27. The compound according to claim 19, which is N- {2 - {(5-dimethyl friend noëthy1-4-methy1-2-th i eny1) methy1th io) ethy1} ethanedi imidami of, or a salt hydrate or solvate thereof. 50 28. The compound of claim 19 which is N- {3- (3-pyrro-lidinomethylphenoxy) propyl} ethanediimidamide, or a hydrate or solvate salt thereof. AT 29. A compound according to claim 19 which is N- {2-f (5-di-> 5 methylaminomethyl-3-thienyl) methylthio} ethyl} ethanediimidamide, or a hydrate or soivate salt thereof. 30. The compound of claim 19 which is N- {2 - {(5-pipé-ridinomethyl-3-thienyl) methylthio} ethyl} ethanediimidamide, or a hydrate or soivate salt thereof. 31. The compound of claim 19 which is N- {3- (6-pipe-ridinomethyl-2-pyridyloxy) propyl} etahendiimidamide, or a hydrate or soivate salt thereof. 32. The compound of claim 19 which is N- {3- (4-pipé-ridinomethyl-2-pyridyloxy) propyl} ethanediimidamide, or a hydrate or soivate salt thereof. 33. The compound of claim 19 which is N- {3- {3- (1,2,2,6-tetrahydro-1-pyridyl) methylphenoxy} propyl} ethanediimidamide, or a hydrate or soivate salt thereof . 34. Process for the preparation of a compound of formula 20 A- (CH2) n.2tcH2) nNRv_ ^ niR v * 25 or of a non-toxic pharmaceutically acceptable salt, hydrate or soivate thereof, according to claim 1 consisting in reacting, preferably at a temperature of about 0 ° C to about 50 ° C and preferably in an inert organic solvent, a compound of formula y î A- (CH2) nZ (CH2) nNH - ^ - C-NHR1 II HN NH with at least one molar equivalent, preferably a molar excess, especially a molar excess of 2-3 moles, of sulfur monochloride, sulfur dichloride or a chemical equivalent thereof, preferably of sulfur monochloride, to produce said compound of formula I. 35 - Process for the preparation of a compound of formula 51 A- (CH2> aZ (CH2) n! IH ^ —C-NHR1 II * HN NH * according to claim 19, consisting in reacting preferably in an inert solvent and at room temperature, a compound of formula A- (CH2) mZ (CH2) nNH v_ ^ NHR1 ΎΛ "V a \ r with a strong mineral acid, preferably hydrochloric acid or to react a compound of formula: A - (CH2) ffiZ (CH2) nNH2 IV with a compound of formula <CH3 ° \ / ° CH3 A - C \ mr \ 'kH? V "V t to produce a compound of formula 52' A-tCH ^ ZÎCH ^ NH ^ / ^ 3 VI 5 h / V and then reacting said compound of formula VI with a compound of formula R ^ Nh ^ ·> ANV 'V * ·