FR2542741A1 - SUBSTITUTED 3,4-DIAMINO-1,2,5-THIADIAZOLES HAVING HISTAMINE H2-RECEPTOR ANTAGONISTIC ACTIVITY - Google Patents

Abstract

H-RECEPTOR ANTAGONISTS OF FORMULA: (CF DRAWING IN BOPI) IN WHICH: A, M, Z, N AND R ARE AS DEFINED HERE, AND THEIR PHARMACEUTICALLY ACCEPTABLE HYDRATE SALTS AND NON-TOXIC SOLVATES ARE NEW ANTI-ULCER AGENTS ARE PREPARED BY CYCLE CLOSURE OF AN ETHANEDIIMIDAMIDE SUBSTITUTED WITH THE FORMULA: (CF DRAWING IN BOPI)

Description

SUBSTITUTED 3,4-DIAMINO-1,2,5-THIADIAZOLES HAVING A

  ANTAGONIST ACTIVITY OF HISTAMINE-H 2 RECEPTOR

  Cross-reference to a related application This request is a continuation of our previous request.

  under processing No. 363,207, filed March 29, 1982.

Summary of the invention

  Some 3- (amino or amino-substituted) -4- (amino-substituted) -1,2,5-

  thiadiazoles having the formula: A (CH 2) m Z (CH 2) n NH NHR 1

<I

s in which:

  A, mni, z, N and Ri are as defined below, and their hydrate salts are

  Non-toxic pharmaceutically acceptable solvents and solvates are

  potent histamine H-2 antagonists that inhibit

  secretion of gastric acid and are useful in the treatment of

  disge- sive ulcers and other pathological conditions of hypersecretion.

  The compounds are prepared by ethanediimide ring closure.

  correspondingly substituted damid of formula: A- (CH 2) m Z (CH) N N

2 M 2 11%

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

mule: A (CH 2) m Z (CH 2) NH 4

N N

  N 11 -s S (O) p and processes for their preparation, wherein the variables: A, mni, Z, N and R 'are similar to the corresponding substituents of

  compounds described and claimed herein.

  However, the compounds described in this British application are oxides or 1,1-dioxides (p is 1 or 2), and compounds of the present invention can not be prepared by any of the methods

  described in said application for the preparation of the compounds of the prior art

  TER AL. Published European Patent Application No. 40,696 describes, inter alia, 3,4-disubstituted-1,2,5-thiadiazole-1-oxides and 1,1-dioxides having the formula:

R- (D (CH 2) -X (CH 2) NH 2

  N) p and processes for their preparation, wherein the variables: R, A, n, X, n, R 1 and R 2 are similar to the corresponding substituents

  compounds described and claimed herein.

  However, the compounds described in said application are also oxides or 1,1-dioxides (p is 1 or 2) and the compounds of

  The present invention can not be prepared by any of the methods

  in that application for the preparation of the compounds of the prior art

  laughing. In the two publications cited above, each of the processes described for the preparation of the compounds of the prior art involves

2-542741

  the use (as starting material or intermediate) of a 1,2,5

  thiadiazole 1-oxide or a 1,1-dioxide having, or groups

  amino, or appropriate "leaving groups" at the 3- and 4- positions.

  The desired substituents at the 3 and 4 positions are then obtained by substitution on the amino groups or by replacement of the "leaving groups". We have done many tests to prepare the compounds of this

  invention by similar methods, ie using a 1,2,5-

  thiadiazole having amino groups or "leaving groups" suitable for positions 3 and 4 as starting material or intermediate Although many variants have been tried, at the same time as the conditions of the invention have been varied. reaction, we do not have

  was able to isolate the compounds according to the invention by this route.

  It has now been found that the compounds according to the present invention

  can be prepared by ring closure of ethanediimidamide

  correspondingly of the formula: A_ (CH 2) m Z (CH) NH-C -C-NH I I-IN

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

Full description

  The present invention relates to histamine H 2 -receptor antagonists of the formula: ## STR2 ## wherein: R 1 represents hydrogen, lower alkyl, fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, R 2 (CH 2) P or 2 P

3 N

  in which: p is equal to 1 or 2;

  R 2 and R 3, independently, each represents hydrogen, alkyl,

  lower, lower alkoxy or halogen; and when R 2 is hydrogen, R 3 may also be trifluoromethyl, or R 2 and R 3 taken together may be methylenedioxy; and R 4 represents hydrogen, lower alkyl or lower alkoxy; im is an integer from 0 to 2 inclusive; N is an integer from 2 to 5 inclusive; Z is sulfur or methylene oxygen; and A represents

-R 5 R 5

R 77

R

N (CH 2) 6 N (CH 2) q 6/25

R RR

R 7

  or N (i or 67 N <CII 2 ') q 6 / N (CH 2) q R 6 / R 6 R in which:

  R 5 represents hydrogen, lower alkyl or lower alkoxy

  laughing; q is an integer from 1 to 4 inclusive; and R 6 and R 7 are each independently lower alkyl, lower alkoxy lower alkyl, wherein the lower alkoxy moiety is at least 2 carbon atoms away from the nitrogen atom, or lower alkyl phenyl and, when R 6 is hydrogen, Rv may also be lower cycloalkyl, or R and R taken together with hydrogen atomy

  to which they are attached may be pyrrolidino, methyl-

  pyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino,

  piperidino, methylpiperidino, dimethylpiperidino, N-methyl-

  piperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hepta-

  methyleneimino, octamethyleneimino, 3-azabicyclo {3,2,2} non-

  3-yl or 3-pyrrolino; and their hydrate salts and solvates

  pharinaceutically acceptable toxins.

  The invention also relates to processes for preparing the compounds

  of formula I and intermediate compounds of formula II.

  Included within the scope of the present invention are all the

  my possible tautomeric, diastereoisomeric forms, and optically active isomers of the compounds of formula I as well as mixtures thereof

  of them used in the description and in the claims, the

  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 6 carbon atoms.

  to 4 carbon atoms The term "lower cycloalkoxy" means a group

  cycloalkyl containing from 3 to 6 carbon atoms The term "non-

  pharmaceutically acceptable compounds "means salts of addition of

  Cides-formed with acids such as hydrochloric acid, brohidric acid, nitric acid, sulfuric acid, acetic acid, propionic acid, fumaric acid, methanesulfonic acid,

  maleic, tartaric, citric, levulinic, benzoic, succinic and

  gists. In the compounds of formula I, R 1 is preferably hydrogen or lower alkyl, or more preferably hydrogen or methyl, or even better, hydrogen. Substituent A is preferably

  substituted phenyl, substituted furyl or substituted thienyl represents

  above, and especially it represents the substituted phenyl group.

  The substituent Z is preferably a sulfur or an oxygen and, when

  A is the substituted phenyl radical, Z is preferably oxygen.

  It is preferred that neither be equal to O or 1, and N to 2 or 3 and that when A represents

  the substituted phenyl radical, m is 0 and N to 3 R 5 is preferably hydrogen or methyl, but especially hydrogen.

  prefers that q is 1 R 6 and R 7 are preferably lower alkyl than

  or at the same time as the nitrogen atom to which they are attached,

  they represent a pyrrolidino or piperidino group.

  The compounds of formula I can be prepared by reaction of a compound of formula II with sulfur monochloride,

  sulfur or chemicals equivalent to these, such as the following

: A (CH 2) Z (CH 2) nm H C-I + II

HN H

52 C 12

  or SC 12 \% / 'A- (CH 2) m Z (CH 2) NHN NH 1

NS /

wherein:

  A, m, Z, N and R 1 are as defined above.

  At least one mole of 52 C 12 or SC 12 must be used per mole of compound II; it is preferred to use an excess of 52 C 12 or SC 12, for example,

  from 2 to about 3 molecules of 52 Cl 2 or S C 12 per molecule of compound II.

  It has been found that S C 12 often gives a coarser product and a yield

  lower purified product and it is usually preferred to use

  ser 52 C 12 to make the reaction The reaction temperature is not critical; It is preferred to conduct the reaction at a temperature of about OC to about 50 ° C and it is extremely convenient to conduct the reaction at room temperature. The reaction time is not critical and it depends on the temperature. reaction time of about

  At about 6 hours at room temperature, it is usually preferred to

  use reaction times of approximately 1 1/2 to 4 hours.

  can be carried out in an inert organic solvent, preferably a

  mixture of an inert organic solvent and dimethylformamide

  especially conduct the reaction in dimethylformamide.

  In a preferred embodiment of the invention, the compounds of formula I have the structure A (CH 2) m Z (CH 2) n NH NHR 1 NSZ wherein: R 1 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 R 6 NC-; 6 / C 2

R 5

R 7 * I 7

\ or \ NCH

R 5 R 55

  Wherein R 5 is hydrogen or methyl, and R 6 and R 7 independently are each methyl or ethyl, and when taken in m, As well as the nitrogen to which they are attached, R 6 and R 7 represent a ring

  pyrrolidino or piperidino; or unsel, a hydrate or a sol-

  non-toxic pharmaceutically acceptable ester of these compounds.

  In the most preferred embodiment, the compounds of formula I have the structure: R 67 R NCH Ia:

R 6 CH 2 CH 2 CI 2 NH HR

N QS / N

  wherein: R 1 is hydrogen or methyl; and

  R 6 and R 7 each represent a methyl or when taken together with

  as long as the hydrogen atom to which they are attached, R 6 and R 7 represent a pyrrolidino or piperidino ring; or a salt, moisturizes

  or nontoxic pharmaceutically acceptable solvate of these compounds.

  In another more preferred embodiment, the

  Formula I have the structure: MB wherein: R 'and Rs each independently represent hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl; or

  a non-toxic hydrate salt or solvate pharmaceutically acceptable

table of these compounds.

  In another preferred embodiment, the compounds of formula I have the structure: NCH 2 R 6 / R 5

H 2 SCII 2 CH 2 NH NHR 1

  wherein R 1 and R 5 each independently represent hydrogen or methyl, and R 6 and R 7 each independently represent methyl or ethyl; or

  a hydrate or solvate salt, non-toxic, pharmaceutically acceptable

table of these compounds.

  In another preferred embodiment, the compounds of formula I have the structure: ## STR1 ##

N N

  wherein each of R1 and R5 is independently hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl; or when taken together with the nitrogen atom at which

  they are attached, R 6 and R 7 represent a piperidic group

  dino, or a salt hydrate or solvate non-toxic pharmaceutical-

acceptable for these compounds.

  As presently contemplated, the most preferred compounds of formula I are: 1) 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole;

  2) 3-Amino-4- {2 - {(5-dimethylaminoniethyl-2-furyl) methylthio} ethylamino

  1,2,5-thiadiazole, 3) 3-amino-4- {2 - {(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio} ethylamino} -1,2,5-thiadiazole; 4) 3-amino-4- {3- (3-pyrrolidinomethylphenoxy) propylamino} -1,2,5-thiadiazole; 3-methylamino-4- {3- (3-piperidinoinethylphenoxy) propylamino} -1,2,5thiadiazole;

  6) 3-Benzylamino-4- {3- (3-piperidinomethylphenoxy) propylamin Q} -1,2,5-

thiadiazole;

  7) 3-Amino-4- {2 - {(5-dimethylamino-methyl-3-thienyl) -methylthio} ethylamino] -

1,2,5-thidiazole;

  8) 3-amino-4- {2 - {(5-piperidinomethyl-3-thienyl) methylthio} ethylamino} -

1,2,5-thiadiazole;

  9) 3-amino-4- {3- (6-piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-

thiadiazole; and

  ) 3-amino-4- {3- (4-piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-

thiadiazole;

  and their non-toxic pharmaceutically acceptable hydrate salts and solvates

tables.

  Intermediates of formula II, used in the preparation of

  Compounds of formula I may even be prepared by various methods.

  In one method, 3- (amino or substituted amino) -4- (substituted amino) -

  Corresponding 1,2,5-thiadiazole 1-oxide of formula III is treated with

  a strong mineral acid (preferably HC 1) to give the compound of formula

  mule II: A (CH 2) m Z (c H 2) N) 1 NHR-H Cl / A- (CH 2) m Z (CH 2) N NHR I

2 N NH

  The reaction can be carried out in an inert solvent and is preferably carried out in methanol.

  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 British patent application

published 2 067 987.

  According to another method, the compounds of formula II may be prepared according to the following reaction scheme:

CH 30 \ OC 3

A (CH 2) m Z (CH 2) n NH 2 + C% NH

IV V

A (CH 2) m Z (CH 2) n NH 2 <CH 3

HN%

R 1 NH 2

A (CH 2) m Z (CH 2) n VI III

  the reaction can be carried out in an inert solvent and is preferably

  The starting materials of formula IV are known or can be easily prepared by known methods.

  for example, by methods described in our patent application

published tannin No. 2,067,987.

  The invention also relates to novel intermediates of the formula: embedded image in which: R 1 represents a hydrogen, a lower alkyl, 2-fluoroethyl, the 2,2,2-trifluoroethyl, allyl, propargyl,

(CH 2) p-

or R 4

(CH 2) p-

  in which: p represents 1 or 2, R 2 and R 2 independently represent each a hydrogen, an alkyl

  lower alkoxy or halogen, and when R 2 represents

  is hydrogen, R 3 may also be trifluoromethyl, or R 2 and R 3 taken together may be methylenedioxy; and R 4 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

7 7 R 5

R \ R \

, 6 / N (CH 2) qy

R 6 R 6 S

R sR

R 7 5 R 5

N (CH 2 CH or 6 / N (CII 2) q

R 6/2 R 6 /

R in which:

  Rs represents hydrogen, lower alkyl or lower alkoxy

  lower, q is an integer from 1 to 4 inclusive; and R 6 and R 7 are each independently lower alkyl, lower alkoxy lower alkyl, wherein the lower alkoxy radical is at least 2 carbon atoms away from the nitrogen atom, or lower alkyl phenyl and, when R 6 represents a hydrogen, R 'can also be a lower cycloalkyl, or R 6 and R 7 taken together with the nitrogen atom

  to which they are attached, may be pyrotechnic groupings

  lidino, methylpyrrolidino, dimethylpyrrolidino, morpholino,

  thiomiorpholino, piperidino, methylpiperidino, dimethylpiperidine,

  dino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopi-

  peridino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo {3,2,2} non-3-yl, or 3-pyrrolino; or a salt hydrate or solvate

of these.

  In a preferred embodiment, intermediates II, have the structure: A (CH 2) m Z (CH 2) n NH of formula II wherein: R 1 is hydrogen or lower alkyl; m is 0 or 1; n is 2 or 3; Z is oxygen or sulfur; and A is R 5 R 7 o 2 NCH 2

R Io-

  or wherein: R 5 represents hydrogen or methyl; and R 6 and R 7 independently are each methyl or ethyl and, when taken together with the nitrogen to which they are attached, R 6 and R 7 represent a pyrrolidino or piperidino ring; or a salt hydrate or solvate no

  pharmaceutically acceptable toxicant thereof.

  In another preferred embodiment, the intermediates of formula II have the structure: R 7 Ia

1 NCFI,

R 5, "CH 2 CH 2 Ci 2 NHR

IN NH

  wherein: R1 is hydrogen or methyl; and R 6 and R 7 each represent a methyl or, when taken together with the nitrogen atom to which they are attached, R 6 and R? represent a pyrrolidino or piperidino ring, or a hydrated salt

or solvate thereof.

  In another preferred embodiment, the intermediates of formula II have the structure:

7

2 I Ib R

HN NH

  wherein: R 1 and R 5 are each independently hydrogen or methyl, and R 6 and R 7 are each independently methyl or ethyl, or

  a salt, a hydrate or a solvate thereof.

  In another preferred embodiment, the intermediates of formula II have the structure:

7 R

NCH H 2 SC I 2 CH 2 NH R Ic

R 6/22 2 2

R \ N 1

HN NH

  wherein: R 1 and R 5 each independently represent hydrogen or methyl; and R 6 and R 7 are each independently methyl or ethyl,

  or a salt, hydrate or solvate thereof.

  In another preferred embodiment, the intermediates of formula II have the structure:

R 5

R 7 OCR CH CH N HR 1 I Id

R / CH 2 OCH 2 CH 2 CH 2 NH

  wherein: R1 and R5 are each independently hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl, or when taken together with the nitrogen atom to which they are attached, R 6 and R 7 represent a piperidino group; or

  a salt, a hydrate or a solvate thereof.

  As presently contemplated, the preferred Formula II intermediates are: 1) N- {3- (3-piperidinomethylphenoxy) propyl} ethanediimidamnlide; 2) N- {2 - {(5-dimethylaminomethyl-2-furyl) methylthio} ethyl} ethanediimidamide;

  3) N- {2 - {(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio} ethyl} ethanol

  nediiamidamide; 4) N- {3- (3-pyrrolidinidinomethylphenoxy) propyl} ethanediimidamide; N- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} ethyl} ethanediimide; 6) N- {2 - {(5-piperidinomethyl-3-thienylmethylthio} ethyl} ethanediimidamide; 7) N- {3- (6-piperidinomethyl-2-pyridyloxy) propyl} -ethanediimidamide; and 8) N- {3- (4-piperidinomethyl-2-pyridyloxy) propyl} -ethanediimidamide;

  or a salt, a hydrate, a solvate thereof.

  For therapeutic use, the compounds pharmacologically

  Formula I will normally be administered in the form of

  pharmaceutical composition comprising as the essential active ingredient (or as an ingredient) at least one compound in its

  the form of a non-toxic pharmaceutically acceptable acid addition salt

  table, in association with a pharmaceutically acceptable vehicle.

  The pharmaceutical compositions can be administered by

  oral, parenteral or rectal suppository.

  A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in the form of a powder.

  or granule, or in the form of dragee or lozenge.

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

  suitable for 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 gastric acid inhibition desired and the potency of the particular compound being used. as to the particular dosage to be used (and the number of times it should be administered daily), is at the discretion of the doctor

  and may vary according to the measurement of the effects of the dosage corresponding to

  particular constancy of a specific patient With the preferred compounds

  according to the invention, each oral dosage unit will contain the active ingredient in an amount of from 2 mg to about 300 mg and preferably about 4 mg

  at about 100 mg The active ingredient will preferably be administered at

  his equals 1 to 4 times a day.

  Histamine H 2 -receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and animals.

  see Brimblecombe et al., J Int Med Res, 86 (1975).

  Cimetidine, a histamine H 2 receptor antagonist, has been shown to be an effective therapeutic agent in the treatment of digestive ulcers, see Gray et al, Lancet, 1, 8001 (1977). Preferred compounds according to the invention have been compared with cimetidine in various assays and found to be more potent than cimetidine both as H 2 -receptor antagonists.

  histamine in the right atrium of isolated guinea pigs and as a

  hibitors of gastric acid secretion in rats and dogs.

  Determination of Gastric Anti-Secretion Activity in Rats with Gastric Fistula Male Long Evans rats weighing approximately 240 to 260 gr at the time of cannula implantation The design and implantation of the steel cannula in the anterior wall of the stomach, near the heart, are substantially as described by Pare et al. (Laboratory Animal Science, 27, 244 (1977)) The fistula components are designed, and the manner of The operation is carried out 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, at will, food and water throughout the recovery period. Animals are not used for testing purposes

  for at least 15 days after the operation.

  Animals are fasted, but they are allowed to take water

  at will for 20 hours before the start of the test procedure.

  Immediately before collection, the cannula is open and the stomach is

  gently washed with 30 to 40 ml of warm salt water or distilled water for

  The catheter is then screwed into the cannula instead of the closure screw and the rat is placed in a rectangular, clear plastic cage measuring 40 cm long, 15 cm wide and 13 cm wide. cm high The bottom of the cage has a slot approximately 1.5 cm wide and 25 cm long from the center to receive the catheter that hangs through the cage. are not restricted during collection periods The rest of the test is performed as described by Ridley et al (Research

  Comm Chem Path Pharm, 17, 365 (1977)).

  Gastric secretions collected during the first hour

  after washing the stomach are discarded because they can be polluted.

  For an oral evaluation, the catheter is then removed from the cannula and

  replaced by the screw closure Water (2 ml / kg) is administered orally

  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 has been attached.

  to collect gastric secretions A sample of 2 hours (this represents the secretion of control) is collected, the catheter is removed and replaced by the screw closure The drug to be tested is then administered orally in volume of 2 ml / kg by Gastric intubation 45 minutes later, the obturator screw is removed again, replaced by the catheter attached to a small plastic vial, and another 2-hour sample is collected. The secretions of the second sample are compared with those of the control sample in order to determine the

effects of the drug to try.

  When the compounds to be tested must be evaluated by way of

  teral, the animal is injected intraperitoneally or intra-pericar-

  or subcutaneously, the vehicle of the compound to be tested in

  2 ml / kg immediately after discarding the initial 60-minute collection.

  A sample of 2 hours (control secretion) is collected and the animal is injected intraperitoneally or subcutaneously with the test compound in volume of 2 ml / kg. An additional sample of 2 hours is collected and its Secretions are compared to those of the control period to determine the effects of the drug Samples are centrifuged and placed in a graduated centrifuge tube for volume determination Titratable acidity is measured by titrating a 1 ml sample at pH 7. 0.02 N NaOH using an automatic burette and an electrometric meter (radiometer) Titratable acid production is calculated as 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 Dose response curves are established and ED 50 values are calculated by regression analysis at least three

  rats are used at each dosage level and a minimum of three

  calves dosing is used for determining a response curve

at a given dose.

Anti-secretion activity

TABLE 1

  of gastric juice in rats with gastric fistula ED 50 scrapport of co-infected power 1 pmol / kg (cimetidine = 1.0) cimetidine 3, 48 1.0

(1.68-5.75) *

example 1 0.094 37

(0.043-0.20)

example 2 0.77 4.5

(0.45-1.4)

Example 3 70.57 Example 4 0.18 20

(0.10-0.36)

95% confidence limit.

  Guinea Pill Trial Isolated from Histamine H-2 Antagonist Antagonism

  Histamine produces increases related to the concentration

  the rate of contraction of the right atria of isolated guinea pigs and spontaneously beating Black et al., Nature, 236, 385 (1972), described

  receptors involved in this effect of histamine as a receptor

  2-histamine, indicating the properties of burimamide, a competing antagonist of these receptors Subsequently, investigations of Hughes and Coret, Proc Soc Exp Biol Med, 148, 127 (1975) and Verma

  and Mac Neill, J Pharmacol Exp Ther, 200, 352 (1977) confirm the con-

  clusion of Black and his collaborators that the chronotropic effect posi-

  tif of histamine in the right atria of isolated transient guinea pigs

  by the receptors-H 2 of the histamine Black and ai, Agents and Actions,

  3, 133 (1973) and Brimblecombe et al, Efd Proc, 35, 1931 (1976) have used

  Straight atria of isolated guinea pigs were used as a means of comparing the activities of histamine H 2 -receptor antagonists. Current comparative studies were performed using a modification of the method described by Reinhardt et al, Agents and Actions, 4, 217

(1974).

  Male guinea pigs of Hartley strain (350 to 450 gr) are sacrificed by a blow on the head The heart is excised and placed in a Petri dish containing a modified oxygenated Krebs solution (95% O 2, 5% C 02) (g / 1 = NaCl 6.6, KCl 0.35, MgSO 4 7H 20 0.295, KH 2 PO 4 0.162, CaCl 2 0.238, NaHCO 3 2.1 and dextrose 2.09) L right atrium flying spontaneously is stripped of foreign tissue and a silk thread (4-0)

  is attached to each end The atrium is suspended in a chamber

  to 20 ml muscle containing an oxygen-modified Krebs solution

  nation maintained at 32 C Atrial contractions are recorded isometrically using a Grass FT 0.03 force displacement transmitter and recordings of force and

  contractions with a Beckman RP Dynograph.

  A rest tension of 1 g is applied to the atrium and it is

  equilibrium in one hour at the end of the equilibrium period.

  In addition, at the bottom, a submaximal concentration of dichlorhydrate is added.

  histamine drate (3 x 10-e M) and washed out to prime the tissue. Histamine is then added to the bath cumulatively using 1/2 log intervals of 10, to give a final concentration. molar bath 1 x 10-7 at 3 x 10-5 The histamine-induced atrial increase is allowed to reach a plateau before the following successive concentrations are added. The maximal response invariably occurs for concentration of 3 x 10-SM Histamine is removed by washing several times, and the atrium is allowed to return to the control level. The test compound is then added to appropriate molar concentrations and, after 30 minutes of incubation, the response to the histamine dose is repeated by adding higher concentrations

than those needed.

  The dissociation constants (KB) are deduced from the Schild points by the method of Arunlakshana O and Schild, HO (Br J Pharmacol 14, 48 (1959)), using at least three dose levels Parallel deviations in the curves dose response are obtained without decreasing the maximum response to the antagonist concentrations used

  and the results are shown in Table 2.

TABLE 2

  Activity in the right auricles of isolated guinea pigs

* 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

  a compound of formula II with a N, N'-thiobisphthalimide having the formula: compound N KB ("moles) compound power ratio KB (cimetidine = 1.0) cimetidine 0.41 (0.21) -O 4) * 1.0 Example I 0.003 (0.001 {1004) 137 Example 4 i 111 0.004 (0.001-0.010) The use of N, N'-thiobisphthalimide instead of 52 CI 2 or SC 12

  to effect the cycle closure reaction has for results of

  The purified products of formula I thus produced are normally pure enough to form crystalline salts directly without the need to proceed beforehand. , to a chromatographic purification. In this process, the starting diimidamide of formula II is reacted with an approximately equimolar amount of N, N'-thiobisphthalimide.

  in an inert organic solvent such as CH 2 C 12.

  the starting damide is used in its trihydrochloride form, to which

  In this case, three molar equivalents of an amine such as triethyl-

  The reaction can be carried out with stirring at room temperature for about 1 hour to complete the reaction. The phthalimide which precipitates from the reaction mixture is then extracted with a base.

  (eg, 10-20% aqueous KOH) and the organic solvent layer.

  that is dried, filtered and concentrated to give the crude compound of

  The N, N'-thiobisphthalimide used in the reaction is a known compound which can be prepared as described in the Canadian Journal of Chemistry, 44, 2111-2113 (1966), or as described below in the

preparation n 1.

  Preparation n 1 N, N'-thiobisphthalimide A cooled solution (0 C) of phthalimide (14.7 g, 0.1 mole) in

  ml of dimethylformamide (DMF) is treated dropwise with di-

  sulfur chloride (5.15 g, 0.05 mol) 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 as DMF solvate, melting point 301-315 C Infra-red spectra

  and NMR are both consistent with the structure.

  On analysis, it is found that the product obtained has the formula: C 16 HN 204 SC 3 H 7 NO, and the following values are obtained: C calculated 57, 42 found 57.50 The DMF solvate may be chloroform of the material above; H 3.80 3.80 eliminated by the point of

N S

57.07

, 29 8.57

  recrystallization in the melting of the product free

  DMF is 320-325 ° C. The NMR spectrum shows that the DMF has been removed.

  On analysis, it is found that the product obtained has the formula: C 16 H 8 N 204 S, and the following values are obtained:

C H N S

  calculated 59.25 2.49 8.64 9.89 found 59.21 2.21 8.91 10.14

  The invention will be better understood with the aid of the following examples.

EXAMPLE 1

  3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -11,2,5thiadiazole

  N- (3- (3-piperidinomethylphenoxy) propyl} ethane

  diimidamide 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 as required) British Patent No. 2,067,987) in 450 ml of methanol is treated with 38 ml of concentrated HCl.

  The result is stirred for 3 hours at room temperature.

  concentration of the solution that is followed by azeotropic

  spades water with absolute ethanol gives colorless crystals.

  These crystals are suspended in 200 ml of absolute ethanol, filtered and dried in vacuo to give 16.6 g (82.6%) of the title compound, mp 205-222 ° C (dec). Recrystallization in a methanol / ethyl acetate mixture, an analytical sample, melting point

206-216 ° C (dec).

  On analysis, it is found that the product obtained has the formula: C 17 H 27 N 50 3 CH 1, 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-amino-4- {3- (3piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole

  A stirred suspension of N- {3- (3-piperidinomethyl) trihydrochloride

  phenoxy) propyl} ethanediimidamnide (2.13 g, 5.0 mmol) (prepared in the

  Step A -} in 20 ml of dimethylformamide (DMF) is treated with mono-

  Sulfuric chloride (2.02 g, 15.0 mmol) and stirred for 4 hours The resulting mixture is cautiously poured into 200 ml of water and made basic with K 2 CO 3 Extraction is carried out with 3 servings

  50 ml of methylenechloride, and after drying over MgSO 4 and concentrating

  The product is purified by preparative HPLC on silica using CH 2 C 12 (100): H (0.5) as mobile phase. The appropriate fractions give 0.89 g of the title compound, which gives, with fumaric acid in Npropanol, 0.76 g (21.4%) of the title compound of the title compound. crystalline fumarate form;

  mp 187-187.5 ° C HPLC indicates a purity of> 99%.

  On analysis, it is found that the product obtained has the formula: (C 17 H 25 N 50 S) 2 C 4 H 404, and the following values are obtained:

C H N S

  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 K 2 C 03 and extracted with HC 2 C 12 CH 2 C 12 is concentrated and the base

  The title compound is extracted by crystallization; melting point 43-47 ° C A portion of the free base is converted into its hydrochloride;

melting point 138-142C.

  On analysis, it is found that the product obtained has the formula: C 17 H 25 N 50 S H Cl, and the following values are obtained:

C H N S

  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-dimethylaminomethyl-2-furyl) methylthio} -ethylamino} -

  1,2,5-thiadiazole A N- {2 - {(5-dimethylaminomethyl-2-furyl) methylthio} ethyl] -ethanediimidamide hydrochloride hydrate 4 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) in 200 ml of methanol is heated slightly to obtain a complete solution solution is then treated with 13.3 ml of HC 1 concentrate 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, mp 166-169 ° C (dec).

  On analysis, it is found that the product obtained has the formula: C 12 H 21 N 50 S 3 HC 1 H 20, and the following values are obtained:

C H N S

  calculated 35.08 6.38 17.05 7.80 found 34.85 6.24 17.45 7.97

  B. 3-amino-4- {2 - {(5-dimethylaminomethyl-2-furyl-methylthio} -ethylamino} -

1,2,5-thiadiazole

  To a stirred solution of N- (2 - {(5-

  dimethylamino-methyl-2-furyl) methylthiolethyl} ethanediimidamide (12.3 g; 0 immoles) (prepared in step A -) in 150 ml of DMF, 7.2 ml of sulfur monochloride (12.1 g) are added (12.1 g; 90 mmol) After stirring at room temperature for 4 hours, approximately half of the DMF is removed under reduced pressure. The remaining black solution is poured into 1 liter of water, made basic with K 2 C 03 and the extract is first extracted with ethyl acetate and then with chloroform. After drying over MgSO 4, filtration and concentration, 9.0 g of a gum are obtained.

  This product is purified by pre-chromatography.

  parative high pressure liquid phase on silica using acetate

  of ethyl (100): 2-propanol (10): NH 40 H (0.5) as mobile phase.

  The appropriate fractions give 1.24 g of the title compound under

form of gum.

  The treatment of part of this product with an equivalent quantity

  12 N HC in methanol gives the hydrochloride of the title compound.

  On analysis, it is found that the product obtained has the formula: C 12 HDN 5520 HCl, and the following values are obtained:

C H N S

  calculated 41.18 5.76 20.02 18.33 found (for 1.65% H 20) 40.54 5.70 19.39 18.44 Treatment of this product with an equivalent amount of acid

  cyclohexylsulfamic acid in acetone gives the cyclohexylsulfamate

  posed of the title, melting point 93-95 C.

  On analysis, it is found that the product obtained has the formula: C 12 H 9 g N 5520 C 6 H 13 N O 3 S, the following values are obtained:

C H N S

  calculated 43.88 6.55 17.06 19.53 found 43.77 6.17 17.21 19.58

EXAMPLE 3

  3-Amino-4 - {(2 - {(5-dimethylaminomethyl-4-methyl-2-thienyl) -methyl-thio} -ethyl Lamino} -1,2,5-thiadiazole A. Trichlorhydrate N- {2- {(5-Dimethylaminomethyl-4-methyl-2-thienyl) methylthio} -ethyl) ethanediimidamide

  A stirred solution of 3-amino-4- {2 - {(5-dimethylamino-methyl-4-

  methyl-2-thienyl) methylthio} ethylamino} -1,2,5-thiadiazole 1-oxide (17.9 g, 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 a nearly colorless crystalline residue The residue is triturated with 200 ml of absolute OC ethanol, filtered and dried to give 16.9 g (80%) of the title compound, mp. 206-220 ° C (dec) Recrystallization from 50% methanol / ethyl acetate gives a dot product

melting point of 210 to 221 C (dec).

  On analysis, it is contested that the product obtained has the formula: C 13 H 23 N 552 3 HCl, and the following values are obtained:

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) -1,2,5-thiadiazole

  To a stirred suspension of N-f 2 - {(5-dimethylamino) trihydrochloride

  methyl-4-methyl-2-thienyl) methylthio} ethyl) ethanediimidamide (6.34 g, 0 mmol) (prepared in step A -) in 60 ml of DMF, 6.1 g (45.0 g. mmol) of sulfur monochloride After stirring for 4 hours at room temperature, the reaction mixture is poured into 800 ml of water, made basic with K 2 C 03, extracted several times with 100 ml portions. The extracts are dried over MgSO 4, filtered and concentrated to give 3.4 g of a black gum containing

  the product is purified by preparative chromatography at high

  liquid phase pressure on silica using CH 2 C 12 (100): 2-propanol (10): NH 4 H (0.5) as mobile phase Further purification is carried out by preparative high pressure liquid chromatography on silica using CH 2 C 12 (100): CH 3 H (2.5): NH 4 OH (0.5) as mobile phase. The appropriate fractions give the compound

  of the title (purity 98 d) Treatment of the product with an equivalent quantity

  Slow H 2 Cl 2 Ndonne the hydrochloride of the title compound.

  On analysis, it is found that the product obtained has the formula: C 13 H 21 N 553 H Cl, and the following values are obtained:

C H N S

  calculated 41.09 5.84 18.43 25.32 found (for 0.51% H 20) 40.78 5.63 18.31 25.44

EXAMPLE 4

  3-Amino-4- {3- (3-pyrrolidinomethylphenoxy) propylamino} -1,2,5-thiadiazo

  Trich N- {3- (3-pyrrolidinomethylphenoxy) propyl} ethane

diimidamide

  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 as

  British Patent Application Publication No. 2,067,987) in 350 ml of methanol is treated with 25.5 ml of concentrated HCl.

  The result is stirred for 3 hours at room temperature.

  The solution is then azeotroped off with absolute ethanol to give the product. The crystalline residue is triturated with 150 ml of absolute ethanol, filtered and dried to give 10.8 g. title compound, m.p. 195-203 C (dec); On analysis, it is found that the product obtained has the formula: C 16 H 25 N 50 3 HC 1, and the following values are obtained:

C H N

  calculated 46.55 6.84 16.97 found 46.55 6.93 16.93 B. 3-amino-4- {3- (3-pyrrolidinomethyl) phenoxy) propyl Lamino} -1,2,5-thiadiazole

  A stirred suspension of N- {3- (3-pyrrolidinomethylene trihydrochloride)

  thylphenoxy) propyl} ethanediimidamide (8.25 g, 20.0 mmol) prepared in step A in 80 ml of DMF is treated with sulfur monochloride.

  (5.4 g, 40.0 mmol) and stirred under nitrogen for 3 hours.

  The concentration of the reaction mixture gives a dark gum which is suspended in 500 ml of water, basified with K 2 C 03 and extracted with 3 times 100 ml of methylene chloride. The extracts are dried over MgSO 4, filtered and concentrated. to give 7.5 g of a dark gum containing the product. The product is purified by preparative chromatography at high pressure in liquid phase on silica using CH 2 C 12 (100): 2-propanol (5): NH 4 OH (0.5) as the mobile phase Fractions containing the desired product are combined and concentrated to give 1.64 g (24.6%) purified title compound. Treatment of the product in absolute ethanol with an equivalent amount of HC 1 2 N gives the hydrochloride of the title compound

  (1.13 g); melting point 138-140C.

  On analysis, it is found that the product obtained has the formula: C 16 H 23 N 50 S H Cl, and the following values are obtained:

C H N S

  calculated 51.95 6.54 18.93 8.67 found 51.97 6.36 18.63 8.76

EXAMPLE 5

  The general procedure of EXAMPLE 1, step A and B is repeated.

  except that 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

  thiadiazole 1-oxide used here is replaced by an equimolar amount

eyepiece of:

  (a) 3-amino-4- {3- (3-dimethylaminomethylphenoxy) propylamino} -1,2,5-thia-

diazole 1-oxide;

  (b) 3-amino-4- {3- (3-diethylaminomethylphenoxy) propylamino} -1,2,5-thia-

diazole 1-oxide;

  (c) 3-amino-4- {3- (2-methylpyrrolidino) methylphenoxy} -propylamino] -

1,2,5-thiadiazole 1-oxide;

  (d) 3-amino-4- {3- {3- (3-methylpyrrolidino) methylphenoxy} -propylamino} -

1,2,5-thiadiazole 1-oxide;

  (e) 3-amino-4- {3- {3- (4-methylpiperidino-methylphenoxy} -propylamino} -

1,2,5-thiadiazole 1-oxide;

  (f) 3-amino-4- {3- (3-morpholinomethylphenoxy) propylamino} -1,2,5-thiadia-

sole 1-oxide;

  (g) 3-amino-4-3 {3- (N-methylpiperazino) methylphenoxy} -propylamino} -

1,2,5-thiadiazole 1-oxide;

  (h) 3-amino-4- {3- (3-diallylaminomethylphenoxy) propylamino} -1,2,5-thia-

diazole 1-oxide;

  (i) 3-amino-4- {3- (3-hexamethyleneiminomethylphenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (j) 3-amino-4- {3- (3-heptamethyleneiminomethylphenoxy) propylamino} -

1,2,5-thiadiazole 1-oxide;

  (k) 3-amino-4- {3- {3- (3-azabicyclo [3,2,2] non-3-yl) methylphenoxy} propyl]

  amino} -1,2,5-thiadiazole 1-oxide; and

  (1) 3-Amino-4 3- {3- (3-pyrrolino) methylphenoxy} propylamino} -1,2,5-thia-

  diazole 1-oxide, respectively, and is thus produced:

  (a) 3-amino-4- [3- (3-dimethylaminomethylphenoxy) propylaminino} -1,2,5thia]

diazole;

  (b) 3-amino-4- {3- (3-diethylaminomethylphenoxy) propylamino} -1,2,5thiadia-

sole;

  (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- {3- (3-morpholinomethylphenoxy) propylamino} -1,2,5-thiadiazole;

  (g) 3-amino-3- {3- (N-methylpiperazino) methylphenoxy} -propylamino} -

1,2,5-thiadiazole;

  (h) 3-amino-4- {3- (3-diallylaminomethylphenoxy) propylamino} -1,2,5thiadia-

zole;

  (i) 3-amino-4- {3- (3-hexamethyleneiminomethylphenoxy) propylamino} -1,2,5-

thiadiazole;

  (j) 3-amino-4- {3- (3-heptamethyleneiminomethylphenoxy) propylamino} -1,2,5-

thiadiazole;

  (k) 3-amino-4- {3- {3- (3-azabicyclo {3,2,2} non-3-yl) methylphenoxy} propyl-

amino} -1,2,5-thiadiazole; and

  (1) 3-amino-4- {3- (3- (3-pyrrolino) methylphenoxy} propylamino} -1,2,5thia-

diazole, respectively.

EXAMPLE 6

3-amino-4- {3- (3-pipridinomethylphenoxy) propylaminol-1,2,5-thiadiazole The present example is a variation of EXAMPLE 1, step B-, i.e. we use less sulfur monochloride and a time

shorter reaction time.

  To a stirred suspension of N- {3- (3-piperidino) trihydrochloride

  methylphenoxy) propyl} ethanediimidamide (12.08 g, 28.3 mmol) in 120 ml of DMF, sulfur monochloride (7.64 g, 56.6 mmol) was

  The mixture is stirred under N 2 for 3 hours. The DMF is removed.

  under reduced pressure to leave a black gum which is suspended in water, made basic with K 2 C 03 and extracted with 3 portions of 100 ml of CH 2 C 12 The combined extracts are dried on MgSO 4, filtered and concentrated to a black gum This gum is purified by preparative chromatography at high pressure in liquid phase on silica

  using CH 2 C 12 (100): 2-propanol (5): NH 4 H (0.5) as the mobile phase.

  The appropriate fractions give 3.1 g of the title product as a dark oil which gives, with fumaric acid in N-propanol, 2.66 g (23.2%) of the title compound as fumarate. crystalline; mp 186-186.5 C HPLC indicates 99% purity. On analysis, it is found that the product obtained has the formula: (C 17 H 25 N 50 S) 2 C 4 H 404, and the following values are obtained:

C H N S

  calculated 56.27 6.71 17.27 7.90 found 56.27 6.96 17.31 7.98

EXAMPLE 7

  3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazo The present example is a variation of EXAMPLE 1, step B -,

  that is, sulfur dichloride is used instead of mono-

sulfur chloride.

  To a stirred suspension of N- {3- (3-piperidino) trihydrochloride

  methylphenoxy) propyl} ethanediimidamide (854 mg, 2 mmol) in 6 ml of DMF under N 2 in an ice bath, S C 12 (206 mg, 2 mmol) is added

  in 2 ml of DMF. The reaction mixture is stirred at room temperature.

  biante and the title compound is produced.

EXAMPLE 8

  3-methylamino-4- {3- (3-piperidinomethylphenoxy) propytamino} -1,2,5thiadia-

  N-methyl-N '- {3- (3-pip-ridinomethyl-phenoxy) -propyl} ethanediimidamide hydrochloride 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 published British Patent Application No. 2,067,987) in 95 ml of methanol is treated with 7.2 ml of concentrated HCl.

  at room temperature for 3 hours, concentrate the solution and

  sidu is triturated with acetone, filtered and dried to give 4.35 g

  (90.4%) of product A sample is recrystallized from isopropyl alcohol

  aqueous vinyl to give the title compound; mp 207-225 ° C

(Dec).

  On analysis, it is found that the product obtained has the formula: ## STR1 ## and the following values are obtained:

C H N

  calculated 49.03 7.33 15.89 found (for 0.94% o H 20) 49.37 7.35 15.71

  B. 3-methylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

thiadiazole

  A mixture of N-methyl-N '- {3- (3-piperidino) trihydrochloride

  methylphenoxy) propyl} ethanediimidamide (3.74 g, 8.47 mmol) (prepared in step A), 34 ml of CH 2 C 12 and 3.5 ml of triethylamide is treated with N, N'-thiobisphthalimide (DMF solvate) (3.36 g, 8.46 mmol) is stirred for 1 hour The mixture is washed with 30 ml of 10% KOH, dried (MgSO 4), filtered, diluted with toluene and concentrated, to give 3.6 g of the product The product is purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (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,

melting point 163.5-164.5 C.

  On analysis, it is found that the product obtained has the formula: C 18 H 27 N 50 S H Cl, and the following values are obtained:

C H N S C 1

  calculated 54.32 7.04 17.60 8.06 8.91 found 54.35 7.07 17.64 8.36 8.86

EXAMPLE 9

  3-Benzylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5thiadiazo N-benzyl L-N '- {3- (3-piperidinomethylphenoxy) propyl) A. trichlorhydrate Ethanediimidamide 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 published British Patent Application No. 2,067,987) in 100 ml of methanol is treated with 7.55 ml concentrated HCl.

  at room temperature for 3 hours, concentrate the solution and

  ture the residue with acetone, filter and dry, giving

  5.16 g (88%) of the title compound; melting point 187-205 ° C (dec).

  On analysis, it is found that the product obtained has the formula: C 24 H 33 N 50 3 H Cl, and the following values are obtained: CHN Cl calculated 55.75 7.03 13.55 20.57 found 54, 88 6.75 13.33 20.20

  B. 3-Benzylamino-4- {3- (3-piperidinomethylphenoxy) propyl Lamino} -1,2,5-

thiadiazole

  A mixture of N-benzyl-N '- {3- (3-piperidinomethyl) trihydrochloride

  phenoxy) propyl) ethanediimidamide (4.73 g, 9.16 mmol) (prepared in the

  A -}, 45 ml of CH 2 C 12 and 3.8 ml of triethylamine is treated with N, N'-thiobisphthalimide (DMF solvate) (3.64, 9.16 mmol) is stirred for 1 hour. The mixture is washed with 44 ml of 10% KOH, dried (MgSO 4),

  filtered, diluted with toluene and concentrated The residue is treated with

  flash matography on 110 g of silica gel (200-400 mesh) using ethyl acetate as eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of H Aqueous Cl

  in 2-propanol gives the hydrochloride of the title compound,

138-141 C.

  On analysis, it is found that the product obtained has the formula: C 24 H 31 N 50 SH Cl, 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

  3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazo The present example is a variant of EXAMPLE 1, step B -,

  that is, N, N'-thiobisphthalimide is used instead of mono-

sulfur chloride.

  A mixture of N- (3- (3-piperidinomethylphenoxy) propyl) -ethanediimidamide trihydrochloride (27.3 g, 64.0 mmol) (prepared in EXAMPLE 1, step A), 250 ml of CH 2 C 12 and 26.6 ml (192.0 mmol) of triethylamine is treated portionwise with N, N'-thiobisphthalimide (DMF solvate) (25.4 g, 64.0 mmol). After stirring at room temperature

  1 hour, the mixture is washed with 120 ml of 20% KOH, dried (MgSO 4), filtered

  The product is taken up in 250 ml of propanol-1 and 10.7 ml of 6N HCl, treated with charcoal for bleaching and filtered on celite. This solution is concentrated in the aqueous solution and is concentrated in 150 ml of toluene and reconcentrated. a volume of 100 ml, diluted with 175 ml of 1% propanol-1 and stored at 0 ° C. to give 20.2 g (82.1%) of crystalline hydrochloride.

  of the title compound, mp 137-138 ° C.

  On analysis, it is found that the product obtained has the formula: C 1.7 H 25 N 50 S HC 1, 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

  3-amino-4- {3- (3-pyrrolidinomethylphenoxy) propylamino} -1,2,5-thiadiazole The present example is a variant of EXAMPLE 4, step B - that is, that is used N, N'-thiobisphthalimide instead of

sulfur monochloride.

  A mixture of N 3- (3-pyrrolidinomethylphenoxy) propyl ethanediimidamide trihydrochloride (22.0 g, 53.0 mmol) prepared in Example 4 Step A, 200 mL of CH 2 C and 22 mL of triethylamine was treated with N, N'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% KOH, dried (Mg 504), filtered, diluted with 100 ml of

  The product is treated with one equivalent of aqueous HCl in propanol-1 to give 13.2 g (67%) of the hydrochloride of the compound.

  of the title; melting point 135-137C.

  On analysis, it is found that the product obtained has the formula: Cl 6 H 23 N 50 S HC 1, and the following values are obtained:

C H N S

  calculated 51.95 6.54 18.93 8.67 found 51.92 6.55 19.30 9.06

EXAMPLE 12

  3-amino-4- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} -ethylamino} -

  1,2,5-thiadiazo N- {2 - {(5-dimethylaminomethyl-3-thienyl) methylthio} ethyl} -ethanediimidamide trihydrochloride A suspension of 3-amino-4 {2 - {(5-dimethylamininoinethyl-3- thienyl) methylthio} ethylamino} -1,2,5thiadiazole 1-oxide (7.8 g, 22.6 mmol) (prepared according to published British Patent Application No. 2,067,987) in 150 ml of methanol is treated with 15, 0 ml concentrated HCl After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of the product. sample is recrystallized in

  methanol-acetone to give the title compound, point of

190-205 C (dec).

  On analysis, it is found that the product obtained has the formula: C 12 N 21 N 552 3 H Cl, 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-dimethylaminomethyl-3-thienyl) methylthio} ethylamino} -

1,2,5-thiadiazole

  A mixture of N- {2 - {(5-dimethylaminomethyl) -3-dihydrochloride

  thienyl) methylthio} ethyl} ethanediimidamide (6.13 g, 15.0 mmol) (prepared in step A -), 60 ml of CH 2 C 12 and 6.3 ml of triethylamine is treated with N, N '-thiobisphthalimide (DMF solvate) (5.96 g, 15.0 mmol) is stirred for one hour The mixture is washed with 100 ml of 10% KOH, dried (MgSO 4), filtered, diluted with toluene and concentrated to give 1 g of the product. Treatment of the product with 0.5 molar equivalents of fumaric acid in 1-propanol gives the fumaric acid salt of the compound, mp 141-143 ° C. The NMR spectrum in DMSO-d indicates

  the presence of approximately 0.12 moles of 1-propanol.

  On analysis, it is found that the product obtained has the formula: (C 12 H 19 N 553) 2 C 4 H 40 O 12 C 3 He O 8, and the following values are obtained:

C H N S

  calculated 43.68 5.61 17.75 24.38 found 43.41 5.53 17.54 24.24

EXAMPLE 13

  3-amino-4- {2- (5-piperidinomethyl-3-thienyl) methylthio} ethylamino} -1,2,5

  N- {2 - {(5-pip-ridinomethyl-3-thienyl-L) -methylthio} -ethyl} ethanediimidamide trihydrochloride

  A suspension of 3-aminino-4- {2 - {(5-piperidinomethyl-3-thienyl) methyl)

  thiolethylamino} -1,2,5-thiadiazole 1-oxide (6.1 g, 15.8 mmol) (prepared according to published British Patent Application No. 2,067,987) in 80 ml of methanol is treated with 10.5 ml After stirring at room temperature for 3 hours, the solution is concentrated and the residue is triturated with 50 ml of 1-propanol, filtered and dried to give 86 g (83%) of the product. A sample is recrystallized. in a mixture

  methanol-acetone, to give the title compound, mp 201-

214 C (dec).

  On analysis, it is found that the product obtained has the formula: C 15 H 25 N 552 3 H Cl, and the following values are obtained:

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-piperidinomethyl-3-thienyl) methylthio} -ethylamino} -

1,2,5-thiadiazo The

  A mixture of N- {2 - {(5-piperidinomethyl-3-thienyl) trihydrochloride

  Methylthio} ethyllethanediimidamide (5.17 g, 11.5 mmol) (prepared in step A -), 48 ml of CH 2 C 12 and 4.8 ml of triethylamine is treated with N, N'-thiobisphthalimide (solvate). The mixture is washed with 90 ml of 10% KOH, dried (MgSO 4), filtered, diluted with toluene and concentrated, gives 4.5 g of the product Treatment of the product with one equivalent of cyclohexylsulfamic acid in methanol gives the cyclohexylsulfamate of

  composed of the title, melting point 142-143 C.

  On analysis, it is found that the product obtained has the formula: Cs 15 H 23 N 553 C 6 H 13 N O 3 S, 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

  The general methods of the procedure of EXAMPLE 1, step A.-, and then of either EXAMPLE 1, step B- or EXAMPLE 10 are repeated.

  except that 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

  thiadiazole 1-oxide used here is replaced by an equimolar equivalent of:

  (a) 3-ethylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (b) 3-allylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (c) 3- (2-propynyl) -4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (d) 3- (3-pyridylmethylamino) -4- (3-piperidinomethylphenoxy) propylamino} -

  1,2,5-thiadiazole 1-oxide; (e) 3- (6-methyl-3-pyridyl) methylamino-4 - {(3 (3-piperidinomethyl-phenoxy) propylamino} -1,2,5-thiadiazole 1-oxide, and (f) 3- (3) 4-methylenedioxybenzylamino) -4- {3- (3-piperidinomethyl-phenoxy) propylamino} -1,2,5-thiadiazole-1-oxide, respectively, and thus produced:

  (a) 3-ethylamino-4- {3- (3-piperidinonimethylphenoxy) 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-pyridyl) methylamino-4- (3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole, and (f) 3- (3,4-methylenedioxybenzylamino) -4- { 3- (3-piperidinomethylphenoxy)

  propylamino) -1,2,5-thiadiazole, respectively.

EXAMPLE 15

  3-amino-4- {3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5thiadiazole

  A. 3-amino-4- {3- (6-piperidinomethyl-2-pyridyloxy) propylaminol-1,2,5-

  thiadiazole 1-oxide A solution of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine (4.65 g, 18.6 mmol) (prepared according to published British Patent Application No. 2,098,988) in 50 ml of methanol is reaction with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.74 g, 18.6 mmol) according to the general procedure described in the British patent application

  No. 2,067,987 to give a solution containing 3-amino-4- (3- (6-piperine)

  dinomethyl-2-pyridyloxy) propylamino} -1,2,5-thiadiazole 1-oxide A sample of

purified specimen melts at 145-147 C.

  B. N- {3- (6-piperidinomethyl-2-pyridyloxy) propyl} ethanediimidamide trihydrochloride A methanol solution of the product prepared in step A - is diluted to 100 ml and 12.4 ml concentrated HC 1 is 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 H 2 C 12. The aqueous layer is concentrated, treated with npropanol and concentrated under vacuum.

  grown to give the title compound as a foam.

  C. 3-amino-4- (3- (6-piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-

  thiadiazole A mixture of the crude product prepared in step B -, in 80 ml of CH 2 C 12 and containing 7.69 ml of tiethylamine is treated with N, N'-thiobisphthalimide (DMF solvate) (7.35). After stirring at room temperature for 1 hour, the mixture is washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution and dried (Na 2 SO 4). 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 mixture

  methanol (95/5) as eluent to give 3.63 g of the title compound as a viscous oil. Treatment of the product with a

  Cyclohexylsulfamic acid equivalent in acetone gives the cyclo-

  hexylsulfamate of the title compound, mp 125-131 ° C.

  On analysis, it is found that the product obtained has the formula: C 16 H 24 N 60 S C 6 H 13 N O 3 S, and the following values are obtained:

C H N S

  calculated 50.07 7.07 18.58 12.15 found 50.02 7.03 18.54 12.14

EXAMPLE 16

  3-Amino-4- {3- (6-dimethylaminomethyl-2-pyridyloxy) propylamino} -1,2,5thia

diazole

  When a methanolic solution of 3- (6-dimethyl) is reacted

  aminomethyl-2-pyridyloxy) propylamine (prepared according to the patent application

  British Patent Publication No. 2,098,988) with 3-amino-4-methoxy-1,2,5-thiadia-

  zole 1-oxide according to the general procedure described in the application

  British Patent No. 2,067,987 and that the 3-

  resulting 4-amino-3- (6-piperidinomethyl-2-pyridyloxy) propylamino-1,2,5thiadiazole 1-oxide according to the general method described in EXAMPLE 1, step A -, and then either by EXAMPLE 1 step B - EXAMPLE 10

  the title compound is thus produced.

EXAMPLE 17

  3-amino-4- {2 - {(6-dimethylaminomethyl-2-pyridyl) methylthio} -ethylamino} -

1,2,5-thiadiazole

  When a 3-amino suspension is successively reacted

  4- {2 - {(6-Dimethylaminomethyl-2-pyridyl) methylthio} ethylamino} -1,2,5thia

  diazole 1-oxide (prepared according to published British Patent Application No. 2,067,987) according to the procedures of EXAMPLE 1, step A -, and then either according to EXAMPLE 1, step B -, or EXAMPLE 10, we produce

thus the title compound.

EXAMPLE 18

  3-amino-4- {2 - {(6-piperidinomethyl-2-pyridyl) methylthio} ethylamino} -

1,2,5-thiadiazo The

  When a 3-amino suspension is successively reacted

  4- {2 - {(6-piperidinomethyl-2-pyridyl) methylthio} ethylamino} -1,2,5thiadia-

  zole 1-oxide (prepared according to published British Patent Application No. 2,067,987) according to the procedures of EXAMPLE 1, step A -, and then either according to EXAMPLE 1, step B -, or according to EXAMPLE 10,

  the title compound is thus produced.

EXAMPLE 19

  We reproduce the general procedure of EXAMPLE 1, step A.-, and then either of EXAMPLE 1, step B -, or of EXAMPLE 10,

  except that 3-amino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-

  thiadiazole 1-oxide used here is replaced by an equimolar amount

eyepiece of:

  (a) 3-amino-4- {3- (3-piperidinomethylthiophenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (b) 3-amino-4- {3- (3-dimethylaminomethylthiophenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (c) 3-amino-4- {3- (3-pyrrolidinomethylthiophenoxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (d) 3-Amino-4- {3- (4-dimethylaminomethyl-2-pyridyloxy) propylamino} -1,2,5-

thiadiazole 1-oxide;

  (e) 3-amino-4- {3- (5-dimethylaminomethyl-3-thienyloxy) 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 thus produced:

  (a) 3-amino-4- {3- (3-piperidinomethylthiophenoxy) propylamino} -1,2,5thia-

diazole;

  (b) 3-amino-4- {3- (3-dimethylaminomethylthiophenoxy) propylamino} -1,2,5-

thiadiazole;

2 542741

  (c) 3-Amino-4- {3- (3-pyrrolidinomethylthiophenoxy) propylamino} -1,2,5-

thiadiazole;

  (d) 3-amino-4- {3- (4-dimethylaminomethyl-2-pyridyloxy) propylamino} -1,2,5

  thiadiazole; (e) 3-amino-4- (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) methylthio} -ethyl

amino} -1,2,5-thiadiazole; and

  (h) 3-amino-4- {2 - {(4-piperidinomethyl-2-pyridyl) methylthio} -ethylamino} -

1,2,5-thiadiazole, respectively.

  The above starting materials are prepared according to the general methods described in British Patent Application No. 2,067,987. The precursors of the starting materials are prepared by

  similar general procedures and methods of

  British 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- (4-pip-ridinomethyl-2-pyridyloxy) propylamino} -1,2,5thiadia-

  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 is found that the product obtained has the formula: C 14 H 23 N 30, and the following values are obtained:

C H N

  calculated 67.44 9.30 16.85 found 67.54 8.98 16.55

  B. 3-amino-4- {3- (4-piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-

  thiadiazole 1-oxide A solution of the product of step A (6.5 g;

  26.0 mmol) in 90 ml of methanol with 3-amino-4-methoxy-1,2,5-thia-

  diazole 1-oxide (3.84 g, 26.0 mmol) according to the general methods of

  254 c 2741 yield described in British Patent Application No. 2,067,987, which

  gives 6.33 g of the product. Recrystallization from a methanol-methanol mixture

  acetonitrile gives the title compound; melting point 154-158 C.

  On analysis, it is found that the product obtained has the formula: C 16 H 24 N 60 S, 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- {3- (4-Piperidinomethyl-2-pyridyloxy) propyl) ethanediimidamide trihydrochloride The product of Step B - (5.0 g, 13.7 mmol) is dissolved in

  ml of methanol and treated with 9.1 ml of concentrated HCl.

  at room temperature for 4.5 hours, the solution is

  evaporated to dryness under reduced pressure to give the title compound.

  D 3-amino-4- {3- (4-piperidinomethyl-2-pyridyloxy) propyl Lamino} -1,2,5-

  thiadiazole A mixture of the product prepared in step C -, in 50 ml of

  CH 2 C 12 and 5.7 ml of triethylamine are treated with N, N'-thiobisphthalate.

  C. (5.44 g, 13.7 mmol) After stirring at ambient temperature for one hour, the mixture is washed with 40 ml of 4N NaOH, water, a saturated aqueous solution of NaCl, dried (Na 2 O 4) 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 mixture. methanol (96/4) as eluent to give 3.44 g of the title compound as an oil

  The treatment of the product with an equivalent of cyclohexyl acid

  sulfamic acid in acetone gives the cyclohexylsulfamate of the compound of

mp 124.5-126C.

  On analysis, it is found that the product obtained has the formula: C 16 H 24 N 60 S C 6 H 13 N O 3 S, and the following values are obtained:

C H N -S

  calculated 50.07 7.07 18; 58 12.15 found 50.47 7.12 18.33 11.87

EXAMPLE 21

  3-amino-4- {3- {3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy} propylamino} -

  1,2,5-thiadiazole The general procedure of EXAMPLE 15 is repeated except that

254,741

  3- (6-piperidinomethyl-2-pyridyloxy) propylamine used here is substituted

* created by an equivalent amount of 3 3- (1,2,3,6-tetrahydro-1-pyridyl)

  methylphenoxy propylamine, which gives 2.31 g of crystalline product.

  toluene gives the title compound, mp 99.5-

104 C.

  On analysis, it is found that the product obtained has the formula: C 17 N 23 Ns OS, and the following values are obtained:

C H N S

  calculated 59.10 6.71 20.27 9.28 found (for 2.19% H 20) 58.78 6? 71 19.90 9.26

Z SA 2741

Claims (35)

CLAIMS I   1. Compound of formula: A (CH 2) m Z (CH 2) N NNHR 1 I N / s in which:   R 1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoro- ethyl, al-lyl, propargyl, R 2 R 3 b & (CH 2> p or R 4 (CH 2) p-   (C 2) p-2 R 3 wherein: p is 1 or 2; R 2 and R 3 independently each represent a hydrogen, a lower alkyl, a lower alkoxy or a halogen, or   when R 2 is hydrogen, R 3 can also be a trifluoro-   methyl, or R 2 and R 3 taken together may be methylene dioxy; and R 4 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 R 5 R 5 R   Embedded image in which: R 5 is hydrogen, lower alkyl or lower alkoxy, q is an integer of from 1 to 4 inclusive, and R 6 and R 2 each independently represent lower alkyl, lower alkoxy lower alkyl wherein the lower alkoxy radical is at least two carbon atoms remote from the nitrogen atom, or lower phenylalkyl, and when R 6 is hydrogen, R 2 may also be a lower cycloalkyl or, R 6 and R 7 taken together with the hydrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino or dimethylpyrrolidino groups,   morpholino, thiomorpholino, piperidino, methylpiperidino, dimethyl-   piperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homo-   piperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo {3,2,2} non-3-yl or 3-pyrrolino; or a non-toxic salt hydrate or solvate   pharmaceutically acceptable thereof.   2. A compound according to claim 1 having the formula: A (CH 2) m Z (CH 2) n NH NHR 1 / in which:   RI is hydrogen, or lower alkyl;   m is 0 or 1; N is 2 or 3; Z is oxygen or sulfur; and A is 7 R 5 R 5 \ NCH ', R 6/6 '2 R R R 5 R 5 7 R 7 R \ R 1   VN 1 CH 2 or NC 2 in which: R 5 is hydrogen or methyl, and R 6 and R 7 independently are each ethyl or methyl, or when taken together with the nitrogen atom to which they are attached, R 6 and R 7 represent a pyrrolidino ring   or piperidino; or a salt hydrate or solvate nontoxic phar-   maceutically acceptable thereof.   3. The compound according to claim 1 having the formula: R   \ 1.NCH l R 6 / CH 2 CH 2 CH 2 N Hh H Rl S   wherein: Rs is hydrogen or methyl; and R 6 and RI are each methyl, or when taken at the same time   that the nitrogen atom to which they are attached, R 6 and R 7 represent   a pyrrolidino or piperidino ring; or a salt hydrate or solvate   non-toxic pharmaceutically acceptable thereof.   4. A compound according to claim 1 having the formula: 7 R 5 6 NCH 2 H 2 SCH 2 CH 2 NH N R b R 6 / N HCH 2 H   wherein: R 'and Rs are each independently hydrogen or methyl, and R 6 and R 7 are each independently methyl or ethyl;   or a non-toxic hydrate salt or solvate pharmaceutically acceptable table of these.   5. A compound according to claim 1 having the formula: wherein: R 1 and R 5 are each independently hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl;   or a non-toxic hydrate and solvate salt pharmaceutically acceptable table of these.   Compound according to claim 1, having the formula: R 7 NCH 4 OCH 2 CH 2 CH 2 NH NNHR N N   wherein: R1 and R5 each independently represent hydrogen or methyl; and R 6 and R? each independently represent methyl or ethyl; or, when taken together with the nitrogen atom to which they are attached, R 6 and R 7 represent a piperidino group;   or a non-toxic hydrate and solvate salt pharmaceutically acceptable table of these.   The compound of claim 1 which is 3-amino-4-   (3- (3-Piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole or a salt   a non-toxic pharmaceutically acceptable hydrate or solvate thereof.   8. The compound of claim 1 which is hydrochloride   3-amino-4- {3- (3-piperidinoniethylphenoxy) propylamino} -1,2,5thiadiazole.   The compound of claim 1 which is 3-amino-4-   {2- {L-dimethylaminomethyl-2-furyl) methylthio} ethylamino} -1,2,5thiadiazole or a non-toxic pharmaceutically acceptable hydrate salt or solvate thereof.   The compound of claim 1 which is 3-amino-4-   {2 - {(5-Dimethylaminomethyl-4-methyl-2-thienyl) methylthioethylamino)   1,2,5-thiadiazole, or a salt hydrate or solvate non-toxic pharmaceu- just acceptable.   A compound according to claim 1, which is 3-amino-4- {3- (3-pyrrolidinomethylphenoxy) propylaminol-1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrate or solvate salt thereof.   12. A compound according to claim 1, which is 3-methylamino-   4- {3- (3-piperidinomethylphenoxy) propylaminol-1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrate salt or solvate thereof.   13. A compound according to claim 1, which is 3-benzylamino   4- {3- (3-piperidinomethylphenoxy) propylamino-1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrate salt or solvate thereof.   The compound of claim 1 which is 3-amino-4-   {2 l (5-Dimethylaminomethyl-3-thienyl) methylthiolethylamino} -1,2,5thidia   zole, or a non-toxic pharmaceutically acceptable hydrate salt or solvate table of it.   A compound according to claim 1, which is 3-amino-4-   {2 - {(5-piperidinomethyl-3-thienyl) methylthiolethylamino} -1,2,5thiadiazole, or a non-toxic pharmaceutically acceptable hydrate or solvate salt of it.   A compound according to claim 1, which is 3-amino-4-   {3- (6-pip-ridinomethyl-2-pyridyloxy) propylamino} -1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrate salt or solvate thereof.   17. A compound according to claim 1, which is 3-amino-4-   (3- (4-Piperidinomethyl-2-pyridyloxy) propylamino} -1,2,5-thiadiazole, or a pharmaceutically acceptable non-toxic hydrate salt or solvate thereof.   18. A compound according to claim 1 which is 3-amino-4-   (3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy) propylamino} -1,2,5-   thiadiazole, or a pharmaceutically acceptable non-toxic hydrate salt or solvate acceptable of it.   19. A compound of the formula: wherein (CH 2) m Z (CH 2) n H II È / IH in which:   R 1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-tri- fluoroethyl, allyl, propargyl, R 2 a 3 R 3 XC 2 p- 3 (c H 2) or R 4 <CH 2) p_-   wherein: p is 1 or 2, R 2 and R 3 are each independently hydrogen, lower alkyl, lower alkoxy or halogen, and when R 2 is hydrogen, R 3 may also be trifluoromethyl, or R 2 and R 3 taken together may be methylenedioxy; and R 4 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 R 5 7 R 5 R 4 / R 6 / N (CH 2) N (CHR / R O S   11 \ N (CH 6 / N (C 12) q N (CH 2 or) R 6 /   Wherein R 5 is hydrogen, lower alkyl or lower alkoxy; q is an integer from i to 4 inclusive; and   R 6 and R 7 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 a phenyl-   lower alkyl, and when R 6 is hydrogen, R 7 may also be lower cycloalkyl or R 6 and R 7 taken together with   the nitrogen atom to which they are attached, may be a group-   pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino,   heptamethyleneimino, octamethyleneimino, 3-azabicyclo {3,2,2} non-   3-yl or 3-pyrrolino; or a salt hydrate or solvate thereof.   The compound of claim 19 having the formula: A- (CH 2) m Z (CH 2) n NH <NHR 1 HN NH   wherein: R is hydrogen or lower alkyl; m is 0 or 1; n is 2 or 3; Z is oxygen or sulfur; and A represents R 5 R 5 NCH 4 R C 2, 6 R 6/2 <or /, R RR R 5 R R   wherein: R 5 is hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl, or when taken together with the nitrogen atom to which they are attached, R 6 and R 7 represent a   pyrrolidino or piperidino ring; or a salt that hydrates or vate of them.   21. The compound of claim 19 having the formula: R NCH 2-4 CH 2 CH 2 CH 2 NH NMR a HN NH   wherein: R 1 is hydrogen or methyl, and R 6 and R 7 are each methyl or, when taken together with the nitrogen atom to which they are attached, R 6 and R 7 represent a pyrrolidino or piperidino ring; or a hydrated salt or solvate thereof.   The compound of claim 19 having the formula: 7 R 5 R NCH 2 7 v H 2522 H HR) HN NH   wherein: R 1 and R 5 each independently represent hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl;   or a salt hydrate or solvate thereof.   23. The compound of claim 19 having the formula: R 7 5 I NHC / ZCH 2 CIH 2 Só 2 CH 22 w N HR I HN NH   wherein: R1 and R5 are each independently hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl;   or a salt hydrate or solvate thereof.   24. The compound of claim 19 having the formula: R 5   R 7 R 6/4 3 2 E 2 CÉ 2 SNHNR 1 I Id RNNCH OCH 2 CH 2 CH 2 N I <d N NH   wherein: R1 and R5 each independently represent hydrogen or methyl; and R 6 and R 7 each independently represent methyl or ethyl; or when taken together with the nitrogen to which they are attached, R 6 and R 7 represent a piperidino group; or a salt hydrate or solvate thereof.   25. A compound according to claim 19 which is N- {3- (3-piperadiene)}   ridinomethylphenoxy) propyllethanediimidamide, or a salt hydrate or solvate of these.   26. A compound according to claim 19 which is N- {2 - {(5-di-   methylaminoethyl-2-furyl) methylthio} ethyl} ethanediimidamide, or a salt hydrate or solvate thereof.   A compound according to claim 19 which is N- {2 - {(5-di-   méthylauaminoéthyl-4-methyl-2-thienyl) methylthio} ethyl} éthanediimidamnide,   or a salt hydrate or solvate thereof.   28. A compound according to claim 19 which is N- {3- (3-pyrrolidone)   lidinomethylphenoxy) propyllethanediinimidaniide, or a salt hydrate or solvate of these.   29. A compound according to claim 19, which is N-1 2 - {(5-di-   methylaminomethyl-3-thienyl) methylthio} ethyl} ethanediimidamide, or a salt hydrate or solvate thereof.   30. A compound according to claim 19, which is N- {2 - {(5-piperyl)}   ridinomethyl-3-thienyl) methylthio} ethyl} ethanediimidamide, or a hydrochloric salt te or solvate of these.   A compound according to claim 19 which is N- {3- (6-piperyl)}   ridinomethyl-2-pyridyloxy) propyl} -etahendiimidamide, or a salt that hydrates or solvate of these.   32. A compound according to claim 19, which is N- {3- (4-piperino)   ridinomethyl-2-pyridyloxy) propyl} ethanediimidamide, or a salt which hydrates or solvate of these.   33. A compound according to claim 19, which is N- {3- {3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy} propylmethanediimidamide, or a salt hydrate or solvate thereof.   34. Process for preparing a compound of formula A (CH 2) m Z (CH 2) ENHNH 1 N $ N or a non-toxic pharmaceutically acceptable salt, hydrate or solvate thereof, according to claim 1 consisting of reacting, preferably at a temperature of about OC to about 50 C and preferably in an inert organic solvent, a compound of formula A (CH 2) Z (CH 2) nl) H / C-NH II with at least one molar equivalent, preferably a molar excess, especially a molar excess of 2-3 mol, sulfur monochloride, sulfur dichloride or a chemical equivalent thereof, preferably sulfur monochloride, to produce said compound of formula I. 35. Process for preparing a compound of formula A (CH 2) z (CH 2) n CNE II HN "H   according to claim 19, which comprises reacting, preferably in an inert solvent and at ambient temperature, a compound of the formula A (CH 2) Z (CH 2) n NH NHR 2 xn <C> III with a strong mineral acid, preferably hydrochloric acid or reacting a compound of formula: A (CH 2) m Z (CH 2) n NH 2 IV with a compound of formula CH 30, OCH 3 V 52 Z 542741   to produce a compound of formula A (CH 2) m Z (CH 2) NH 2 -C VI 1 / H   and then reacting said compound of formula VI with a compound of formula R 1 NH 2.