CH655111A5 - 3- (AMINO OR SUBSTITUTED AMINO) -4- (SUBSTITUTED AMINO) -1,2,5-THIADIAZOLE. - Google Patents

Description

The present invention relates to compounds of the formula I which are in particular histamine Ha receptor antagonists:

20 A- (ch2) mz {CH2) "NE

_ NH. _NKR

25th

and process for their preparation, the radicals A, m, Z,

n and R 'are similar to the radicals disclosed and claimed in the present invention. However, the compounds described there are 1-oxides or 1,1-dioxides (p stands for 1 or 2), and the compounds according to the invention cannot be produced by methods such as those used to prepare the compounds according to the prior art will.

The published European Patent Application No. 40 696 describes, inter alia, 3,4-disubstituted- 35

1,2,5-thiadiazole-l-oxides and 1,1-dioxides of the general or

Formula:

V

wherein R1 represents a hydrogen atom, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

R-0-

(CH2) n-x- (CH2) nua

(CH2) -

2 p and process for their preparation, the radicals R, A, n, X, m, R1 and R2 being similar to the corresponding substituents of the compounds described and claimed herein. However, the compounds described herein are also 1-oxides or 1,1-dioxides (p = 1 or 2), and the compounds of the present invention cannot be obtained by any of the methods for producing the compounds of the prior art.

In the two publications mentioned above, each of the processes described for the preparation of the compounds according to the prior art comprises the use (as starting material or intermediate) of a 1,2,5-thiadiazoI-1-oxide or 1,1-dioxide, which has either amino groups or suitable leaving groups at the 3 or 4 positions. The desired substituents at the 3- and 4-positions can then be obtained by substitution on the amino groups or by replacing the "leaving groups". Extensive attempts have been made to prepare the compounds of the invention in a similar manner, i.e. by using 1,2,5-thiadiazole, which stands for amino groups or suitable leaving groups, in which p stands for 1 or 2, R2 and R3 independently of one another represent a hydrogen atom, lower alkyl, lower alkoxy or a halogen atom, and, if R2 stands for a Is hydrogen, R3 can be trifluoromethyl, or R2 and R3 together can be methylenedioxy and R4 45 can be a hydrogen atom, lower alkyl or lower alkoxy; m represents an integer from 0 to 2 inclusive; n represents an integer from 2 to 5 inclusive; Z represents an oxygen, sulfur atom or methylene; and A for

\

H (CH-)

y

/ TR

6; KtCVq-7 ^ -

R.

<CH

e /

'2 o is R5 is hydrogen, lower alkyl or lower-65 koxy; q represents an integer from 1 to 4 inclusive and R6 and R7 each independently of the other lower alkyl, lower alkoxy, lower alkyl, the lower alkoxy radical being at least two carbon atoms from the nitrogen atom

655 111

6

is distant, or phenyl-lower alkyl, and, if R6 is a hydrogen atom, R7 can also be cyclo-lower alkyl, or R6 and R7 together with the nitrogen atom to which they are attached, pyrrolidino, methylpyrrolodino, dimethylpyrrolidono, 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-pyrroltino; and pharmaceutically acceptable salts, hydrates and solvates thereof.

The present invention also relates to a process for the preparation of the compounds of the formula I and compounds of the formula II as agents for the preparation according to the invention of the compounds of the formula I.

The present invention includes all possible tautomers, diastereoisomers and optically active isomers of the compounds of the formula I and mixtures thereof. The term lower alkyl used in the description of the invention stands for a straight-chain or branched alkyl group which contains I to 6 carbon atoms. The term “lower alkoxy” stands for a straight-chain or branched alkoxy group which comprises 1 to 4 carbon atoms. “Cyclone lower alkoxy” stands for a cycloalkyl group which contains 3 to 6 carbon atoms. The term "pharmaceutically acceptable salts" means acid addition salts which are mixed with acids, e.g. Hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, tartaric, citric, laevulinic, benzoic, succinic and the like are formed.

In the compounds of formula I, R 'preferably represents a hydrogen atom or lower alkyl, more preferably a hydrogen atom or methyl and most preferably a hydrogen atom. The substituent A is preferably the substituted phenyl group, the substituted furyl group or the substituted thienyl group as shown above, and is most preferably the substituted phenyl group. The substituent Z is preferably a sulfur or oxygen atom and, if A is the substituted phenyl radical, Z is preferably an oxygen atom. Preferably m is 0 or 1 and n is 2 or 3, and when A is the substituted phenyl group, m is preferably 0 and n is preferably 3. R5 is preferably a hydrogen atom or methyl and most preferably a hydrogen atom. Q is preferably 1. R6 and R7 are preferably lower alkyl, or together with the nitrogen atom to which they are attached, pyrrolidino or piperidino.

The compounds of formula I are prepared according to the invention by reacting a compound of formula II with sulfur monochloride (S2CI2) or sulfur dichloride (SCh), as listed below:

a- (ch2) mz (ch,) _ kh-ç ç-nkr

HN

\H

S2C12

or

SCI,

V /

A "(CH2) In2 (CH2) nNHN

Ti

10th

20th

25th

wherein A, m, Z, n and R1 have the meanings given above. At least 1 mole of S2CI2 or SCh must be used per mole of compound II; an excess of S2CI2 or SCh, e.g. about 2 to 3 moles of S2CI2 or SCh per mole of Compound II. It has been found that SCI2 often results in a crude product and a lower amount of purified product. We normally prefer S2CI2 for the reaction.

The reaction temperature is not critical; the reaction is preferably carried out at a temperature of from 0 ° C. to about 50 ° C. It is best to carry out the reaction at ambient temperature. The response time is not critical and depends on the temperature. A reaction time of about 30 minutes to about 6 hours is normally used. At ambient temperature, reaction times of about 1 Vi to 4 hours are usually preferred. The reaction can be carried out in an inert organic solvent, preferably a mixture of an inert organic solvent and dimethylformamide. The reaction is most preferably carried out in dimethylformamide.

According to a preferred embodiment according to the invention, the compounds of the formula I have the following structure:

1

a- (ck-,) Z (ch-) nh 4. m ■ in n

NHR

30th

wherein R1 is a hydrogen atom or lower alkyl, m is zero or 1 and n is 2 or 3, Z is an oxygen atom and A is

\

sAV

R "

I.

/ rn \

"O

or

NCH--

, 6/2

N '

50

55

II

in which R5 represents a hydrogen atom or methyl, and R6 and R7 each independently represent methyl or ethyl, or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring, or a pharmaceutically acceptable salt, hydrate or solvate from that.

According to a more preferred embodiment, the compounds of the formula I have the structure Ia:

60

^ NCH.-c / 2

Ia ch2ch2ciî2nh

65

.NKR1

wherein R 'represents a hydrogen atom or methyl, and R6

7

655 111

and R7 each represent methyl or, together with the nitrogen atom to which they are attached, represent a pyrrolidino or piperidino ring; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

According to another more preferred embodiment, the compounds of the formula I have the structure Ib:

»C„ 2 ^ y o ck „sch_ch, nh

VT

"• w *

Ib in which R1 and R5 each independently represent a hydrogen atom or methyl, and R "and R" independently of one another represent methyl or ethyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

According to a further preferred embodiment, the compounds of the formula I have the structure 1c:

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] -l, 2,5-thiadiazole and

5 10. 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy ^ ro-pylamino] -1,2,5-thiadiazole; and their pharmaceutically acceptable salts, hydrates and solvates.

The compounds of the formula II used in the preparation of the compounds of the formula I can themselves be prepared using various processes. In one process, the corresponding 3- (amino or substituted amino) -4-substituted amino-1,2,5-thiadiazole-1-oxide of Formula III is treated with a strong mineral acid (preferably HCl) to form the compound of the formula II to get.

A- (CH2) jnZ (CH2) nNH.

\

> 6 /

nck.

h 1 A

t.7

: h2sch2ch2nk nhr

20th

25th

v

ü

nkr

III

• Ic

HCl

V

wherein R1 and R5 each independently represent a hydrogen atom or methyl and R6 and R "each independently represent methyl or ethyl;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

According to a further preferred embodiment, the compounds of the formula I have the structure Id

30th

nhr ii

, 6 /

nck.

K

_ÄL

J

-OCH2CH2CH2NH

Vi

nkr '

The reaction can be carried out in an inert solvent and is preferably carried out in methanol. The reaction temperature is not critical; the reaction is most preferably carried out at room temperature. The compounds of formula III are known or can be easily prepared by the methods described in 40 British Patent 2,067,987.

According to an alternative method, the compounds of formula II can be obtained according to the following reaction scheme.

45

a- (ce,) z (ck,) nh. in the

2 n wherein R1 and R5 each independently represent a hydrogen atom or methyl and R6 and R ~ each independently represent methyl or ethyl, or together with the nitrogen atom to which they are attached represent a piperidino radical; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The currently most preferred compounds of formula I are:

1,3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thi adi azo 1,

2. 3-amino-4-2 - [(5-dimethylaminomethyl-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-pyrrolidinomethyIphenoxy) 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-dimethylaminomethyl-3-thienyl) methylthio] ethylamino} -1,2,5-thiadiazole,

ch3 °

/ C

HN ^

/ 0CK3

nnh

IV

50

55

V

a- (ce.) z (ch_) nh. 2 n 2 n hn '

r1nh,

\

och

"C

V

A- <cV »z <CH2'nNIi \

b5

y nkr

'nh

The reaction can be carried out in an inert solvent, and preferably in methanol. From-

655 111

8th

Gear materials of formula IV are known or can be easily prepared by known methods such as those described in our published British patent application 2,067,987.

On the other hand, the invention relates to the new compounds of formula II as execution agents for carrying out the method according to the invention:

A- (CH,) Z (CK-) NH z m z n

NHR

// w

HN NH

II

A- (CH2) az (CHj) "NHv ^

wherein R1 is a hydrogen atom, lower alkyl, 2-fluoro-ethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

are those in which R1 is a hydrogen atom or lower alkyl, m is zero or 1, n is 2 or 3, Z is an oxygen or sulfur atom and A is

II

_7

KCr * -.5 .5 / 2

R

i

V

\

6 / CS2-

oaer

20th

7x

ICE2'p "

where p is 1 or 2, R2 and R3 each independently represent a hydrogen atom, lower alkyl, lower alkoxy or halogen, and if R2 is a hydrogen atom, R3 can also be trifluoromethyl, or R2 and R3 together methylenedioxy and R4 a hydrogen atom , Lower alkyl or lower alkoxy; m is an integer from 0 to 2 inclusive: n is an integer from 2 to 5 inclusive; Z represents an oxygen atom, sulfur atom or methylene; and A stands for s / cs

25, in which R5 represents a hydrogen atom or methyl, and R6 and R "each independently represent methyl or ethyl, or together with the nitrogen to which they are attached represent a pyrrolidino or piperidino ring.

3o According to another preferred embodiment, the compounds of the formula II have the structure IIa:

IIa

CK2CK2CH2NK NKR1

// \\

\ (CK2) q

HN

NH

ode \ / (CI125 q ~ T ^ y

• N '

wherein R 'represents a hydrogen atom or methyl, and R6 and R "each represent methyl, or together with the nitrogen atom to which they are attached represent a pyrrolidino-45 or piperidino ring.

According to a preferred embodiment, the compounds of the formula II have the structure IIb:

R

wherein R5 is a hydrogen atom, lower alkyl or lower alkoxy, q is an integer from 1 to 4 inclusive and R6 and R? each independently mean lower alkyl, lower alkoxy-lower alkyl, the lower alkoxy radical being at least two carbon atoms from the nitrogen atom, or phenyl-lower alkyl, and, if R6 represents a hydrogen atom, R "can also be cyclo-lower alkyl, or R6 and R7 together with the nitrogen atom, to which they are bonded, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethylene-imino, 3-azimethylabino, 3.2.2] can mean non-3-yl or 3-pyrrolino, or a salt, hydrate or solvate thereof.

Preferred compounds of formula II

\

NCH--

6/2

R-

I.

H2SCH2CK2NH.

wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R6 and R "each independently represent methyl or ethyl.

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

Ile

R,

, 6 /

NCK.

LlXaS — CH2SCI12CH2NH NHR1

S

// \\ HN NH

9

655111

wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R6 and R7 are each independently methyl or ethyl.

According to a further preferred embodiment, the compounds of the formula 11 have the structure Ild:

Ild

> 6 /

, NCH-

OCK2CH2CH2NH

n

KR

NH

wherein R1 and R5 independently represent a hydrogen atom or methyl and R6 and R7 each independently represent methyl or ethyl, or together with the nitrogen atom to which they are attached mean piperidino.

The most preferred compounds of formula II are:

1. N- [3- (3-piperidinomethylphenoxy) propyl] etheriimide amide,

2. N- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl} ethane diimidamide,

3. N- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl} ethiimidamide,

4. N- [3- (3-pyrridinomethylphenoxy) propyl] ethane diimidamide,

5. N- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl} ethiimidamide,

6. N- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethyl [-

äthandiimidamid,

7. N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] äthandi-imidamide and

8. N- [3- (4-piperidonomethyl-2-pyridyloxy) propyl] ethandiimidamide.

For therapeutic use, the pharmacologically active compounds of the formula I are normally administered as a pharmaceutical agent which, as an active ingredient, contains at least one compound according to the invention in its basic form or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable carrier.

The pharmaceutical compositions can be administered orally, parenterally or rectally as suppositories. A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be made into tablets, put in powder or pellet form in a hard gelatin capsule, or in the form of a lozenge or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injections or as an aqueous or non-aqueous, liquid suspension. The pharmaceutical compositions are produced by conventional methods suitable for the desired preparation.

The dosage of the compounds according to the invention depends not only on factors such as the weight of the patient, but also on the degree of gastric acid inhibition desired and the effectiveness of the compound used. The doctor decides which dose to use (and the number of administrations per day) and can be varied depending on the specific circumstances and the patient.

In the preferred compounds of the invention, each oral dosage unit contains the active ingredient in an amount from about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 mg. The active ingredient is preferably administered in equal doses 1 to 4 times a day.

Histamine hi-receptor antagonists have been shown to be potent inhibitors of gastric secretion in animals and humans, Brimblecombe et al., J. Int. Med. Res., 3, 86 (1975). Clinical evaluations of the histamine H2 receptor 5 antagonist cimethidine showed that it is an effective therapeutic for the treatment of peptic ulcer, Gray et al., Lancet, 1, 8001, (1977). Some of the preferred compounds according to the invention were compared with cimethidine in various tests and were found to be stronger than cimethidine, both as a histamine H2-receptor antagonist tested on the isolated right atrium of the guinea pig and as an inhibitor of gastric acid. Secretion in rats and dogs.

15 Determination of gastric anti-secretion effects in rats with gastric fistula

Male Long Evans rats weighing approximately 240 to 260 g were used in the cannula implantation. The type of implantation of the stainless steel cannula into the front wall of the forestomach is carried out essentially as described by Pare et al. [Laboratory Animal Science, 27, 244 (1977)]. The fistula components are determined and the operation is performed exactly as described in the above reference.

After the operation, the animals are kept individually in cages with a solid bottom with sawdust and are given food and water ad libitum during the entire recovery period. The animals are not used for test purposes for at least 15 days after the 30 surgical procedure.

The animals are fasted before the test, but give water ad libitum 20 hours before the test. Immediately before collecting the secretion, open the cannula and wash the gastric juice with 30-40 ml warm saline or distilled water to remove all residues. The catheter is then screwed into the cannula at the place where the screw plug used to be and the rat is placed in a light, rectangular plastic cage that is 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a 40 slot about 1.5 cm wide and 25 cm long which runs in the middle and through which the catheter exits. In this way, the rat is not restricted and can move freely in the cage during the collection times. Otherwise, the test is carried out as described by Ridley et al. described-45 ben [Research Comm. Chem. Pharm., 17.365 (1977)].

The gastric secretions collected during the first hour after washing the stomach are discarded as they may be dirty. For oral evaluation, the catheter is then removed from the cannula and replaced with the 5o screw plug. 2 ml / kg of water are given orally by gastric intubation and the rat is left in the cage for 45 minutes. The screw plug is then loosened and replaced by a catheter that carries a small plastic bottle and catches the gastric secretions. A 2-hour 55 sample is collected (this is control secretion), the catheter is removed and replaced with the screw plug. The test compound is then given orally in a volume of 2 ml / kg by gastric intubation. 45 minutes later, the screw plug is opened again, replaced by the 60 catheter with a small plastic bottle attached, and another 2-hour sample is collected. The secretions in the second sample are compared to those of the control sample to determine the effect of the compound tested.

65 If the test compounds are evaluated parenterally, the animal is i.p. or s.c. the test compound carrier is injected in an amount of 2 ml / kg. Immediately beforehand, the initially obtained, collected during 60 minutes

655 111

10th

Discarded solution. A 2 hour sample (control secretion) is collected and the animals are then either injected i.p. or s.c. the test compound in an amount of 2 ml / kg.

Another 2 hour sample is collected, these secretions compared to those of the control to determine the effect of the drug.

The samples are centrifuged and placed in a graduated centrifuge tube for volume determination. Titrable acid is measured by titrating a 1 ml sample to pH 7.0 and 0.02 N NaOH using an autoburette and an electronic pH meter (radiometer). The titratable acid output is calculated in micro equivalents by multiplying the volume in milliliters by the concentration of milliequivalents per liter.

The results are expressed as percent inhibition based on the control readings. Dose response curves are set up and ED 50 values are calculated by regression analysis. At least 3 rats are used for each dose and at least 3 doses are used to determine the dose response curve.

Table 1

Gastric anti-secretion activity, tested in the rat with gastric fistula

connection

EDso sc

Effectiveness ratio

umole / kg

(Cimethidine = 1.0)

Cimethidine

3.48 (1.68-5.75) *

1.0

Example I

0.094 (0.043-0.20)

37

Example 2

0.77 (0.45-1.4)

4.5

Example 3

-0.5

~ 7

Example 4

0.18 (0.10-0.36)

20th

* 95% confidence limit

Histamine Hs receptor antagonism, tested on isolated guinea pig atria

Histamine causes concentration-dependent increases in the contractions of isolated, spontaneously beating right auricles of guinea pigs. Black et al., Nature, 236, 385 (1972) described the receptors involved in this action of histamine as histamine Ha receptors when they reported the properties of burinamide, an antagonist of these receptors. Later investigations by Hughes and Coret, Proc. Soc. Exp. Biol. Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol. Exp. Ther., 200, 352 (1977) confirmed the conclusions of Black and co-workers that the positive chronotropic effect of histamine on isolated right guinea pig atria is mediated by histamine Ha receptors. Black et al., Agents and Actions, 3, 133 (1973) and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) used isolated right auricles of guinea pigs to compare the effects of Hista-min Hz receptor antagonists. The present comparative studies were carried out using a modification of the procedure performed by Reinhardt et al., Agents and Actions, 4,217 (1974).

Male Hartly strain guinea pigs (350-450 g) were killed by a blow to the head. The heart was removed and placed in a petri dish containing oxygenated (95% O2, 5% CO2) modified cancer solution (g / liter: NaCl 6.6; KCl 0.35, MgS04-7H20 0.295, KH2PO4 0.162 , CaCh 0.238, NaHCCb 2.1 and dextrose 2.09). The spontaneously beating right atrium was cleared of other tissues and a silk thread (4-0) was attached to each end. The atrium was suspended in a 20 ml muscle chamber containing oxygenated modified cancer solution kept at 32 ° C. The atrial contractions were recorded isometrically with a Grass FT 0.03 force transducer and the contraction force and speed were recorded with a Beckman RP Dynograph.

A permanent pull of 1 g was applied to the atrium, in this state the preparation was left to stand for 1 hour. A submaximal concentration of histamine dihydrochloride (3.10_6M) was then added to the bath and washed out to prepare the tissue. Then histamine was added cumulatively at 10 intervals in Vi log, so that final bath concentrations of 1.10 to 3 × 10-5 mol were obtained. The histamine-induced increase in ventricular beats had to be leveled out before the next concentration was reached. Maximum response was always at a dose of 3 x 10 JM. The histamine was washed out several times and the atrium was returned to the control value. Then the test compound was added at appropriate molar concentrations and after a 30 minute incubation the response to the histamine dose was repeated, the higher concentrations being adjusted as required. The dissociation constants (Kß) were calculated from the Schild curves using the method of Arunlakshana, O. and Schild, H.O. [Br. J. Pharmacol, 14,48, (1959)], whereby at least 3 dose units were used as a basis. Parallel shifts in dose-response curves were obtained without reducing the maximum response at the antagonist concentrations used. The results are shown in Table 2.

Table 2

Activity on isolated right guinea pig atria

Connection N

KB (u.Mol)

Effectiveness

relationship

(Cimethidine = 1.0)

Cimethidine 20

0.41 (0.210-0.64) *

1.0

Example 1 12

0.003 (0.001-0.004)

137

Example 4 11

0.004 (0.001-0.010)

102

* 95% confidence limit

The compounds of formula I can also by ring closure of a compound of formula II with N, N'-thio-bisphthalimide of the formula:

getting produced.

The use of N, N'-thiobisphthalimide instead of S2CI2 or SCh for the ring closure gives both higher and purer yields of compounds of the formula I. The crude products of the formula I thus produced are normally pure enough to form crystalline salts directly,

without prior chromatographic purification.

In this process, the diimidamide of the formula II used as the starting product is reacted with an approximately equimolar amount of N, N'-thiobisphthalimide in an inorganic inert solvent, such as CH2Cl2. The diimidamide is preferably used in the form of its trihydrochloride salt, in which case three molar equivalents of an amine,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

11

655 111

such as triethylamine, may be added to the reaction mixture to neutralize the trihydrochloride salt. The reaction can be carried out by stirring at room temperature for about 1 hour to ensure the completion of the reaction. The phthalimide that precipitates from the reaction mixture is then extracted with a strong base (e.g. 10-20% aqueous KOH) and the organic solvent is dried, filtered off and concentrated to give the crude product of the compound of formula I. The N, N'-thiobisphthalimide which is used is a known compound which can be prepared as described in the Canadian Journal of Chemistry, 44, 2111-2113 (1966) or as described below. '

Preparation of N, N'-thiobisphthalimide

5.15 g (0.05 mol) of sulfur dichloride are added dropwise to a cooled solution (0 ° C.) of 14.7 g (0.1 mol) of phthalimide in 80 ml of dimethylformamide (DMF), and the mixture is left inside after the addition Heat from 4 hours to 20 ° C, collect the solid and dry to give 12.5 g of the title compound as a DMF solvate, mp. 301-315 ° C. Both the IR and NMR spectra are consistent with the structure.

Analysis for C.aH8N204S-C3H7N0:

C H N S calculated 57.42 3.80 10.57 8.07%

found 57.50 3.80 10.29 8.57%

The DMF solvate can be removed from the substance by recrystallization in chloroform. The mp of the DMF-free product is 320-325 ° C. No DMF could be seen in the NMR spectrum.

Analysis for CióHsNìOjS:

C H N S

calculated 59.25 2.49 8.64 9.89%

found 59.21 2.21 8.91 10.14%

example 1

3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] - 1,2,5-thiadiazole

A. N- [3- (3-piperidinomethylphenoxy) propyl] äthandiimida-mid-trihydrochloride

A suspension of 17.1 g (47.0 mmol) of 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide [prepared in accordance with the published GB- Patent application 2,067,987] in 450 ml of methanol with 38 ml of concentrated HCl, the solution obtained is stirred for 3 hours at room temperature, the solution is concentrated and the water is removed azeotropically with absolute ethanol, giving colorless crystals. This is 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 to 220 ° C. (dec.). Recrystallization from 50% methanol / ethyl acetate gives an analytical sample with mp. 206-216 ° C (dec.).

Analysis for C17H27N5O • 3HC1:

C H N

calculated 47.84 7.08 16.41%

found 47.56 7.18 16.75%

B. 3-Amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

A stirred suspension of 2.13 g (5.0 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] ethane diimide trihydrochloride [prepared in step A] in 20 ml of dimethylformamide (DMF) is mixed with 2.02 g (15.0 mmol) sulfur monochloride, stirred for a further 4 hours, pour the resulting mixture carefully into 200 ml of water and make basic with K2CO3. Then extracted with 3 x 50 ml of methylene chloride,

dries over MgSCh and concentrated to give 2.1 g of a dark gummy product. The product is purified by means of HPLC chromatography on silica, using CH2Ch (100): 2-propanol (10): NH40H (0.5) as the mobile phase. The suitable fractions give 0.89 g of the title compound, from which 0.76 g (21.4%) of the title compound are obtained as fumarate salt with mpumaric acid in n-propanol, mp. 187-187.5 ° C. Purity according to H PLC> 99%.

Analysis for (Cn ^ sNsOS ^^^ O .: 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 K2CO1, extracted with CH2CI2 and concentrated with CH2CI2 and the CHaCh phase is concentrated, the free base of the title compound crystallizing, mp 43-47 ° C. Part of the free base is converted into the hydrochloride salt, mp. 138-140 ° C.

Analysis for CtTHasNsOS-HCl:

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} -ethandiimidamide trihydrochloride hydrate

A suspension of 6.59 g (20.0 mmol) of 3-amino

4- {2 - [(5-dimethylaminomethyl-2-furyl) methyIthio] ethylamino-no} -l, 2,5-thiadiazole-l-oxide [prepared according to published GB patent application 2,067,987] heated in 200 ml of methanol one slowly to achieve a complete solution. Then 13.3 ml of conc. HCl, stirred for a further 2.4 hours at room temperature, concentrated the solution and triturated the residue with 70 ml of absolute ethanol. The crystals are filtered off and dried in vacuo to give 4.3 g (52%) of the title compound, mp. 166-169 ° C (dec.).

Analysis for C.2H2.N50S-3HCl-H20: 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) methylthioethylamino} -1,2,5-thiadiazole

To a stirred suspension of 12.3 g (30.0 mmol) of N- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl} -ethandiimidamide trihydrochloride hydrate [prepared in stage A] in 150 ml of DMF is added 7.2 ml of sulfur monochloride (12.1 g, 90 mmol), stirred for a further 4 hours at room temperature, removed about half of the DMF under reduced pressure, poured the remaining black solution into 1 liter of water, made basic with K2CO3 and extracted first with ethyl acetate and then with chloroform. After drying over MgSCh, filter and concentrate to give 9.0 g of a black, rubbery product containing the product. This is purified by means of HPLC chromatography on silica, using ethyl acetate (100): 2-propanol (10) -NH40H (0.5) as the mobile phase. The appropriate fractions give 1.24 g of the title compound as a gummy product.

Treatment of parts of this product with an equivalent amount of 2N HCl in methanol gives the hydrochloride salt of the title compound.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

655 111

12

Analysis for C12H10N5S2O • HCl:

C H N S

calculated 41.18 5.76 20.02 18.33%

found 40.54 5.70 5.70 19.39 18.44% (corr. for 1.65% H2O)

Treatment of the product with an equivalent amount of cyclohexylsulfamic acid in acetone gives the cyclohexylsulfamate salt of the title compound, mp. 93-95 ° C.

Analysis for CiaHi ^ NsSiO-CöHuNChS: 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) methylthio] ethylamino} -1,2,5-thiadiazole

A. N- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl} ethandiimidamide trihydrochloride

A stirred solution of 17.9 g (50.0 mmol) of 3-amino-4- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino} -1,2,5- thiadiazole-1-oxide (prepared according to the general method described in published GB patent application 2,067,987) in 500 ml of methanol with 33 ml of conc. HCl, stirred for a further 3 hours, concentrated the reaction mixture and removed excess water by azeotropic concentration with absolute ethanol, giving an almost colorless crystalline residue. The residue is triturated with 200 ml of absolute ethanol at 0 ° C., filtered and dried, giving 16.9 g (80%) of the title compound, mp. 206-220 ° C. (dec.). Recrystallization from 50% methanol / ethyl acetate gives a product with mp. 210-221 aC (dec.).

Analysis for Ci3H23N5S2 • 3 HCl:

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 6.34 g (15.0 mmol) of N- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl} ethiimidamide trihydrochloride [prepared in step A] in 60 ml DMF is added 6.1 g (45.0 mmol) of sulfur monochloride, stirred for 4 hours at room temperature, the reaction mixture is poured into 800 ml of water, made basic with K2CO3 and extracted several times with 100 ml of methylene chloride. The extracts are dried over MgSO-t, filtered and concentrated to give 3.4 g of a black, gummy product. This is purified by preparative HPLC chromatography on silica, using CH2Cl2 (100): 2-propanol (10): NH40H (0.5) as the mobile phase. Further purification is achieved by additional HPLC chromatography on silica, using CH2Ch (100): CH30H (2.5): NH40H (0.5) as the mobile phase. The appropriate fractions give the title compound (purity ~ 98%). Treatment of the product with an equivalent amount of 2N HCl gives the hydrochloride salt of the title compound.

Analysis for C13H21N5S3- HCl:

C H N S

calculated 41.09 5.84 18.43 25.32%

found 40.78 5.63 18.31 18.31 25.44% (corr. for 0.51% H2O)

Example 4

3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamino] -

1,2,5-thiadiazole

A. N- [3- (3-pyrrolidinomethylphenoxy) propyl] äthandiimida-mid-trihydrochloride

A suspension of 13.4 g (38.3 mmol) of 3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamino] -1,2,5-thia-diazole-1-oxide [prepared according to the published GB patent application 2,067,987] in 350 ml of methanol is treated with 25.5 ml of conc. HCl, the resulting solution was stirred at room temperature for 3 hours, the solution was concentrated, and then the water was removed azeotropically with absolute ethanol to obtain the product. The crystalline residue is triturated with 150 ml of absolute ethanol, filtered and dried, giving 10.8 g of the title compound, mp. 195-203 ° C (dec.).

Analysis for C.r, H25N50-3HCl:

C H N calculated 46.55 6.84 16.92%

found 46.55 6.93 16.93%

B. 3-Amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

A stirred suspension of 8.25 g (20.0 mmol) of N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethiimidamide trihydrochloride [prepared in Step A] in 80 ml of DMF is treated with 5.4 g (40.0 mmol) of sulfur monochloride, stirred for 3 hours under a nitrogen atmosphere and concentrated the reaction mixture, giving a dark, rubber-like product which is suspended in 500 ml of water. Then made basic with K2CO3, extracted with 3 x 100 ml of methylene chloride, the extracts dried over MgSCh, filtered and concentrated, giving 7.5 g of a dark gummy product. This is purified by means of HPLC apparatus chromatography on silica, using CH2Ch (100): 2-propanol (5): NH40H (0.5) as the mobile phase. The fractions containing the desired product 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 salt of the title compound (1.13 g), mp. 138-140 ° C.

Analysis for C.chaiNsOS-HCl:

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 procedure described in Example 1, stages A and B is repeated, the 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide used there being replaced by an equimolar one A lot of:

(a) 3-amino-4- [3- (3-dimethylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(b) 3-amino-4- [3- (3-diethylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(c) 3-amino-4-) 3- [3- (2-methylpyrrolidino) methylphenoxypropylamino} -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,

(0 3-amino-4- [3- (3-morpholinomethyIphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(g) 3-amino-4- {3- [3- (N-methylpiperazino) methylphe-noxy] propylamino | -1,2,5-thiadiazole-1-oxide,

(h) 3-amino-4- [3- [3-diallylaminomethylphenoxy) propylamino] -1,2,6-thiadiazole-1-oxide,

(i) 3-amino-4- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

b5

13

655 111

(j) 3-amino-4- [3- (3-heptamethylene-iminomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(k) 3-Amino-4- {3- [3- (3-azabicyclo [3.2.2] non-3-yl) methylphenoxy] propylamino} -l, 2,5-thiadiazole -1-oxide or

(1) 3-Amino-4- {3- [3- (3-pyrrolino) methylphenoxy] propylamino} -l, 2,5-thiadiazole-1-oxide replaced. You get

(a) 3-amino-4- [3- (3-dimethylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(b) 3-amino-4- [3- (3-diethylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(c) 3-amino-4- {3- [3- (2-methylpyrrolidino) methylphenoxy] propylamino} -1,2,5-thiadiazole,

(d) 3-amino-4-J3- [3- (3-methylpyrrolidino) methylphenoxy] propylamino} -1,2,5-thiadiazole,

(e) 3-amino-4-j3- [3- (4-methylpiperidino) methylphenoxy] propylamino} -1,2,5-thiadiazole,

(f) 3-amino-4- [3- (3-morpholinomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(g) 3-amino-4- {3- [3- (N-methylpiperazino) methylphe-noxy] prophylamino} -1,2,5-thiadizole,

(h) 3-amino-4- [3- (3-diallylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(i) 3-amino-4- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(j) 3-amino-4- [3- (3-heptamethyleniminomethylphenoxy) propylamino] -1,2,5-thiadiazole,

(k) 3-Amino-4- {3- [3- (3-azabicyclo [3.2.2] non-3-yl) methylphenoxy] propylamino} -l, 2,5-thiadiazole or

(1) 3-Amino-4- {3- [3- (3-pyrrolino) methylphenoxy] propylamino} -1,2,5-thiadiazole.

Example 6

3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

This represents a modification of stage B of Example 1, using less sulfur monochloride and choosing a shorter reaction time.

7.64 g (56.6 mmol) of sulfur monochloride are added to a stirred suspension of 12.08 g (28.3 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] ethiimidamide trihydrochloride in 120 ml of DMF, and the mixture is stirred Mix for 3 hours under Na atmosphere and remove the DMF under reduced pressure to give a black, rubbery product; this is suspended in water, made basic with K2CO3 and extracted with 3 x 100 ml of CH2CI2. The combined extracts are dried over MgSC> 4, filtered and concentrated to give a black, gummy product. This gummy product is purified by preparative HPLC chromatography on silica, using CH2Cl2 (100): 2-propanol (5) :) NH40H (0.5) as the mobile phase. The appropriate fractions give 3.1 g of the title compound as a dark oil which, with fumaric acid in n-propanol, gives 2.66 g (23.2%) of the title compound as a crystalline fumarate salt, mp. 186-186.5 ° C. Purity according to HPLC 99%. Analysis for (CnH2sN50S) 2-C4H404;

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-thiadiazole

This represents a modification of stage B of Example 1, using sulfur dichloride instead of sulfur monochloride.

To a stirred suspension of 854 mg (2 mmol)

N- [3- (3-piperidinomethylphenoxy) propyl] ethiimidamide trihydrochloride in 6 ml of DMF in an ice bath is added under N2 206 mg (2 mmol) of SCI2 in 2 ml of DMF, the mixture obtained is stirred at room temperature and the title compound is obtained.

Example 8

3-methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

A. N-Methyl-N '- [3- (3-piperidinomethylphenoxy) propyl] ethane diimidamide trihydrochloride

A suspension of 4.13 g (10.9 mmol) of 3-methylamino-4- [3- (3-piperidinomethylphenoxy) -propyla-mino] -l, 2,5-thiadiazole-1-oxide [prepared in accordance with the published UK patent application 2,067,987] in 95 ml of methanol with 7.2 ml of concentrated HCl, stirred for 3 hours at room temperature, concentrated the solution and triturated the residue with acetone. Then filtered and dried to give 4.35 g (90.4%) of the desired product. A sample of this is recrystallized from aqueous isopropyl alcohol to give the title compound, mp.

207-225 ° C (dec.).

Analysis for C.8H29N5O • 3 HCl:

C H N calculated 49.03 7.33 15.89%

found 49.37 7.35 15.71%

(corr. for 0.94% H2O)

B. 3-Methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

A mixture of 3.74 g (8.47 mmol) of N-methyl-N '- [3- (3-piperidinomethylphenoxy) propyl] ethane imidamide trihydrochloride [prepared in Step A], 34 ml of CH 2 Cl 2 and 3.5 ml of triethylamine is treated with 3.36 g (8.46 mmol) of N, N'-thiobisphthalimide (DMF solvate) and stirred for 1 hour. The mixture is then washed with 30 ml of 10% KOH, dried (MgSCU) diluted with toluene and concentrated to give 3.6 g of the product. This product is purified by flash chromatography on 90 g silica gel (63-38 (im, [230 to 400 mesh)) using ethyl acetate-methanol (95: 5) as eluent to give 1.9 g (62%) of the title compound Treatment of this product with an equivalent amount of aqueous HCl in 1-propanol gives the hydrochloride salt of the title compound, mp 163.5 to 164.5 ° C.

Analysis for Ci8H27NsOS-HCl:

C H N S Cl 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] - 1,2,5-thiadiazole

A. N-Benzyl-N '- [3- (3-piperidinomethylphenoxy) propyl] ethandiimidamide trihydrochloride

A suspension of 5.14 g (11.3 nmol) of 3-benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] - 1,2,5-thiadiazole-1-oxide [prepared in accordance with the published GB- Patent application 2 067 987] in 100 ml of methanol with 7.5 ml of conc. HCl, stirred for 3 hours at room temperature, concentrated the solution and triturated the residue with acetone. The mixture is then filtered and dried, giving 5.16 g (88%) of the title compound, mp. 187-205 ° C. (dec.)

Analysis for C24H33N5O • 3HC1:

C H N Cl calculated 55.75 7.03 13.55 20.57%

found 54.88 6.75 13.33 20.20%

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

655111

14

B. 3-Benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole

A mixture of 4.73 g (9.16 mmol) of N-benzyl-N '- [3- (3-piperidinomethylphenoxy) propyl] -äthandii-midamide trihydrochloride [prepared in step A], 45 ml of CH 2 Cl 2 and 3 is added , 8 ml of triethylamine with 3.64 g (9.16 mmol) of N, N'-thiobisphthalimide (DMF solvate) and stirred for one hour. The mixture is then washed with 44 ml of 10% KOH, dried (MgSO-i), filtered, diluted with toluene and concentrated. The residue is chromatographed by means of flash chromatography on 110 g of silica gel (63-38 Jim, [230-400 mesh]), using ethyl acetate as the eluent. 3.1 g (77%) of the title compound are obtained. Treatment of this product with an equivalent amount of aqueous HCl in 2-propanol gives the hydrochloride salt of the title compound, mp 138-141 ° C.

Analysis C24H31 NsOS • HCl:

C H N S 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-thiadiazole

This example represents a modification of stage B of Example 1 using N, N'-thiobisphthalimide instead of sulfur monochloride.

A solution of 27.3 g (64.0 mmol) of N- [3- (3-piperidino-methylphenoxy) propyl] ethaniimidamide trihydrochloride [prepared in Example 1, Step A], 250 ml of CH 2 Cl 2 and 26.6 ml (192 mmol) of triethylamine are treated in portions with N, N'-thiobisphthalimide (DMF solvate) (25.4 g, 64.0 mmol), stirred for one hour at room temperature, the mixture is washed with 120 ml of KOH, dried (on MgSO4), filtered and focused. Then it is taken up in 150 ml of toluene and concentrated again. The product is then taken up in 250 ml of 1-propanol and 10.7 ml of 6N HCl, treated with decolorizing carbon and filtered through Celite. This solution is concentrated to 100 ml, diluted with 175 ml of dry 1-propanol and stored at 0 ° C., giving 20.2 g (82.1%) of the crystalline hydrochloride salt of the title compound. Mp

137-138 ° C.

Analysis for C17H25N5OS - HCl:

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

This example is a modification of Example 4, stage B, using N, N'-thiobisphthalimide instead of sulfur monochloride.

A mixture of 22.0 g (53.0 mmol) of N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethane diimidamide trihydrochloride [prepared in Example 4, step A], 200 ml of CH 2 Cl 2 and 22 ml of triethylamine are added with 21.2 g (53.0 mmol) of N, N'-thiobisphthalimide (DMF solvate), stirred for 1 hour at room temperature, the mixture was washed with 100 ml of 20% KOH, dried (MgSÛ4), filtered, diluted with 100 ml of toluene and concentrated. The product is treated with 1 equivalent of aqueous HCl in 1-propanol, giving 13.2 g (67%) of the hydrochloride salt of the title compound, mp 135-137 CC. Analysis for C16H23N5OS • HCl:

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-thiadiazole

A. N- {2 - [(5-Dimethylaminomethyl-3-thienyl) methylthio] ethyl | -äthandiimidamide trihydrochloride

A suspension of 7.8 g (22.6 mmol) of 3-amino

4- (2 - [(5-Dimethylaminomethyl-3-thienyl) methylthio] ethylamino-no} -i, 2,5-thiadiazole-1-oxide [prepared according to published GB patent application 2,067,987] in 150 ml of methanol the mixture is stirred with 115.0 ml of concentrated HCl, stirred for 3 hours at room temperature and then the solution is triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of the product is recrystallized from methanol-acetone, giving the title compound, mp. 190-205 ° C, (dec.).

Analysis CnNaiNsSa-SHCl:

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) methyl-thioethylamino} -1,2,5-thiadiazole

A mixture of 6.13 g (15.0 mmol) of N- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl} -ethandiimidamide trihydrochloride [prepared in Step A], 60 ml of CH2CO2 and 6 , 3 ml of triethylamine are treated with 5.96 g (15.0 mmol) of N, N'-thiobisphthalimide (DMF solvate), stirred for 1 hour, the mixture is washed with 100 ml of 10% KOH, dried (MgS04), filtered , diluted with toluene and concentrated to give 5.1 g of the product. Treat the product with 0.5 molar equivalents of fumaric acid in 1-propanol to give the fumaric acid salt of the compound, mp 141-143 ° C. The NMR spectrum in DMSO-d & shows the presence of approximately 0.12 moles of 1-propanol.

Analysis for (Ci2HioN5S3) 2-CiH404-0.12C3H80: 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) methyIthio] ethylamino} -1,2,5-thiadiazole

A. N- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethyH-ethane-diimidamide trihydrochloride

A suspension of 6.1 g (15.8 mmol) of 3-amino

4- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethylamino \ -1,2,5-thiadiazole-1-oxide [prepared according to published GB patent application 2,067,987] in 80 ml of methanol is treated with 10.5 ml conc. HCl, stir for 3 hours at room temperature and then concentrate the solution. The residue is triturated with 50 ml of 1-propanol, filtered and dried, giving 5.86 g (83%) of the product. A sample is recrystallized from methanol / acetone to give the title compound, mp. 201-214 ° C (dec.).

Analysis Ci5H2sN5S2-3HCl:

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] ethylamine} -1,2,5-thiadiazole

A mixture of 5.17 g (11.5 mmol) of N- {2 - [(5-piperidomethyl-3-thienyl) methylthio] ethyl} ethandimidamide tri-hydrochloride [prepared in Step A], 48 ml CH2CI2 and 4.8 ml of triethylamine are mixed with 4.57 g (11.5 mmol) of N, N'-thiobisphthalimide (DMF solvate), stirred for 1 hour, the mixture is washed with 90 ml of 10% KOH, dried (MgS04 ), fil-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

35

15

655 111

triert, diluted with toluene and concentrated to give 4.5 g of the product. Treatment of the product with 1 equivalent of cyclohexylsulfamic acid in methanol gives the cyclohexylsulfamate salt of the title compound, mp 142-143 ° C.

Analysis for CisHhsNsSj-OHnNCbS: 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 procedures of Example 1, Step A, and then either Example 1, Step B, or Example 10 are repeated, using the 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1 used there , 2,5-thiadiazol-1-oxide replaced by an equimolar amount of:

(a) 3-ethylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] - 1,2,5-thiadiazole-1-oxide,

(b) 3-AUylamino-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- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(e) 3- (6-methyl-3-pyridyl) methylamino-4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide or

(f) 3- (3,4-methylenedioxybenzylamino) -4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide is obtained

(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-pyridyl) methylamino-4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole or

(f) 3- (3,4-methylenedioxybenzylamino) -4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole.

Example 15

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

A. 3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide

A solution of 4.65 g (18.6 mmol) of 3- (6-pyridinomethyl-2-pyridyloxy) propylamine [prepared according to published GB patent application 2 098 988] in 50 ml of methanol is mixed with 2.74 g ( 18.6 mmol) of 3-amino-4-methoxy-1,2,5-thiadiazole-I-oxide according to the method described in published GB patent application 2,067,987 to obtain a solution containing 3-amino Contains 4- [3- (6-piperidomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1 oxide. A cleaned sample melts at 145 to 147 ° C.

B. N- [3- (6-Piperidinomethyl-2-pyridyloxy) propyl] äthandi-imidamide trihydrochloride

A methanolic solution of a product prepared in stage A is diluted to 100 ml, then 12.4 ml of conc. Add HCl, stir the solution at room temperature for 18 hours, concentrate and dissolve the residue in 80 ml of water. Then extracted twice with CH2Cl2, concentrated the aqueous phase, treated with n-propanol and concentrated under high vacuum 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 stage B in 80 ml of CH 2 Cl 2, which contains 7.69 ml of triethylamine, is treated with 7.35 g (18.5 mmol) of N, N'-thiobisphthalimide (DMF solvate), and the mixture is stirred for 1 hour Room temperature, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SC> 4), filtered and evaporated under reduced pressure to give the crude product. The product is purified by flash chromatography on 100 g silica gel (63-38 µm [32-400 mesh]) using ethyl acetate / methanol (95: 5) as the eluent. 3.63 g of the title compound are obtained as a viscous oil. Treatment of the product with one equivalent of cyclohexylsulfamic acid in acetone gives the cyclohexylsulfamate salt of the title compound, mp 125.5-131 ° C.

Analysis for CH ^ NàOS-CtHuNOiS: 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] -1,2,5-thiadiazole

By reacting a methanolic solution from

3- (6-Dimethylaminomethyl-2-pyridyloxy) propylamine [made according to published GB patent application

2 098 988] with 3-amino-4-methoxy-l, 2,5-thiadiazole-1-oxide according to the general process described in GB patent application 2,067,987 and by reacting the 3-amino

4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -

1,2,5-thiadiazol-1-oxide successively according to the general procedure described in Example 1, step A and then either according to Example 1, step B or according to Example C, the title compound is obtained.

Example 17

3-Amino-4- {2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino (-1,2,5-thiadiazole

When a suspension of 3-amino-4- {2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino} -1,2,5-thia-diazole-1-oxide [prepared according to published GB Patent application 2 067 987] reacted in succession according to the process of Example 1, stage A and then either according to Example 1, stage B or according to Example 10, then the title compound is obtained.

Example 18

3-Amino-3- | 2 - [(6-piperidinomethyl-2-pyridyl) methylthio] ethyl lamino} -1,2,5-thiadiazole

When a suspension of 3-amino-4- {2 - [(6-piperi-dinomethyl-2-pyridyl) methylthio] ethylamino} -1,2,5-thiadiazol-l-oxide [prepared according to published GB - Patent application 2 067 987] reacted in succession according to the procedure of Example 1, stage A and then either according to Example 1, stage B or according to Example 10, the title compound is obtained.

Example 19

The general procedure of Example 1, Step A is repeated and then either the procedure of Example 1, Step B or Example 10, using the 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] used there. 1,2,5-thiadiazole-1-oxide replaced by an equimolar amount of:

(a) 3-amino-4- [3- (3-piperidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

655 111

16

(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] ethylamino} -1,2,5-thiadiazole-1 oxide or

(h) 3-Amino-4- {2 - [(4-piperidinomethyl-2-pyridyl) methylthio] ethylamino} -l, 2,5-thiadiazole-l-oxide.

You get:

(a) 3-amino-4- [3- (3-piperidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole,

(b) 3-amino-4- [3- (3-dimethylaminomethylthiophenoxy) propylamino] -1,2,5-thiadiazole,

(c) 3-amino-4- [3- (3-pyrrolidinomethylthiophenoxy) propyl amino] -1,2,5-thiadiazole,

(d) 3-amino-4- [3- (4-dimethylaminomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole,

(e) 3-amino-4- [3- (5-dimethylaminomethyl-3-thienyloxy) propylamino] -1,2,5-thiadiazole,

(0 3-amino-4- [3- (5-piperidinomethyl-3-thienyloxy) propylamino] -1,2,5-thiadiazole,

(g) 3-Amino-4- {2 - [(4-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino} -1,2,5-thiadiazole or

(h) 3-Amino-4- {2 - [(4-piperidinomethyl-2-pyridyl) methylthio] ethylamino | -1,2,5-thiadiazole.

The above-mentioned starting materials are prepared according to the general procedures described in published GB patent application 2,067,987. The precursors of the starting materials are prepared according to the procedures and general analog procedures described in UK Patent Applications 2,067,987,2,098,988, 2,063,875 and published European Patent Application No. 49,173.

Example 20

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

A. 3- (4-Piperidinomethyl-2-pyridyloxy) propylamine

If one follows the general process for the preparation of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine described in GB patent application 2 098 988, the 2-chloro-6-methylpyridine used there being replaced by 2-bromo-4- methylpyridine, then the title compound is obtained as an oil.

Analysis for C14H23N3O:

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 from stage A (6.5 g, 26.0 mmol) in 90 ml of methanol is mixed with 3.84 g (26.0 mmol) of 3-amino-4-methoxy-l, 2.5- thiadiazole-1-oxide according to the general methods described in GB patent application 2,067,987, yielding 6.33 g of a product. Recrystallization from methanol / acetonitrile gives the title compound, mp. 154-158 ° C.

Analvse for CiôHmN & OS:

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] ethandi-imidamide trihydrochloride

The product of stage B (5.0 g, 13.7 mmol) is dissolved in 80 ml of methanol, treated with 9.1 ml of conc. HCl, stirred for 4.5 hours at room temperature and then concentrated the solution to dryness under reduced pressure to give the title compound.

D. 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propyla-mino] -1,2,5-thiadiazole

A mixture of the product obtained in stage C in 50 ml of CH 2 Cl 2 and 5.7 ml of triethylamine is treated with 5.44 g (13.7 mmol) of N, N'-thiobisphthalimide (DMF solvate), stirred for 1 hour at room temperature, washed then the mixture with 40 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na2SC> 4), filtered and concentrated under reduced pressure to give the crude product. The product is purified by "flash" chromatography on 90 g silica gel (63 to 38 µm [32 to 400 mesh]) using ethyl acetate / methanol (96: 4) as the eluent. This gives 3.44 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexylsulfamic acid in acetone gives the cyclohexylsulfamate of the title compound, mp 124.5-126 ° C.

Analysis for CiüH24Nü0S-Cf.Hi3N03S: 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-pyridylmethyl) phe-noxy] propylamino} -1,2,5-thiadiazole

The general procedure of Example 15 is repeated, the 3- (6-piperidinomethyl-2-pyridyloxy) propylamine used there being replaced by an equivalent amount of 3- [3- (l, 2,3,6-tetrahydro-l- pyridylmethyl) phenoxy] propylamine. This gives 2.31 g of the product. Recrystallization from toluene gives the title compound, mp. 99.5-104 ° C.

Analysis for C1-H33N5OS:

C H N S calculated 59.10 6.71 20.27 9.28%

found 58.78 6.71 19.90 9.26%.

(corr. for 2.19% H2O)

5

io

15

20th

25th

30th

35

40

45

50

55

G

Claims (15)

655111 1 ! l \ (CK,, N (Ch25q ; / 655111 1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 18. The compound of claim 1 which is 3-amino-4- {3- [3- (1,2,3,6-tetrahydro-1-pyridylmethyl) phenoxy] propylamino} -1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 19. A process for the preparation of a compound of the general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof as claimed in claim 1, characterized in that a compound of general formula II: Id 1 a- (ch_) z (ch_) nh nhr 1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 17. A compound according to claim 1, namely 3-amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propylamine] - 1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 2 m 2 ti {2 - [(5-piperidino-methyl-3-thienyl) methylthio] ethyl} ethiimidamide or N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] ethiimidamide. 35. Compounds according to claim 23, namely N- [3- (4-piperidinomethyl-2-pyridyloxy) propyl] äthandiimidamid, or N {3- [3- (l, 2,3,6-tetrahydro-l-pyridyl) methylphe -noxy] -propyl} äthandiimidamid. wherein R1 represents a hydrogen atom or methyl, and R6 and R7 each signify methyl, or together with the nitrogen atom to which they are attached signify a pyrrolidino or piperidino ring. 26. Compounds according to claim 23 of the general formula IIb: H2SCK2ch2NH ■ ÎH. NKR1 / ri HN NH The 3- (amino or substituted amino) -4- (substituted amino) -l, 2,5-thiadiazoles of the general formula I. IIb A_ {CH2) rr.Z (CK2) nNH \ H ■ NHR {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl} - äthandiimidamid. 34. Compounds according to claim 23, namely N- '2 2 2 // HN NH rt wherein R1 and R5 independently represent a hydrogen atom or methyl, and R6 and R7 each independently represent methyl or ethyl, or together with the nitrogen atom to which they are attached form a piperidino radical. 29. A compound according to claim 23, which is N- [3- (3-pipe-ridino-methylphenoxy) propyl] ethiimidamide. 30. The compound of claim 23, namely N- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl} äthandiimidamid. 31. A compound according to claim 23 which is N- {2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl} ethiimidamide. 32. Compound according to claim 23, namely N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethane diimidamide. 33. Connection according to Claim 23, namely N- 2. m £ n / w hn nh ii wherein R \ A, Z, m and n have the meanings given in claim 1, with at least one molar equivalent, sulfur monochloride or sulfur dichloride, to give a compound of the general formula I and the compound obtained, if appropriate, into a pharmaceutically acceptable one Salt, hydrate or solvate thereof. 15 20. The method according to claim 19, characterized in that the reaction takes place at 0-50 ° C and preferably in one of the reaction to inert solvents. 21. The method according to claim 19 or 20, characterized in that the compound of formula II with a molar 20 ren excess and preferably with a molar excess of 2-3 moles of sulfur monochloride or sulfur dichloride. 22. The method according to claim 19, 20 or 21, characterized in that reacted with sulfur monochloride Turns 25. 23. Compounds of the general formula II: k- (ch -) _ z (ce -) _ nh 2 m / n 30th ^ NKR ii where R1 is a hydrogen atom, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, 35 or means in which p is 1 or 2, R2 and R3 each independently represent a hydrogen atom, lower alkyl, lower alkoxy or halogen atom, and, if R2 represents a 50 hydrogen atom, R3 can also mean trifluoromethyl, or R2 and R \ together methylenedioxy and R4 may be 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 represents an oxygen or sulfur atom or methylene, and A represents \ </ M (CH2, q r- 2. Compounds according to claim 1 of the formula I, in which R1 represents a hydrogen atom or lower alkyl, m represents 0 or I, n represents 2 or 3, Z represents oxygen or sulfur and A for the formulas: 50 wherein R1 and R5 are independently hydrogen or methyl, and R6 and R: are independently methyl or ethyl; or pharmaceutically acceptable salts, hydrates or solvates thereof. 2 D or ^ M -2) p- • N ' is in which R5 represents a hydrogen atom or methyl and R6 and RT each independently represent methyl or ethyl, or, together with the nitrogen atom to which they are attached, form a pyrrolidino or piperidino ring, 20 or pharmaceutically acceptable salts, hydrates or solvates thereof are. 2nd PATENT CLAIMS 1. Compounds of general formula I: x- (CHj! nz (CB ^ NKjna1 Fl V in which R1 represents hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, * CH2 3-Amino4- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthioj-ethylaminoj-l, 2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 15. A compound according to claim 1, namely 3-amino 3rd 655 111 independently of one another denote methyl or ethyl; or pharmaceutically acceptable salts, hydrates or solvates thereof. 3. Compounds according to claim 1 of the general formula Ia: where p is 1 or 2, R2 and R3 are each independently hydrogen, lower alkyl, lower alkoxy or halogen, and when R2 is hydrogen, R3 can also be trifluoromethyl, or R2 and R3 taken together are methylenedioxy, and R4 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 represents oxygen, sulfur or methylene; and A has the following meanings: 25th Ia ch2ch2ch2nk 30th lr ~ i k \ / b NKR where R 'represents a hydrogen atom or a methyl radical, wherein 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, wherein the lower alkoxy radical is at least 2 carbon atoms from the nitrogen atom, or are phenyl lower alkyl, or if R6 is Is hydrogen, R7 can also be cyclone lower alkyl, or R6 and R7, together with the nitrogen atom to which they are attached, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2 , 3,6-tetra-hydropyridyl, homopiperidino, heptamethyleneimino, octa-methyleneimino, 3-azabicyclo [3.2.2] non-3-yl or 3-pyrrolino; or pharmaceutically acceptable salts, hydrates or solvates thereof. 4th is where 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, wherein the lower alkoxy group is at least 2 carbon atoms from the nitrogen atom, or phenyl-lower alkyl , and, if Rfi represents a hydrogen atom, R7 can also be cyclo-lower alkyl, or R6 and R7, together with the nitrogen atom to which they are attached, a pyrrolidino, methylpyrrolino, dimethylpyrrolidino, morpholino, thiomorpholine, Piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tretrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo [3.2.2] non-3- yl or 3-pyrrolino radical mean as means for carrying out the process according to claim 19. 24. Compounds according to claim 23 of the general formula II: A- (CH2) raZ (cH2) nNH NKR HN u v NH wherein R1 is a hydrogen atom or lower alkyl, m represents 0 or 1, n represents 2 or 3, Z represents an oxygen or sulfur atom, and A represents the formulas: v yc! V wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R "and R ~ independently of one another represent methyl or ethyl. 27. Compounds according to claim 23 of the general formula Ile: \ 4- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethylamino} -1,2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 16. A compound according to claim 1 which is 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] - 5 655 111 wherein A, m, Z, n and R1 have the meanings given below, and their pharmaceutically acceptable salts, hydrates and solvates, are especially strong Hista-min-H2 receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of peptic Ulcer and other pathological hypersecretions. The compounds are prepared by ring closure of the correspondingly substituted ethanediimidamides of the formula II pen »at the 3- and 4-position, as starting materials or as an intermediate. Although numerous variants were used together with different reaction conditions, we were unable to obtain the compounds according to the invention in this way. It has now been found that the compounds of the present invention can be prepared by ring closure of the correspondingly substituted ethanediimidamides of the formula II a- (ck2) mz (ch2) nnh ^ - (- kkr2 II A- (CH2) nZ (CH2) nNH-C. HN -C ^ NHR HN II The published GB application 2,067,987 describes 3,4-disubstituted-l, 2,5-thiadiazole-l-oxides and 1,1-dioxides of the formula A- (CH,) Z (CH,) NH "-1 "5 IIa 25th NCH- • OCH2CH2CH2NH NHR1 HN NK fn <\ - I 30 wherein R5 represents a hydrogen atom or methyl, and R6 and R7 each independently represent methyl or ethyl, or, together with the nitrogen atom to which they are attached, form a pyrrolidino or piperidino ring. 25. Compounds according to claim 23 of the general formula IIa: NCH-- IIa JCH ^ CH ^ CH ^ NH. NKR1 5. Compounds according to claim 1 of the general For-55 mei Ic: 60 ^ nch2 —y ^ j3 \ -ck2sch2ch2nk nkr1 ■ ^ H, - No. wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R6 and R7 each independently , 6 / NCH- CH2SCII2CH2NH NHR Yi HN NH Ile II 20th wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R6 and R7 each independently represent a methyl or ethyl radical. 28. Compounds according to claim 23 of the general formula Ild: , 6 / nch. -] - -4r- och.ch, ch_nh Ini N N \ s / ' NHR wherein R1 and R5 each independently represent a hydrogen atom or methyl, and R6 and R: independently represent methyl or ethyl, or, together with the nitrogen atom to which they are attached, form a piperidino radical or pharmaceutically acceptable salts, hydrates or solvates thereof . 6. Compounds according to claim 1 of the general formula Id: 7. A compound according to claim 1 which is 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thia-diazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 8. A compound according to claim 1 which is 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thia-diazole hydrochloride. 9. A compound according to claim 1, namely 3-amino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -l, 2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate from that. 10. A compound according to claim 1, namely 3-amino-4- | 2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino} -l, 2,5-thiadiazole, or a pharmaceutically acceptable salt , Hydrate or solvate thereof. 10 rows \ rf or NCH- 11. A compound according to claim 1 which is 3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamine] -1, 2,5-thiadiazole, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 12. A compound according to claim 1 which is 3-methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] 13. A compound according to claim 1 which is 3-benzyla-mino-4- [3- (3-piperidinomethylphenoxy) propylamino] - 14. A compound according to claim 1, namely 15 The compounds II themselves can be prepared by various processes.