DD210909A5 - METHOD FOR PRODUCING SUBSTITUTED 3,4-DIAMINO-1,2,5-THIADIAZONE COMPOUNDS - Google Patents

Abstract

Process for the preparation of novel histamine H 2-receptor antagonists and intermediates for their production. According to the inventive method can be prepared substituted Aethandiimidamid intermediate products of general formula II. Histamine H 2-receptor antagonists of the general formula I can be obtained from these intermediates by ring closure according to the process of the invention, in which A, m, Z, n u. R high 1 have the meanings indicated. The compounds of general formula I and their non-toxic, pharmaceutically acceptable salts, hydrates and solvates are valuable anti-ulcer agents.

Description

Process for the preparation of substituted 3,4-diamino-1,2,3-thiadiazole compounds which are histamine H -, receptor antagonists.

Field of application of the invention

The invention relates to a process for the preparation of substituted 3,4-diamino-l, 2,5-thiadiazole compounds which are histamine H_ receptor antagonists. These compounds inhibit gastric acid secretion and are useful in the control of peptic ulcer and other pathological hypersecretions.

i'fü 1 ^ * 152285

Characteristic of the known technical solutions

Published UK Application 2 067 987 describes 3,4-disubstituted-1,2,5-thiadiazole-1-oxides and 1,1-dioxides of the formula

ΙΓ \

N N

(O) _p

: I;. 5 · /: ;; :: ./ ' -. ...

and processes for their preparation, wherein the radicals A, m, Z, η and R are similar to the radicals disclosed and claimed in the present application. However, the compounds described therein are 1-oxides or 1,1-dioxides (p is 1 or 2), and the compounds of this invention can not be prepared by the methods used to prepare the prior art compounds.

Published European Patent Application no. 40,696 describes inter alia 3,4-disubstituted-1,2,5-thiadiazole-1-oxides and 1,1-dioxides of the general formula:

R-- (CH ₂ ) _n -X- (CH) NH

~ 2

and processes for their preparation, wherein the radicals R, @, n, X, m, R and R are similar to the corresponding substituents of the compounds described and claimed herein. However, those are described there. Compounds also 1-oxides or 1,1-dioxides (p = 1 or 2) and the compounds of the present invention can not be obtained by any of the methods for preparing the compounds of the prior art.

In the two above-mentioned publications, each of the processes described for the preparation of the prior art compounds comprises the use (as starting material or intermediate) of a 1,2,5-thiadiazole-1-oxide or -1,1-dioxyd which either Amino groups or suitable leaving groups in the 3- or. 4 position has. "The desired substituents in the 3- and 4-positions are then obtained by substitution on the amino groups or by" j "of the" leaving groups. "Far-reaching attempts have been made to prepare the compounds of the invention in a similar manner, ie ·.

by giving 1,2-thiadiazoles

Amino groups or suitable "leaving groups" in the 3- and 4-position, als.Ausgangsmaterial, or used as an intermediate. Although numerous variants were used together with different reaction conditions, one was unable to obtain the compounds of the invention in this way.

Object of the invention

The aim of the invention is the development of a new process for the preparation of 3- (amino or substituted amino) -4- (substituted amino) -1,2,5-thiadiazoles of general formula I:

" ^iCH 2 K ^{Z (CH} 2 ⁾ n ^NI S ^

Ti

Ti

wherein A, m, Z, η and R have the meanings given below, as well as their non-toxic pharmaceutically acceptable salts, hydrates and solvates.

Explanation of the essence of the invention

It has now been found that the compounds of general formula I according to the invention:

^(CH 2

wherein A, m, Z, η and R have the meanings given below-L, by ring closure of the correspondingly substituted Äthandiimidamids the general formula II :.

A- (CH ₂ ) _β ζ (CH ₂ ) _n NH-r_r. _NHR l

can be produced.

The inventively prepared 3- (amino or substituted amino) 4- (substituted-amino) -1,2,5-thiadiazoles of general formula I are strong histamine H ^ receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of peptic ulcer and other pathological hypersecretions.

The present invention thus relates to a process for the preparation of histamine H-receptor antagonists of the formula I:

A- (CH ₂ ) _m Z (CH ₃ J _n N

R ^{1 represents} a hydrogen atom, (lower) alkyl / 2-fluoroethyl, 2 / 2,2-trifluoroethyl, allyl, propargyl,

stands,

2 3

in which ρ is 1 or 2, R and R independently of one another denote a hydrogen atom, (lower) alkyl, (lower) alkoxy or a halogen atom,

2 3

and, when R is a hydrogen atom, R is tri-

2 3

fluoromethyl, or R and R together

4 can denote methylenedioxy and R can denote a hydrogen atom, (lower) alkyl or (lower) alkoxy;

m is an integer from 0 to 2 inclusive; η is an integer from 2 to 5 inclusive; Z is an oxygen, sulfur atom or methylene

means; and A for

, N (CH ₂ )

/ ^NiGH 2> q

or

stands,

R is a hydrogen atom, alkoxy;

finally 4 means and R and R

(lower) alkyl or (lower) -q is an integer from 1 to

each

independently of one another (lower) alkyl, (lower) alkoxy- (lower) alkyl, wherein the (lower) alkoxy radical is at least two carbon atoms removed from the nitrogen atom, or phenyl (lower) alkyl, and, when R is a hydrogen atom, Smoke

Or R and R together with the nitrogen atom to which they are attached, pyrrolidino, methylpyrrolidino, dimethylpyrrolidono, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3, 6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo [3.2. 2] may be non-3-yl or 3-pyrrolino; and non-toxic pharmaceutically acceptable salts, hydrates and solvates thereof.

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 means a straight-chain or branched alkyl group containing 1 to 6 carbon atoms. The term "(lower) alkoxy" means a straight or branched alkoxy group comprising 1 to 4 carbon atoms. "Cyclo (lower) alkoxy" means a cycloalkyl group containing from 3 to 6 carbon atoms.

The term "non-toxic pharmaceutically acceptable salts" means acid addition salts which are acid-substituted, e.g. Hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, tartaric, citric, levulinic, benzoic, succinic, and the like.

In the compounds of the formula I, R is preferably 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, the substituted furyl or substituted thienyl as shown above, and most preferably the substituted phenyl. The substituent Z is preferably a sulfur or oxygen atom and, when A is the substituted phenyl radical, Z is preferably an oxygen atom. Preferably, m is 0 or 1 and η is 2 or 3, and

.When A is the substituted phenyl radical, m is 0 and η is 3. R is preferably a hydrogen atom

or methyl, and most preferably a hydrogen atom.

6 7 '

Preferably, q is 1. R and R are preferably ^1-way (lower) alkyl, or together with the nitrogen atom to which they are attached, pyrrolidino or piperidino.

The compounds of formula I can be prepared by reacting a compound of formula II with sulfur monochloride (S ₂ Cl ₂ ), sulfur dichloride (SCl ₂ ) or chemical equivalents thereof as listed below:

A-

(CH ₂ J _n NH-CC-NHR ³ HN NH

II

S ₂ Ci ₂

or SCl.,

N /

A- (CH,) Z (CH ₅ ) NH.

wherein A, m, Z, η and R have the meanings given above. At least 1 mole of S ₃ Cl ₂ or SCl ₉ should be used per mole of Compound II; It is preferable to use an excess of S CL or SCl ₃ , eg about 2 to 3 moles

or

SCl ₂ per mole of compound II. It has been found that SCl ₂ often gives a more crude product and a smaller amount of purified product. We normally prefer S ₃ Cl ₃ 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. "The reaction is best carried out at ambient temperature The reaction time is not critical and depends on the temperature 30 minutes to about 6 hours At ambient temperature, reaction times of about 1½ to 4 hours are normally preferred The reaction can be carried out in an inert organic solvent

be, preferably a mixture of an inert organic solvent and dimethylformamide.

Most preferred is the reaction in dimethylformamide

carried out.

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

A-

(CH

wherein R represents a hydrogen atom or (lower) alkyl, m is zero or 1 and η is 2 or 3, Z is an oxygen atom and A is

R *

R " UJ V

or

wherein R is hydrogen or methyl, and R and R are each independently methyl or ethyl, or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidine ring.

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

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

wherein R is a hydrogen atom or methyl, and R and R are each methyl, or together with the nitrogen atom to which they are attached, a pyrrolidino or piperdinoring; or a non-toxic pharmaceutically acceptable salt, hydrate or solvate thereof.

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

wherein R and R each independently represent a hydrogen atom or methyl, and R and R independently represent methyl or ethyl; or a non-toxic, pharmaceutically acceptable salt,. Hydrate or solvate thereof.

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

R ⁵ • 10 ^ -i-77 ^ H ₂ SCn ₂ CH ₂ NH. .NHR ¹ IC

wherein R and R each independently represent a hydrogen atom or methyl and R and R independently of one another each represent methyl or ethyl; or a non-toxic pharmaceutically acceptable salt, hydrate or solvate thereof.

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

OCH ₂ CH ₂ CH ₂ NH

// W NK

Wherein R and R are each independently hydrogen or methyl and R and R are each independently methyl or ethyl, or taken together with the nitrogen to which they are attached, represent a piperidino group; or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

The currently most preferred compounds of formula I are:

, "

1) 3-AnUnO ^ - [3- (3-piperidinomethylphenoxy) propylamino] -! , 2,5-thiadiazole;

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-pyrrolidinomethylphenoxy) 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- [(S-dimethylaminomethyl-S-thienyl-methylthio] ethyl-amino) -1,2,5-thiadiazole,

8) 3-Amino-4-p-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

10) 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propylamino] -1, 2, 5-thiadiazole,

11) 3-AmXnO - ^ - Cs-f3- (1,2,3,6-tetrahydro-1-pyridyl) -. methylphenoxy] -propylamino} -1,2,5-thiadiazole,

or non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof. ,

The intermediates of formula II used in the preparation of the compounds of formula I can themselves be prepared by various methods. 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 give the compound of formula To receive II.

III

HCl

A- (CH,) Z (CH ₅ ) NH 2. m zn

NHR ^J

II

The reaction can be carried out in an inert solvent and is carried out, preferably 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 readily prepared by methods such as described in British patent 2,067.

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

\ _NH

IV

A- (CH,) Z (CH,) NHV / ⁰ C "* ζ τη η * \ / J

hl

VI

R ¹ NH

A- (CH.

η /

.nhr

III

The reaction may be carried out in an inert solvent, and preferably in methanol. The starting materials of formula IV are known or can be readily prepared by known methods such as described in our published British Patent Application 2,067,987.

On the other hand, the invention relates to a novel process for the preparation of intermediates of general formula II:

A- (CH ₂ ) _TO Z (CH

in which R is a hydrogen atom, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,

R ²

or

is standing, 2 3

wherein ρ is 1 or 2, R and R each independently represent a hydrogen atom, (lower) alkyl, (lower) alkoxy or halogen, and

2 3

when R represents a hydrogen atom, R also

2 3 may be trifluoromethyl, or R and R together

4 methylenedioxy and R is a hydrogen atom, (lower) alkyl

or (lower) alkoxy may mean; 15

m is an integer from 0 to 2 inclusive; η is an integer from 2 to 5 inclusive; Z represents an oxygen atom, sulfur atom or methylene; and ^A stands for

R ⁵ JR ⁵

7. -7

or

wherein R is a hydrogen atom, (lower) alkyl or (lower) alkoxy, q is an integer from 1 to 4, inclusive, and R and R are each independently (lower) alkyl, (lower) alkoxy (lower) alkyl, said (lower) alkoxy is at least two carbon atoms away from the nitrogen atom,

or phenyl (lower) alkyl, and when

6 7

R represents a hydrogen atom, R also. Cyclo (lower) alkyl, or R and R together with the nitrogen to which they are attached, pyrrolidono, methylpyrrolidino, dimethyl pyrrolidino, morpholines), 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.

, According to a preferred embodiment, the intermediates of the formula II have the structure IIs

^A ~ ^iCH 2 ⁾ m ^ZiCH 2 ⁾ n ^NH v / ^NHr

wherein R is a hydrogen atom or (lower) alkyl

1 is, η is 2 or 3, Z is an oxygen or sulfur atom, and

or

stands in which

R is a hydrogen atom or methyl, and R and R are each independently of one another methyl or ethyl, or together with the nitrogen to which they are bonded, a pyrrolidino

or piperidino ring; or a non-toxic pharmaceutically acceptable salt, hydrate or solvate thereof.

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

Ha

wherein R is a hydrogen atom or methyl,

6 and R and R are each methyl, or together with the nitrogen atom to which they are attached,

a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

According to a preferred embodiment, the intermediates of the formula II have the structure Hb:

HN NH

wherein R and R each independently represent a hydrogen atom or methyl, and R and R each independently represent methyl or ethyl; or a salt, hydrate or solvate thereof.

According to another preferred embodiment, the intermediates of formula II have the stuktür lic:

CH ₂ SCH ₂ CH ₂ NH. .NHR ¹

HN NH

wherein R and R are each independently

   '' '' '6' 7

Hydrogen or methyl, and R and R are each independently methyl or ethyl; or a salt, hydrate or solvate thereof.

According to another preferred embodiment, the intermediates of the formula II have the structure Hd:

OCH ₂ CH ₂ CH ₂ NH J ¹ HRI

jri '

HN NH

Wherein R and R are independently hydrogen or methyl and R and R are each independently methyl or ethyl, or taken together with the nitrogen atom to which they are attached, are piperidino; or a salt, hydrate or solvate thereof.

The most preferred intermediates of formula II are:

1) N- [3- (3-piperidinomethylphenoxy) propyl] ethyl ^ imidamide,

2) N- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylpäthandiimidamide,

3) N - {2- (S-dimethylaminomethyl) -methyl-thienyl) -methylthio] -ethyl} -äthandiimidamide,

4) Nr [-3- (3-pyrrolidinomethylphenoxy) propyl] ethanediimidamide,

5) N- {2 - [(S-dimethylaminomethyl-S-thienyl) methylthio] -äthylfäthandiimidamid,

6) N- "{2- [(S-piperidinomethyl-S-thienyl) methylthio] -äthyIäthandiimidamid,

7) N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] -äthandiimidamide and

8) N- [3- (4-piperidonomethyl-2-pyridyloxy) propyl] -äthandiimidamid;

9) N- {3- [3- (1,2,3,6-tetrahydro-1-pyridyl) -methoxy-phenoxy] -propyl-iodothiimidamide,

or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologically active compounds of formula I are normally administered as a pharmaceutical agent containing as active ingredient at least one compound of the invention in its oasiic form or in the form of a non-toxic pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable carrier.

The pharmaceutical agents can be administered orally, parenterally or rectally as suppositories.

A wide variety of pharmaceutical forms can be used. Thus, when a solid carrier is used, the preparation can be made into tablets, powdered or pelletized in a hard gelatin capsule, or in the form of a troche or lozenge. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injections or as an aqueous or nonaqueous liquid suspension The pharmaceutical compositions are prepared 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. desired gastric acid inhibition and the effectiveness of the compound used. Which dose to use

(and the number of administrations per day) is decided by the doctor 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 of 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 dosages 1 to 4 times daily.

Histamine H "receptor antagonists have been shown to be potent inhibitors of gastric secretion in animals and humans, Brimblecombe et al., Jv Int. Med. Res., 3 ^, 86 (1975). Clinical evaluations of the histamine H ₂ receptor antagonist cimethidine demonstrated that it is an effective therapeutic for the treatment of peptic ulcer, Gray et al., Lancet, λ_, 8001, (1977). Some of the preferred compounds of the present invention were compared to cimethidine in various assays and found to be stronger than cimethidine, both as a histamine H ^ receptor antagonist tested on the guinea pig isolated right atrium and as an inhibitor of gastric acid secretion in rats and dogs.

Determination of gastric antisecretory activity in rats with gastric fistula

Male Long Evans rats weighing approximately 240 to 260 g were used in the cannulation of the cannula. The manner of implantation of the stainless steel cannula into the anterior wall of the forestomach is performed 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.

ν 1

After the operation, the animals are kept individually in cages with solid soil with sawdust and get food and water ad libitum during the entire recovery time. The animals will not be used for testing at least 15 days after surgery.

Before the test, the animals are fasted, but give water ad libitum 20 hours before the test. Immediately before collecting the secretion, open the cannula and gently wash the stomach with 30 - 40 ml of warm saline or distilled water to remove any residue. Then screw the catheter into the cannula where the screw plug used to be, and place the rat in a clear rectangular plastic cage that is 40 cm long, 15 cm wide, and 13 cm high. The bottom of the cage has a slot about 1.5 cm wide and 25 cm long, which runs in the middle and through which the catheter emerges. In this way, the rat is not restricted and can move freely in the cage during collection times. Otherwise, the experiment is carried out as described by Ridley et al. described [Research Comm. Chem. Pharm., 17 , 365, (1977) 1.

The gastric secretions collected during the first hour after washing the stomach are discarded because they may be contaminated. For oral evaluation.

The catheter is then removed from the cannula and replaced by the screw plug. 2 ml / kg of water are given orally by gastric intubation and the rat is left in the cage for 45 minutes. After that, the screw plug is loosened and replaced with a catheter », which is a small one

Plastic surface carries and the gastric secretions fields. A 2-hour sample is collected (this is the control secretion), the catheter is removed and replaced with the cap screw. Then, the test compound is orally administered in a volume of 2 ml / kg by gastric intubation. 45 minutes later, the screw plug is reopened, replaced with the catheter to which a small plastic vial is 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 to determine the tested compound.

If the test compounds are evaluated parenterally, the animal is given i.p. or s.c «. the carrier of the test compound is injected in an amount of 2 ml / kg. Immediately before, the initially obtained solution collected for 60 minutes is discarded. Collect a 2 hour sample (control secretion) and then inject the animals either i.p. or s.c. the test compound in an amount of 2 ml / kg. Another 2 hour sample is collected, these secretions are compared with 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. Titreric acid is measured by titrating a 1 ml sample to pH 7.0 with 0.02N NaOH using a. Autoburette and an electronic pH meter (radiometer). The titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the concentration of milliequivalents per liter.

The results are expressed as percent inhibition relative to the control readings. Dose response curves are set up and .ED ₅₀ values calculated by regression analyzes. At least 3 rats are used for each one dose and at least 3 dosages are used to determine the dose-response curve.

table

Gastric antisecretory activity> tested on the 1.5 rat with gastric fistula

connection

ED ₅₀ se

95% confidence limit

efficiency ratio

μmole / kg (Cimethidin = 1.0) Cimethidin 3.48 (1.68-5.75) ^t: 1.0 example 1 0.094 (0.043-0.20) 37 Example 2 ". 0.77 (0.45-1.4) 4.5 , Example 3 A-0.5 ¹ '"< ~ 7"; , Example 4 0.18 (0.10-0.36) . * · 20 ·: · -

Histamine H receptor antagonism, tested on isolated guinea pig atria

Histamine causes concentration-dependent increases in the contractions of isolated, spontaneously beating atria of guinea pigs. Black et al., Nature, 236, 385 (1972) described the receptors involved in this effect of histamine as histamine H receptors when they reported the properties of burinamide, an antagonist of these receptors. "Later Hughes and Coret, Proc. Soc Exp. Biol. Med., 148 , 127 X1975) and Verma and McNeill, J. Pharmacol. Exp. Ther., 200 , 352 (1977) affirmed the conclusions of Black and co-workers that the positive chronotropic Effect of histamine on isolated right guinea pig atria mediated by histamine H 'receptors, Black et al., Agents and Actions, 3, 133 (1973) and Brimblecombe et al., Fed Proc., 3_5, 1931 (1976) isolated right atria of guinea pigs »

to the effect of histamine H ₂ receptor '

To compare antagonists. The present comparative studies were conducted using a modification of the method described by Reinhardt et al. ,] Agents and Actions, 4 _f 217 (1974). '

Male guinea pigs from the Hartly tribe (350-450 g) were killed by a blow to the head. The heart was removed and placed in a Petri dish containing oxygenated C95% O, 5% CO ") modified Krebs solution (g / liter: NaCl 6.6;

KCl α35, MgSO ₄ "7H ₂ O 0.295, KH ₃ PO ₄ 0.162, CaCl ₂ 0.238, NaHCO ₃ 2.1, and dextrose 2.09.) The spontaneously beating

right atrium was freed of other tissues and a silk thread (4-0) was attached to each end. The atrium was suspended in a 20 ml muscle chamber oxygenated modified Krebs solution contained, which was maintained at 32 ⁰ C. The atrial contractions were recorded isometrically with a Grass FT 0.03 force transducer and the force and rate of contraction were recorded on a Beckman RP Dynograph.

A permanent tensile force of 1 g was applied to the atrium, in which state the preparation was released. Stand for 1 hour. Thereafter, a submaximal concentration of histamine dihydrochloride (3.1O.M) was added to the bath and washed out to prepare the tissue. Histamine was then added cumulatively to the bath at 1/2 log 10 intervals to give final bath concentrations of 1.10. to 3 × 10 mol. The histamine-induced increase in heart chamber beats was allowed to settle before the next concentration was discontinued. Maximum response was achieved at a dose of 3 χ 10 M each time. The histamine was washed several times, allowing the atrium to return to the control value. Then, the test compound was added in appropriate molar concentrations, and after a 30-minute incubation, the study of the response

3Q to the histamine dose, with the higher concentrations adjusted as needed.

The dissociation constants (K _n ) were calculated from the SchiId

ti

Curves according to the method of Arunlakshana, 0. and Shield, H.O. [Br. J. Pharmacol, t4, 48, (1959), based on at least 3 dosage units. Parallel shifts in dose-response curves were obtained without decreasing maximum response at the antagohist concentrations used. The results are shown in Table 2.

Table 2

Activity on isolated right guinea pig atria

Efficacy Connection N K (μΜοΙ) ratio. '

(Cimethidine = 1.0)

Cimethidine 20 0.41 (.0.21-0.64) ⁺ 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 the formula I can.

also by ring closure of a compound of the formula II with N, N ¹ -thiobisphthalimide of the formula:

getting produced.

The use of Ν, Ν'-thiobisphthaliinide instead of S ₃ Cl ₃ or SCl ₃ for ring closure gives both higher and purer yields of compounds of formula I. The crude products of formula I thus prepared are normally pure enough to be directly crystalline Salts without previously required chromatographic purification.

In this process, the starting diimide of formula II is reacted with an approximately equimolar amount of Ν, Ν'-thiobisphthalimide in an inorganic inert solvent such as CH ₃ Cl ₂ . Preferably, the diimideamide is used in the form of its trihydrochloride salt, in which case three molar equivalents of an amine, such as triethylamine, are added to the reaction mixture to neutralize the trihydrochloride salt. The reaction can be carried out by stirring at room temperature for about 1 hour to ensure completeness of the reaction. The phthalimide precipitated from the reaction mixture is then extracted with a strong base (eg 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 Ν, Ν'-thiobisphthalimide used in the present invention is a known compound wxe can be prepared in Canadian Journal of Chemistry, 4 ±, 2111-2113 (1966) or as described below.

Preparation of N, N'-thiobisphthalimide

To a cooled solution (O ⁰ G) of 14.7 g (0.1 mol) of phthalimide in 80 ml of dimethylformamide (DMF) is added dropwise 5.15 g (0.05 mol) of sulfur dichloride *, the mixture after addition within from 4 hours to 20 ⁰ C, collect the solid and dry to give 12.5 g of Titeiverbindung as DMF solvate, mp. 301-315 ° C> Both the IR and the NMR spectrum are in accordance with

the structure. .

Analysis for

20 calculated: found:

The DMF solvate can be removed from the substance by recrystallization in chloroform. The mp of the DMF-free product is 320-325 ⁰ C. In the NMR spectrum no DMF was seen more.

30

C , 42 H 80 N 57 S OE7 57 50 3 80 10 29 8th, 57 57 3 10 8th,

Analysis for C _ls I 8 2 4 * 25 H , 49 N , 64 S , 89 '·.-.-'.-' G- ' 21 2 , 21 8th 91 9 , 14 calculated: 59, 2 8th 10 found: 59,

35

Example 1 .

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

A. N- [3- (3-Piperidinomethylphenyl) propyl] ethanediimidamide 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 according to published GB Patent Application 2,067,987] in 450 ml of methanol with 38 ml of concentrated HCl, the resulting solution is stirred for 3 hours at room temperature, the solution is concentrated and the water is removed azeotropically with absolute ethanol to give 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. 205-220 ⁰ C (decomp.). Umkristailisation of 50% methanol / ethyl acetate gives an analytical sample with mp. 206-216 ° C (decomp.)

Analysis for C ₁₇ H. _{? 7} N ₅ O-3HC 84 H , 08 N 41 C 56 7 , 18 16 75 calculated: 47 7 16 found: 47

B. 3-amino-4-v [3- (3-piperidinomethylphenoxy) propylamino] -

V 5YV ^ 1,2,5 "thiadiazole

A stirred suspension of 2.13 g (5.0 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] -thathiirnidine diamine trihydrochloride [prepared in step A] in 20 ml of dimethylformamide (DMP) at 2.02 g (15.0 mmol) sulfur monochloride, stirred for a further 4 hours, the resulting mixture is carefully poured into 200 ml of water and made basic with K ₂ CO ₃ . It is then extracted with 3 χ 50 ml of methylene chloride, dried over MgSO 4 and concentrated to give 2.1 g of a dark gummy product. The product is purified on silica by HPLG chromatography using GH ₂ GIj (IOO): 2-propanol (10): NH.OH (0.5) as the mobile phase. The appropriate fractions give 0 * 89 g of Titölverbihdung, from which with fumaric acid in nHPröpariol 0.76 g (21.4%) of Tite! Compound is obtained as a crystalline Fumaratsalz] purity according to HPLC> 99%.

Fumarate salt, m.p. 187-187> 5G.

-. ;

Analysis for (C ₁₇ H ₂₅ N ₅ OS)

C H , 71 ^N , 27 S 90 calculated: 56.27 6 , 36 17 , 98 7 , 08 found: 56.09 6 16 8th

A portion of the fumarate is suspended in water, neutralized with K ₂ CO ₃ , extracted with CH ₂ Cl _2, and concentrated with CH ₂ Cl ₂ , concentrating the 'CH ₂ Cl ₂ phase to crystallize the free base of the title compound, m.p. 43-47 ⁰ C * part of de * free B.ase is converted to the hydrochloride salt, mp. 138-140 ⁰ C. ·

* - 32 -

Analysis for C ₇ H ₂₅ N ₅ OS-HCl:

C 18 H , 83 N 24 S 35 calculated: 53 14 6 , 88 18 , 49 8th , 74 found: 53 6 18 8th

10

Example 2

3-Amino-4 - "{2- [(5-dimethylaminomethyl-2-furyl) methyl]

thioj-ethylamine-1, 2, 5-thiadiazole.

15

A. N- {2- [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl ] -äthandiimidamid-trihydrochloridhydrat

A suspension of 6.59 g (20.0 mmol) of 3-amino-4-{2 - ((5-dimethylaminomethyl-2-furyl) methylthio] ethylamine / 1, 2, 5-thiadiazole 1-oxide [produced 200 ml of methanol are slowly heated to obtain a complete solution, then treated with 13.3 ml of concentrated HCl, stirred for a further 2.4 hours: at room temperature, the solution is concentrated and the residue is triturated with 70 ml of absolute ethanol. the crystals are filtered and dried in vacuo to give 4.3 g <52% ') of the title compound, mp. 166-169 ⁰ C (dec.).

Analysis for C ₁₂ H ₂₁ N

35 calculated: found:

C , 08 H , 38 N , 05 S 80 35 85 '6 24 17 45 7 97 34 6 17 7

For example, 3-amino-4- {2 * [(5-dimethylaminomethyl-2-furyl) - ^: methylthio] ethylamino} -1,2,5-thiadiazole

To a stirred suspension of 12.3 g (30.0 mmol) of N- {Ir- [ (5-dimethylamino-5-methyl-2-fluoro) methylthio] ethyl} -ätharidiimidamid-trihydrochlorid hydrate [prepared in step A] in 150 ml of DMF 7.2 ml of sulfur monochloride (12.1 g, 90 mmol) are stirred for a further 4 hours at room temperature, about half of the DMF is removed under reduced pressure, the remaining black solution is poured into 1 liter of water, basic with K ₃ CO ₃ and extracted first with ethyl acetate and then with chloroform. After drying over MgSO 4, filter and concentrate to give 9.0 g of a black, gummy product containing the product. This is purified by HPLC on silica, using ethyl acetate (100): 2-propanol (10) -TNH ₄ OH (0.5) as the mobile phase. The appropriate fractions give 1.24 g of the title compound as a gummy product.

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

''. ';;'.;;"; - ''' . ··. Analysis for C ₁₂ H ₁₉ N ₅ S ₂ O

C H N S

calculated: 41.18 5.76 20.02 18.33% found: (corr.

for 1.65% H ₂ O) 40.54 5.70 19.39 18.44%

Treatment of the product with an equivalent amount of cyclohexyl sulfamic acid in acetone gives the cyclohexylsulfamate salt of the title compound, m.p. 93-95 ° C. ?: ': - ^ Vv-; ;;;;: · - .. ·. ; .

Analysis for

calculated: found:

.- 'C. . .- Λ-ν: - H , 55 N , 06 S , 53 % 43.88 6 17 17 , 21 19 , 58 % 43m77 6 17 19

S ρ j

3-Amino-4 - \ 2- [{5-dimethylaminomethyl} -1,4-methyl-2-thienyl) ethylthio] ethylaminoj-1,2,5-thiadiazole

A. N- £ 2- [{5-diynes ⁱ thyl ¹ ami'noraethyiV4-methyl.-2-thiority'l) '· ¹ -'. ' methylthio] ethyl] ethanimidamide 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 is added thiadiol-1-oxide (prepared according to the general procedure described in published British Patent Application 2,067,987) in 500 ml of methanol containing 33 ml of conc. HCl, stirring for an additional 3 hours, concentrating the reaction mixture and removing excess water by azeotroping with absolute ethanol to give an almost colorless crystalline residue. The residue is triturated with 200 ml of absolute ethanol at 0, ⁰ C, filtered and dried to give 16.9 g (80%) of the title compound, FP 206 - 220 ⁰ C (dec.) Umkristalli-

C , 92 H 20 N , 56 S 17 36 , 76 6 , 33 16 97 15 , 54 36 6 16 15

Solution of 50% methanol / ethyl acetate gives a product with mp 210-221 ° C (dec.).

Analysis for

calculated: found:

B. 3 ⁱ -amino-4 {2-ί (S-dimethylaminomethyl - ^ - methyl - ^ - thienyl) methylthio] ethylHo) -1,2,5-thiadiazole

To a stirred suspension of 6.34 g (15.0 mmol) of N- {2- (S-dimethylaminomethyl) -methyl-1-thiethyl) -methylthio] ethyl} -äthandiimidamid-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 KjCO- and extracted several times with 100 ml of methylene chloride. The extracts are dried over MgSO ₄ , filtered and concentrated to give 3.4 g of a black, gummy product. This is purified by preparative HPLC chromatography on silica, using CH ₂ Cl ₂ (IOO): 2-propanol (10): NH.OH (0.5) as the mobile phase. ,

Further purification is achieved by additional HPLC chromatography on silica, using CH ₂ Cl ₂ (100): CH ₃ OH (2.5): NH ₄ OH (0.5) as the mobile phase. The appropriate fractions give the title compound (purity <v98%). The treatment

3 g of the product with an equivalent amount of 2N HCl gives the hydrochloride salt of the Ti compound.

Analysis for C ₁ , H ₉₁ N ₁ -S, * HCl

C H N S

calculated: 41.09 5.84 18.43 25.32%

found: (corr

0.51% H ₂ O) "40.78 5.63 18.31 s 5.44% 10

Example 4

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

A. N- [3- (3-pyrrolidinomethylphenoxy) propyl] -äthandiimid amide-trihydrochloride '

A suspension of 13.4 g, (38.3 mmol) of 3-amino-4- [3- (3-pyrrolidinomethyl-phenoxy) propylamino] -1,2,5-thiadiazole-i-oxide {prepared according to published GB -Patentanmeldung 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 azeotroped with absolute ethanol to give the product. The crystalline residue is triturated with 150 ml of absolute ethanol, filtered and dried, yielding 10.8 g. Title compound ", m.p. 195-203 ⁰ C (decomp.).

Analysis for ^C 16 ^H 2 5N ₅ O'3HCl: H , 84 N , 92 C 6 , 93 16 , 93 calculated: 46,55 6 16 found: 46,55

3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylarhino] 1,2,5-thiadiazole ,

A stirred suspension of 8.25 g (20.0 mmol) of N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride [prepared in step A] in 80 ml of DMF is treated with 5.4 g (40.0 mmol) sulfuric acid, stirred for 3 hours under nitrogen atmosphere and concentrated the reaction mixture, giving a dark, rubbery product, which is suspended in 500 ml of water * then made basic with K ₅ CO ₃ , extracted with 3 χ 100 ml Methylenchiorid, dried the extracts over MgSO 4, filtered and concentrated to give 7.5 g of a dark gummy product. This is ratchigt by means of HPLC on HPLC silica using CH ₂ Cl ₂ (IOO): 2-propanol (5) VNH ₄ OH (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 138M40 ° C.

Analysis for C _lg H 3N ₅ OS HC 95 H , 54 N , 93 S , 67 C 97 6 , 36 18 , 63 8th , 76 calculated: 51 6 18 8th found: 51

Example 5 5

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

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

(b) 3-amino-4- [3- (3-dihydroxypropylamino] -1, 2,5-thiadiazole-i-oxide,.

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

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

(e) 3-amino-4- {3- [3- (4-methylpiperidino) -methylphenoxy] -propylamihoi-1,2,5-thiadiazole-1-oxide ,

(f) 3-amino-4- {3- (3-morpholinomethylphenoxy) propylamino] -1,2,5-thiadiazole-i-oxide,

(g) 3-Amino-4- {3- [3- (N-methylpiperazino) methylphenoxy] ™ propylaminojl-1, 2, 5-thiadiazol-i-oxide,

(h) 3-Amino-4- [3- (3-diallylamino-methyl-phenoxy) -propyl-amino] -

1, 2,5-thiadiazole-i-oxide, (i) 3'-amino-4 - [3- (3-hexamethyleneiminomethylphenoxy) -propyl-amino] -1,2,5-thiadiazole-1-oxide, (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) -methyl-phenoxy ] -propylaminoJ _y-1 2,5-thiadiazole-1-oxide, or (1) 3-amino-4- {3- [3- (3-pyrrolino) methylphenoxy] propylaminoj-1, 2, 5-thiadiazol-1- oxide

replaced. You get that

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

(b) 3-amino-4- [3- (3-diethylamihomethylphenoxy) propylamine] 1,2,5-thiadiazole,

(c) 3-Amino-4- {3- [3- (2-methyl-pyrrolidino) methylphenoxy] '· *' propylarainoJ-1, 2, 5-thiadiazole,

(d) 3-amino-4-f3- [3- (3-methylpyrrolidino) methylphenoxy] -propylamino} -1,2,5-thiadiazole,

(e) 3-Amino-4-t3- [3- ^(4-i methylpiperidino) methylphenoxy] -propylattiino} -1,2,5-thiadiazole,

(f) 3-amino-4- [3- (3'-morpholino-methylphenoxy) propylamino] -1,2,5-thiadiazole,

(g) 3-Atnino-4 - f 3 - [3- (N -methylpiperazino) inethylphenoxy] propylamino} -1,2,5-thiadiazole,

(h) 3-Amirio-4 · ⁴ - [3- (3-diallylaminomethylphenoxy) propylattiino] -1 , 2, 5-thiadiazole, (i) 3-Amino-4- [3- (3-hexamethyleneiminomethylphenoxy) propyl]

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

(k) 3-Amino-4- {3- [3- (3-azabicyclo-13.2.2] non-3-yl) methylphenoxy] -propylamino] -1,5-thiadiazole

or (1) 3-amino-4- {3- [3- (3-pyrrolino) methylphenoxy] propylamino J- 1,2,5-thiadiazole.

Example 6

3-Amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -T , 2,5-thiadiazole

This represents a variation of Step B of the example, using less sulfur monochloride and choosing a shorter reaction time.

To a stirred suspension of 12.08 g (28.3 mmol) of N- [3- {3-piperidinomethylphenoxy) -propyl] -äthandiimidamidtrihydrochlorid in 120 ml of DMF are added 7.64 g (56.6 mmol) of sulfur monochlide, stirred the mixture .3 hours under N "atmosphere and the DMF is removed under reduced pressure to obtain a black, rubbery product / this is suspended in water, basified with K ₂ CO ₃ and extracted with 3 χ 100 ml of CH ₂ Cl ₂ , The combined extracts are dried over MgSO ₄ , filtered and concentrated to give a black, gummy product. This gummy product is purified by preparative HPLC chromatography on silica, using CH ₂ Cl ₂ (IOO): 2-propanol (5); NH ₄ OH (o, 5) as the mobile phase. The appropriate fractions give 3.1 g of the title compound as a dark oil, which gives, with fumaric acid in n-propanol, 2.66 g (23.2%) of the title compound as a crystalline fumarate salt, m.p. 186-186.5 ° C. Purity by HPLC 99%.

Analysis for (C ₁₇ H ₂₅ N ₅ OS) ₂ -C ₄ H ₄ O ₄ :.

35 calculated: found:

C / 27 H / 71 N / 27 S 90 56 , 27 6 / 96 17 / 31 7 , 98 56 6 17 7

example 7

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

This represents a variation of Step B of Example 1, using sulfur dichloride instead of sulfur monochloride.

To a stirred suspension of 854 mg (2 mmol) of N- [3- (S-piperidinomethylphenoxy) propyl] ethanediamide amide trihydrochloride in 6 ml of DMF in an ice bath is added under N_ 206 mg (2 mmol) of SCI ₃ in 2 ml of DMF, stirred the resulting! - mixture at room temperature and receives the title compound.

Example 8

   *.

3-methylamino-4- [3- (3-piper idinome thy lphenoxy) propyl 1- amino] -1 ₇ 2 _f 5-thiadiazol

' N-methyl-N ¹ - [3- (3-piperidinyl thypoxy) propyl] -äthandiimidamid-trihydrochloride

, A suspension of 4.13 g (10.9 mmol) of 3-methylamino-4- [3- (3-piperidinomethylphosphinolpropylamino] -1,2,5-thiadiazole-1-oxide is added. prepared according to published GB Patent Application 2,067,987] in 95 ml of methanol with 7.2 ml of concentrated HCl, stirred for 3 hours at room temperature, the solution concentrated and the residue triturated with acetone. It is then filtered and dried to give 4.35 g (90.4%) of the desired product. A sample of this is crystallized from aqueous isopropyl

alcohol to give the title compound, m.p. 207-225 ° C (dec.).

Analysis for C ₁₈ H ₂₉ N ₅ O '

C H N calculated: 49.03 7.33 15.89%

found (corr. for 49.37 7.35 15,71% '"0,94% H ₂ O)

For example, 3-methylamino-4- [3- (3-piperidinomethylphenoxy) -propylamino ] -1,2,5-thiadiazole * ;

A mixture of 3.74 g (8.47 mmol) of N-methyl-N ¹ - [3- (3-piperidinomethylphenoxy) propyl] -äthandiimidamid-trihydrochloride [prepared in step A], 34 ml CH_C1 ₂ and 3.5 ml Triethylamine is treated

with 3.36 g (8.46 mmol) of N, N ¹ -thiobisphthalimide (DMF solvate) and stirred for 1 hour. The mixture is then washed with 30 ml of 10% KOH, dried (MgSO 4), diluted with toluene and concentrated to give 3.6 g of the product. Purify this product by flash chromatography on 90 g of silica gel (63r38 μm, 230-2400 mesh) using ethyl acetate-methanol (95: 5) as the eluent. This gives 1.9 g (62%) of the title compound. The 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 ⁰ C.

Analysis for C ₁₈ H ₂₇ N ₅ OS-HCl:

C , 32 H - · N 60 S , 06 Cl 91 calculated: 54 35 7 , 04 17 , 64 8th , 36 8th, 86 found: 54 7 , 07 17 8th 8th,

Example 9 5

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

A. N-Benzyl-N · - [3- (3-piperidihomethylphenoxy) propyl] -äthandiimidamide trihydrochloride __

A suspension of 5.14 g (11.3 mmol) of 3-benzylamino-4- [3- (3-piperidinomethylphenoxy) -propylamino] -1,2,5-thiadiazole-1-oxide [prepared according to 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, the solution is concentrated and the residue is triturated with acetone. Then it is filtered and dried to give 5.16 g (88%) of the title compound, mp 187-205 ° C (dec.).

Analysis for C-.Η - N ₁ -O-3HCl: 24 33 5

• calculated: C 75 H , 03 N , 55 Cl , 57 found: 55 , 88 7 75 13 , 33 20 20 54 6 13 20

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] -äthandiimidamid-trihydrochloride [prepared in step A], 45 ml of CH ₃ Cl ₂ and 3.8 ml of triethylamine

with 3.64 g (9.16 mmol) of Ν, Ν'-thiobisphthalimide (DMF solvate) and stirred for one hour. Then you wash

The mixture is washed with 44 ml of 10% KOH , dried (MgSO 4), filtered, diluted with toluene and concentrated. The residue is chromatographed by means of "flash" chromatography on 110 g of silica gel (63-38 μm, (230-400 mesh)), ethyl acetate being used as eluent.

applies. This gives 3.1 g (77%) of the title compound., Treatment of this product with an equivalent amount of aqueous HCl in 2-propanol yields the hydrochloride salt of the title compound, mp. 138-141 ⁰ C.

Analysis C ₂₄ H ₃₁ N ₅ OS

calculated: 1 O C 80 H 80 1 N 77 6 S Cl 48 found: 60 , 53 6 , 64 1 4 99 6 , 76 7, 47 i s ρ i e 1 60 6 4 91 7, B e

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

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

A solution of 27.3 g (64.0 mmol) of N-l3- (3-piperidinomethylphenoxy) propyl] -äthandiimidamid-trihydrochloride [prepared in Example 1, step A1, 250 ml of CH ₂ Cl ₂ and 26.6 ml (192, mmol) of triethylamine are treated in portions with Ν, Ν'-thiobisphthalimide (DMF solvate) (25.4 g, 64.0 mmol), stirred for one hour at room temperature, the mixture is washed with 120 ml KOH, dried (on MgSO ₄ ) filtered and concentrated.

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 was concentrated to a 100 ml, diluted with 175 ml of dry 1-propanol and keeps it on at 0 ⁰ C to obtain 20.2 g (82.1%) of the crystalline Hydröchloridsalzes the title compound is obtained. , M.p. 137-138 ⁰ C.

Analysis for C - I I ₂₅ N ₅ OS , 18 H , 83 N 24 S 35 C , 78 6 , 74 18 , 52 8th, 66 calculated: 53 6 18 8th, found: 52

Example 11 . ,.; ...... 'V''' :. '' ·.

3-Amino-4- [3- (3-pyrrolidinomethylphenoxy) propylaminol- ^{1,2,5-thiadiazole,::} .. · - · _;.: .- , .-. ,,

! ν'Γ: 'y ..''\p' ^ r ^ f: ^j: M ^{': ^':} '' ''^-;"···'·"."'"''"' ^V - '. / · This example illustrates a modification of Example 4, Step B to give Ν, Ν'-Thiobisphthalimid instead of Schwefelinonochiorid used.

A mixture of 22.0 g (53.0 mmol) of N- [3- (3-pyyrolidinomethylphenoxy) propyl] -äthandiimidamid-trihydrochloride [prepared in Example 4 _# step A], 200 ml of CH ₉ Cl and 22 ml of triethylamine is added with 21.2 g (53.0 mmol) of Ν, Ν'-thiobisphthalimide (DMF solvate), stirred for 1 hour at room temperature, the mixture is washed with 100 ml of 20% KOH, dried (MgSO ₄ ), filtered. Diluted with 100 ml of toluene and concentrated.

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

Mp 135-137 ⁰ C. ₂₃ N ₅ O 95 H 54 N / 93 S / 67 Analysis for C ₁₆ H. 92 6 / 55 18 / 30 8th / 06 10 C 6 19 9 51 / calculated: 51 / found: 15 12 B e i s ρ i e 1

3-Amino-4- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthioj- ethylamino] j * -1, 2 , 5-thiadiazole

A. N- [2- [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl ] -äthandiimidamid-trihydrochloride

A suspension of 7.8 g (22.6 mmol) of 3-amino-4-2-t (5-dimethylamihomethyl-3-thienyl) methylthio] ethylamino-1,2,5-thiadiazole-i-oxide [prepared , according to the published GB patent application 2 o67 987] in 150 ml of methanol is treated with 115.0 ml of conc. HCl, stirred for 3 hours at room temperature and then concentrated. The residue is triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of the product. A sample is recrystallized from methanol-acetone to give the title compound, mp. 190-205 ⁰ C, (dec.).

Analysis C ₁₇ N 21 ^N 5 ^S 2 • 3 HCl: 25 H , 92 N 13 C , 03 5 , 93 17 , 39 calculated: 35 5 17 found: 35

3-Amino-4- {2- [(S -dimethylaminomethyl-S-thienyl) * -methylthio] -ethylamino} -1,2,5-thiadiazole

A mixture of 6.13 g (15.0 mmol) of N- "f2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl} -äthandiimidamid-trihydrochloride [prepared in step A], 60 ml of CH ₂ CO ₂ and 6.3 ml of triethylamine are treated with 5.96 g (15.0 mmol) Ν, Ν'-ΤΙιίο-bisphthalimide (DMF solvate), stirred for 1 hour, the mixture is washed with 100 ml of 10% KOH, dried ^ ^M 9 ^SO 4 ^ 'is filtered, diluted with toluene and concentrated to give 5.1 g of the product The product is treated with 0.5 molar equivalents of fumaric acid in 1-propanol to give the fumaric acid salt of the compound, m.p. -143 ° C.

The NMR spectrum in DMSO-dg shows the presence of about 0 * 12 moles of 1-propanol.

Analysis for (C ₁₂ H ₁₉ N ₅ S ₃ ) ₂ -C ₄ H ₄ O ₄ -0.12 C ₃ HgO: 30

        , , , '' '. ^::::. ''C , 68 H , 61 N 75 S , 38 calculated: 43 , 41 5 , 53 17 , 54 24 24 found: 43 5 17 24

Example 13 5

3-Amino-4- {2 - [(S -piperidinomethyl-S-thienyl) -methylthio] -äthy! Amino- 1, 2,5-thiadiazole '-

A. N-f2 - [(S-piperidinomethyl-S-thienyl) methylthio] -äthyi} -äthan-diimidainiä-trihydrochloride

A suspension of 6.1 g (15.8 mmol) of 3-amino-4- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] -ethylaminq} -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 of conc. HCl, stirred for 3 hours at room temperature and then concentrated the solution. The residue is triturated with 50 ml of 1-propanol, filtered and dried to give 5.86 g (83%) of the product. A sample is recrystallized from methanol / acetone to give the title compound, mp. 201-214 ⁰ C (dec.).

Analysis C ₁₅ H ₃₅ N ₅ S ₂ * 3HCl:

C 13 H , 29 N 60 S , 29 calculated: 40 97 6 , 47 15 , 28 14 , 63 found: 39 6 15 14

B. 3-Amino-4- {2- [(5-piperidinomethyl-3-thienyl) methylthio] ethylhyI-1, 2,5-thiadiazole . ^ _-

A mixture of 5.17 g (11.5 mmol) of N- {2 - [(5-piperidinomethyl-3-thienyl) -methylthio] ethyl} -äthandimidamid-trihydrochloride [manufactured in Sfcife A],

48 ml of CHCl and 4.8 ml of triethylamine are mixed with 4.57 g (11.5 mmol) of Ν, Ν'-thiobisphthalimide (DMF solvate), stirred for 1 hour, the mixture is washed with 90 ml of 10% KOH , dried (MgSO ₄ ), filtered, diluted with toluene and concentrated to give 4.5 g of the product. The treatment of the product with 1 equivalent of cyclohexylsulfamic acid in methanol gives the Cyclohexylsulfamatsalz of the title compound, mp. 142-143 ⁰ C.

Analysis for C 5H ₃₃ N ₅ S ₃ '15

C 96 H , 61 N , 31 S , 38 calculated: 45 , 61 6 , 41 15 , 46 23 48 found: 45 6 15 23

'At game 14    ; ,   \. ,^::;:,':; ,: \. '..;-';>.

Repeat the general procedure of Example 1, Step A, and then either Example 1, Step B, or Example 10 to give the 3-amino used therein ^ 4 ⁱ - [3- (3-piperidinomethylphenoxy) propylamino] - 1,2,5-thiadiazole-i-oxide replaced by an equimolar amount; 'to:', '''. _: .:.; ' / '.,'

(a) 3-ethylamino-4- [3- (3-piperidinomethylphenoxy) propyl

amino] -1,2,5-thiadiazole-i-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 i-oxide,

(d) 3- (3-pyridylmethylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole i-oxide

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

(f) 3- (3,4-methylenedioxybenzylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2, 5-thiadiazole-1-oxide

this is how you get

(a) 3-ethylamino-4-F3- (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-piperidihOmethylphenoxy) ^ - propylaminoj-1, 2, 5-thiadiazole.

(e) 3 -. (6-Methyl-3-pyridyl) methylamino-4- [3- (3-piperidonomethylphehoxy) propylamino] -1,2,5-thiadiazole or

(f) 3- (3,4-methylenedioxybenzylamino) -4- [3- (3-piperidinomethy lphenoxy) propylamino] -1, 2, 5-thiadiazo3 ..

,

Example 15 5

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

A. 3-Amino O - [3- (e -piperidinomethyl - ^ - 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 charged 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 4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide. A purified sample melts at 145 to 147 ^° C.

B. N-L3- (6-piperidihomethyl-2-pyridyloxy) propyl] ethane diimidamide trihydrochloride '-.

A methanolic solution of a product prepared in step A is diluted to 100 ml, then 12.4 ml of conc. HCl, the solution is stirred for 18 hours at room temperature, concentrated and the residue dissolved in 80 ml of water. It is then extracted twice with CH ₂ Cl ₂ , the aqueous phase concentrated, 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 step B in 80 ml of CH CL, containing 7.69 ml of triethylamine, treated with 7.35 g (18.5 mmol) Ν, Ν'-thiobisphthalimide (DMF solvate), stirred for 1 hour at room temperature, the mixture is washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na ₃ 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 (63-38 μπι (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. The treatment of the product with one equivalent. Cyclohexylsulfamic in acetone yields the Cyclohexylsulfamatsalz the title compound, mp 125.5 -. 131 ⁰ C.

Analysis for C ₁₆ H ₂₄ N ₆ O C · C * U H O ₃ S: N 58 S 15 C 7 18 54 12 14 calculated: 50 , 07 7 , 07 18-, 12 found: 50 , 02 , 03

Example 16

3-Amino-4- [3- (6-dimethylaminomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole -

By reacting a methanolic solution of 3- (6-dimethylaminomethyl-2-pyridyloxy) propylamine.

! prepared according to published GB Patent Application 2,098,988] with 3-amino-4-methoxy ^ 1. _{/ 2/5-thiadiazole-1-oxide} in accordance with the GB patent application 2,067,987 and general procedure by reacting the obtained 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamine ·] -1 1,2,5-thiadiazole-1-oxide is prepared successively according to the general procedure described in Example 1, stage A and then either according to example 1, stage B or according to example C, the title compound.

Example 17

3-Amino-4-χ2-ί (6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino} -1,2,5-thiadiazole __ ^ ____ ^ _ ^ _ ^ __

When adding a suspension of 3-amino-4 - {2- ί (6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamihq} -1 # 2 _# 5-thiadiazole-1-oid {prepared according to published GB patent application 2 No. 067 987] are reacted successively according to the procedures of Example 1, step A and then either according to example 1, step B or according to example 10, then the Tite! Compound is obtained.

B e i s pi el 18

3-Amino-4- {2-ί (6-piperidinomethyl-2-pyridyl) methylthioj äthylaminoj ~ 1, 2,5-thiadiazol

If a suspension of 3-amino-4- {2 - [(6-piperidinomethyl-2-pyridyl) methylthio] ethylamino} -1 , 2 , 5-thiadiazole-1-oxide [prepared according to the published

- 54 1

UK Patent Application 2,067,987j is sequentially reacted according to the procedures of Example 1, Step A and then either according to Example 1, Step B or Example 10, to give the title compound.

Example 19

Repeat the general procedure of Example 1, Step X and then either the procedure of Example 1, Step B or Example 10, wherein the 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1 used therein 2,5-thiadiazole-1-oxide replaced by an equimolar amount of:

(a) 3-Amino-4-l * 3- (3-piperidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole-i-oxide, Cb) 3-amino-4- [3- (3-dimethylaminomethylthiophenoxy) "·

propylaminol-i, 2,5-thiadiazole-1-oxide, (c) 3-amino-4- [3- (3-pyrrolidinomethylthiophenoxy) -

\. -. '. *

propylaminö] -1,2,5-thiadiazol-i-oxide,

(d) 3-Amirio-4-t3- (4-dimethylaminomethyl-2-pyridyloxy) -propylamino] -1,2,5-thiadiazole-1-oxide

(e) 3-Amino-4-t3- (5-dimethylaminomethyl-3-thienyloxy) -propylamino] -1,2,5-thiadiazole-i-oxide,

(f) 3-Amino-4- [3- (5-piperidinomethyl-3-thJLenyloxy) ⁱ propylamino] -1,2,5-thiadiazole-1-oxide,

(g) 3-amino-4- {2 - [(4-dimethylaminomethyl-2-pyridyl) -methylthio] -ethylaminoj-1,2,5-thiadiazole-i-oxide or

Ch) 3-Amino-4- {i2- [(4-piperidinomethyl-2-pyridyl) -methylthio] ethylaminoj-1,2,5-thiadiazole-i-oxide.

- 55 This gives ^

(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-Ainino-4- [3- (3-pyrrolidinomethylthiophenoxy) propylamino] -1, 2, 5-thiadiazole,

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

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

(f) 3- ^i-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 * 20

The above-mentioned starting materials are prepared according to the general procedures described in published GB patent application 2 067 987. The precursor compounds of the starting materials are prepared in accordance with the methods and general analogous procedures described in U.K. Patent Nos. 2,067,987, 2,098,988, 2,063,875 and in published European patent application No. 49. are described.

:: '' ·. ' ^: '..;''; , -. , :

Example 20 5

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

A. 3- (4-piperidinomethyl-2-pyridyloxy) propylamine 10

Following the general procedure described in British Patent Application 2,098,988 for the preparation of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine, replacing the 2-chloro-6-methylpyridine used there with 2-bromo-4- methylpyridine, then the title compound is obtained as an oil.

Analysis for C ₁₄ H ₅₃ N ₃ O:

20

calculated ·: found:

3-Amiho ^ 4- [3- (4-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide

A solution of the product from step A (6.5 g, 26.0 mmol) in 90 ml of methanol is added with 3.84 g (26.0 mmol) of 3-amino-4-methoxy-1,2,5- thiadiazole-1-oxide according to the general procedures described in British Patent Application 2,067,987, to give 6.33 g of a product. Recrystallization from methanol / acetonitrile gave the title compound, mp. 154-158 ⁰ C. Analysis for C ₁₆ ^11? ^

calculated: found:

C , 44 H 30 N 85 67 , 54 9 , 98 16 , 55 67 8th 16

C , 73 H , 64 ^N , 06 S 80 52 72 6 30 23 , 32 8th # 74 52 6 23 8th

C. N- [3- (4-piperidonomethyl-2-pyridyloxy) propyl] -ethane diimidamide trihydrochloride ___ ^

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

10

D. 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) -

propylamino] -1,2,5-thiadiazole,

A mixture of the product obtained in Step 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 Room temperature, then the mixture is washed with 40 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, whereby the crude product is obtained. The product is purified by flash chromatography on 90 g silica gel (63 to 38 mm (32 to 400 mesh)) using ethyl acetate / methanol (96: 4) as the eluent. This gives 3.44 g of Titelyerbindung as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gives the cyclohexyl sulfamate of the title compound mp 124.5-126 ° C.

^:; · -. '';^;; - '; , . ' . ''' · Analysis for C ₁₆ H ₂₄ N ₆ OS ⁴ C ₆ H ₁

calculated: 35 found:

C , 07 H , 07 N , 58 S 15 50 , 47 7 12 18 , 33 12 , 87 50 7 18 11

Example 21

3-Amino-4 - {3-t3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy] propylaminoVi, 2,5-thiadiazole

The general procedure of Example 15 is repeated, replacing the 3- (6-piperidinomethyl-2-pyridyloxy) propylamine used therein with an equivalent amount of 3- [3- (1,2,3,6) tetrahydro-1 -pyridyl) methylphenoxy] propylamine, to give 2.31 g of the product. Recrystallization from toluene gives the title compound, mp. 99.5 - Ίθ4 ⁰ C.

Analysis for C.-H- N ₅ OS:

C H N S

calculated: 59,10 6,71 20,27 9,28% found (corr

2.19% H ₂ O) 58.78 6.71 19.90 9.26%.

Claims (1)

- ^ J f ϊ "dung san s Pruch Process for the preparation of a compound of the general formula I: A- (CH ₉ ) _Z (CH ₉ ) N "fc III A Ii S f Yt "V in which R is hydrogen, "(lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,        ''. '·' '-,' 'H 3 in which ρ is 1 or 2, R and R are each independently hydrogen, (lower) alkyl, (lower alkoxy) alkoxy or halogen, and when 2 '-' - '. '3 R is hydrogen, R also trifluorinethyl  '' '' '· 2' can be, or combine R and R together    '' '   Methylene dioxy, and R is hydrogen, (lower) alkyl or (lower) alkoxy); 35 *. rc: UC. M * Λ FiOOR R m is an integer from 0 to 2 inclusive; η is an integer from 2 to 5, inclusive; Z is oxygen, sulfur or methylene; and
A has the following meanings: 7f 7 ^R \ rK ^R \ or wherein R is hydrogen, (lower) alkyl or (lower) alkoxy, q is an integer from 1 to 4 inclusive, and R and R are each independently (lower) alkyl, - (lower) alkoxy (lower) alkyl, wherein the (lower) alkoxy radical is at least 2 carbon atoms removed from the nitrogen atom , or phenyl (lower) alkyl, or when R. is hydrogen, R can also be cyclo (lower) alkyl, or R and R, together with the nitrogen atom to which they are attached, are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, Morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidine O, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, oc tame thy lenimino, 3-azabicyclo [3.2.2] non-3-yl or 3-pyrrolino can form; or non-toxic pharmaceutically acceptable salts, hydrates or solvates thereof.  i .. ', characterized in that, preferably in an inert solvent and at room temperature, a compound of general formula HI: wherein R, A and Z and m and η have the meanings given above, with a strong inorganic acid, preferably hydrochloric acid, to give a compound of general formula II, or, that a compound of general formula IV: A- (CH ₂ ) _m Z (CH ₂ ) _n NH ₂ 25 IV -ΐ ·· - ':'; .. '. , " ^':;,' 'C^y' ' wherein A and Z and m and η are those given above Possess meanings, with a connection of general formula V:                 · ·. ; ·:. · · to a compound of general formula VI: A- (GH ₂ I _n Z (CH ₂ ) _n NH _N , OC _VI HN and then the resulting compound of general formula VI with a compound of the general formula R NH ^, wherein R has the meanings given above, to a compound of general formula II
implements, and in that the resulting compound of general formula II: A- (CH _{2) n} Z (CH ₂ J _n NH, "" I «Ρ» Η " where R, A, Z, m and η are those given above Have meanings preferably at a temperature from about 0 ° to about 50 ° C, and preferably in a reaction-inert organic solvent
with at least one molar equivalent, preferably a molar excess, and more preferably a molar excess of from 2 to 3 moles, -63- Sulfur monochloride, sulfur dichloride or a chemical equivalent thereof, preferably weightless monochloride, to give a compound of general formula I.