DE3311281A1 - THIADIAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING IT - Google Patents

Description

· ": · :: · rrv- · :: ···" 331128I

PROF. DR. DR. J. REITSTÖTTER DR. WERNER KINZEBACH DR. ING. WOLFRAM BUNTE (, »» β-, βτβΐ

.ή-

RIDER KILLER. KINZEOACH 6 PARTNER PATENT LAWYERS

P.O. Box 7βο. οβοοο Munich 43 APPROVED REPRESENTATIVES AT

EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

PHONE. (OSS) 2 71 85 63 TEi-EX: OS2152OS ISAR D BAUERSTRASSE 22. D-SOOO MUNICH

VNR: 104 523

Munich, March 28, 1983

OUR FILES:

M / 2 4 061

Using subject RE

BRISTOL-MYERS COMPANY
45, Park Avenue

New York / NY. 10154,
United States

Thiadiazole derivatives, processes for their preparation and pharmaceuticals containing them

Certain 3- (amino or substituted amino) -4- (substituted amino) -1,2 / 5-thiadiazoles of general formula I.

A- (CH ₂ ) _mZ (CH ₂ J _n NH ^ _r

Ii \

wherein A, m, Z, η and R have the meanings given below, and their non-toxic pharmaceutically acceptable salts, hydrates and solvates, are strong histamine H ₂ 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 appropriately substituted athanediimidamides of the formula II

GB published application 2,067,987 describes 3,4-disubstituted-i, 2,5-thiadiazole-1-oxides and 1,1-dioxides of the formula

A- (CH ₂ J _1n Z (CH ₂ I _n NH. Jt ¹

N N

^<0) _P.

and a process for their preparation _r where the radicals A, m, Z, η and R are similar to the radicals disclosed and claimed in the present application. 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 prepared by means of processes such as are used to prepare the compounds according to the prior art.

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

and process for their preparation, wherein the residues

1 2

R ₇ A, n, X, m, R and R are 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 processes for preparing the compounds of the prior art.

Included in the above two publications the use of any of the processes described for the preparation of the compounds according to the prior art (as starting material or intermediate) of a 1,2,5-thiadiazole-1-oxide or -1,1-dioxide, which has either amino groups or suitable leaving groups at the 3- or 4-positions. The desired subs + i tuen ten at the 3- and 4-position is then obtained through Substitution on the amino groups or by replacing the "leaving groups". It became far-reaching Attempts have been made to prepare the compounds of the invention in a similar manner, i.

by using 1,2,5-thiadiazole, which Having amino groups or suitable "leaving groups" at the 3- and 4-positions as starting materials or as an intermediate. Although numerous variants along with different ones Reaction conditions were used, we were not able to use the inventive method in this way Get connections.

It has now been found that the compounds of the present invention can be prepared by ring closure of the appropriately substituted athanediiraidamide of the formula II

10 ^A - ^{C Vm ^Z < ^CH 2> n ^NH 7, ^c

HN

II

HN

The intermediate compounds II themselves can be prepared by various processes.

The present invention relates to Histmain-H «- Receptor antagonists of the formula I:

^A ~ ^(CH 2 ^

wherein

R for a hydrogen atom, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyly propargyl,

< ν - (CH ₂ ) _ρ - or ■ Η ι 35 R ³ ^ Θ - CCH ₂ ) _ρ - •

stands,

- r-

2 3 where ρ stands for 1 or 2, R and R independently of one another are hydrogen, (lower) alkyl, (lower) alkoxy or a halogen atom,

2 3

and, when R stands for a hydrogen atom, R tri-

2 3 can mean fluoroethyl, or R and R together

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

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

R ⁵ 5

_R 7 j_ _R 7? ⁵

^ ^{N (CH} 2 ^} q-TT "V '^ ^ΝίαΗ 2 ^

R ^ ₀ / R ⁶

^x NO 1 P 'I!

or

stands,

R is a hydrogen atom, (lower) alkyl or (lower) -

Is alkoxy ;. q is an integer from 1 to one

finally 4 and R and R each independently of one another (lower) alkyl, (lower) alkoxy- (lower) alkyl, wherein the (lower) alkoxy radical has at least two carbon atoms from the nitrogen atom is removed, or phenyl (lower) alkyl, and when R is a hydrogen atom, R also

Cyclo (lower) alkyl can mean, or R and R together with the nitrogen atom to which they are attached, pyrrolidino, methy! pyrrolidino, dimethylpyrrolidono, Morpholino, Thiomorpholine, Piperidino, Methy! Piperidino, Dimethylpiperidino, N-Methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, Heptamethyleneimino, octamethyleneimino, 3-azabicyclo- [3.2.2] non-3-yl or can be 3-pyrrolino; and non-toxic, pharmaceutically acceptable salts, Hydrates and solvates thereof.

The present invention also relates to processes for the preparation of the compounds of formula I and of intermediate compounds of the formula II.

The present invention includes all possible tautomers, diastereoisomers

and optically active isomers of the compounds of the formula I and mixtures thereof. The at the Description of the invention used term (lower) alkyl) stands for a straight-chain or branched alkyl group containing 1 to 6 carbon atoms. The term "(low) alkoxy" represents a straight-chain or branched alkoxy group which contains 1 to 4 carbon atoms. "Cyclo (lower) alkoxy" stands for a cycloalkyl group, which contains 3 to 6 carbon atoms.

The term "non-toxic pharmaceutically acceptable salts" means acid addition salts which contain Acids, e.g. hydrogen chloride, hydrogen bromide, nitric, Sulfuric acid, acetic acid, propionic acid / fumaric acid-methanesulfonic acid / maleic acid, Tartaric acid / citric acid, laevulinic acid, benzoic acid, succinic acid and the like are formed.

Ä6-

In the compounds of the formula I, R preferably represents a hydrogen atom or (lower) alkyl, even more preferably for a hydrogen atom or methyl and most preferably for a hydrogen atom. The substituent A is preferably the substituted phenyl radical, the substituted furyl radical or substituted Thienyl radical as shown above and is most preferably the substituted phenyl radical. The substituent Z is preferably a sulfur or oxygen atom and, if A, 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 for 3. R is preferably a hydrogen atom or methyl and most preferably a hydrogen atom. Preferably q is 1. R and R are preferred (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:

- Tj -

A-

(CH _{2) n} NH-C C-NHR

HN

CN

S ₂ Ci ₂

or
SCl.,

A- (CH ₀ ) Z (CH,) MH ,. , Z in JL Ti X, <r

(ι \

where A, m, Z, η and. R have the meanings given above. At least 1 mole of S ₀ Cl ₃ or SC1_ should be used per mole of compound II; an excess is preferably used

or SCl

e.g. about 2 to 3 moles

or

SC1_ per mole of compound II. It has been found that SC1 "often gives a crude product and a lesser amount of purified product. We "usually prefer S ₀ Cl _{3 for the reaction}

The reaction temperature is not

critical; preferably man.die reaction results at a temperature of ⁰ C C to about 50 ⁰ C. It is best to introduce the reaction at

Ambient temperature. The reaction time is not critical and depends on the temperature. Typically, a reaction time of about 30 minutes to about 6 hours is used. At ambient temperature reaction times of about 1 1/2 to hours are usually preferred. The reaction can carried out in an inert organic solvent

, preferably a mixture of an inert organic solvent and dimethylformamide. Most preferably, the reaction is carried out in dimethylformamide.

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

A- (CH,) Z (CH ₂₎ _NH

NHR

where R is 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

NCH

or

in which R is a hydrogen atom or methyl, and R and R are each independently of one another Mean methyl or ethyl, or together with the nitrogen atom to which they are attached, form a pyrrolidino or piperidino ring.

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

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

Ia 1

.NHR

• '' * V-S

wherein R represents a hydrogen atom or methyl, and R and R each represent methyl, or together with the nitrogen atom to which they are attached represent a pyrrolidino or piperdino ring; 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 one another for methyl or ethyl; or a non-toxic, pharmaceutically acceptable salt, . Hydrate or solvate thereof.

·· ·· Jj ι izö ι

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

wherein R and R each independently represent a hydrogen atom or methyl and R and R are each independently methyl or ethyl; or a non-toxic, pharmaceutical one compatible salt, hydrate, or solvate thereof.

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

OCH ₂ CH ₂ CH ₂ NH .NHR ¹ Id

wherein R and R are each independent of one another

6 7 denote hydrogen atom or methyl and R and R in each case independently of one another methyl or ethyl, or together with the nitrogen atom, on that they are bound represent a piperidino radical; or a non-toxic, pharmaceutically acceptable one Salt, hydrate or solvate thereof.

34

Currently the most preferred compounds

of formula I are:
5

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

2) 3-Amino-4- 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino -1,2,5-thiadiazole;

3) 3-Amino-4- 2 - [(S-dimethylaminomethyl - ^ - methyl-2-thieny1) methylthio] ethylamino -1,2,5-thiadiazole;

4) 3-Amino-4- [3- (3-pyrrolidinomethy! Phenoxy) 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- ¹ ^ - [(S-dimethylaminomethyl-S-thienyl) -methylthio] ethylamino / -1,2,5-thiadiazole,

2 ^ 8) 3-Amino-4- ^ 2 - [(S-piperidinomethyl-S-thienyl) -

methylthio] ethylamino} -1,2,5-thiadiazole, 9) 3-Amino-4- [3- (6-piperidinomethyl2-pyridyloxy) propylamino] -1,2,5-thiadiazole and

10) 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) - ■ propylamino] -1,2,5-thiadiazole; and their non-toxic, pharmaceutically acceptable salts, hydrates and solvates.

The intermediates of the formula II used in the preparation of the compounds of the formula I can ~~ itself produced with the help of various processes will. In one method, the corresponding 3- (amino- or substituted amino) -4-substituted Amino-1,2,5-thiadiazole-1 ~ oxide of the formula III treated with a strong mineral acid (preferably HCl), to obtain the compound of formula II.

A- (CH ₂ ) _m Z (CH ₂ J _n NH

-W-

• 3a

NHR ^J

III

HCl

A- (CH-) Z (CH-) NH _x , NHR ^J

HN NH

II

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 carried out. The compounds of formula III are known or can be readily prepared by processes as described in British Patent 2,067,987.

In an alternative process, the compounds of the formula II can be obtained according to the following reaction scheme will.

A- (CH ₂ ) ^ Z (CH ₂ ) _n NH ₂

IV

ft K β «

-w-. 33

A- (CH,) Z (CH-)

HN ^/

OCH.

VI

R ¹ NH.

A- (CH ₂ ) _n 2

NHR

III

The reaction can be carried out in an inert solvent, and preferably in methanol. the Starting materials of the formula IV are known or can easily be prepared by known processes such as those described in our published British patent application 2,067,987 are.

On the other hand, the invention relates to new intermediates of the formula II:

- (CH ₂ ) _ro Z

_n NH _x ^ N

II

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

. 31. · ■

stands, 2 _

where ρ stands for 1 or 2, R and R each independently of one another a hydrogen atom, (lower) alkyl, (lower) alkoxy or halogen, and

2

when R stands for a hydrogen atom, so does R

2 may be trifluoromethyl, or R and "R together

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

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

or

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

e ο <s *

"* Ira ~

. 3s

or phenyl (lower) alkyl, UiId ₇ if R stands for a hydrogen atom, R also cyclo (lower).

6 7 can be alkyl, or R and R together with the nitrogen atom _/ to which they are attached, pyrrolidono, methylpyrrolidino, dimethy! Pyrrolidino, morpholino _? Thiomorpholines, piperidino, methy! Piperidino, dimethylpiperidino, N-methy! Piperazine, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo [3.2.2] non-3-yl or 3-pyrrolino mean may, or a salt, hydrate or solvate thereof.

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

^A " ^tCH 2 ⁾ m ^{Z (CH} 2 ⁾ n ^NH v /

Yi

HN NH

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

R ⁵

t.y

η - 36.

or

is where

R denotes a hydrogen atom or methyl, and

6 7
R and R each independently represent methyl or ethyl, or together with the "nitrogen to which they are attached, represent a pyrrolidino or piperidino ring; or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

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

H ₂ CH ₂ CH ₂ NH ^^ -NHR

Yi

HN NH

Ha

3Q where R stands for a hydrogen atom or methyl, and R and R each represent methyl, or together with the nitrogen atom to which they are attached, mean a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

ei β "

fica $> ο ♦ * **

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

R ^ JL

_D 6

»- ^ - ⁵ ^ CH ₂ SCH ₂ CH ₂ MH. NHR ^J

HN

wherein R and R are each independently of one another

f "7

Mean hydrogen atom or methyl, and R ° and R in each case, independently of one another, are methyl or ethyl; or a salt, hydrate or solvate thereof.

According to another preferred embodiment the intermediate products of formula II have the structure lic:

-— * '' A-CH ₂ SCH ₂ CH ₂ NH NHR ¹ '

iri

HN NH

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

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

jo I IZo

- Vf -

wherein R and R independently of one another represent a hydrogen atom or methyl and R and R in each case independently of one another methyl or ethyl, or together with the nitrogen atom on that they are bound to mean piperidino; or a salt, hydrate or solvate thereof.

The most preferred intermediates of formula II are:

1) N- [3- (3-piperidinomethylphenoxy) propyl] ether> handi imidamide,

2) N- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylf-ethane imidamide,

3) N - {* 2- [(S-dimethylaminomethyl - ^ - methyl - ^ - thienyl) methylthio] ethyl} ethane diimidamide,

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

5) N- \ 2- [(S-dimethylaminomethyl-S-thienyl) methylthio] ethyl} ethanediimidamide,

6) N- J2- [(S-piperidinomethyl-S-thienyl) methylthio] -äthylfäthandiimidamid,

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

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

or a salt, hydrate or solvate thereof.

• <a β

For therapeutic use, the pharmacological active compounds of formula I normally administered as a pharmaceutical agent, which as active ingredient at least one compound according to the invention in its basic form Form or in the form of a non-toxic pharmaceutically acceptable acid addition salt, together with one pharmaceutically acceptable carrier, contains "

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

A wide variety of pharmaceutical forms can be used. So can if a solid support is used The preparation is processed into tablets, in powder or pellet form in a hard gelatin capsule be given, or in the form of a lozenge or lozenge. Becomes a liquid carrier The preparation can be used as a syrup, emulsion, soft gelatin capsule, sterile solution for injections or as an aqueous or non-aqueous, liquid suspension. The pharmaceutical means are after conventional, suitable for the desired preparation produced by conventional methods.

The dosage of the compounds according to the invention depends not only on factors such as the patient's weight, but also on the degree of gastric acid inhibition desired and the effectiveness of the connection used. What dose to use

(and the number of administrations per day) is decided by the doctor and may depend on the specific circumstances and the patient can be varied.

11281

B, one of the preferred compounds according to the invention each oral dose unit contains the active ingredient in an amount of about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 mg. J3e, r active ingredient is preferred in equal Governments administered 1 to 4 times daily.

Histamine H ₂ receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and humans, Brimblecombe et al. _# J ·. Int. Med. Res., 3i, 86 (1975). Clinical evaluations of the histamine H_ receptor antagonist cimethidine indicated that it is an effective therapeutic for the treatment of peptic ulcer, Gray et al., Lancet, J_, 8001, (1977). Some of the preferred compounds according to the invention were compared with cimethidine in various tests, and they were found to be stronger than cimethidine, both as a His tamin-H ,, receptor antagonist tested on the isolated right atrium of the guinea pig and as an inhibitor of gastric acid Secretion in rats and dogs.

Determination of gastric antisecretion activity in rats with gastric fistula

Male Long Evans rats weighing approximately 240 to 260 g were used to implant the cannula. The manner in which the stainless steel cannula is implanted into the anterior wall of the forestomach is essentially as described by Pare et al. [Laboratory Animal Science, 2Ί_, 244 (1977)]. The fistula components are determined and the operation is performed exactly as described in the reference above.

After the operation, the animals are kept individually in solid-bottomed cages with sawdust and get food and water ad libitum during the entire recovery period. The animals are at least Not used for testing 15 days after surgery.

The animals are fasted before the test, but water is given ad libitum 20 hours before the test. Direct Open the cannula before collecting the secretion and washes the stomach gently with 30-40 "ml of warm saline solution or distilled water to remove any residue. Then you screw the catheter into the Cannula at the point where the locking screw used to be, and puts the rat in a clear, rectangular one Plastic cage that is 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slot of about 1.5 cm wide and 25 cm long, which is in the

runs through 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 experiment is carried out as described by Ridley et al. described [Research Comm. Chem. Pharm., 17, 365, 1977)].

The gastric secretions collected during the first hour after washing the stomach are discarded, as they could be dirty. For oral assessment, the catheter is then removed from the cannula and replaced by the locking screw = 2 ml / kg of water are given orally by gastric intubation and leaves the rat in the cage for 45 minutes. Then the screw plug is loosened and

3g 'replaced by a catheter that has a small

3311201

Carrying plastic bottles and collecting gastric secretions. A 2 hour sample is collected (dies represents the control secretion), the catheter is removed and through the locking screw replaced. Then the test compound is given orally in a volume of 2 ml / kg by gastric intubation. 45 minutes later the locking screw is opened again, replaced by the catheter, on which a small Plastic vial is attached, and another 2 hour sample is collected. The secretions in the second sample are compared with those of the control sample to determine the effect of the tested compound determine.

When the test compounds are evaluated parenterally, the animal is given i.p. or s.c. the carrier of the test compound injected in an amount of 2 ml / kg. Immediately beforehand, the initially obtained while The solution collected for 60 minutes is discarded. Collect a 2 hour sample (control secretion) and inject the Animals then either i.p. or s.c. the test compound in an amount of 2 ml / kg. Another 2 hour rehearsal "is collected, these secretions are compared with those of the control in order to determine the effect of the drug to determine.

The samples are centrifuged and placed in a graduated centrifuge tube for volume determination. Titratable 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 measured in Microequivalents are calculated by dividing the volume in milliliters with the concentration in milliequivalents multiplied per liter.

β ι *

β * a

The results are expressed as percent inhibition relative to the control readings "dose-response curves are established and ED, -.. Computed ₀ ~ values by regression analysis One uses a minimum of 3 rats each for one dose and at least 3 dose levels are used to determine the dose-response Curve used.

Tabel

Gastric antisecretion activity tested at the Rat with gastric fistula

link

ED ₅₀ SC µmole / kg

95% confidence limit

Efficacy ratio (cimethidine = 1.0)

Cimethidine 3.48
(1.68-5, 75) ^+: 1.0. example 1 0.094
(0.043-0 , 20) 37 Example 2 0.77
(0.45-1. 4) 4.5 Example 3 -v 0.5 • Example 4 0.18
(0.10-0, 36) 20th

- 36 -

Histamine H ₂ receptor antagonism, tested in isolated guinea pig atria

Histamine caused concentration-dependent increases in the contractions of isolated, spontaneously beating right atria from Meerschweinchen..Black et al., Nature, 236, 385 (1972) described the receptors involved ₉ receptors in this effect of histamine as histamine H, as they reported the properties of burinamide, an antagonist of these receptors. Later studies by Hughes and Coret, Proc. Soc. Exp. Biol. Med. _T 148 , 127 X1975) and Verma and McNeill, J. Pharmacol. Exp. Ther., 20O ₇ 352 (1977) confirmed the conclusions of Black and coworkers that the positive chronotropic effect of histamine on isolated right guinea pig atria is mediated by histamine ^ receptors. Black et al., Agents and Actions, 3_, 133 (1973) and Brimblecombe et al., Fed. Proc, 3_5, 1931 (1976) used isolated right atria from guinea pigs /

to compare the effects of histamine H ₂ ~ receptor antagonists. The present comparative studies were carried out using a modification of the procedure carried out by Reinhardt et al., Agents and Actions, 4_, 217 (1974).

_ Male guinea pigs of the Hartly strain (350-450 g) were killed by a blow to the head. The heart was removed and placed in a Petri dish in which oxygenated C95% O ", 5% CO _? ) modified Krebs solution was found (g / liter: NaCl 6.6; KCl 0/35, MgSO ₄ '7H ₂ O 0.295, KH ₂ PO ₄ 0.162, CaCl ₂ 0.238, NaHCO ₃ 2.1 and dextrose 2.09) . The spontaneously striking one

. 45.

right atrium was stripped 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 Krebs solution which, kept at 32 ⁰ C. The atrial contractions were recorded isometrically with a Grass FT 0.03 force transducer and the contraction force and rate recorded with a Beckman RP Dynograph.

A sustained tensile force of 1 g was applied to the atrium, and the specimen was left in this state Stand for 1 hour. Then a submaximal concentration of histamine dihydrochloride (3.10 M) added to the bath and washed out to prepare the tissue. Then the bath histamine became cumulative added at 1/2 log 10 intervals so that one

- 1-5

Final bath concentrations of 1.10 to 3 χ 10 moles were obtained. The histamine-induced increase in ventricular beats was allowed to level off before the next concentration was set. Maximum response occurred each time at a dose of 3 × 10 M. The histamine was washed out several times and the atrium was allowed to return to the control value. Then, the test compound was added at appropriate molar concentrations and, after a 30-minute incubation, the investigation of the response was ^au f histamine Dosxs repeated, with the higher concentrations were adjusted as necessary.

- 47 -ι ■. k <0 -

The dissociation constants (K-.) Were derived from the shield

Jd

Curves according to the method of Arunlakshana, 0. and Schild, H.O. [Br. J. Pharmacol, Jj4, 48, (1959) based on at least 3 dose units. Parallel displacements of the Dose-response curves were obtained without the maximum response at the antagonist concentrations used to diminish. The results are shown in Table 2.

Table 2

15th Activity isolated 0 ^K B / 41 right Guinea pig atria Effectiveness 0 Jd , 003 relationship link N 0 , 004 (μΜοΙ) (Cimethidine = 1.0) 20th 1.0 Cimethidine 20th (0.21-0, 64) , 004) 137 example 1 12th (0.001 - 0 , 010) 102 Example 4 11th (0.001 - 0

+

95% confidence limit

_one The compounds of formula I of the formula II with N, N can also by ring closure of a compound of formula ¹ -Thiobisphthalimid:

getting produced.

The use of N, N'-thiobisphthaliinide instead of S ₃ Cl ₂ or SCl ₂ 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 be directly crystalline Form salts 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 CH ₇ Cl ₇ . Preferably the diimidamide 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 that the reaction is complete. The phthalimide which 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 formula I compound . The N, N'-thiobisphthalimide used in the present invention is a known compound as can be prepared in the Canadian Journal of Chemistry, 4j4, 2111-2113 (1966) or as described below.

Preparation of N, N ¹ -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, after the addition, the mixture is left within heat from 4 hours to 20 C, collecting the solid and dried to give 12.5 g of the title compound as a DMF solvate is obtained, mp. 301-315 ⁰ C. Both the IR and the NMR spectrum are in accordance with

15 of the structure.

Analysis for

C HN 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 ⁰ C. The NMR spectrum was seen no more DMF.

Analysis for C ₁₆ HgN ₂ O ₄ S:

30th

calculated: found:

35

C. , 25 H , 49 N , 64 S. , 89 59 , 21 2 , 21 8th , 91 9 , 14 59 2 8th 10

example 1
5

3-Amino-4- [3- (3-piperidinome thy / phenoxy) propylamino] , 2,5-thiadiazole

A. N- [3- (3-Piperidinomethy! Phenoxy) propyl] ethane diimide amide trihydrochloride

A suspension of 17.1 g (47.0 mmol) of 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-i-oxide [prepared according to the published GB Patent Application 2,067,987] in 4 50 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, giving colorless crystals. This is suspended in 200 ml of absolute ethanol, filtered and dried in vacuo to give 16.6 g (82.6%), mp obtains the title compound. 205-220 ⁰ C (dec.). Recrystallization from 50% methanol / ethyl acetate

results in an analytical sample with melting point 206-216 ° C (dec.)

Analysis for CH ₀ -N ₁ -O

30 calculated: found:

C. 84 H 08 N / 41 47, 56 7, 18th 16 , 75 47, 7 / 16

35

B. 3-Amino-4- [3- (3-Piperidinome thy! Phenoxy) propylamino]. 1,2,5-thiadiazole

A stirred suspension of 2.13 g (5.0 mol) of N- [3- (3-piperidinomethylphenoxy) propyljäthandiimidamid-trihydrochloride [prepared in stage A] in 20 ml of dimethylformamide (DMF) with 2.02 g (15, 0 mol) sulfur monochloride, stir for a further 4 hours, carefully pour the mixture obtained into 200 ml of water and make it basic with K “CO_. It is then extracted with 3 × 50 ml of methylene chloride and dried over MgSO. and concentrated to give 2.1 g of a dark gummy product. The product is purified by HPLC chromatography on silica, using CH_C1 (100): 2-propanol (10): NH ₄ OH (0.5) as the mobile phase. The appropriate fractions give 0.89 g of the title compound, from which 0.76 g (21.4%) of the title compound is obtained as a crystalline fumarate salt with fumaric acid in n-propanol «
Purity according to HPLC> 99%.

Fumarate salt, m.p. 187-187.5 C.

C. , 27 H 71 N , 27 S. , 90 56 , 09 6, 36 17th , 98 7th , 08 56 6, 16 8th

Analysis for

calculated:
found:

Part of the fumarate is suspended in water, neutralized with K ₇ CO ₃ , extracted with CH ₃ Cl ₂ and concentrated with CH-Cl ₂ and the CH _{2 Cl 2} phase concentrated, the free base of the title compound crystallizing out, melting point 43 -47 ⁰ C. a portion of the free B.ase is converted to the hydrochloride salt, mp. 138-140 ⁰ C.

SA

Analysis for C ₇ H ₂₅ N ₅ OS-HCl:

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

Beis piel

3-Amino-4 - {2- [(5-dimethylaminomethyl - 2 - furyl) methyl thio] ethylamino} -1,2,5-thiadiazole

A. N- {2- [(5-Dimethylaminoinethyl-2-furyl) methylthiojä thy Ij- -ä thand i imidamid- trihydrochloridehydr at

A suspension of 6.59 g (20.0 mmol) of 3-amino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylaminoj-1,2,5-thiadiazole-1-oxide [prepared according to published GB patent application 2,067,987] in 200 ml of methanol is heated slowly in order to achieve complete dissolution. Then added .man with 13.3 ml of conc. HCl, stir for a further 2.4 hours at room temperature, concentrate the solution and triturate the residue with 70 ml of absolute ethanol. The crystals are filtered and dried in vacuo to give 4.3 g (52%), mp obtains the title compound. 166-169 ⁰ C (dec.)

Analysis for C ₁₂ H ₂₁ N ₅ OS

35 calculated: found:

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

B. 3-Amino-4- ^ 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -1,2,5-thiadiazole

To a stirred suspension of 12.3 g (3O O ₇ mmol) of N- {2-t (5-dimethylaminomethyl-2-f uryl) methylthio] ethyl} äthandiimidamid-trihydrochloridhydrat [prepared in Step A] in 150 ml of DMF there 7.2 ml sulfur monochloride (12.1 g, 90 mmol), stir for a further 4 hours at room temperature, remove about half of the DMF under reduced pressure, pour the remaining black solution into 1 liter of water, make with K _? CO_ basic 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 chromatography on silica using ethyl acetate (100): 2-propanol (10) -NH 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. 30th

Analysis for C ₁₂ H ₁₉ N ₅ S ₂ O-HCl:

C HNS

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%

β *

-M-

• 53

Treatment of the product with an equivalent amount of cyclohexylsulfamic acid in acetone gives this Cyclohexylsulfamate salt of the title compound,

M.p. 93-95 ° C. 2 ^H 19 ^N 5 S ₂ OC ₆ H ₁₃ N O ₃ S: 55 N , 06 S. .53% Analysis for C ₁ 17th 17th / 21 19th .58% 10 C. H 17th 19th 43.88 6, calculated: 43m77 6, found: 15th 3 B e > ± s ρ ie 1

3-Απιϊηο ~ 4-χ2- [(5-dimethylaminomethyl-4-methyl-2-thienyl) -

methylthio] ethylaminoj-1,2,5-thiadiazole

A. N- £ 2-1 (S-dimethylaminomethyl ^ -methyl ^ -thienyl) -methylthio] ethyl / ethanediimidamide trihydrochloride

A stirred solution of 17.9 g (50.0 mmol) of 3-amino-4- {2- [(S-dimethylaminomethyl - ^ - methyl - ^ - thienyl) n \ ethylthio] ethylamino} - 1,2 is added , 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, stir for a further 3 hours, concentrate the reaction mixture and remove excess water by azeotropic concentration with absolute ethanol, an almost colorless crystalline residue being obtained. The residue is triturated with 200 ml absolute ethanol at 0 ⁰ C, filtered and dried to give 16.9 g (80%) of the title compound, mp 206-220 ° C (dec.) Umkristalli-

- "" '331128I

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

• 5k

Sation from 50% methanol / ethyl acetate gives a product with melting point 210-221 ° C (dec.).

Analysis for

calculated:
found:

B. 3-Amino-4 £ 2- [(S-dimethylaminomethyl ^ -methyl ^ - thienyl) -methylthio] ethylaminoj-1,2,5-thiadiazole

To a stirred suspension of 6.34 g (15.0 mmol) of Ν- · {2-ί (S-dimethylaminomethyl ^ -methyl ^ -thienyl) methylthio] ethyl ethanediimidamide trihydrochloride [prepared in stage A] in 60 ml of DMF 6.1 g (45.0 mmol) of sulfur monochloride are stirred for 4 hours at room temperature, the reaction mixture is poured into 800 ml of water, made _{basic with K 3} CO ₃ 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 ₉ Cl ₉ (100): 2-propanol (10): NH ₄ 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 - 98%). The treatment

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

Analysis for

CHNS

calculated: . 41.09 5.84 18.43 25.32%

found: (corr. for

0.51% HO) 40.78 5.63 18.31 s5.44%

10

Example 4

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

A. N- [3- (3-Pyrrolidinomethylphenoxy) propyl] ethane diimide amide trihydrochloride

20- A suspension of 13.4 g (38.3 mmol) of 3-amino-4- [3- (3-pyrrolidinomethyl-phenoxy) propylamino] -1,2,5-thiadiazole-i-oxide [manufactured in accordance with published UK patent application 2,067,987] in 350 ml of methanol are treated with 25.5 ml of conc. HCl, the resulting solution was stirred for 3 hours at room temperature, concentrates the solution and then removes the water azeotropically with absolute ethanol, thereby obtaining the product. The crystalline residue is triturated with 150 ml of absolute ethanol,

filtered and dried to give 10.8 g of the title compound, mp 195-203 ° C. (decomp.).

Analysis for C _1ir H "-N _c O · 3HCl:

35

calculated:

found:

C. , 55 H , 84 N , 92 46 , 55 6th , 93 16 , 93 46 6th 16

■ ·· j j ι ι

-Vf-

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

A stirred suspension of 8.25 g (20.0 mol) of N- [3- (3-pyrrolidinomethylphenoxy) propyljäthandiimidamid-trihydrochloride [prepared in step A] in 80 ml of DMF is treated with 5.4 g (40.0 mmol) Sulfur monochloride, stir for 3 hours under a nitrogen atmosphere and concentrate the reaction mixture to give a dark, gummy product which is suspended in 500 ml of water. Then it is made basic with K_CO, extracted with 3 × 100 ml of methylene chloride, the extracts are dried over MgSO., Filtered and concentrated, giving 7.5 g of a dark, gummy product. This is purified by means of apparatus-based HPLC chromatography on silica, using CH ₂ Cl_ (100): 2-propanol (5): NH.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. The treatment of the product in absolute ethanol with an equivalent amount of 2N HCl are the hydrochloride salt of the title compound (1.13 g), mp. 138-140 ⁰ C.

Analysis for C ₁₆ H ₂₃ N
30th

calculated: found:

C. , 95 H , 54 N , 93 S. , 67 51 , 97 6th , 36 18th , 63 8th , 76 51 6th 18th 8th

θ Ο β ·. 4 »

5 *.

Example 5
5

The procedure described in Example 1, Steps A and B is repeated using the one used therein 3-Amino-4- [3- (3-piperidinomethylphenoxy) propylamino] 1,2,5-thiadiazole -1-oxide by an equimolar amount from:

(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-i-oxide,

(c) 3-Amino-4 - {, 3- [3- (2-methy! pyrrolidino) methylphenoxypropylamino} -1,2,5, thiadiazole-1-oxide

(d) 3-Amino-4- {3- [3- (3-methylpyrrolidino) methylphenoxy3-propylamino} -1,2,5-thiadiazole-i-oxide,

(e) 3-Amino-4- {3- [3- (4-methylpiperidino) methylphenoxy] propylamino ^ -1 , 2, 5-thiadiazole-1-oxide,

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

(g) 3-Amino-4- {3- [3- (N-methylpiperazino) methylphenoxy] propylamino ^ -1,2,5-thiadiazole-1-oxide,

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

(i) 3-Amino-4- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] -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 13.2-2] non-3-yl) methylphenoxy] propylamino J-1, 2,5-thiadiazole-1-oxide or

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

replaced. One obtains

■ β *

(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- χ3- [3- (2-methy! pyrrolidino) methylphenoxy] propylaminoj-1,2,5-thiadiazole,

(d) 3-Amino-4- {3- [3- (3-methy! pyrrolidino) methylphenoxy] propylamineq] - 1,2,5-thiadiazole /

(e) 3-Amino-4- C3- [3- (4-methylpiperidino) methylphenoxy] propylamino ^ -1 , 2 /5-thiadiazole,

(f) 3-Amino-4- [3- (3-morpholinome.thylphenoxy) propylamino] 1,2,5-thiadiazole,

(g) 3-Amino-4- {3- [3- (N-methylpiperazino) methylphenoxy] propylamino} • -1 , 2,5-thiadiazole,

(h) 3-Amino-4- [3- (3-diallylaminomethylphenoxy) propylamino] -1, 2,5-thiadiazole, (■>) 3-Amino-4- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] -1,2 / 5-thiadiazole,

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

(k) 3-Amino-4- [Ϊ3- [3- (3-azabicyclo [3.2.2] non-3-yl) methyl-. phenoxy] propylaminoj-1/2/5-thiadiazole or

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

• «ft t>»

. 59-

Example 6
5

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

This is a modification of stage B of the example, using less sulfur monochloride and choose a shorter response 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] ethane diimidamide trihydrochloride in 120 ml of DMF, and the mixture is stirred 3 Hours under a normal atmosphere and the DMF is removed under reduced pressure, a black, gummy product being obtained / this is suspended in water, made _{basic with K 3} CO ₃ and extracted with 3 × 100 ml of CH ₂ Cl ₃ . . The combined extracts are dried over MgSO ₄ , filtered and concentrated to give a black, gummy product. This guinmi-like product is purified by means of preparative HPLC chromatography on silica, using CH ₂ Cl ₂ (100): 2-propanol (5): NH ₄ OH (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, melting point 186-186.5 ° C. Purity according to HPLC 99%.

Analysis for (C, ^ H _OC N _C OS) "
1 / e.g. b 2

35 calculated: found:

-H.O .: 4 4 4

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

44 -

60 ·

Example 7
5

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

This is a modification of stage B of Example 1, using sulfur dichloride instead of Sulfur monochloride used.

₃ - 206 mg (2 mmol) of SCl ₂ in 2 ml of DMF are added under N to a stirred suspension of 854 mg (2 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] ethanediidimidamide trihydrochloride in 6 ml of DMF in an ice bath , stirs the received. Mixture at room temperature and obtain the title compound.

Example 8

3-methylamino ~ 4- [3- (3-piperidinomethylphenoxy) propyl-

amino] -1,2,5-thiadiazole

A. N-Methyl-N '- [3- (3-piperidinomethylphenoxy) propyl] - ethandi imidamide trihydrochloride

A suspension of 4.13 g (10.9 mmol) of 3-methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1 is added, 2,5-thiadiazole-1-oxide [prepared in accordance with 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 triturate the residue with acetone. It is then filtered and dried, leaving 4.35 g (90.4%) of the desired product is obtained. A sample of it is crystallized from aqueous isopropyl

• * f ft ♦ f

alcohol around, whereby you get the Tite! compound, Mp 207-225 ° C (dec.).

Analysis for

CHN calculated: 49.03 7.33 15.89%

found (corr. for 49.37 7.35 15.71% '0.94% H ₂ O)

B. 3-methylamino-4- [3- (3-piperidinomethylphenoxy) propyl-

arnino] -1,2,5-thiadiazole

A mixture of 3.74 g (8.47 mmol) of N-methyl-N ¹ - [3- (3-piperidinomethylphenoxy) propyl] ethane diimidamide trihydrochloride [prepared in step A], 34 ml of CH ₂ Cl ₂ and 3, 5 ml of triethylamine are treated

with 3.36 g (8.46 mmol) of N, N ¹ -thiobisphthalimide (DMF solvate) and stir 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. This product is purified by "flash" chromatography on 90 g of silica gel (63-38 μm, (230 to 400 mesh)) using ethyl acetate-methanol (95: 5) as the eluent. 1.9 g (62%) of the title compound are obtained. 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. I ö £ a I N ₅ OS-I H , 04 N , 60 S. , 06 Cl 91 C. 7th , 07 17th , 64 8th , 36 8th, 86 calculated: 54 , 32 7th 17th 8th 8th, found: 54 , 35

11281

s -

6a

Example 9
5

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

A. N-Benzyl-N ¹ - [3- (3-piperidinomethylphenoxy) propyl] - ethanediimidamide trihydrochloride

A suspension of 5.14 g (11.3 mmol) is added 3-Benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1 , 2,5-thiadiazole-i-oxide [prepared according to published UK patent application 2,067,987] in 100 ml of methanol with 7.5 ml of conc. HCl, stir for 3 hours at room temperature, concentrate the solution and triturate the residue with acetone. Then it is filtered and dried, whereby

5.16 g (88%) of the title compound are obtained, melting point 187-205 ° C. (decomp.)

Analysis for C.
έ 24 ^H 33 N ₅ O-31 H , 03 N , 55 Cl , 57 C. 7th , 75 13th , 33 20th , 20 calculated: 55 , 75 6th 13th 20th found: 54 , 88

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

A mixture of 4.73 g (9.16 mmol) is added. N-Benzyl-N '- [3- (3-piperidinomethylphenoxy) propyl] ethane diimidamide trihydrochloride [prepared in step A], 45 ml CH ₂ Cl ₂ and 3.8 ml triethylamine with 3.64 g (9.16 mmol ) Ν, Ν'-thiobisphthalimide (DMF solvate) and stir for one hour. Then you wash

. 63.

the mixture with 44 ml of 10% KOH, dry (MgSO.), 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)), 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'ergibt the Hydra chloride salt of the title compound, mp. 138-141 ⁰ C.

Analysis of CHN ₅ OS-HCl:

HN S Cl

6.80 14.77 6.76 7.48%

6.64 14.99 6.91 7.47% 20

3-Amino-4- [3- (3-piperidinomethy! Phenoxy) propylamino] -1, 2,5-thiadiazole

This example represents a modification of stage B of Example 1, where Ν, Ν'-thiobisphthalimide used instead of sulfur monochloride.

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

calculated: 1 0 C. , 80 found: 60 , 53 i s ρ i e 1 60 B e

- 4-5 -

■ 6 <t-

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 charcoal and filtered through Celite. This solution is concentrated to 100 ml, diluted with 175 ml of dry 1-propanol and stored at 0 ^° C., 20.2 g (82.1%) of the crystalline hydrochloride salt of the title compound being obtained., Mp. 137- 138 ⁰ C.

Analysis for C ₁₇ H ₂₅ N ₅

calculated: found:

Example 11

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

C. , 18 H , 83 N , 24 S. , 35 53 , 78 6th , 74 18th , 52 8th , 66 52 6th 18th 8th

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

A mixture of 22.0 g (53.0 mmol) of N- [3- (3-pyyrolidinomethylphenoxy) propy1] ethane diimidamide trihydrochloride [prepared in Example 4, stage A], 200 ml of CH-Cl and 22 ml of triethylamine were added one 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 (MgSO ₄ ), filtered, diluted with 100 ml of toluene and concentrated.

. 6s.

The product is treated with 1 equivalent of aqueous HCl in 1-propanol, 13.2 g (67%) of des Hydrochloride salt of the title compound is obtained Mp 135-137 ° C.

Analysis for
10

calculated: found:

Example 12

3-Amino-4- {2- [(5-dimethylaminomethyl-3-thienyl) methyl thio] ethylamino-1,2,5-thiadiazole

A. N- "J2- [(S-dimethylaminomethyl-S-thienyl) methylthiojethyl } -äthandiimidamid-trihydrochloride

C. , 95 H , 54 N , 33 S. , 67 51 , 92 6th , 55 18th , 30 8th , 06 51 6th 19th 9

A suspension of 7.8 g (22.6 mmol) of 3-amino-4- £ 2- [(5-dimethylaminomethy.l-3-thienyl) methylthio] -

äthylaminoj ™ 1,2,5-thiadiazole-1-oxide [prepared according to the published GB patent application 2 o67,987] in 150 ml of methanol is mixed with 115.0 ml of conc. HCl, stir for 3 hours at room temperature and then concentrate the solution. The residue is triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of the product. A sample is crystallized from methanol-acetone to to give the title compound, mp. 190-205 ⁰ C, (dec.).

Analysis C ₁₀ N ₀₁ N ₁ -S ₉ -SHCl:

calculated: found:

C. , 25 H , 92 N , 13 35 , 03 5 , 93 17th , 39 35 5 17th

B. 3-Amino-4- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino} -1,2 / 5-thiadiazole

A mixture of 6.13 g (15.0 mmol) of N- ^ 2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] äthyljäthandiimidamid-trihydrochloride [prepared in stage A], 60 ml of CH ₃ CO ₂ and 6, 3 ml of triethylamine are treated with 5.96 g (15.0 mmol) of Ν, Ν'-thiobisphthalimide (DMF solvate), stirred for 1 hour, the mixture is washed with 100 ml of 10% KOH, dried (MgSO.), filtered, diluted with toluene and concentrated to give 5.1 g of the product. The product was treated with 0.5 molar equivalents of fumaric acid in 1-propanol to give the fumaric acid salt of the compound, mp. 141-143 ⁰ C.

The NMR spectrum in DMSO-d shows the presence from about 0.12 moles of 1-propanol.

Analysis for (C ₁₃ H ₁₉ N ₅ S ₃ ) ₂ -C ₄ H ₄ O ₄ '0.12C ₃ HgO: 30

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

35

Example 13
5

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

A. N-f2 - [(S-piperidinomethyl-S-thienyi) methylthioj -ethyl-ethane-diimidamide-trihydrochloride

A suspension of 6.1 g (15.8 mmol) of 3-amino-4- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] -ethylaminoj-1,2,5-thiadiazole-1-oxide [prepared according to the published GB patent application 2,067,987] in 80 ml of methanol is treated with 10.5 ml of 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, 5.86 g (83%) of the product being obtained. A sample is crystallized from methanol / acetone to to give the title compound, mp. 201-214 ⁰ C (dec.).

analysis

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

B. 3-Amino-4- {2 - [(5-piperidinomethyl 1-3-thienyl) methylthio] ■ ethy laminj-1,2,5-thiadiazole

A mixture of 5.17 g (11.5 mmol) of N- {2 - [(5-piperidinomethyl-3-thienyl) -methylthio] äthylj- äthandimidamid-trihydrochloride [produced in Stfe A],

- / rs -

48 ml of CH Cl ₂ and 4.8 ml of triethylamine are mixed with 4.57 g (11.5 mmol) of Ν, Ν'-thiobisphthalimide (DMF solvate), the mixture is stirred for 1 hour, and the mixture is washed with 90 ml of 10% strength KOH, dry (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 ₁ -F
15th

calculated: found:

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 therein , 2,5-thiadiazole-i-oxide replaced by an equimolar amount of:
(a) 3-Ethylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

C. , 96 H , 6 1 N , 31 S. , 38 45 , 61 6th , 4 1 15th , 46 23 , 48 45 6th 15th 23

(b) 3-Allylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(c) 3- (2-Propynyl) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(d) 3- (3-pyridylmethylamino) -4- [3- (3-piperidinomethylphenoxy) propy laminoj-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-piperidinomethy! phenoxy) propylamino] -1 , 2 , 5-thiadiazole T-oxide

so you get

(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) -A- [3- (3-piperidinomethylphenoxy) -propylaminoj-1,2,5-thiadiazole,

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

(f) 3- (3,4-Methylenedioxybenzylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole.

TO

Example 15
5

3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] , 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) '3- (6-pyridinomethyl-2-pyridyloxy) propylamine [manufactured in accordance with UK published patent application 2,098,988] in 50 ml of methanol, 2.74 g (18.6 mmol) are added 3-Amino-4-methoxy-1,2,5-thiadiazole-1-oxide according to the process described in published GB patent application 2,067,987, wherein one a solution is obtained which contains 3-amino-4-13- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1, Contains 2,5-thiadiazole-1-oxide. A cleaned sample melts at 145 to 147 ° C.

B. N- [3- (6-piperidinomethyl-2-pyridyloxy) propyljethane diimidamide trihydrochloride

A methanolic solution of a product prepared in stage A is diluted to 100 ml then 12.4 ml conc. HCl is added, the solution is stirred at room temperature for 18 hours, concentrated and dissolves the residue in 80 ml of water. Then it is extracted twice with CH Cl, the concentrated aqueous phase, treated with n-propanol and concentrated under high vacuum, whereby the Title compound is obtained as a foam.

■ 53- -

YES

C. 3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamine?] -1, 2, 5-thjadiazole

A mixture of the crude product prepared in stage B in 80 ml of CH ₂ Cl ₃ , which contains 7.69 ml of triethylamine, is treated with 7.35 g (18.5 mmol) of N, N'-thiobisphthalimide (DMF solvate), and stirred 1 hour at room temperature, the mixture was washed with 50 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product. The product is purified by flash chromatography on 100 g of silica gel (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. The treatment of the product with one equivalent of cyclohexylsulfamic acid in acetone gives the Cyclohexylsulfamatsalz of the title compound, mp 125.5 -. 131 ⁰ C.

Analysis for

CHNS

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) propyl amino] -1,2,5-thiadiazole

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

Made in accordance with the UK published patent application 2,098,988] with 3-amino-4-methoxy-1,2,5-thiadiazole-1-oxide according to the general method in GB patent application 2,067,987 and by reacting of the obtained 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-i-oxide sequentially according to the general procedure described in Example 1, Step A and then either according to example 1, stage B or according to example C, the title compound is obtained.

Example 17

3-Amino-4-t2-L (6-dimethylaminomethyl-2-pyridyl) methylthio] ethylaminoJ-1 , 2, 5-thiadiazole

If you have a suspension of 3-amino-4- {2- [(6-dimethylaminomethy1-2-pyridyl) methylthio] ethylaminoj-1,2,5-thiadiazole-1-oxide [prepared in accordance with UK published patent application 2,067,987] in sequence converted according to the procedure of Example 1, stage A and then either according to Example 1, Step B or according to Example 10, then the title compound is obtained.

Example 18

3-Amino-4 - {_ 2- ϊ (6-piperidinomethyl-2-pyridyl) methylthioJethylaminoj- 1,2,5-thiadiazole

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

Τ3

GB patent application 2 067 987j reacted in succession according to the method of example 1, step h and then either according to example 1, step B or according to example 10, the title compound is obtained.

Example 19

Repeat the general procedure of Example 1, Step A and then either the procedure of Example 1, stage B or example 10, wherein the 3-i? Toiino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide used there replaced by an equimolar amount of:

Ca) 3-Amino-4-l'3- (3-piperidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole-i-oxide,

(b) 3-Amino-4- [3- (3-dimethylaminomethylthiophenoxy) -

propylamino] -1,2,5-thiadiazole-i-oxide, Cc) 3-Amino-4- [3- (3-pyrrolidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole-i-oxide,

(d) 3-Amino-4- [3-C4-dimethylaminomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide,

(e) 3-Amino-4- [3-CS-dimethylaminomethyl-S-thienyloxy) propylamino] -1,2,5-thiadiazole-i-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 } - 1,2,5-thiadiazole-i-oxide.

One obtains:

(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) propylamino] -1,2,5-thiadiazole,

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

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

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

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

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

The above-mentioned starting materials are prepared according to those described in the published UK patent application 2,067,987. The precursor compounds of the starting materials is prepared according to the procedures and general analogous procedures described in UK patent applications 2,067,987, 2,098,988, 2,063,875 and in published European Patent Application No. 49 are described.

T-S

example

20th

3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propyl amine] * - 1,2,5-thiadia2ol

10 15

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

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

20th

Analysis for C

calculated: found:

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

25th

B. 3-Amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propyl amino] -! , 2,5-thiadiazole-i-oxide ■

A solution of the product from stage A (6.5 g, 26.0 mmol) in 90 ml of methanol is added with 3.84 g (26.0 mmol) 3-amino-4-methoxy-1,2,5-thiadiazole-1-oxide according to the general procedures described in GB patent application 2,067,987, 6.33 g of a product being obtained. Recrystallization from methanol / acetonitrile gives

the title compound, Fp. 1 73 54-1 58 C. , 06 S. , 80 Analysis for C., H ", N ^
16 24 6 OS: 72 , 32 8th , 74 C. H N 8th expected: 52, 6, 64 23 found: 52, 6, 30th 23

- 59- -

C. N- [3- (4-piperidonomethyl-2-pyridyloxy) propylj -ethane diimidamide trihydrochloride

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

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

propylamino] -1,2,5-thiadiazole

A mixture of the product obtained in stage C in 50 ml of CH_C1 "and 5.7 ml of triethylamine is treated with 5.44 g (13.7 mmol) of N, N ¹ -thiobisphthalimide (DMF solvate), stirred for 1 hour at room temperature, The mixture is then washed with 40 ml of 4N NaOH, water, saturated aqueous NaCl solution, dried (Na SO.), filtered and concentrated under reduced pressure to give the crude product. The product is purified by "flash" chromatography on 90 g of 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. The treatment of the product with one equivalent of cyclohexylsulfamic acid in acetone gave the cyclohexyl sulfamate of the title compound, mp 124.5 -. 126 ⁰ C. ·

Analysis for C ₁₆ ^H 24 ^N 6 ° , 07 ₁₃ NO 3 ^S: N , 58 S. , 15 C. , 47 H 18th , 33 12th , 87 calculated: 50 7, 07 18th 11th found: 50 7, 12th

Example 21

3-Amino-4- {3- [3- (1,2,3,6-tetrahydro-1-pyridyl) methyl phenoxy] propylaminol-1,2,5-thiadiazole

The general procedure of Example 15 is repeated using the 3- (6-piperidinomethyl-2-pyridyloxy) propylamine used therein replaced by an equivalent amount of 3- [3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy] propylamine. This gives 2.31 g of the product. Recrystallization from toluene gives the title compound, melting point 99.5-104.degree.

Analysis for C ₇ B ₃ N OS:

C H NS

calculated: 59.10 6.71 20.27 9.28%

found (corr. for

2.19% H ₂ O) 58.78 6.71 19.90 9.26%.

Claims (36)

Claims (1.) Compounds of the general formula I: A- (CH ₂ ) _m Z (CH ₂ ) _n NIL K 1} where R stands for hydrogen, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, N ^ λ or 2 _, where ρ is 1 or 2., R and R each independently of one another hydrogen, (lower) alkyl, (lower) alkoxy or halogen, and if 2 3 R stands for hydrogen, R also trifluoromethyl 2 can be 3, or R and R taken together 4 _o _ mean methylenedioxy, and R for hydrogen, (lower) alkyl or (lower) alkoxy)? m is an integer from 0 to 2 inclusive; η is an integer from 2 to 5 inclusive; Z represents oxygen, sulfur or methylene; and
A has the following meanings: N- (CH-) ■ ₆ /. 2 q -β- · - & ■ or wherein R is hydrogen, (lower) alkyl or (lower) alkoxy, g is an integer from 1 to including 4 and R and R each independently of one another (lower) alkyl, - (lower) alkoxy (lower) alkyl, wherein the (lower) alkoxy radical has at least 2 carbon atoms from the nitrogen atom is removed, or PhenyKlower) alkyl, or when R is hydrogen, R also Cyclo (lower) alkyl can be, or R and R, together with the nitrogen atom to which they are attached are bound, Pyrrolidino, Methylpyrrolidino, - Dimethy! pyrrolidino, Morpholino, Thiomorpholino, Piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, Homopiperidino, heptamethyleneimino, octamethyleneimino, Can form 3-azabicyclo [3.2.2] non-3-yl or 3-pyrrolino; or non-toxic, pharmaceutical compatible salts, hydrates or solvates thereof. AT THE ·· 2. Compounds according to claim 1 of the formula Ι A- (CH ₂ ) _n Z (CH ₂ J ₁₁ NH _n ^ NHR ¹ means, where R is a hydrogen atom or (lower) alkyl / m is 0 or 1, η is 2 or 3, Z is oxygen or sulfur and A is the formulas: Rl - ^k NCH. or is where R is a hydrogen atom or methyl 6 7
and R and R each independently represent methyl or ethyl, or, together with the nitrogen atom to which they are attached. W I I fc- W -A- form a pyrrolidino or piperidino ring, or non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof. 3. Compounds according to claim 1 of the general Formula Ia: 10 where R is a hydrogen atom or a methyl radical stands, and R and R both mean methyl, · or together with the nitrogen atom to which they are bonded represent a pyrrolidino or piperidino ring; or non-toxic, pharmaceutically acceptable salts / hydrates or solvates thereof. 4. Compounds according to claim 1 of the general formula Ib: 7 R NCH ₂ -A ¹ ^ r-CH ₂ SCH ₂ CH ₂ NH. NHR ^{r6 /} S / lit- wherein R and R independently of one another represent a hydrogen atom or methyl, and R and R independently of one another are methyl or ethyl; or non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof. 5. Compounds according to claim 1 of the general formula Ic: -CH ₂ SCn ₂ CH ₂ NH ^ NHR ^. _Ic 30 wherein
R and R each independently represent a hydrogen atom or methyl, and R and R each independently represent methyl or ethyl · - D ~ mean; or non-toxic. , pharmaceutically acceptable salts, hydrates or solvates thereof. 6. Compounds according to claim 1 of the general formula: OCH ₂ CH ₂ CH ₂ NH. . NHR ¹ ■ // w N N wherein R and R each independently represent a hydrogen atom or methyl, and R and R independently of one another are methyl or ethyl, or, together with the nitrogen atom to which they are attached are bound, form a piperidino radical or non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof. '■ 7. A compound according to claim 1, namely 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate, or solvate thereof. 8. The compound of claim 1 which is 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole hydrochloride. 9. A compound according to claim 1, namely 3-amino-4- \ 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl aminol -1,2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 10. A compound according to claim 1, namely 3-amino-4- \ 2- [ (5-dimethylaminomethyl-4-methyl-2'-thienyl) methylthio] äthylaminoj »-1,2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 11. Compound according to claim 1, namely 3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamino] -1,2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate, or solvate thereof. 12. Compound according to claim 1, namely 3-methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5- thiadiazole, or a non-toxic, pharmaceutical compatible salt., hydrate or solvate thereof. 13. The compound of claim 1 which is 3-benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1 , 2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 14. Compound according to claim 1, namely 3-amino-4- ^< (2- [(S-dimethylaininomethyl-S-thienyl) methylthio] -äthylaminoj * "- 1, 2,5-thiadiazole, or a non-toxic, pharmaceutical compatible salt, hydrate or solvate thereof. 15. Compound according to claim 1, namely 3-amino-4- \ 2- [(5-piperiäinomethyl-3-thienyl) methylthio] -äthylaminoj »-1, 2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. T6. ' A compound according to Anspruch- Λ-, namely 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino-1, 2, 5-thiadiazole, or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 17. A compound according to claim 1, namely 3-amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propylamino] - .1, 2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 18. Compound according to claim 1, namely 3-amino-4- \ 3- [3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxyj propylaminoj * -1,2,5-thiadiazole, or a non-toxic, pharmaceutically acceptable salt, hydrate or solvate thereof. 19. Compounds of the general formula II: 5 Il " where R is a hydrogen atom, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, Propargyl, R ² ^ - (CH.) - ^or
3 ^, ■ ² P
IT ⁵ ' means, 2 3 where ρ is 1 or 2, R and R each. independently of one another a hydrogen atom, (lower) alkyl, (lower) alkoxy or halogen atom 2
mean, and when R stands for a hydrogen atom, R can also mean trifluoromethyl, or R and R, 4 together denote methylenedioxy, and R is a hydrogen atom, (lower) alkyl or (lower) alkoxy " can be; m is an integer from 0 to 2 inclusive, η is an integer from 2 to 5 inclusive; Z represents an oxygen or sulfur atom or methylene,
and ο ο ι ι ^. υ ι - 10 - A for or Ν ' is where R is a hydrogen atom, (lower) alkyl or (lower) Is alkoxy, q is an integer from 1 to 4 inclusive, and R and R each independently stands for (lower) alkyl, (lower) alkoxy (lower) alkyl, in which the (lower) Alkoxy radical is at least 2 carbon atoms away from the nitrogen atom, or phenyl (lower) -alkyl, and, when R stands for a hydrogen atom, R can also be cyclo (lower) alkyl, or R and R, together with the nitrogen atom to which they are attached, a pyrrolidino, methylpyrrolidino, Dimethy! Pyrrolidino'-, morpholino-, Thiomorpholine, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, Homopiperidino, heptamethyleneimino, octamethyleneimino-, 3-azabicyclo [3.2.2) non-3-yl- or 3-pyrrolino radical, or a salt, hydrate or solvate thereof. 20. Compounds according to claim 19 of the general formula II: HN where R is a hydrogen atom or (lower) alkyl, m is 0 or 1, η is 2 or 3, Z is an oxygen or sulfur atom, and A stands for the formulas: or wherein R represents a hydrogen atom or methyl stands, and R and R are each independently methyl or ethyl, or, together with the nitrogen atom to which they are attached a pyrrolidino or piperidino ring Dilden; or a salt, hydrate or solvate thereof. • ¥ Ψ 4 - 12 - 21. Compounds according to claim 19 of the general formula Ha: H ₂ CH ₂ CH ₂ NH ^^ MHR ^J Il W HN NH wherein R stands for a hydrogen atom or methyl, and R and R each represent methyl, or together with the nitrogen atom to which they are attached are bonded represent a pyrrolidino or piperidino ring; or a salt, Hydrate or solvate thereof. 22. Compounds according to claim 19 of the general formula Hb :. HN iri wherein R and R each independently of one another denote a hydrogen atom or methyl, and R and R independently of one another are methyl or ethyl; or a salt, hydrate or solvate thereof. ► *. f. Φ ft ι · ♦ - 13 - 23. Compounds according to claim 19 of the general formula lic: SCIUCH ₄₅ NH . NHR ¹ VV 2 4 2 \ • HN NH wherein R and R each independently represent a hydrogen atom or methyl, and R and R each independently one Mean methyl or ethyl radical; or a salt hydrate or solvate thereof. 24. Compounds according to claim 19 of the general 2Q formula Ud: R ⁷ _{6 /} ^NCH Hi -Ij- ^ h ₂ Ch ₂ CH _2n H w _im RR ^^ M ^ r \ / · HN NH 3Q wherein R - and R independently of one another are a Are hydrogen atom or methyl, and R and R each independently represent methyl or Ethyl, or together with the nitrogen atom to which they are attached, a piperidino radical form; . or a salt, hydrate or solvate thereof. 25. A compound according to claim 19, namely N- [3- (3-piperidino-methylphenoxy) propyl] ether diimidamide or a salt, hydrate or solvate thereof. 26. Compound according to claim 19, namely N- £ 2- [(5-D.imethylaminomethyl-2-furyl) methylthio] äthylj ethanediimidamide, or a salt, hydrate or solvate thereof. 27. Compound according to claim 19, namely N-r2-L (5-dimethylaminomethyl-4-methyl-2-thienyl) -methylthio] äthylj? ethanediimidamide, or a salt, Hydrate or solvate thereof. 28. A compound according to claim 19, namely N- [3- (3-Pyrrolidinome thy lphenoxy) propyl] ethane diimidamide, or a salt, hydrate or solvate thereof. -29. The compound of claim 19 which is N- {2 - [(5-dimethyl-aminomethyl-3-thienyl) methylthio] ethyIf ethanediimidamide, or a salt, hydrate or solvate thereof. 30. Compound according to claim 19, namely N- ^ 2 - [(5-piperidino-methyl-3-thienyl) methylthio] äthylj> äthandiimidamid, or a salt, hydrate or Solvate of it. 31. A compound according to claim 19, namely N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] ethane diimidamide, or a salt ₁ hydrate or solvate thereof. 32. Compound according to claim 19 / namely N- [3- (4-piperidinomethyl-2-pyridyloxy) propyl] ethane diimidamide, or a salt, hydrate or solvate thereof. 33. A compound according to claim 19, namely H- [ 3- [3- (1,2,3,6-tetrahydro-1-pyridyl) methylphenoxy] propyl / ethane diimidamide, or a salt, hydrate or solvate thereof. 34. Process for the preparation of a compound of the general formula I or a non-toxic, pharmaceutically acceptable salt, hydrate or sulfate thereof according to claim 1, characterized in that one, preferably at a temperature of about 0 ° to about 50 C and preferably in an organic solvent that is inert to the reaction, a compound of the general formula II: ^A - in which R, A, Z, m and η have the meanings given above, with at least one molar equivalent, preferably a molar excess and in particular preferably a molar excess of 2 to 3 moles, sulfur monochloride, sulfur dichloride or a chemical equivalent thereof, preferably sulfur monochloride, to one Compound of general formula I converts. 35. A process for the preparation of a compound of the general formula II according to claim 19, characterized in that one, preferably in an inert solvent and at room temperature, a compound of the general Formula III: A- (CH ₂ ) _m Z (CH ₂ J _n NH, -NHR ίί where R, A. and Z as well as m and η have the meanings given above, Reacts with a strong inorganic acid, preferably hydrochloric acid, or, 25th ·· * ·, ** «IQ ft · · * 4 B - 17 that a compound of the general formula IV A- (CH-) Z (CH,) ₅ IV 10 wherein A and Z as well as m and η have the meanings given above, with a compound of general formula V: ^CH 3 ° \ .OCH ₃ to a compound of the general formula VI: ^(CH 2 ^} n ^NH \ / ° ^ ^H 3 VI reacts and then the compound of the general formula "VI obtained with a compound of general formula R NH »can react. 35 36. Medicaments containing at least one compound according to claims 1 to 18 as active ingredient, optionally in connection with a medicament carrier and pharmaceutically compatible additives.