CS250229B2 - Method of 3,4-diamino-1,2,5-thiadiazole derivatives' production - Google Patents

Description

(54) A method for producing 3,4-diamino-1,2,5-thiadiazole derivatives.

The invention relates to a process for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives.

British Patent No. 2,067,987 describes 3,4-disubstituted-1,2,5-thiadiazole-1-oxides and -1,1-dioxides of the formula

AND

wherein the substituents A, m, Z, n and R 1 are similar to the substituents in the compounds produced by the process of the invention. However, they are 1-oxides or 1,1-dioxides, moreover, the compounds produced by the process according to the invention cannot be obtained by any of the processes described in this patent for the preparation of compounds of the above formula wherein p is an integer of 1 or 2 .

European Patent Publication No. 40,696 discloses, inter alia, 3,4-disubstituted 250229

-1,2,5-thiadiazole-1-oxides and -1,1-dioxides of the formula

where

R, A, η, X, m, R 1 and R 2 have a similar meaning to the corresponding substituents in the compounds produced by the process of the invention. However, they are 1-oxides or 1,1-dioxides, in which the known 1 or 2, moreover, the compounds produced by the process according to the invention cannot be obtained by any of the processes described above.

In the two patents mentioned above, the compounds are prepared by using 1,2,5-thiadiazole-1-oxide or 1,1-dioxide, which has readily cleavable groups on the amino group at the 3 and 4 positions. The desired substituents at these positions can then be obtained by amino substitution or leaving group substitution. A number of attempts have been made to obtain the compounds of the invention in a similar manner, i.e. using a 1,2,5-thladlazole derivative with an amino group or a suitable leaving group at the 3 and 4 positions of the starting material or intermediate.

All these experiments, including various variations of the reaction conditions, did not allow the compound of the invention to be obtained in the manner described.

It has now been found that the compounds of the present invention can be obtained by ring closure in the correspondingly substituted ethanediimidamide of formula II

NH HN

Intermediates of formula (II) can be obtained by various methods.

The present invention relates to a process for the preparation of 3,4-dlamino-1,2,5-thiadiazole derivatives of the general formula I

where

R1 represents a hydrogen atom, a straight or branched chain alkyl of 1 to 6 carbon atoms or a group

Z represents an oxygen atom or a sulfur atom, and

And means one of the groups

where

R ⁵ represents a hydrogen atom or an alkyl of 1 to 5 carbon atoms,

R 6 and R ⁷ independently represent or form alkyl radicals having 1 to 5 carbon atoms

R6 and R7 together with the nitrogen atom to which they are attached a pyrrolidine, piperidine or 1,2,3,6-tetrahydropyridyl ring, as well as non-toxic, pharmaceutically acceptable salts, hydrates and solvates thereof, characterized in that: reacting at a temperature of 0 to 50 ° C, preferably in an inert organic solvent, a compound of formula II

HN NH m is an integer of 0 or 1, n is an integer of 2 or 3,

(1

A, R 1, Z, m and n are as defined above, with at least one. molar equivalent, preferably with a molar excess, of 2 to 3 moles of S2Cl2 or SCI2, preferably S2Cl2, as well as non-toxic, pharmaceutically acceptable salts, hydrates and solvates thereof.

The present invention includes all tautomeric forms, diastereoisomeric forms, and optically active isomers of the compounds of Formula I and mixtures thereof. By non-toxic pharmaceutically acceptable salt is meant an acid addition salt such as hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, tartaric, citric, levulic, benzoic, succinic and the like.

In the compounds of formula I, R @ ¹ is hydrogen or alkyl of 1 to 5 carbon atoms, especially hydrogen or methyl, most preferably hydrogen; A is preferably. substituted phenyl, substituted furyl or substituted thienyl, preferably substituted phenyl. Preferably, Z is a sulfur atom or an oxygen atom, and when A is a substituted phenyl moiety, Z is preferably an oxygen atom. A preferred value for m is 0 or 1 and for n is 2 or 3, when A is a substituted phenyl radical, m is preferably 0 and preferably 3. R5 is preferably hydrogen or methyl, in particular. hydrogen atom. R ⁶ and R ⁷ are preferably alkyl of 1 to 5 carbon atoms or form, with the nitrogen atom to which they are attached, a pyrrolidine or piperidine ring.

Compounds of formula (I) may be obtained by reacting compounds of formula (II) with sulfur chlorides S2Cl2 or SCI2 according to the following scheme:

^with 2 ^C1 2 or sci ₂

(П where

A, m, Z, and R ¹ are as defined above. It is desirable to use at least 1 mole of S 2 Cl 2 or SC 12 per mole of compound of formula (II), but it is preferable to use an excess of these, for example 2 to 3 moles, per mole of compound of formula (II). It has been shown that using SC1-2 often yields less pure product or lower yield of pure product, therefore it is preferable to use S2Cl2.

The reaction temperature is not critical, usually the reaction is carried out at a temperature of 0 to 50 ° C, preferably at room temperature. The reaction time is also not critical and is temperature dependent. Usually the reaction takes from 30 minutes to 6 hours, at room temperature usually from 1.5 to 4 hours. The reaction can be carried out in. an inert organic solvent, preferably in a mixture of an inert organic solvent and dimethylformamide, especially dimethylformamide.

In a preferred embodiment of the process of the present invention, compounds of formula (I) may be represented

In (!) Where

R1 is hydrogen or lower alkyl,

AND

Z represents an oxygen or sulfur atom; and

A is any of m is an integer of 0 or 1, n is an integer of 2 or 3,

where

R ⁵ represents a hydrogen atom or methyl, and

R ⁶ and R ⁷ are each independently methyl or ethyl or form R ⁶ and R ⁷ together with the nitrogen atom to which they are attached a pyrrolidine or piperidine ring, as well as non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof.

In another preferred embodiment of the process according to the invention, compounds of formula Ia can be obtained

(/and where

R ¹ represents hydrogen or methyl,

R ⁶ and R ⁷ are methyl or form a nitrogen atom to which they are attached a pyrrolidine or piperidine ring, as well as non-toxic, pharmaceutically acceptable salts, hydrates or solvates thereof.

In another preferred embodiment of the process of the invention, compounds of formula Ib can be obtained

where

R ¹ and R ⁵ are each independently hydrogen or methyl,

R ⁶ and R ⁷ are independently methyl or ethyl; or a nontoxic farm ceutického acceptable salts, hydrates or solvates thereof.

According to a further preferred embodiment of the process according to the invention, compounds of formula Ic can be obtained

(fc) where

R ¹ and R ⁵ are each independently hydrogen or methyl,

R ⁶ and R ⁷ are each independently methyl or ethyl, as well as non-toxic, pharmaceutically acceptable salts, hydrates or solvates of these compounds.

According to a further preferred embodiment of the process according to the invention, the compounds of the formula Id can be obtained

where

R ¹ and R ⁵ are each independently hydrogen or methyl,

R ⁶ and R ⁷ are each independently methyl or ethyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a piperidine ring as well as non-toxic, pharmaceutically acceptable salts, hydrates or solfates of these compounds.

The most preferred compounds of Formula I are the following:

(1) 3-amino-4- [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 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino] -1,2,5-thiadiazole, 3-amino-4- [3- (3- pyrrolidinomethylphenoxy) propylamino] -1,2,5-thiadiazole,

5) 3-methylamino-4- [3- (3-piperidinomethyl-phenoxy-propylamino) -1,2,5-thiadiazole

6) 3-benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole;

(7) 3-amino-4- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] methylamino] -1,2,5-thladiazole;

8) 3-β-ώ-4- 2 - [(5-plperidinomethyl-3-thienyl) methylthio] ethylamino] -1,2,5-thiadiazole;

9) 3-amino-4t [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole; and

10) 3-amino-4- [3- (4-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole, as well as non-toxic, pharmaceutically acceptable salts, hydrates and solvates thereof.

The intermediates of formula (II) used to produce the compounds of formula (I) may be obtained in various ways. In one of these processes, the corresponding 3- (amino or substituted amino) -4- (substituted amino) -1,2,5-thiadiazole-1-oxide of formula III is reacted with a strong inorganic acid, preferably hydrochloric acid. to form a compound of formula II according to the following reaction scheme:

A - (. CH © (CH © Л

A \ NH NH

The reaction may be carried out in an inert solvent, preferably methanol. The reaction temperature is not critical, the procedure is usually carried out at room temperature. The compounds of formula (III) are known or can be obtained in a known manner, for example according to British Patent Specification 2,067,987.

Compounds of formula (II) may also be obtained according to the following reaction scheme:

сно осн ₂ ^ ^H ₂ V ^(f 2 ⁺ VC у)

NH NH (iv) (v)

Ψ

A- (CH 2 Z (CH 2) _and NH 4)

HN NH

R ^ NH NH

Ψ h nhrI

W

HN ^Z \ h 'c — c.

The (OCH ₃ ) ( _III ) (II) reaction can be carried out in an inert solvent, preferably methanol. The starting compounds of formula (IV) are known or can be obtained in a known manner, for example, in British Patent Application No. 2,067,987.

For therapeutic use, the compounds of formula (I) which are pharmacologically active are administered in the form of compositions comprising, as an essential component, at least one of the aforementioned compounds in free or non-toxic form. a pharmaceutically acceptable acid addition salt in association with a pharmaceutically acceptable carrier.

The compositions may be administered orally, parenterally or rectally in the form of suppositories. A wide variety of pharmaceutical forms can be used. When a solid carrier is used, the preparation may be a tablet, hard gelatin capsule, powder, pellet or sublingual tablet. The liquid carrier may be a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution or a liquid suspension of an aqueous or non-aqueous nature. All of these compositions are prepared in conventional manner.

The doses of the compounds according to the invention depend not only on the weight of the patient, but also on the degree of inhibition of gastric acid required and on the efficacy of the substance used. The decision can be made by any physician and can vary from patient to patient.

When using preferred compounds, it will generally be appreciated that when administered orally, an effective dose will be in the range of 2 to 300 mg, preferably 4 to 100 mg. This dose will be given 1 to 4 times a day.

Histamine H ₂ -receptor antagonists have been shown to be potent inhibitors of gastric acid secretion in both animals and humans, as described, for example, in Brimblecombe et al., J. Int. Copper. Res., 3, 86 (1975). Clinical evaluations of histamine Щ-receptor antagonists such as cimetidine have been shown to be effective drugs for gastric ulcers, the results of which are reported in particular in Gray et al., Lancet, 1, 8 001 (1977). Some preferred compounds produced by the method of the invention have been compared to cimetidine in various experiments and appear to be more potent than cimetidine in antagonizing histamine H-receptors on the isolated right atrium of guinea pig even in inhibiting gastric acid secretion in rats and dogs.

Determination of antisecretory efficacy in gastric fistula rats.

Male Oong Eva.ns rats weighing 240-260 g were used, and a cannula was inserted at this weight. Implantation of the stainless steel cannula into the anterior stomach was performed according to the method of Pare et al. (Laboratory Animal Science, 27, 344 (1977)). Cannula parts and surgical

1 «the procedure exactly matches that of that publication. After the procedure, the animals are housed individually in cages with a solid floor and sawdust and are fed and fed ad libitum during recovery. The animals are used for the experiment at the earliest 15 days after surgery. The animals are not fed for 20 hours prior to the experiment, but water is administered ad libitum. Immediately. before collection, the cannula is opened and the stomach is gently washed with 30 to 40 ml of warm saline or distilled water to remove any residual contents. The catheter is then screwed into the cannula instead of the stopper and the rat is placed in a 40 cm long, 15 cm wide and 13 cm high transparent plastic cage. At the bottom of the cage is a slot with a length of 25 cm and a width of 1.5 cm, with this slot hangs the catheter downwards. Thus, the rat can move freely in the cage during collection. The remaining circumstances of the experiment are identical to those of Ridley et al. (Research Comm. Chem. Path. Pharm., 17, 365 (197-7)).

The contents of the stomach collected within the first hour after washing the stomach are discarded, then the catheter is removed from the cannula and replaced with a stopper. 2 ml of water are introduced into the stomach by oral gavage and the animal is returned to the cage for 45 minutes. The plug is then removed and replaced with a catheter to which a small plastic bottle is attached to collect the stomach contents. In this way, a control sample is taken as gastric secretion within 2 hours. The catheter is then removed and replaced with a stopper. The test substance was orally administered by gavage in a volume of 2 ml / kg. After 45 minutes, the stopper is replaced by a catheter with a small plastic bottle and the secretion sample is taken again within 2 hours. By comparing this sample with a control sample, the potency of the test substance can be determined.

If the test substance is to be evaluated parenterally, it should be administered to the test animals intraperitoneally or subcutaneously at a volume of 2 ml / kg immediately after the initial 60-minute collection is postponed.

A sample is taken over 2 hours and then the animals are dosed with the test substance intraperitoneally or subcutaneously in a volume of ml / kg. An additional secretion sample is taken over 2 hours and the effect of the test substance can be determined by comparing both samples.

Centrifuge the samples and determine their volume. The titratable acidity is measured by titrating the sample in a volume of 1 ml to pH 7.0 with 0.02 N sodium hydroxide using an Autoburet instrument and an electrometric pH meter (Radiometer). The titratable acid is converted to microequivalents by multiplying the volume in ml. acid concentration in milliequivalents per liter.

Final results are expressed as percent inhibition compared to control. Dose-effect curves are plotted and ED is calculated by regression analysis; _{) 0} . At least 3 rats are used for each dose and at least different doses are used. determination of dose and effect of the test substance. The results are shown in Table 1 below.

Table 1

Antisecretory efficacy in gastric fistula rats

Compound ED50 subcutaneously micromoles / kg Efficiency ratio (cimetidine = 1.0) cimetidine 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 ~ 0.5 ~ 7 Example 4 0.18 (0.10—0.36) 20 May

Note to Table 1: * 95 ·% confidence limits.

(1972) report that histamine H ₂ -receptors are implicated in this effect _; burimamide is reported to be a competitive antagonist of these receptors. Other experiments described in Hughes and Coret, Proc. Soc. Exp. Biol. Med., 148, 127 (1975); and Verma and Mc. Nelil, J. Pharmacol. Exp. Ther., 200, 352 (1977) support the conclusion of Black and coworkers that the positive chromotropic effect of histamine on isolated right guinea pigs

Antagonism against histamine H ₂ receptors on isolated guinea pig atrium

Histamine induces an increase in contractility to isolated spontaneously. beating atrium of the guinea pig heart, this effect is concentration-dependent. Black et al., Nature, 236, 385

The atrium is mediated through histamine H ₂ -receptors. Black et al. Agente and Actions, 3, 133 (1973) and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) enjoyed the isolated guinea pig right atrium for comparison of the effect of histamine _H2. Receptor. Our experiments were carried out according to a modification of this procedure by Reinhardt et al., Agents and Actions, 4, 2.17 (1974).

The experiment was carried out by killing Hartley male guinea pigs weighing 350-450 g with a wound to the head. Hearts were excised and placed into a petri dish containing oxygenated ^{(95 / v} oxygen, 5% carbon dioxide) modified Krebs solution which contains in grams per liter: NaCl 6.6, KC1 0.35, MgSO ₄ .7 H ₂ O 0.295, K H - PO 4 0.162, CaCl ₂ 0.238, NaHCO ₃ 2.1 and dextrose 2.09.

The self-beating right atrium is separated from the other tissues and a silk thread (4-0) is attached to each end. The hall is placed in a 20 ml bath containing oxygenated modified Krebs solution at 32 ° C. Atrial contractions are recorded isometrically with a Grass FT 0.03 transducer, frequency and counter-rate records are recorded with a Beckman RP Dynograph.

A resting load of 1 g is hung on the anteroom and the anteroom is allowed to equilibrate for 1 hour. At the end of this time, a submaximal concentration of histamine dihydrochloride (3 x 10 -10 mol) was added to the bath and the bath was washed. Histamine is then added to the bath cumulatively using a 1/2 log 10 interval to a final molar concentration of 1 x 10 ⁷ to 3 x 10 ⁵ . The increase in histamine-induced frequency is allowed to stabilize before the next concentration is added. Maximum response always occurs at a concentration of 3 x 10 ^-5 moles.

The histamine is washed several times and the atrial state returns to the control value. Paik. the test substance is added at the appropriate molar concentration and after incubation for 30 minutes the dose-response monitoring of the histamine effect is repeated with the addition of higher concentrations if necessary.

Dissociation constants (K _B ) were derived according to the method of Arunlakshana O. and Schild HO [Br. J. Pharmacol. 14, 48 (19519)] using at least three doses. Parallel shifts of the dose-response curves were obtained without decreasing the maximal response at the concentration of antagonist used, as shown in Table 2.

Table 2

Effectiveness on isolated right atrium of guinea pig

Compound N Kb (micromoles) Effect ratio (cimetidine - 1.0) cimetidine 20 May 0.41 (0.21 - 0.64) * 1.0 Example 1 13 0.003 (0.001 - 0.004) 137 Example 4 11 0.004 (0.001—0.010) 102

* 95% confidence limit

It is also possible to obtain the compounds of the formula i by ring closure in the compound of the formula ii with N, N N-thiobisphthalimide of the formula

By using N, N'-thiobisphthalimide in place of S ₂ Cl ₂ or SC ₁₂ to close the ring, the compounds of formula (I) can be obtained in higher yield and higher purity. The crude compounds of formula (i) obtained above are generally sufficiently pure to form crystalline salts without prior chromatographic purification.

In this process, the starting diimidamide of formula (ii) is reacted with an approximately equimolar amount of N, N‘-thiobisphthalimide in an inert organic solvent such as methylene chloride.

Preferably, the starting diimidamide is used in the form of its trihydrochloride, in which case three molar equivalents of the amine, for example triethylamine, are used which are added to the reaction mixture to neutralize the trihydrochloride. The reaction is carried out with stirring at room temperature and takes about an hour. The phthalimide which precipitates from the reaction mixture is then extracted with a strong base, for example an aqueous solution of 10 to 20% potassium hydroxide, the organic solution is dried, filtered and evaporated to give the crude product of formula (i). N, N'- thlobisphthalimide, which is the starting material for this process, is a known compound obtainable by the method described in Canadian Journal of Chemistry, 44, 2111-2113 (1966) or as further described in Preparation No. 1.

The invention will be illustrated by the following preparation and the following examples.

Preparation 1

N, N‘-thiobisphthalimide

To a solution of 14.7 g (0.1 mol) of phthalimide in 80 ml of dimethylformamide (DMF) cooled to 0 ° C was added dropwise 5.15 g (0.05 mol) of SCI 2. The solid was collected and dried to give 12.5 g of the title compound as a dimethylformamide solvate, m.p. 301 DEG-315 DEG C. The IR, IR spectrum was consistent with the expected structure of the resulting solid. product.

Analysis for C ₁₆ H ₈ N ₂ O ₄ S. C3H7NO calculated:

57.52% S, 3.80% H, 10.57% N, 8.07% S, found:

% C, 57.50;% H, 3.80;% N, 10.29;

The solvate can be converted to the free material by recrystallization from chloroform. The melting point of the free substance is 33/0 to 325 ° C. It is also apparent from the NMR spectrum that dimethylformamide has been removed.

Analysis of C ₁₆ H ₈ N ₂ O ₄ S calculated:

% C, 59.25;% H, 2.49;% N, 8.64;

% C, 59.21;% H, 2.21;% N, 8.91;

Example 1

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

A. N- [3- (3-Piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride

A suspension of 17.1 g (47.0 mmol) of 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,4-thiadiazole-1-oxide (prepared according to British Patent Specification 2,067,987) in 450 ml of methanol is mixed with 38 ml of concentrated hydrochloric acid. The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated and water was removed by azeotropic distillation with absolute ethanol to give colorless crystals. The crystals were suspended in 200 ml of absolute ethanol, filtered, and dried in vacuo to give the title compound (16.6 g, 82.6%), m.p. 205 DEG-222 DEG C. dec. Recrystallization from 50% methanol in ethyl acetate gave an analytical sample, m.p. 206 DEG-216 DEG C. with decomposition.

Analysis for C ₁₇ H 27 N ₅ O. 3 HCi: calculated:

47.84% C, 7.08 ° / o H, 16.41% N, found:

H, 7.18; N, 16.75.

B. 3-Amino-4- [3- (3-piperldinomethylphenoxy) propylamino] -1,2,5-thladiazole

A suspension of 2.13 g (5.0 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] ethandiimidamidtrihydrochloridu (prepared in Step A) in 20 mL DMF was treated with 2.02 g (15.0 mmol) with ₂ Cl ₂ and the mixture was stirred for 4 hours. The resulting mixture was carefully poured into 200 mL of water and then basified with potassium carbonate. The mixture was extracted with methylene chloride (3 x 50 ml) and dried (MgSO4) and concentrated to give 2.1 g of a dark colored gum which contained the title compound. This product was purified by high pressure liquid chromatography on oxide. silica using 100: 10: 0.5 methylene chloride, 2-propanol and ammonia as the mobile phase. 0.89 g of the title compound is obtained from the appropriate fractions. After mixing with fumaric acid in n-propanol, 0.76 g of the title compound is obtained in 21.4% yield as a crystalline fumarate, m.p. 187-187.5 ° C. HPLC analysis showed a purity of > 99%.

Analysis for (C ^ HH ^^O ^ ^ · CHHHOO):

H, 6.71; N, 17.27; S, 7.90. Found:

H, 6.36; N, 16.98; S, 8.08.

A portion of the fumarate is suspended in water, neutralized with potassium carbonate, and extracted with methylene chloride. The extract was concentrated and the free material crystallized. The title compound is obtained, m.p. 43-47 T. A portion of this product is converted to the hydrochloride, m.p. 138-140 ° C.

Analysis for C 17 H 25 N 5 OS. HCi: calculated:

% C, 53.18;% H, 6.83;% N, 18.24;

% C, 53.14;% H, 6.88;% N, 18.49.

Example 2

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

A. N - {- [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl] ethanediimidamide trihydrochloride hydrate

Suspension of 6.59 g (20.0 mmol) of 3-amino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino [1,2,5-thiadiazole-1-oxide prepared according to British No. 2,067,987 in 200 ml of methanol is carefully heated to complete dissolution, followed by the addition of 13.3 ml of concentrated hydrochloric acid. The solution is stirred at room temperature for 2.5 hours, then the solution is evaporated to dryness and the residue is triturated with 70 ml of absolute ethanol. The crystals were collected by filtration and dried in vacuo to yield 52% yield 4.3 g, m.p. 166-169 C with decomposition ^L.

Analysis for C H _{O 2} N ₅ OS _{2 liters.} 3 HCl. H ₂ O: calculated:

% C, 35.08;% H, 6.38;% N, 17.05.

% C, 34.85;% H, 6.24;% N, 17.45.

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

To a suspension of 12.3 g (30.0 mmol) of N- (2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl] ethanediimidamide trihydrochloride hydrate prepared according to Step A in 150 ml of dimethylformamide was added 7.2 ml of S ₂ Cl with stirring. ₂ (12.1 g, 90 mmol) The mixture was stirred at room temperature for 4 hours, then about half of the dimethylformamide was removed under reduced pressure, the remaining black solution was poured into 1 liter of water, basified with potassium carbonate and extracted first with ethyl acetate. After drying over magnesium sulphate, filtration and evaporation, 9.0 g of a black gum containing the title compound are obtained, which material is purified by preparative high pressure liquid chromatography on silica using a mixture of ethyl acetate, 2-propanol and ethyl acetate as the mobile phase. ammonia in a ratio of 100: 10: 0.5 The appropriate fractions were collected to give 1.24 g of the title compound as a gum oily material.

A portion of this material was reacted in methanol with an equivalent amount of 2 N hydrochloric acid to give the hydrochloride of the title compound.

Analysis for C ₁₂ H ⁹ N _{4 5} S2O. HC1:

calculated:

% C, 41.18;% H, 5.76;% N / 20.02%;

% C, 40.54;% H, 5.70;% N, 19.39;

(Corrected to 1.65% water.)

When treated with an equivalent amount of cyclohexylsulfamic acid in acetone, the title compound is cyclohexylsulfamate, m.p. 93-95 ° C.

Analysis for C ^ HH ^N ^O O. C _G H _{I 3} NO ₃ S: Calculated:

H, 6.55; N, 17.06; S, 19.53. Found:

% H, 6.17;% N, 17.21;% S, 19.58.

Example 3

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

A. N - [2 - [(5-Dimethylammomethyl-4-methyl-2-thienyl) methylthio] ethyl] ethanediimidamide trihydrochloride

A solution of 17.9 g (50.0 mmol) of 3-amino-4- [2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino-1,2,5-thiadiazole-1-oxide, prepared in accordance with British patent specification 2,067,987 in 500 ml of methanol is mixed with stirring with

33.3 ml of concentrated hydrochloric acid. After stirring for 3 hours, the mixture was concentrated and excess water was removed by azeotropic distillation with absolute ethanol to give an almost colorless crystalline residue. The residue is treated with 200 ml of absolute ethanol at 0 ^° C, filtered and dried to give the title compound (16.9 g, 80%), mp 203-220 ° C, mp. Recrystallization from 50% methanol in ethyl acetate gave the product with a melting point of 221 U with decomposition.

Analysis for C ^ HH ^ NrN ^O. 3 HC1:

calculated:

Found: C, 36.92; H, 6.20; N, 16.56; S, 15.17.

C 36.76, H 6.33, N 16.97, 15.54% 3.

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

To a suspension of 6.34 g [15.0 mmol] of N- {2 - [(5-dimothylammomethyl-4-methyl-4-thienyl) methylthio] ethyl] ethanediimidamide trihydrochloride prepared in Step A in 60 ml of dimethylformamide was added with stirring 6.1 g ( 45.0 mmol) C-Cl-.

The mixture was stirred at room temperature for 4 hours, poured into 800 ml of water, basified with potassium carbonate and extracted several times with 100 ml of methylene chloride each time. The extracts were dried (MgSO4), filtered and evaporated to give 3.4 g of a black gum. This material was purified by preparative high pressure liquid chromatography on silica. using methylene chloride, 2-propanol and ammonia 100: 10: 0.5 as the mobile phase. Further purification was also carried out by preparative high-pressure silica chromatography using a 100:: 2.5: 0.5 mixture of methylene chloride, methanol and ammonia as the mobile phase. The appropriate fractions were collected and the resulting product was obtained in a purity of about 98%. When the resulting product is treated with an equivalent, the hydrochloride of the title compound is obtained.

Analysis for СщН-хЫгДз HC1: calculated:

% H, 5.84;% H, 18.43;% S, 25.32;

40.78% C, 5.63% H, N 18.31%, S 25.44% (corrected for a water content of 0.51%).

Example 4

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

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

A suspension of 13.4 g (38.3 mmol) of 3-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylmethyl] [1,2,5 [thiadiazole [1-oxide] prepared according to British Patent Specification No. 2 CC7 987 in 350 ml of methanol are mixed with

25.5 ml of concentrated hydrochloric acid.

The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated by azeotropic removal of water with absolute ethanol to give the title product as a crystalline residue which was triturated with 150 ml of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195 DEG-203 DEG C. with decomposition.

Analysis for C16H2SN5O. 3 HC1:

calculated:>

% C, 46.55;% H, 6.84;% N, 16.97.

H, 6.93; N, 16.93.

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

To a suspension of 8.25 g (20.0 mmol) of [[3- (3-pyrrolidinomethylphenoxy) propyl] ethanedilmidamide trihydrochloride prepared according to Step A in 80 ml of dimethylformamide was added 5.4 g (40.0 mmol) of S2Cl2 and the mixture was stirred at room temperature. Stir for 3 hours under nitrogen. The reaction mixture was concentrated to give a dark colored gum which was suspended in 500 mL of water, basified with potassium carbonate and extracted three times with 100 mL of methylene chloride. The extracts were dried (MgSO4), filtered and concentrated to give 7.5 g of a gum.

This product was purified by preparative high pressure liquid chromatography on silica using 100: 5: 0.5 methylene chloride, 2-propanol and ammonia as the mobile phase. The fractions containing the resulting product were combined and evaporated to give 1.64 g of purified product in 24.6% yield. When this product is mixed in absolute ethanol with an equivalent amount of 2 N hydrochloric acid, 1.13 g of the hydrochloride of the title compound is obtained, m.p. 138-140 ° C.

Analysis for C ^ HH ^ sOS. HC1:

calculated:

% C, 51.95;% H, 6.54;% N, 18.93;

% C, 51.97;% H, 6.36;% N, 18.63.

Example 5

The procedure of Example 1, steps A and B was repeated except that 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiazol-4-ol was replaced by the equimolar. (a) 3-amino-4- [3- (3-dimethylaminomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide; (b) 3-amino-4- [3- (3-diethylaminomethyl) enoxy) propylamino] -1,2,5-thiadiazole-1-oxide, (c) 3-amino-4- {3- [3- (2-methylpyrrolidino-methylphenoxy) propylamino] [1,2,5 [ [thiadiazobl-oxide, d] 3-amino-4-} 3- [3- (3-methylpyrrolidino) methylphenoxy] propylamino] -1,2,5-thiadiazole-1-oxide, (e) 3-amino-4-; 3- [3- (4-methylpiperidino) methylphenoxy] propylamino] -1,2,5-thiadiazole-1-oxide, (f) 3-amino-4- [3- (3-methylphenoxy) phenoxy] Jpropylaminoj-1S-thladiazole-

-1-oxide, (g) 3-amino-4- [3- (N-methylpiperazino) methylphenoxy] propylamino-1,2,5-thiadiazole-1 H- 13 [amino] [4 [[3- (3 diallylaminomethyl [phenoxy) propylamino] -1,2,5,5-hiadiazole-1-oxide, (i)]] - 4- [3- (3- hexamethyleniminamethylphenoxy) propylamino] -1,2,5-. -thiadiazole-1-oxide, (J) -amino- [3- (3-heptamethylethylmethyphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide, (k) 3-amino-4- { 3- [3- (3-azabicyclo) -2.2,3.2Znon-3-yl} methylphenoxy] propylamino [1,2,5-thiadiazolo [1 [oxide] or (1) 3 [amino-4-; 3 [[ 3- (3-pyrrolidinomethyl-phenoxy) -propyl-amino | [1,2,5 [thiadiazole [-1-oxide] to give (a) 3 [amino] [4 [[3- (3-dihydro-1-ylamino) -methylamine]] enoxy] propylamino] -1,2,5-thiadiazole, (b) 3 [amino-4- [3- (3 [diethylaminomethyl [phenoxy) propylamino]] - 1,2,5 [thiadiazole, (c] 3-amino [4- [3- [3- (2-Methyl) pyrido] methylphenoxy] propylamine (c '[1,2,5tha] [diazole, (d) 3-amino-4- | 3- [3- (3) -methylpyrrolidino] methylphenoxy] propylamine о} -1,2,5-thiadiazole, (e) 3-amino-4-methyl [3- (α-methylpiperidino) methylphenoxy] propylamino _] ^L 1,2,5 [iadhiadiazole, (f) 3taminO [4 [[3- (3-Morpholinomethylphenethoxy) propylamino] -1,2,5 [thiadiazole, (g) 3-amino] -4- [3- (N-methyl-phenoxy) methylphenoxy] propylamino] [1,2,5] -thiadiazole, (h) 3-Amino [4 [(3- (3-diailyl) nomethyl [phenoxy) propylamino] -1,2,5-thiadlzole.

(i) 3-Amino [4 [[3- (3-hexamethylenimido [methylphenoxypropylamine] -1,2,5-thiadiazole], (f) 3-amino-4- [3- [3-heptamethylenimido [nomethylphenoxy] propylamino] t1,2] (5) thiadlazole, (k) S-amino-4-β-3- (3-azabicyclo [3.2.2] non-3-yl] methylphenoxy] propylamino} [1,2,5-hiadiazole and (1) 3-amino-4- Β 3 [[3- (3-pyrrolino) methylphenoxy] propyl amine [1,2,5-thiadiazole.

Example 6

3-piperazin-4- [3- (3 [piperazinomethylphenyl) propylamino] -1,2,5-hiadiazole

This is a variation of Example 1, Step B, using a shorter reaction time and less S ₂ Cl ₂ .

To a stirred suspension of 12.08 g (28.3 mmol) of N- [3- (3-piperidinomethylphenoxy] propyl] ethaudilldaunide trihydrochloride <1 in 120 ml of dimethylformamide was added 7.64 g (58.6 mmol) of S ₂ Cl ₂ and the mixture was The mixture was stirred for 3 hours in an atmosphere.

Dimethylformamide was removed under reduced pressure to give a black rubbery material which was suspended in water, basified with potassium carbonate and extracted three times with 100 ml of methylene chloride. The extracts are combined, dried over magnesium sulfate, filtered, and concentrated to a gum which is purified by preparative high pressure liquid chromatography on silica using methylene chloride / 2-propanol / ammonia 100: 5: 0.5 as the mobile phase. 3.1 g of the title compound are obtained in the form of a dark oil, from which 2.66 g of the title compound can be obtained in the form of a crystalline nimarate at 23.2%. mp 186-186.5 ° C. High pressure liquid chromatography confirmed a purity of 99%. ”

Analysis for ₍₂₅ Ο17Η Ν5Ο3) 2.B ^ H / A Calculated:

% H, 6.71;% N, 17.27;% S, 7.90.

% H, 6.93;% M, 17.31;% S, 7.98%.

Example 7

3 [amino] [3- (3-piperidomethylphencxy) propylamino] [1,2,5-hiadiazole

AND

28

This is a variation of Example 1, Step B using ₂ instead S2CI2 SC1.

To a stirred suspension of 854 mg (2 mmol) of N- [3- (3-piperidinomethylphenoxy] propyl] ethanediimidamide trihydrochloride in 6 mL of dimethylformamide under an ice bath under an ice bath was added SC1 < 2 (206 mg, 2 mmol) in 2 mL of dimethylformamide. The mixture was stirred at room temperature to give the same title compound as in Example 1.

Example 8

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

Λ. N-methyl-N- [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride

A suspension of 4.13 g (10.9 mmol) of 3-methylamino-4- [3- [3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide prepared according to the method of British Patent Specification 2,067 987 in 95 ml of methanol was treated with 7.2 ml of concentrated at room temperature for 3 hours, the solution was evaporated and the residue triturated with acetone, filtered and dried to give 4.35 in 90.4% yield. g of the final product. A sample of this product was recrystallized from aqueous isopropyl alcohol to give the title compound, mp 207-225 ° C with decomposition.

Analysis for C ₈ H ₂ <) N5O. 3 HC1:

calculated:

% C 49.03%,% H 7.33,% 15.89 N, found:

H, 7.35; N, 15.71.

(Corrected to 0.94% water content.)

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

A mixture of 3.74 g (8.47 mmol) of N-methyl-N '- [3- (3-piperidinomethyphenoxy) propyl] -ethanediimidamide trihydrochloride prepared according to Step A, 34 ml of methylene chloride and 3.5 ml of triethylamine is mixed with 3 ml. 36 g [8.46 mmol] of N, N'-thiobisphthalimide in the form of a solvate with dimethylformamide and stirred for an hour. The mixture is washed with 30 ml of 20% potassium hydroxide, dried over magnesium sulfate, filtered, diluted with toluene and evaporated to give 3.6 g of the title compound. The product was purified by chromatography on 90 g of silica gel (230-400 mesh), eluting with ethyl acetate / methanol (95: 5) to give the title compound (1.9 g, 62%). When this product is reacted with an equivalent amount of an aqueous solution of hydrochloric acid in 1-propanol, the hydrochloride of the title compound is obtained, m.p. 163.5-164.5 ° C.

Analysis for C ^ HHv ^O OS. HCl: calculated:

C 54.42, H 7.04, N 17.60, S 8.06,

8.91% Cl, found:

H, 7.07; N, 17.64; S, 8.36; Cl, 8.86.

Example 9

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

A. N-Benzyl-N - [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide 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 British Patent Specification 2,067 987 in 100 ml methanol was mixed

7.55 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue triturated with acetone, filtered and dried to give 5.16 g (88%) of the title compound, mp 187-205 ° C. for decomposition.

Analysis for C ^ HH ^NsO. 3 HC1:

calculated:

H, 7.03; N, 13.55; Cl, 20.57. Found:

% C, 54.88;% H, 6.75;% N, 13.33.

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

A mixture of 4.73 g (9.16 mmol) of N-benzyl-N '- (3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride prepared according to Step A, 45 ml of methylene chloride and 3.8 ml of triethylamine is mixed with 3.64 g (9.16 mmol) of N, N'-thiobisphthalimide as a solvate with dimethylformamide and stirred for 1 hour. The mixture was washed with 44 ml of 10% potassium hydroxide solution, dried over magnesium sulfate, filtered, diluted with toluene and evaporated. The residue is chromatographed on 110 g of silica gel with a particle diameter of 230-400 mesh using ethyl acetate as eluent to give 3.1 g (77%) of the title compound. The product was mixed with an equivalent amount of aqueous solution of chlo250229 hydrocyanic acid in 2-propanol to give the hydrochloride of the title compound, m.p.

138-141 ° C.

Analysis for C94H3N5OS. HC1:

calculated:

% C, 60.80;% H, 6.80;% N, 14.77;

7.48% Cl, found:

C, 60.53; 6.64. % H, 14.99% N, 6.91% S, 7.47% CL

Example 10

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

This is a variation of Example 1 of Step В using N, N‘-thiobisphthalimide instead of S ^CH.

A mixture of 27.3 g (64.0 mmol) of N- [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride prepared according to Example 1, Step A, 250 ml of methylene chloride and

26.6 ml (192.0 mmol) of triethylamine are treated portionwise with 25.4 g (64.0 mmol) of N, N‘-thiobisphthalimide solvate with dimethylformamide. The mixture was stirred at room temperature for one hour, washed with 120 ml of 20% potassium hydroxide solution, dried over magnesium sulfate, filtered and evaporated, the residue was mixed with 150 ml of toluene and the solution was evaporated again. The resulting product was dissolved in 250 ml of 1-propanol with 10.7 ml of 6 N hydrochloric acid, decolourised charcoal was added and the mixture was filtered through a pad of Celite.

The solution was concentrated to 100 mL, diluted with 175 mL of anhydrous 1-propanol and stored at 0 ° C to give 20.2 g of the title compound as a crystalline hydrochloride (82.1%), mp 137-138 ° C.

Analysis for C ₁₇ H ₂₅ N ₅ OS. HC1:

calculated:

% C, 53.18;% H, 6.83;% N, 18.24;

% C, 52.78;% H, 6.74;% N, 18.52.

Example 11

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

Is this a variation of Example 4, step B, using N, N'-thiobisphthalimide instead of S ' ₂ C1 _? .

A mixture of 22.0 g (53.0 mmol) of N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride prepared according to Example 4, Step A, 200 ml of methylene chloride and 22 ml of triethylamine was mixed with 21.2 g (53, 0 mmol) of N, N'-thiobisphthalimide in the form of a solvate with dimethylformamide. The mixture was stirred at room temperature for one hour and then washed with 100 ml of 20% potassium hydroxide solution, dried over magnesium sulfate, filtered, diluted with 100 ml of toluene and evaporated. The product was treated with 1 equivalent of aqueous hydrochloric acid in 1-propanol to give 13.2 g (07%) of the title compound as a hydrochloride, m.p. 135-137 ° C.

Anal. HC1:

calculated:

% C, 51.95%; H, 6.54;% N, 18.93%;

C 51.92, H 6.55, N 19.30, S 9.06, Example 12

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

A. N - [2 - [(5-Dimethylaminomethyl-3-thienyl) methylthio] ethyl} ethanediimidamide trihydrochloride

A suspension of 7.8 g (22.6 mmol) of 3-amino-4- [2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino} -1,2,5-thiadiazoloxide prepared according to the method of the British patent application No. 2 C67 987 in 150 ml of methanol was mixed with 15.0 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue was triturated with 1-propanol, filtered and dried to give the title compound (7.38 g, 80%). A sample of this product was recrystallized from methanol / acetone to give the title compound, m.p. 190 DEG-205 DEG C. with decomposition.

Analysis for C12H21N5S9. 3 HC1:

calculated:

% C, 35.25;% H, 5.92;% N, 17.13.

H, 5.93; N, 17.39.

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] ethyl] ethanediimidamide trihydrochloride prepared according to Step A, 60 ml of methylene chloride and 6.3 ml of triethylamine is mixed with 5.96 g (15.0 mmol) of N, ^C -thiobisftalimidu form a solvate with dimethylformamide and stirred for one hour. Then mix for

The product was washed with 100 ml of 10% potassium hydroxide, dried over magnesium sulfate, filtered, diluted with toluene and evaporated to give 5.1 g of the title product. This product was treated with 0.5 molar equivalent of fumaric acid in 1-propanol to give the salt of the resulting product with fumaric acid, m.p. 141-143 ° C. NMR spectrum in _DMSO-d6 shows the presence of approximately 0.12 moles of L-propanol.

Analysis for (C ^ HH ^ NNsSjO): C ₄ H ₄ O _4. 0.12 C ₃ H ₈ O:

calculated:

% C, 43.68;% H, 5.61;% N, 17.75;% S, 24.38;

% H, 43.41;% H, 5.53;% N, 17.54

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

A. N- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethyl} ethanediimidamide trihydrochloride

A suspension of 6.1 g (15.8 mmol) of 3-amino-4- [2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethylamino-1,2,5-thiadiazole-1-oxide prepared according to the method of British patent specification No. 2,067,987 in 80 ml of methanol was treated with 10.5 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue was triturated with 1-propanol (50 ml), filtered and dried to give 5.86 g (83%) of the product. A sample of this product was recrystallized from methanol / acetone to give the title compound, mp 201-214 ° C with decomposition.

Analysis for CJ5H25N5S2.3 HCl:

calculated:

H, 6.29; N, 15.60; S, 14.29. Found:

39.97% C, 6.47% H, 15.28% N, 14.63% S.

B. 3-Amino-4- (2 - [(5-plperidinomethyl-3-thienyl) methylthio] ethylamino) -1,2,5-thladlazole

A mixture of 5.17 g (11.5 mmol) of N- [2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethyl] ethanediimidamide trihydrochloride prepared according to Step A, 48 ml of methylene chloride and 4.8 ml of triethylamine is mixed with 4.57. g (11.5 mmol) of N, N'-thioblsphthalimide in the form of a solvate with dimethylformamide and stirred for 1 hour. The mixture is then washed with 90 ml of 10% potassium hydroxide, dried over magnesium sulfate, filtered, diluted with toluene and evaporated to 4.5 g of product. This product was treated with 1 equivalent of cyclohexylsulfonic acid in methanol to give the title product cyclohexylsulfamate, m.p. 142-143 ° C.

Analysis for C ₁ 5 H 3 N ₅ S _{2 3 l.} C ₆ H _1S NO3S:

calculated:

% H, 6.61;% N, 15.31;% S, 23.38.

% C, 45.61;% H, 6.41;% N, 15.46.

Example 14

The general procedure of Example 1, Step A, and then either Example 1, Step V or Example 10 was repeated except that 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2 Replace 5-thiadiadazole-1-oxide with an equimolar amount of any of the following:

(a) 3-ethylamino-4- [13- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide; (b) 3-allylamino-4- [3- (3-piperidinomethyl) f] enoxy) propylamino] -1,2,5-thiadiazole-1-oxide; (c) 3- (2-propynyl) -4- [3- (3-piperidinylmethylphenoxy) propylamino] -1,2,5-thiadiazole- 1-oxide, (d) 3- (3-pyridylmethylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide, (e) 3- (6- methyl-3-pyridyl) methylamino-4- (3- (3-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 to give (a) 3-ethylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5- (b) 3-allylamino-4 - [: 3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole; (c) 3- (2-propynyl) -4- [3- (3- piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole; (d) 3- (3-pyridylmethylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole; h exylsulfemate of the title compound, m.p.

125.5-131 ° C.

(e) 3- (6-methyl-3-pyridyl) methylamino-4-

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

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

Analysis for C ₁₆ H ₄ N ₆ OS. C6HJ3NO3S:

calculated:

H, 7.07; N, 18.58; 12.15%.

WITH,

Example 15

3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-hiadiazole found:

% C, 50.02;% H, 7.03;% 18.54.

N, 12.14% S.

r

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

A solution of 3.65 (18.6 mmol) of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine prepared according to British Patent Specification No. 2,098,988 in 50 ml of methanol is reacted with 2.74 g (18.6 mmol) 3-amino-4-methoxy-1,2,5-thiadiazole-1-oxide prepared according to the method of British Patent Specification No. 2 Q67 987 to give a solution containing 3-amino-4- [3- ( 6-Piperidinomethyl-2-pyridyloxy] propylamino] -1,2,5-thiadiazole-1-oxide The purified sample had a melting point of 145-147 ° C.

Β. N- (3- (6-piperidinomethyl-2-pyridyloxy) propyl] ethanediimidamide trihydride chloride

The methanol solution of the product prepared according to Step A was diluted to 100 ml and 12.4 ml of concentrated hydrochloric acid was added. The solution was stirred at room temperature for 18 hours, then evaporated and the residue was dissolved in 80 ml of water and extracted twice with methylene chloride. The aqueous layer was evaporated, treated with n-propanol and evaporated under high vacuum to give the title product as a foam.

C. 3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-hiadiazole

A mixture of the crude product from Step B in 80 ml of methylene chloride containing 7.69 ml of triethylamine was treated with 7.35 g (18.5 mmol) of N, N ⁱ -thiobisftalimidu in DMF solvate. The mixture was stirred at room temperature for one hour, then washed with 50 ml of 4N sodium hydroxide, water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the crude product. The product was purified by chromatography on 100 g of silica gel (230-400 mesh), eluting with ethyl acetate / methanol (95: 5) to give 3.63 g of the title compound as a viscous oil. This product was mixed with 1 equivalent of cyclohexylsulfamic acid in acetone to give the cyclo

3-Amino-4- [3- (O-dimethylammomethyl-β-pyridyloxy) propylamino) -1,2,5-thiadiazole

When a methanol solution of 3- (6-dimethylaininomethyl-2-pyridyloxy) propylamine prepared according to British Patent Specification No. 2,098,988 is reacted with 3-amino-4-methoxy-1,2,5-thiadiazole-1. by the oxide method, according to British Patent Specification 2,067,987 and the resulting 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide is sequentially introduced. in the reaction of Example 1, Step A, and then either according to Example 1, Step B or Example 10, the resulting product is obtained.

Example 17

3-Amino-4-; 2 - ((6-dimethylaminomethyl-2H-4-yl) methylthio] ethylamino] -1,2,5-thiadiazole

In the case of a suspension of 3-amino-4- [2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino] -1,2,5-hiadiazole-1-oxide prepared according to British Pat. 2,067,987 is sequentially reacted according to the procedure of Example 1, Step A, and then either according to Example 1, Step B or Example 10 to obtain the final product.

Example 18

3-81-4-4-12 - ((6-piperidinylmethyll-2-pyridyl) methylthio] ethylamino, -1,2,5-thiadiazole

In the case of a suspension of 3-amino-4- [6- (piperidinomethyl-2-pyridyl) methylthio] ethylamino-1,2,5-thiadiazole-1-oxide prepared according to British Patent Specification 2,067,987, by reacting stepwise according to the procedure of Example 1, Step A and then either according to Example 1, Step B. or Example 10, the resulting product is obtained.

Example 19

The procedure of Example 1, step A is repeated, and then either of Example 1, step

B, or according to Example 10, except that 3-amino 4- [3- (3-piperidinomethylphenethoxy) propylamino] -1,2,5-hiadiazole-1-oxide is replaced by an equimolar amount of any of the following:

(a) 3-amino-4- [3- (3-piperidinomethylthiophenoxy) propylamino] -1,2,5-thiadiazole-1-oxide; (b) 3-amino-4- [-3- (3-dimethylaminomethylthiophenoxy) (propylamino) -1,2,5-hiadiazole-1-oxide, (c) 3-amino-4- [2 - [- (5-dimethylaminomethyl-3-thienyl] methylthio] ethylamino] -1,2,5- (d) 3-amino-4- {2 - ((5-piperidinomethyl-3-thienyl) methylthio] ethylamino) -1,2,5-thiadiazole-1-oxide; (e) 3-amino- 4- [3- (5-dimethylaminomethyl-3-thienyloxy) propylamino] -1,2,5-thiadiazole-1-oxide; (f) 3-amino-4- [3- [5-piperidinomethyl-3-thienyloxy]] propylamino] -1,2,5-thiadiazole-1-oxide, (g) 3-amino-4- | 2 - [(4-dimethylaminomethyl-2-pyridyl] methylthio] ethylamino | -1,2,5-thiadiazole -1-oxide or (h) 3-amino-4- [2- ['(4-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino] -1,2,5-thiadiazole-1-oxide to give (a) ) 3-amino-4- [3- (3-piperidinomethylthiophenoxy-0-propylamino) -1,2,5-thiadiazole, (b) 3-amino-4- [ _: 3- (3-dimethylaminomethylthiophenoxy) propylamino] -1 , 2,5-thiadiazole, (c) 3-a mino-4- [2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino [1,2,5-thiadiazole, (d) 3-amino-4-; 2 - [(5-piperidinomethyl-3-thienyl)] (methyl) thio] ethyl amino-1,2,5-thiadiazole, (e) 3-amino-4- [3- (5-dimethylaminomethyl-3-thienyloxy) propylamino] -1,2,5-thiadiazole, (f) 3 -amino-4- [3- (5-piperidinomethyl-3-thienyloxy) propylamino] -1,2,5-hiadiazole, (g) 3-amino-4-β - [(4-dimethylaminomethyl-2- pyridyl) methylthio] ethylamino-1,2,5-thiadiazole or (h) 3-amino-4H2 - [(4-piperidinolithiyl-2-pyridyl) methylthio] ethylamino) -1,2,5-thiadiazole.

Example 20

3-Amino-4- [3- (4-plperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-Hladiazole

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

When the general procedure for the preparation of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine described in British Patent No. 2,098,988 is repeated except that 2-chloro-6-methylpyridine is replaced by 2-bromo -4-methylpyridine to give the title compound as an oil.

Analysis for 0 ^ 23 ^ 0:

calculated:

% C, 67.44;% H, 9.30;% N, 16.85.

H, 8.98; N, 16.55.

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

-1-oxide

A solution of 6.5 g (26.0 mmol) of the product of Step A in 90 mL of methanol was treated with 3.84 g (26.0 mmol) of 3-amino-4-methoxy-1,2,5-thiadiazole- 1-oxide, as generally described in British Patent No. 2,067,987, to give 6.33 g of the title compound, after recrystallization from methanol / acetonitrile, to give the product, m.p. 154-158 ° C. .

Analysis for C is HNcOS:

calculated:

% C, 52.73;% H, 6.64;% N, 23.06;% S, 8.80.

% C, 52.72;% H, 6.30;% N, 23.32.

C. N- [3- (4-Piperidinomethyl-2-pyridyloxy) propyl] ethanediimidamide trihydrochloride

5.0 g (13.7 mmol) of the product of Step B are dissolved in 80 ml of methanol and 9.1 ml of concentrated hydrochloric acid are added. The mixture was stirred at room temperature for 4.5 hours, then evaporated to dryness under reduced pressure to give the title product.

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

A mixture of the product of Step C in 50 ml of methylene chloride and 5.7 ml of triethylamine was treated with 5.44 g (13.7 mmol) of N, N'-thiobisphthalimide solvate with dimethylformamide and stirred at room temperature for 1 hour. Wash with 40 ml of 4N sodium hydroxide, water, saturated aqueous sodium chloride solution, dry over sodium sulfate, filter and concentrate in vacuo to give the crude product.

The product was purified by chromatography on 90 g of silica gel (230-400 mesh), eluting with ethyl acetate: methanol (96: 4) to give 3.44 g of the title compound as a viscous oil. Treated with 1 equivalent of cyclohexylsulfamic acid in acetone to give the cyclohexylsulfamate of the title product, m.p. 124.5-126 ° C.

Analysis for C ₁₆ H ₂₄ N ₆ OS. C ₆ H ₁₃ NO ₃ S:

calculated:

H, 7.07; N, 18.58; S, 12.15. Found:

% C, 50.47;% H, 7.12;% N, 18.33;

Example 21 Dyl-methyl-phenoxy-propylamino-1,2,5-thiadiazole

The procedure described in Example 15 was repeated except that the 3- (6-piperidinomethyl-2-pyridyloxy) propylamine used as the starting product in the above example was replaced with an equivalent amount of 3- [3 (1,2,3,6-tetrahydro) 1-pyridyl) methylphenoxy] propylamine to give the title compound (2.31 g), which was crystallized from toluene to give the title compound, m.p. 99.5-104 ° C.

Analysis for C ₁₇ H ₂₃ N ₅ OS:

calculated:

59.10% C, 6.71 o / ₀ h, 20.27 O / o N, 9.28 »/ o S, found:

58.78 O / C of 6.71 _0/0 H, 19.90% N, 9.26% P.

(Corrected for 2.19% H ₂ O)

3-Amino-4- {3- (3- (1,2,3,6-tetrahydro-1-pyrrole)

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of the general formula I (O wherein R ¹ is hydrogen, alkyl of 1-6 carbon atoms, straight chain or branched; m is an integer 0 or 1, n represents an integer 2 or 3, Z represents an oxygen atom or a sulfur atom, And means one of the groups R5 to 5 R ⁶ is hydrogen or alkyl of 1 carbon atoms, and R 7 is independently C 1 -C 5 alkyl or forms R 6 and R 7 together with the nitrogen atom to which they are attached a pyrrolidine, piperidine or 1,2,3,6-tetrahydropyridyl ring as well as 1 non-toxic, pharmaceutically acceptable salts, hydrates and solvates thereof, characterized in that: reacts at a temperature of 0 to 50 ° C, preferably in an inert organic solvent, with a compound of formula II HN NHR ¹ / Λ NH (II) wherein A, R1, Z, m and n are as defined above, with at least one molar equivalent, preferably with a molar excess of 2 to 3 moles, of S2Cl2 or SC12, preferably S2Cl2. 2. A process according to item 1 for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of the general formula I, in which all the symbols have the meaning given in item 1, except for the symbol A, where A represents is substituted in the 2-position by reacting at a temperature of 0 to 50 ° C, preferably in an inert organic solvent, a compound of formula II