HU188742B - Process for producing substituted 3,4-diamni-1,2,5-thiadiazoles and pharmaceutical compositions of hystamine-h2-receptor antagonistic aczivity containing them as active agents - Google Patents

Description

The novel compounds are useful in medicine for inhibiting gastric acid secretion, particularly in the treatment of gastric and duodenal ulcers.

This invention relates to novel histamine H _r receptor antagonist, (l) substituted 3,4-diamino-formula, 2,5-thiadiazoles - E wherein

R ¹ is hydrogen, (C 1 -C 4) alkyl, or phenyl (C 1 -C 4) alkyl, m is 0 or 1, n is 2 or 3,

Z is oxygen or sulfur,

A is a group of formula (c), (d), (e) or (f)

^R5 is hydrogen, (1-4C) alkyl,

R ^e and R ⁷ are each independently (C 1 -C 4) alkyl, or

R ^e and R ⁷ , together with the nitrogen atom to which they are attached, may also be pyrrolidino, piperidino or '1,2,3,6-tetrahydropyridyl-1 - groups, and pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof.

No. 067,987 British Patent Application Publication No. 3,684,125 discloses 3,4-disubstituted-1,2,5-thiadiazole-1-oxides and -1,1-oxides of formula (VII) and processes for their preparation; the symbols A, Z, R ', m and n in formula (VII) have the same meaning as the corresponding symbols in formula (I) described above. However, the compounds described herein are in each case 1-oxides or 1,1-dioxides (ρ = 1 or 2); in addition, the compounds of the present invention cannot be prepared according to the process for the preparation of the compounds described in our earlier patent application ¹⁵ .

No. 40,696. Description of our European patent application discloses, inter alia, various (VIII) of general formula 3.4 - disubstituted - ²⁰ 1,2,5 - thiadiazole - 1 - oxide and 1,1-dioxide, as well as processes for their preparation; is A, X, m and n in the general symbols in the formula (VIII) is also similar to the corresponding signals occurring phen ₂₅ described below appears in formula (I) report. However, the compounds described in the cited European Patent Application are also in each case 1-oxides or 1,1-dioxides (p = 1 or 2), and the compounds of the present invention cannot be prepared according to any of the methods described for the preparation of the compounds described therein.

In each of the processes described for the preparation of the compounds described in the two previous patents cited above, 1,2,5-thiadazole-1-oxides or -1,1-dioxides are used as starting materials or intermediates which have either amino or contain interchangeable groups.

Substituents at the 3- and 4-position in the final products described are then formed either by substitution of the amino groups present in said starting compounds or intermediates or by substitution of the substituent groups for the desired substituents. Extensive experiments have been carried out to attempt to prepare the novel compounds of the present invention in a manner similar to that described in the preceding patents, i.e. 1,2,5-thiadiazoles having amino groups at the 3- and 4-positions or suitable interchangeable groups. as a starting compound or intermediate in the preparation of our desired new compounds. Although these procedures have tried several different versions for this purpose, by varying the reaction conditions in various ways, either in one case the novel compounds of the present invention prepared according to the procedures described in the cited previous application ⁶⁰ written.

However we have found that the appropriate formula is as defined above (I) to novel substituted 3,4-diatnino- 1,2,5-thiadiazoles can be prepared by treating an appropriately substituted (II) ⁵ ethane diimide ring closure of amides of formula

By way of 188 742; the symbols R ', Z, A, m and n in formula (II) have the same meaning as given in formula (I). The process for preparing the starting compounds of formula (II) according to the invention will also be described below.

The process of the invention also includes the preparation of all possible tautomeric forms, diastereoisomeric forms and optically active isomers of the compounds of formula (I) as defined above, and mixtures thereof. The invention also relates to the preparation of hydrates, solvates and pharmaceutically acceptable non-toxic salts thereof; "Pharmaceutically acceptable non-toxic salts" includes, in particular, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, fumaric acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, levulinic acid, benzoic acid, succinic acid, succinic acid, by acid addition salts formed with toxic acids.

In the compounds of formula (I), R ¹ is preferably hydrogen or (C 1 -C 4) -alkyl, particularly preferably hydrogen or methyl, but especially hydrogen. Substituent A is preferably phenyl, furyl or thienyl substituted as defined above, particularly preferably phenyl as defined above. Z is sulfur or oxygen, when A is substituted phenyl, then Z is preferably oxygen, m is 0 or 1 and n is 2 or 3; when A is substituted phenyl, then m is preferably 0 and n is preferably 3. ^R5 place preferably hydrogen or methyl, especially hydrogen but may. R * and R ⁷ may each be C 1 -C 4 alkyl, or the two substituents together with the nitrogen atom may preferably be pyrrolidino or piperidino.

Compounds of formula (I) as defined above are prepared by reacting a compound of formula (II) with sulfur monochloride (S ₂ Cl ₂ ), sulfur dichloride (SC ₁₂ ) or bisphthalimidosulfide according to the present invention, as described above. (A) Scheme A; in formulas (II) and (I) in Scheme (A), A, Z, R ¹ , m and n are as defined above.

In the process of the invention, at least about 1 mole of sulfur monochloride or sulfur dichloride is used per mole of the starting compound (II); however, it is preferred to use the sulfur monochloride or sulfur dichloride in excess, i.e., about 2 to about 2 mol per liter of compound (Π). We have found that, by using sulfur dichloride case often less pure and thus the yield of the purified product is lower than kénmonoklorid application of the reaction product ^(obtained, it is usually preferred;. When the above reaction is carried out sulfur monochloride The reaction temperature employed is not critical; it is generally preferred to carry out the reaction at a temperature of from about 0 ° C to about 50 ° C, most preferably at room temperature, the reaction time being of no particular importance in the process of the invention, generally the reaction time required depending on the reaction temperature used. it may normally be from about 30 minutes to about 6 hours. If the reaction is carried out at room temperature, the preferred reaction time may be from about 1.5 hours to about 4 hours. or in an inert organic solvent, preferably a mixture of a reaction inert solvent and dimethylformamide; however, it is particularly preferred to carry out the reaction in dimethylformamide.

Preferably, the process of the present invention provides compounds of formula (I) which correspond to the more general formula (Γ); in this formula

R is hydrogen or (C1-C4) alkyl,

Z represents oxygen or carbon, m = 0 or 1, n = 2 or 3,

A 'is a group of formula (c'), (d '), (e') or (P) and

R ^s ' is hydrogen or methyl,

P ⁶ 'and R ⁷ each independently represent methyl or ethyl, or the two signals together with the adjacent nitrogen atom represent pyrrolidino or piperidino.

This preferred embodiment of the process of the invention also encompasses the preparation of pharmaceutically acceptable nonloxic salts, as well as hydrates and solvates of the compounds of formula (Γ).

In a particularly preferred embodiment of the process of the invention, the compounds of formula (I) are the compounds of formula (Ia) and pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof; in formula (Ia)

R ¹ 'is hydrogen or methyl,

R ⁶ 'and R ⁷ ' respectively represent a methyl group, or the two symbols together with the adjacent nitrogen atom represent a pyrrolidino or piperidino group.

In another particularly preferred embodiment of the process of the present invention, the compounds of formula (I) are the compounds of formula (Ib) and pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof; in formula (lb)

R '' and R ⁵ 'independently of one another are hydrogen or methyl,

R ⁶ '' and R ⁷ '' independently of one another are methyl or ethyl,

In another particularly preferred embodiment of the process according to the invention, the compound of formula (I) is the compound of formula (Ic)

188,742; and pharmaceutically acceptable non-toxic salts, hydrates, and solvates thereof; in formula (Ic)

R ¹ 'and R ⁵ ' independently of one another are hydrogen or methyl,

R ^e '' and R ⁷ '''independently of one another are methyl or ethyl.

In another particularly preferred embodiment of the process according to the invention, the compounds of formula (I) are prepared as compounds of the general formula (Id), as well as pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof; in the general formula (Id)

R ¹ 'and R ⁵ ' independently of one another are hydrogen or methyl,

R ⁶ * and R ⁷ *, independently of one another, are methyl or ethyl, or the two symbols together with the adjacent nitrogen atom represent a piperidino group.

Thus, among the compounds of formula (I) obtainable by the process of the invention, the following are particularly preferred;

1.3-Amino-4- (3- (3-piperidinomethyl-phenoxy)

- 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,

4. 3-Amino-4- (3- (3-pyrrolidinomethyl-phenoxy)

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

5. 3-methylamino -4- (3- (3-piperidinomethyl-phenoxy) -propylamino] -1,2,5-thiadiazole;

6. 3-Benzylamino -4- (3- (3-piperidinomethyl)

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

7. 3-Amino-4- (2 - ((5-dimethylaminomethyl-3

- thienyl) methylthio] ethylamino) - 1,2,5 - thiadiazole,

8. 3-amino-4- (2 - ((5-piperidinomethyl-3-thienyl) methylthio] ethylamino) -1,2,5-thiadiazole;

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

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

The starting materials of formula (II) according to the invention may be prepared by various processes. In one such process, the corresponding 3- (amino or substituted amino) -4 (substituted amino) -1,2,5-thiadiazoloxide of formula (Π1) wherein R ¹ , A, Z, m and n are is as defined in formula (I) - treated with a strong mineral acid, preferably hydrochloric acid, to give the corresponding compounds of formula (II). This reaction of Scheme B is carried out in a solvent inert to the reaction, preferably methanol. The reaction temperature is not critical; the reaction is conveniently carried out at room temperature. The compounds of formula (Ifi) are either known compounds or can be readily prepared in a manner analogous to that described in U.S. Pat. British Patent Application Publication No. 4,194,198.

Compounds of formula (II) may also be prepared as illustrated in Scheme (C), for a compound of formula (IV) wherein A, Z, m and n are as defined in formula (I). Reaction of 1,2-dimethoxyethane-1,2-dimethyl of formula V with the resulting compound of formula VI with an amine of formula R ³ NH ₂

in these formulas, A, Z, m, n and R 'are as defined in formula (I) by reaction. These reactions are carried out in a solvent inert to the reaction, preferably methanol. The starting compounds of formula (VI) are either known or can be readily prepared in a manner analogous to that known, for example, in U.S. Patent No. 2,067,987. in the United Kingdom Patent Application.

Particularly preferred intermediates of the present invention include the following compounds;

1. N - (3- (3-piperidinomethyl-phenoxy) -propyl]

- ethane-diimidamide,

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

3. N - (2 - [(5-dimethylaminomethyl-4-methyl-2)

- thienyl) methylthio] ethyl] ethane diimidamide,

4. N - (3- (3-pyrrolidinomethyl-phenoxy) -propyl]

- ethane-diimidamide,

5. N - (2 - ((5-dimethylaminomethyl-3-thienyl) methylthio) ethyl] ethane diimidamide,

6. N - (2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethyl] ethane diimidamide,

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

8. N- (3- (4-piperidinomethyl-2-pyridyloxy) propyl] ethane diimidamide, and salts, hydrates and solvates thereof.

The pharmacologically active compounds of formula (I) obtainable by the process of the present invention are generally used as pharmaceutical compositions in conventional forms; these pharmaceutical compositions contain (as one or more active ingredients) at least one compound of the formula I in the form of a base or a pharmaceutically acceptable non-toxic acid addition salt thereof, together with a pharmaceutically acceptable carrier.

Such pharmaceutical compositions may be formulated for oral, parenteral or rectal administration. A variety of pharmaceutical formulations can be used for these purposes. so

When a solid carrier is used, the pharmaceutical composition may be in tablet or pill form or as a powder in hard gelatine capsules. When a liquid carrier is used, the composition may be a syrup, emulsion, liquid in a soft gelatine capsule, sterile solution for injection, or suspension in an aqueous or non-aqueous liquid carrier. For rectal administration, conventional suppositories may be prepared. Such pharmaceutical compositions may be prepared by methods known in the art and conventional for such purposes.

The mode of administration of the compounds of the present invention will depend not only on the weight of the subject to be treated, but also on the degree of inhibition of the stomach acid desired and the potency of the compound employed. The amount of dose to be used in each case and the number of doses to be administered each day will vary depending upon the judgment of the physician and will vary with the condition and individual circumstances of the subject being treated. preferably from about 4 mg to about 100 mg. The active ingredient is preferably administered in divided doses of 1 to 4 daily doses.

Previously, histamine H ₂ receptor antagonists have been shown to effectively inhibit gastric acid secretion in humans and animals, cf. Brimblecombe et al., J. Int. Med. Res., 3, 86 (1975). Some of the preferred compounds of the present invention have been compared to the known and used cimetidine for this purpose; a clinical evaluation of cimetidine, known as a histamine H ₂ receptor antagonist, has shown that this compound is an effective drug in the treatment of gastric and duodenal ulcers; cf. Gray et al., Chain, 1, 8001 (1977). In the above comparative experiments, it has been found that the preferred novel compounds of the invention are both more potent than cimetidine as histamine H ₂ receptor antagonists (used in isolated right guinea pig atrium) and as gastric acid secretion inhibitors (rats and dogs).

Determination of anti-gastric acid secretion effect in gastric ulcer rat

Male "Long Evans" rats weighing about 240 to 260 g at the time of cannula implantation were used for the experiments. The shape of the stainless steel cannula and the method of administration to the anterior wall of the animal's stomach were substantially the same as described by Pare et al., Laboratory Anim Science, 27, 244 (1977). The components of the fistula and the surgical procedure used were exactly as described in the cited literature. Following surgery, the animals were housed separately in solid bottom cages with sawdust; the animals were provided with food and drinking water as desired throughout the healing process. The animals were not used for experimental purposes for at least 15 days after surgery.

During the experiments, the animals were fasted for 20 hours before the start of the experiment, but were given water as desired. The cannula was opened immediately before collection of gastric juice and the animals' stomach was gently washed with 30-40 ml of saline or distilled water to remove any residual gastric contents. The catheter was then screwed into the cannula in place of the closure screw and the rat was placed in a clean, plastic, brick-shaped cage 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage had a central slit about 1.5 cm wide by 25 cm long that allowed the catheter to be led out of the cage. In this way, the rat was uninhibited and was able to move freely in the cage at the time of collection of gastric fluid. The remainder of the experiments are reported in Ridley et al., Research Comm. Chem. Path. Pharm., 17, 365 (1977)].

The gastric fluid collected during the first four hours after gastric lavage was discarded as it may have been contaminated. The catheter was then removed from the cannula for oral evaluation and screwed into place. Water was administered orally by gastric intubation to the rat at a volume of 2 ml / kg, and the animal was returned to the cage for 45 minutes. The stopper screw was then removed and a catheter was screwed into place, to which a small plastic vessel was attached to collect the selected gastric fluid. The fluid collected during the two hours (corresponding to the control period of the experiment) was captured, and the catheter was removed and the closure screw was inserted into the ointment. At this time, the active compound to be tested was also administered crally by gastric intubation in a volume of 2 ml / kg. After 45 minutes, the cannula screw was removed again and replaced with a catheter with a small plastic pot; Thus, a further 2 hours was collected for a selected gastric fluid sample. This latter sample was then compared to a sample taken in the Control section of the experiment to determine the effect of the test drug.

For parenteral administration, the test drug was administered to the animals by intraperitoneal or subcutaneous injection in a liquid vehicle at a volume of 2 ml / kg. First, immediately after the injection of the selected gastric fluid within the first 60 minutes of the experiment, the vehicle was administered in an amount as described above; the liquid selected during the 2 hour control period was collected and then administered by intraperitoneal or subcutaneous injection of the test substance in the above-mentioned volume vehicle. After a further 2 hours, the gastric flow selected after administration of the drug was collected5

188,742 and this was compared with a sample of fluid selected in the control section to determine the effect of the test drug.

These determinations were made by centrifuging the samples by placing the sample in a volumetric centrifuge tube to determine the volume. The titratable acidity was then determined; Samples of 1 ml were titrated with 0.02 N sodium hydroxide solution to pH 7.0. Titration was performed in an "Autoburet" apparatus using a "Radiometer" electrometric pH meter. The titratable acidity was calculated in micro equivalents by multiplying the acid concentration in milliequivalents per liter by the volume of sample in milliliters.

The results obtained are expressed as percent inhibition relative to control. Dose-response curves were constructed and ED ₅₀ values were calculated by regression analysis. For each dosing level, at least 3 rats were tested and at least 3 dosing levels were used to construct the dose response curve.

The results of the experiments described above are summarized in Table 1 below; the experiments were carried out with the compounds described in Examples 1, 2, 3 and 4 of the present specification in addition to the cimetidine used for comparison.

Table 1

Determination of anti-gastric acid secretion effect in θθ gastric lavage rat

Compound ED _J0 sc μπιοί / kg Effect ratio (cimetidine 0 = 1.0 cimetidine 3.48 (1.68 to 5.75) * 1.0 15 Example 1 0,094 (0.043 to 0.20) 37 Example 2 0.77 (0.45 to 1.4) 4.5 > 0 Example 3 -0.5 ΰ Example 4 0.18 (0.10 to 0.36) 20 * 95% confidence limit. 3

Histamine H ₂ -receptor antagonist activity in isolated guinea pig atrium

Depending on the concentration of histamine, B increases the degree of contractility in the isolated spontaneous right-wing atrium of guinea pigs; Black et al., 1972, Natur, 236, 385, described receptors that contribute to this effect of histamine as histamine H ₂ receptors when they reported the properties of burimamide as a competitive antagonist to these receptors. In subsequent investigations, Hughs and Coret - Proc. Soc Exp Bioi. Med., 148, 127 (1975) - and Verma and McNeill, J. Phannacol. Exp. Ther. 200, 352 (1977), confirmed the conclusion of Black et al. That the positive chronotropic effect of histamine on isolated right guinea-pig heart is mediated by histamine H ₂ receptors. Black et al., Agents and Actions, 3, 133 (1973); and Brimb'ecombe et al., Fed. Proc., 35, 1931 (1976) - Isolated guinea-pig heartworm was used to compare the effects of histamine H ₂ receptor antagonists. The present autumn comparative studies were carried out according to a modified form of the procedure described by Reinhardt et al., Agents and Actions 4, 217 (1974).

Male guinea pigs of Hartley strain (350-450 g body weight) were sacrificed on the head, the heart was excised and an oxygenated (95% O ₂ , 5% CO ₂ ) modified Krebs's solution (6.6 g / l sodium chloride, 35 g / l potassium chloride, 0.25 g / l magnesium sulfate heptahydrate, 0.162 g / l potassium dihydrogen phosphate, 0.238 g / l calcium chloride, 2.1 g / l sodium bicarbonate, and 2.09 g / l dextrose) in a petri dish. The right heartbeat spontaneously beating was cut from the other tissues and a silk thread (4 - 0) was attached to each end. The heart parcel thus fitted was suspended in a 20 ml muscle chamber containing 32 ° C oxygenated modified Krebs solution. Cardiac contractions were recorded isometrically with a Grass FT 0.03 force shift transducer; the contractile force and contractile speed were recorded with a Beckman RP RPG,

A 1 g resting tension was applied to the coronary artery and allowed to equilibrate for 1 hour. At the end of the equilibrium period, histamine dihydrochloride was added to the bath at a concentration of subnaxima (3 x 10 ^G ) and washed to prepare the tissue for the experiment. Cumulative histamine was then added to the bath at half-hanging intervals of 10, so that the final concentration of histamine in the bath was between 1 · 10 · ⁷ and 3 · ^s . During the increase in histamine concentration, all histamine lags were

188 The increase in the rate of contraction caused by the new dose of histamine reaches a resting level before adding another dose of histamine to the bath. The maximum response in all cases there was a 3 · 10 ^"5 M concentration. The histamine was then removed by multiple washes and waited until the heart atria returned to the control rate. Next, a solution of the test compound corresponding molar kocentrációban inkubáltatás and administered at 30 min after histamine ¹ again, if necessary, towards higher concentrations.

Dissociation constants were determined (based on R _B Schild diagrams O. Arunlakshana and Η O. Schild [Br. J. Pharmacol. 14, 48 (1959)] methods ^one instrument, using at least three dose levels. The dose- obtained parallel shifts response curves, the maximum response obtained antagonistakoncentrációknál insignifi- used without approval ₂ the results are given in table No. 2. table cimetidine applied in the same conditions for comparison. -.. chemical name - N - cyano

- N '- methyl - N' - {2 - [(5 - methyl - 1H - imidazole ₂

- 4 - yl) - methylthio] ethyl} guanidine.

In our co-pending US patent application (Thomas A. Montzka), it is disclosed that compounds of formula (I) corresponding to the above definition can be prepared from the corresponding compounds of formula (II) by the bis-phthalimidosulfide of formula (IX) through the ring. However, using bis-phthalimide sulfide as the chemical equivalent for ring closure 31 instead of sulfur monochloride or sulfur dichloride, the crude compound of formula (1) is obtained in a purer form and in higher yields. The crude compounds of formula (I) thus obtained are directly pure enough to be used without crystallization to form crystalline salts.

In this process, the diimidamides of formula (II) used as starting materials, wherein A, Z, R ¹ , m and n are as defined above, are reacted with about equimolecular amounts of the bis-phthalimidosulfide in an inert organic solvent. , example ul in dichloromethane. Preferably, the starting compound adimide amide is used in the form of its trihydrochloride salt by adding 3 molar equivalents of an amine such as triethylamine to neutralize the trihydrochloride salt. The reaction is suitably carried out at room temperature with stirring for about 1 hour to ensure complete reaction. The phthalimide precipitated from the reaction mixture is then extracted with a strong base such as 10-20% aqueous potassium hydroxide, and the separated organic solvent phase is dried, filtered and evaporated; to give the corresponding crude compound of formula (I).

The bis-phthalimidosulfide used as starting material in the above version of the process is known from, for example, the method described in Canadian Journal of Chemistry, 44, 2111-2113 (1966), or the following I. s. starting material may be prepared as described in the Preparation Example.

Practical embodiments of the process according to the invention are described in the above-mentioned No. 1. the following examples illustrate the preparation of the starting material; however, it should be noted that the scope of the invention is in no way limited to these particular embodiments.

Example 1, starting material bis-phthalimidosulfide

To a solution of phthalimide (14.7 g, 0.1 mol) in dimethylformamide (80 ml) cooled to 0 ° C was added dropwise sulfur dichloride (5.15 g, 0.05 mol). The mixture was then allowed to warm to 20 ° C and stirred for 4 hours. The precipitated solid product is isolated and dried; thus

Table 2

Determination of activity in isolated right atrium of guinea pigs

Compound N K _B (pmol) Effect (cimetidine = 1.0) cimetidine 20 0.41 (0.21-0.64) * 1.0 Example 1 12 0.003 (0.001-0.004) 137 Example 4 11 0.004 (0.001-0.010) 102

* 95% confidence limits.

188,742 gave 12.5 g of bis-phthalimidosulfide in the form of a dimethylformamide solvate, m.p. 301-315 ° C. The infrared (IR) and nuclear magnetic resonance (NMR) spectra of the product are consistent with the expected structure of the compound.

Analytical data based on the formula Ci ₆ H ₈ N ₂ O ₄ S · C ₃ H ₇ NO:

calculated: C 57.42%, H 3.80%,

N, 10.57%, S, 8.07%; found: C 57.50%, H 3.80%,

N, 10.29%, S, 8.57%.

From the dimethylformamide solvate obtained above, the dimethylformamide can be removed by recrystallization of the product from chloroform. The product thus obtained, free of dimethylformamide, melts at 320-325 ° C. The NMR spectrum of the product showed that the dimethylformamide was removed.

Analytical data according to the formula C ₁₆ H ₈ N ₂ O ₄ S:

calculated: C 59.25%, H 2.49%,

N, 8.64%, S, 9.89%; found: C 59.21%, H 2.21%,

N, 8.91%, S, 10.14%.

Example 1

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

A) N - [3- (3-piperidinomethyl-phenoxy) -propyl]

ethane diimidamide trihydrochloride

17.1 g (47.0 mmol) of 3-amino-4- (3- (3-piperidinomethyl-phenoxy) -propylamino] -1,2,5-thiadiazole-1-oxide, disclosed in British Patent Publication No. 2,067,987. The suspension was stirred at room temperature for 3 hours, then concentrated and the water was removed by azeotropic distillation with absolute ethanol. , slurried in 200 ml of absolute ethanol, filtered and dried under vacuum to give 16.6 g of N- [3- (3-piperidinomethyl-phenoxy) -propyl] -ethanediimidamide trihydrochloride (theoretical yield 82.6). m.p. 205-222 DEG C., by recrystallization from 50% methanol / ethyl acetate to give an analytical sample. mp 206-216 ° C with decomposition.

Analysis for C ₁₇ H ₂₇ N ₅ O · 3 HCl:

calculated: C 47.84%, H 7.08%,

N, 16.41%;

found: C 47.56%, H 7.18%,

N, 16.75%.

B) 3-Amino-4- (3- (3-piperidinomethyl-phenoxy) -propylamino] -1,2,5-thiadiazole

2.13 g of a suspension of N - (3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide trihydrochloride (5.0 mmol), prepared as described in A above, was stirred in 20 ml of dimethylformamide. 2.02 g (15.0 mmol) of sulfuric chloride were added and the mixture was stirred for 4 hours. The resulting reaction mixture was then carefully poured into water (200 mL) and basified with potassium carbonate. The aqueous mixture was then extracted with dichloromethane (3 x 50 mL), the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by preparative HPLC chromatography on silica gel with 100 parts of dichloromethane and 10 parts of 2-propanol. and 0.5 parts of ammonium hydroxide as the mobile phase. From the fractions containing the desired product 0.89 g of 3-amino-4

- (3- (3-piperidinomethyl-phenoxy) -propylamino]

1,2,5-thiadiazole is obtained which is salted with fumaric acid in n-propanol to give 0.76 g of crystalline fumarate (21.4% of theory), m.p. 187-187.5 ° C. HPLC showed the product to be more than 99% pure.

Analytical data: (C ₁₇ H _2? N ₅ OS) ₂ C ₄ H ₄ O ₄ :

calculated: C 56.27%, H 6.71%,

N, 17.27%; S, 7.90%;

found: C56.09%, H6.36%,

N, 16.98%, S, 8.08%.

A portion of the fumarate salt obtained above was suspended in water, neutralized with potassium carbonate and extracted with dichloromethane. The dichloromethane solution was evaporated to crystallize the free base; m.p. 43-47 'C. Part of this free base is converted into the hydrochloride salt in the usual manner; the hydrochloride melts at 138-140 ° C.

Analytical data based on the formula Ci ₇ H ₂₅ N ₅ OS · HCl:

calculated: C 53.18%, H 6.83%,

N, 18 *, 24%, S, 8.35%; found: C 53.14%, H 6.88%,

N, 18.49%, S, 8.74%.

Example 2

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

A) N - {2 - [(5-Dimethylaminomethyl-2-furyl) methylthio] ethyl} ethane diimidamide trihydrochloride hydrate

188,742

6.59 g (20.0 mmol) of 3-amino-4- (2 - ((5-dimethylaminomethyl-2-furyl) methylthio] ethylamino) -1,2,5-thiadiazole-1-oxide prepared as described in British Patent Application 2,067,987, slurried in 200 ml of methanol, gently warmed until complete dissolution, and then treated with concentrated hydrochloric acid (13.3 ml) and stirred at room temperature for 2.5 hours. The solution was evaporated and the residue was triturated with 70 ml of absolute ethanol. The crystalline product was collected by filtration and dried in vacuo to give 4.3 g of N- (2 - [(5-dimethylaminomethyl-2)

(furyl) methylthio] ethyl) ethane diimidamide trihydrochloride (52% of theory), m.p. 166-169 ° C.

Analytical data based on the formula C ₂ H _{2 J} N _s OS · 3 HCl · H ₂ O:

calculated: C 35.08%, Η 6.38%,

N, 17.05%; S, 7.80%; Found: C, 34.85; H, 6.24;

N, 17.45%, S, 7.97%.

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

12.3 g (30.0 mmol) of N - (2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl) ethane · diimidamide

trihydrochloride hydride, prepared as described in Section A above, was suspended in 150 ml of dimethylformamide and 7.2 ml (12.1 g, 90 mmol) of sulfur monochloride was added with stirring. After stirring at room temperature for 4 hours, about half of the dimethylformamide was evaporated under reduced pressure. The remaining black solution! The reaction mixture was poured into water (1 L), made basic with potassium carbonate and extracted with ethyl acetate and then with chloroform. The organic solvent extract was dried over anhydrous magnesium sulfate, filtered and evaporated. 9.0 g of a black resinous crude product are obtained, which is purified by preparative HPLC on silica gel using a mixture of 100 parts ethyl acetate, 10 parts 2-propanol and 0.5 parts ammonium hydroxide as the mobile phase. Fractions containing the desired product

1.24 g of 3-amino-4- (2 - ((5-dimethylaminomethyl)

2 - furyl) methylthio] ethylamino) -1,2,5 - thiadiazole is obtained in the form of a resin.

A portion of this product was treated with an equivalent amount of 2N methanolic hydrochloric acid to give the hydrochloride salt of the title compound.

Analytical data based on the formula C ₁₂ H ₁₉ N ₅ S ₂ O - HCl:

calculated: C 41.18%, H 5.76%,

N, 20.02%; S, 18.33%;

found: C 40.54%, H 5.70%,

N, 19.39%; S, 18.44% (corrected for 1.65% H ₂ O).

The product thus obtained is treated with an equivalent amount of cyclohexylsulfamic acid in acetone to give the cyclohexylsulfamate salt of the title compound, m.p. 93-95C.

Analytical data based on the formula C ₂ H ₁₉ N _s S ₂ O · C ₆ H, ₃ NO ₃ S:

calculated: C 43.88%, Η 6.55%,

N, 17.06%; S, 19.53%;

found: C 43.77%, Η 6.17%,

N, 17.21%; S, 19.58%.

Example 3

3-Amino-4- (2 - [(5-dimelilaminometil4-methyl-2-thienyl) methylthio] ethylamino} -1,2,5-thiadiazole

A) N - (2 - ((5-Dimethylaminomethyl-4-methyl-2-thienyl) -methylthio] -ethyl) -ethane-diimidamide tetrachloride

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 which is disclosed in U.S. Patent No. 2,067,987. was prepared in accordance with the general procedure described in British Patent Application Publication No. 3,900,600, which was suspended in 500 ml of methanol and 33.3 ml of concentrated hydrochloric acid was added with stirring. After stirring for a further 3 hours, the mixture was concentrated and the excess water was removed by azeotropic distillation with absolute ethanol. The residue was obtained as an almost colorless crystalline product, which was triturated with 200 ml of absolute ethanol cooled to 0 ° C, filtered and dried. 16.9 g of N - (2 - [(5 - dimethylaminomethyl - 4 - methyl)

(2-thienyl) methylthio] ethyl) ethane diimidamide trihydrochloride (80% of theory) is obtained, m.p. 206-220 ° C. After recrystallization from 50% methanol / ethyl acetate, the product melts at 210-221 ° C with decomposition.

Analysis for C ₁₃ H ₂₃ N _s S ₂ · 3 HCl:

calculated: C 35.92%, Η 6.20%,

N, 16.56%, S, 15.17%;

found: C 36.76%, H 6.33%,

N, 16.97%, S, 15.54%.

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

- thiadiazole

6.34 g (15.0 mmol) of N - (2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl) ethane diimidamide trihydrochloride, prepared as described in section A above. pre-suspended in 60 ml of dimethylformamide and to this suspension 6.1 g (45.0 g) are added with stirring.

188,742 mmol) of sulfur monochloride. After stirring at room temperature for 4 hours, the reaction mixture was poured into 800 ml of water, made basic with potassium carbonate and extracted several times with 100 ml of dichloromethane each time. The dichloromethane phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated; 3.4 g of a black resinous crude product are obtained. This was purified by preparative high performance liquid chromatography on silica gel using a mixture of 100 parts dichloromethane, 10 parts 2-propanol and 0.5 parts ammonium hydroxide as the mobile phase. Fractions containing the desired product gave the title compound in about 98% purity. This product was treated with an equivalent amount of 2N hydrochloric acid to give the hydrochloride salt of the title compound.

Analytical data based on the formula Ci ₃ H ₂ iN ₅ S ₃ · HCl:

calculated: C 41.09%, H 5.84%,

N, 18.43%, S, 25.32%;

Found values corrected for 0.51% H ₂ O: C 40.78%, H 5.63%,

N, 18.31%, S, 25.44%. NMR (dimethylsulfoxide-d + D, O): σ = 2.12 (singlet, 3H, thiophen-methyl),. 2.72 [singlet + triplet, 8H, (CH ₃ ) ₂ - - (CH ₂ ) ₂ -]

3.42 (triplet, 2H, _-CH2 -N =)

3.98 (s, 2H +, CH ₂ -S +

DOH)

4.38 (singlet, 2H, -CH ₂ -N = (

6.82 (singlet, 1H, thiophene-H0.

Example 4

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

A) N - [3- (3-Pyrrolidinomethyl-phenoxy) -propyl]

ethane diimidamide trihydrochloride

13.4 g (38.3 mmol) of 3-amino-4- [3. (3-pyrrolidinomethyl-phenoxy) -propylamino] -1,2,5

- thiadiazole 1-oxide, which is disclosed in U.S. Patent No. 2,067,987. Prepared as described in British Patent Application Publication No. 3,600,400, suspended in 350 ml of methanol, 25.5 ml of concentrated hydrochloric acid are added to the suspension, and the resulting solution is stirred at room temperature for 3 hours. The reaction mixture is then concentrated, the water is removed by azeotropic distillation with absolute ethanol and the resulting crystalline residue is triturated with 150 ml of absolute ethanol. The product thus obtained is filtered off and dried; 10.8 g of N- [3- (3-pyrrolidinomethyl-phenoxy) -propyl] -ethane diimidamide trihydrochloride are obtained, m.p. 195-203 ° C.

Analytical data based on the formula C ₆ H _{2 S} N ₅ O · 3 HCl:

calculated: C 46.55%, H 6.84%,

N, 16.97%. Found: C, 46%, H, 6.93%,

N, 16.93%. ¹

B) 3-Amino-4- [3- (3-pyrrolidinomethyl-phenoxy) -propylamino] -1,2,5-thiadiazole

8.25 g (20.0 mmol) of N - [3- (3-pyrrolidinomelyl)

phenoxy) propyl] ethane diimidamide trihydrochloride, prepared as described in Section A above, suspended in 80 ml of dimethylformamide with stirring

Sulfur monochloride (5.4 g, 40.0 mmol) was added and the mixture was stirred under a nitrogen atmosphere for 3 hours. The reaction mixture was then evaporated to give a dark resin which was suspended in water (500 mL), basified with potassium carbonate and extracted three times with ICO-100 mL dichloromethane. The combined dichloromethane extract was dried over anhydrous magnesium sulfate, filtered and evaporated; 7.5 g of a dark colored resinous crude product are obtained. This was purified by preparative HPLC using a mixture of 100 parts dichloromethane, 5 parts 2-propanol and 0.5 parts ammonium hydroxide as the mobile phase. The fractions containing the desired product were combined and evaporated. 1.64 g of purified 3-amino-4- [3- (3-pyrrolidinomethyl) is obtained

(phenoxy) propylamino] -1,2,5-thiadiazole (24.6% of theory). This product was treated with an equivalent amount of 2N hydrogen chloride in absolute ethanol to give the hydrochloride salt of the title compound (1.13 g); mp 138-140 ° C.

Analytical data based on the formula C ₁₆ H ₂₃ N _s OS · HCl:

calculated: C 51.95%, H 6.54%,

N, 18.93; S, 8.67%;

thiolated values: C, 51.97%, H, 6.36%,

N, 18.63%, S, 8.76%.

Example 5

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

This example is a variant of Example 1, Step B, using a smaller amount of sulfur monochloride and a shorter reaction time.

To a suspension of 12.08 g (28.3 mmol) of N - [3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide-trihydrochloride in 120 ml of dimethylformamide are stirred 7.54 g (56.6 mmol) of sulfur monochloride was added and the mixture was stirred under a nitrogen atmosphere for 3 hours. Then the dimethyl10

-101

188,742 formamide is evaporated under reduced pressure; the resulting black resin was suspended in water, basified with potassium carbonate and extracted with dichloromethane (3 x 100 mL). The combined dichloromethane extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give a black gum again. It was purified by preparative HPLC using silica gel, mobile phase 100 parts dichloromethane, 5 parts

Using a mixture of 2-propanol and 0.5 parts of ammonium hydroxide. Fractions containing the desired product gave 3.1 g of the title compound as a dark oil; This gives 2.66 g of crystalline fumarate salt (23.2% of theory) in fumaric acid in n-propanol, m.p. 186-186.5 ° C. HPLC showed 99% purity.

Analytical data according to (CnH ₂₅ N ₅ OS) ₂ · C ₄ H ₄ 0 ₄ :

calculated: C 56.27%, H 6.71%,

N, 17.27%; S, 7.90%;

Found: C, 56.27; H, 6.96;

N, 17.31%; S, 7.98%.

Example 6

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

This example is a variant of Example 1, Step B, using sulfur dichloride instead of sulfur monochloride.

854 mg (2 mmol) of N- [3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide trihydrochloride are suspended in 6 ml of dimethylformamide and stirred under a stream of nitrogen in an ice bath. A mixture of sulfur dichloride (2 mmol) and dimethylformamide (2 mL) was added. The reaction mixture was stirred at room temperature and worked up as described in the previous examples; The title compound is thus obtained.

Example 7

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

A) N-Methyl-N '- [3- (3-piperidinomethyl-phenoxy-propyl) -ethane-diimidamide - trihydrochloride

4.13 g (10.9 mmol) of 3-methylamino -4- (3- (3-piperidinomethyl-phenoxy) -propylamino] -1,2,5-thiadiazole-1-oxide, which was prepared according to U.S. Pat. Prepared in the same way as described in British Patent Application Publication No. 6,122, to a suspension of 95 ml of methanol was added 7.2 ml of concentrated hydrochloric acid. 4.35 g (90.4% of theory) of the title compound are obtained, and a sample of this product is recrystallized from aqueous isopropanol to give the purified compound, m.p. 20 DEG-225 DEG C. with decomposition.

Analytical data for C ₁₈ H ₂₄ N ₅ O · 3 HCl:

calculated: C 49.03%, H 7.33%,

N, 15.89;

ta values (corrected for 0.94% H ₂ O: C 49.37%, H 7.35%,

N, 15.75%.

B) 3-Methylamino-4- [3- (3-piperidinomethyl)

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

3.74 g (8.47 mmol) of N-methyl-N '- [3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide trihydrochloride (prepared as described in Section A), 34 ml of dichloro methane and 3.5 mL of triethylamine are added 3.36 g (8.46 mmol) of bisphthalimidosulfide (in the form of a dimethylformamide solvate) and the mixture is stirred for 1 hour. The reaction mixture was then washed with 30 ml of 10% potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, diluted with toluene and concentrated. This gave 3.6 g of the title compound, which was purified by chromatography on 90 g of silica gel (230-400 mesh) eluting with 95: 5 ethyl acetate: methanol. 1.9 g (62% of theory) of the title compound are obtained. This product was treated with an equivalent amount of aqueous hydrochloric acid in 1-propanol; the hydrochloride salt thus obtained

163.5-164.5 'C-are.

Analytical data based on the formula C ₈ H ₂₇ N ₅ OS · HCl:

calculated: C 54.32%, H 7.04%,

N, 17.60%, S, 8.06%,

Cl 8 91% Found: C 54.35%, H 7.07,

N, 17.64%, S, 8.36%,

Cl, 8.86%.

Example 8

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

A) N-Benzyl-N '- (3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide - trihydrochloride

5.14 g (11.3 mmol) of 3-benzylamino-4 - [3 - (3

- piperidino - methyl - phenoxy) - propylamino] - 1,2,5

- thiadiazole 1-oxide, which is disclosed in U.S. Patent No. 2,067,987. was prepared as described in U. S. Patent Application Serial No. 4,900,400, suspended in 100 ml of methanol, and to this suspension was added 7.55 ml of concentrated hydrochloric acid. The mixture was brought to room temperature11

-111

After stirring for 3 hours at 188,742, the resulting solution was evaporated, the residue triturated with acetone, filtered and dried. 5.16 g (88% of theory) of the title compound are obtained, m.p. 187-205 ° C.

Analytical data for C ₂₄ H „N _S O · 3 HCl:

calculated: C 55 75%, H 7.03%,

N, 13.55%, Cl, 20.57%;

found: C 54.88%, H 6.75%,

N, 13.33%, Cl, 20.20%.

B) 3-Benzylamino -4- (3- (3-piperidinomethyl)

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

4.73 g (9.16 mmol) of N-benzyl-N '- [3- (3-piperidinomethyl-phenoxy) -propyl] -ethane-diimidamide trihydrochloride (prepared as described in Section A), 45 ml of dichloro of methane and 3.8 ml of triethylamine are added 3.64 g (9.16 mmol) of bisphthalimidosulfide (in the form of a dimethylformamide solvate) and the mixture is stirred for 1 hour. The reaction mixture was then washed with 44 ml of 10% potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, diluted with toluene and concentrated. The residue was purified by chromatography on 110 g of silica gel (230-400 mesh); eluting with ethyl acetate. 3.1 g (77% of theory) of the title compound are obtained. This product

2-propanol treated with an equivalent amount of aqueous hydrochloric acid; the hydrochloride salt of the title compound, m.p. 138-141 ° C.

Analysis data for C ₂₄ H ₃₁ N _s OS · HC! formula:

calculated: C 60.80%, H 6.80%,

N, 14.77%, S, 6.76%,

Cl, 7.48%;

found: C 60.53%, H 6.64%,

N, 14.99%, S, 6.91%,

Cl, 7.47%.

Example 9

3-Amino-4- [3- (3-piperidinomethylphenoxy) -propylamino] -l, 2,5-thiadiazol

This example is a variant of Example 1, Step B, wherein bis phthalimidosulfide is used in place of sulfur monochloride.

27.3 g (64.0 mmol) of N - (3- (3-piperidinomethyl)

- phenoxy) propyl] ethane diimidamide trihydrochloride (prepared as in Example 1 (A)) was added in portions to 250 ml of dichloromethane and 26.6 ml (192.0 mmol) of triethylamine. 4 g (64.0 mmol) of bis-phthalimidosulfide (in the form of a dimethylformamide solvate). After stirring at room temperature for 1 hour, the mixture was washed with 120 ml of 20% potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was dissolved in 150 mL of toluene and evaporated again. The product thus obtained is taken up in 250 ml of 1-propanol, 10.7 ml of 6N hydrochloric acid are added, the mixture is clarified with activated carbon and filtered through a "Celite" filter. The resulting solution was concentrated to a volume of 100 ml, diluted with 175 ml of anhydrous I-propanol and allowed to stand at 0 ° C to crystallize the product. The crystalline hydrochloride of the title compound (20.2 g, 82.1% of theory) is obtained, m.p. 137-138 ° C.

Analytical data based on the formula Ci ₇ H ₂₅ N _s OS · HCl:

calculated: C 53.18%, H 6.83%,

N, 18.24%; S, 8.35%; found: C 52.78%, H 6.74%,

N, 18.52%, S, 8.66%.

Example 10

3-Amino-4- [3- (3-pirrolidinometilfenoxi) -propylamino] -l, 2,5-thiadiazol

This example is a variant of Example 4, Step B, wherein bis phthalimidosulfide is used in place of sulfur monochloride.

22.0 g (53.0 mmol) of N- [3- (3-pyrrolidinomethyl-phenoxy) -propyl] -ethane-diimidamide trihydrochloride (prepared as in Example 4 (A)), 200 ml of dichloro To a mixture of methane and 22 ml of triethylamine was added 21.2 g (53.0 mmol) of bis-phthalimide sulfide (in the form of a dimethylformamide solvate). After stirring at room temperature for 1 hour, the mixture was washed with 100 ml of 20% potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was diluted with 100 ml of toluene and concentrated. The product thus obtained is treated with an equivalent amount of aqueous hydrochloric acid in 1-propanol to give 13.2 g of the hydrochloride salt of the title compound (67% of theory), m.p. 135-137 ° C.

Analytical data based on the formula C ₁₆ H ₂ , N ₅ OS · HCl:

calculated: C 51.96%, H 6.54%,

N, 18.93%, S, 8.67%; Found: C, 51.92; H, 6.55;

N, 19.30%, S, 9.06%.

Example 11

3-Amino-4- {2 - [(5-dimetilaminometil3 tieml) methylthio] ethylamino} 1,2,5-thiadiazole

A) N - {2 - [(5-Dimethylaminomethyl-3-thienyl) methylthio] ethyl] ethane diimidamide trihydrochloride

-121

188,742

7.8 g (22.6 mmol) of 3-amino-4- (2 - ((5-dimethylaminomethyl-3-thienyl) methylthio) ethylamino} -1,2,5-thiadiazole-1-oxide

No. 067,987 was prepared as described in British Patent Application Publication No. 3,600,600, slurried in 150 ml of ⁵ methanol and

Concentrated hydrochloric acid (15.0 ml) was added. After stirring at room temperature for 3 hours, the solution was concentrated, the residue was triturated with 1-propanol, filtered and dried; This gives 7.38 ^{l of} the title compound (80% of theory). A sample of this product was recrystallized from a mixture of methanol and acetone; the title compound thus purified melted at 190-205 ° C with decomposition. ¹⁵

Analytical data according to the formula C ₁₂ H ₂₁ N ₅ S ₂ · 3 HCl:

calculated: C 35.25%, H 5.92%, 20

N, 17.13;

Found: C, 35.03%, H, 5.93%,

N, 17.39%.

B) 3-Amino -4- (2 - ((5-dimethylaminomethyl-25

- thienyl) methylthio] ethylamino} -1,2,5 - thiadiazole

6.13 g (15.0 mmol) of N - (2 - ((5-dimethylaminomethyl-3-thienyl) methylthio) ethyl} ethane diimidamide trihydrochloride [prepared in the same manner as in section A above). To a mixture of dichloromethane (60 mL) and triethylamine (6.3 mL) was added bisphthalimidosulfide (5.96 g, 15.0 mmol) (dimethylformamide solvate) and the mixture was stirred for 1 hour. The filtrate was washed with a ³⁵ % potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was diluted with toluene and concentrated to give 5.1 g of crude product, 0.5 molar equivalent in 1-propanol. treated with fumaric acid to ⁴⁰ to yield the fumaric acid salt of the title compound, mp 141-143 ° C. the product is absorbed d ₆ -dimethyl sulfoxide nuclear magnetic resonance spectrum shows that the product is about 0.12 mole of 1-propanol is present.

Analysis calculated for (C ₁₂ H ₉ N ₅ S ₃ ) ₂ C ₄ H ₄ O ₄ · 0.12 C ₃ H _S O ^: 50 calculated: C 43.68%, H 5.61%,

N, 17.75%; S, 24.38%;

found: C 43.41%, H 5.53%,

N, 17.54%, S, 24.24%.

6.1 g (15.8 mmol) of 3-amino-4- (2 - [(piperidinomethyl-3-thienyl) methylthio] ethylamino} -1,2,5-thiadiazole I-oxide - 067,987, prepared as described in British Patent Application Serial No. 067,987, suspended in 80 ml of methanol and added to 10.5 ml of concentrated hydrochloric acid. Filtration and drying gave 5.86 g (83% of theory) of the title compound. A sample of this product was recrystallized from methanol / acetone to give the title compound, which was purified by melting at 201-214 ° C. .

Analytical data based on the formula C ₅ H _{2 5} NjS ₂ · 3 HCl:

calculated: C 40.13%, H 6.29%,

N, 15.60%, S, 14.29%;

found: C 39.97%, H 6.47%,

N, 15.28%, S, 14.63%.

B) 3-Amino-4- (2 - ((5-piperidinomethyl-3

- thienyl) methylthio] ethylamino} - 1,2,5 - thiadiazole

5.17 g (11.5 mmol) of N - [2 - [(5-piperidinomethyl)

3-Thienylmethylthio] ethyl} ethane diimidamide trihydrochloride (prepared as described in Section A), a mixture of 48 ml of dichloromethane and 4.8 ml of triethylamine, 4.57 g (11.5 g). bis-phthalimycosulfide (in the form of a dimethylformamide solvate) and stirred for 1 hour. The reaction mixture was then washed with 90 ml of 10% potassium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was diluted with toluene and concentrated. 4.5 g of the title compound are obtained, which is reacted with 1 equivalent of cyclohexylsulfamic acid in methanol to give the cyclohexylsulfamate salt of the title compound, m.p. 142-143 ° C.

Analytical data based on the formula Ci _S H ₂₃ N ₅ S ₃ C _e H ₁₃ NO ₃ S:

calculated: C 45.96%, H 6.61%,

N, 15.31%; S, 23.38%;

found: C 45.61%, H 6.41%,

N, 15.46%, S, 23.48%.

Example 13

3-amino-4- (3- (6-piperidinometil2-pyridyloxy) propylamino] -1,2,5-thiadiazole

Example 12

3-Amino-4- (2 - [(5-piperidinometil3-thienyl) methylthio] ethylamino} 1,2,5-thiadiazole

A) N - (2 - ((5-piperidinomethyl-3-thienyl) methylthioethyl} ethane diimidamide trihydrochloride

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

4-65 g (18.6 mmol) of 3- (6-piperidinomethyl-2-pyridyloxy) -propylamine, m.p. was prepared as described in U. S. Patent Application Publication No. 5,198,198, 50 ml methanol13

-13,888,742 and reacted with 2.74 g (18.6 mmol) of 3-amino-4-methoxy-1,2,5-thiadiazole-1-oxide as described in British Patent Application 2,067,987. In this way, 3-amino-4- (3- (6-piperidinomethyl-2) -amino-4- (3- (6-piperidinomethyl-2)) was obtained

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

- a solution of the oxide is obtained. The purified sample of this product melts at 145-147 ° C.

Β) N - (3- (6-piperidinomethyl-2-pyridyloxy) propyl] -ethane-diimidamide - trihydrochloride

The methanolic solution of the product obtained in (A) above was diluted to 100 ml and 12.4 ml of concentrated hydrochloric acid was added. After stirring at room temperature for 18 hours, the solution was concentrated, the residue was dissolved in water (80 ml) and the aqueous solution was extracted twice with dichloromethane. The separated aqueous layer was evaporated, n-propanol was added and the mixture was completely evaporated under high vacuum; the title compound is obtained in the form of a foam.

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

To the crude product obtained in Section B above is added 80 ml of dichloromethane and 7.69 ml of triethylamine, followed by the addition of 7.35 g (18.5 mmol) of bis-phthalimidosulfide (in the form of dimethylformamide solvate). treated. After stirring at room temperature for 1 hour, the mixture was washed with 50 ml of 4N sodium hydroxide solution, followed by water, followed by saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was obtained as a crude product. This was chromatographed on 100 g silica gel (230-400 mesh) eluting with 95: 5 ethyl acetate: methanol to give 3.63 g of the purified title compound as a viscous oil. This product is reacted with an equivalent amount of cyclohexylsulfamic acid in acetone to give the cyclohexylsulfamate salt of the title compound. mp 125.5-131 ° C.

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

calculated: C 50.07%, H 7.07%,

N, 18.58%, S, 12.15%;

found: C 50.02%, H 7.03%,

N, 18.54%, S, 12.14%.

Example 14

3-Amino-4- [3- (6-dimethylaminomethyl-2-pyridyloxy) propylamino] -l, 2,5-thiadiazol

- (6 - Dimethylaminomethyl - 2 - pyridyloxy) - propylamine - which is disclosed in U.S. Patent No. 2,098,988. was prepared as described in British Patent Application Publication No. 3,3-methanol-3-amino 14

Reaction with methoxy - 1,2,5 - thiadiazole - 1 - oxide according to U.S. Patent No. 2,067,987. and the resulting 3-amino -4- (3- (6-piperidinomethyl)

2 - pyridyloxy) propylamino] -1,2,5 - thiadiazole 1-oxide according to the general procedure described in Example 1 (A) of this specification and subsequently either in Example 1 (B) or in Example 10. The reaction was carried out as described in Example ^{1 to} give the title compound ¹ θ.

Example 15

3-Amino-4- {2 - [(O-dimetilamÍnometiÍ2-pyridyl) methylthio] ethylamino} 1,2,5-thiadiazol

- Amino - 4- {2 - ((6 - dimethylaminomethyl - 2

Pyridyl) methylthio] ethylamino} - 1,2,5 - thiadiazole

oxide as defined in U.S. Patent No. 2,067,987. prepared according to the procedure described in Example 1 (A) ₂₅ and subsequently either in Example 1 (B) or in Example 10; the title compound is obtained.

Example 16

3-Amino-4- (2 - [(6-piperidinomethyl-2-pyridyl) -mylthio] -ethylamino} -1,2,5-thiadiazole

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

3-Amino-4- {2 -] (6-piperidinomethyl-2-pyridyl) -methylthio] -ethylamino-1,2,5-thiadiazole 1-oxide, which is disclosed in U.S. Patent No. 2,067,987. prepared according to the procedure described in Example 1, section A) and subsequently reacted as described in either Example 1, section B or Example 9; the title compound is obtained.

Example 17

In the manner described in Example I, Section A, and thereafter, either in Example 1, Section B or 55 ^ζ ; EXAMPLE 1 was carried out by substituting 3-amino-4- (3- (3-iperidinomethyl-phenoxy) -propyl-amino] -1,2,5-Cadiazol-1-oxide mentioned therein as starting material; compounds are used in equimolar amounts in the following amounts:

(a) 3-amino-4- (3- (3-piperidinomethylthio-phenoxy) -propylamino] -1,2,5-thiadiazole-1-oxide, (b) 3-amino-4- (3- (3) - dimethylaminomethylthio-phenoxy) -propylamino] -1,2,5-thiadiazole I 65 oxide,

-141

188 742 (c) 3-Amino-4- (3- (3-pyrrolidinomethylthio-phenoxy) -propylamino] -1,2,5-thiadiazole-1-oxide, (d) 3-amino-4- (3- (4-dimethylaminomethyl-2-pyridyloxy) -propylamino] -1,2,5-thiadiazole 1-oxide, (e) 3-amino-4- (3- (5-dimethylaminomethyl-3)

- (thienyloxy) -propylamino] -1,2,5-thiadiazole-1-oxide, (f) 3-amino-4- (3- (5-piperidinomethyl-3-thienyloxy) -propylamino] -1,2, 5-Thiadiazole -1-1 oxide, (g) 3-Amino-4- (2 - ((4-dimethylaminomethyl 2-pyridyl) methylthio) ethylamino} -1,2,5-thiadiazole

- 1 - oxide, (h) 3 - Amino-4- (2 - ((4-piperidinomethyl - ^2-1 pyridinyl) - methylthio] - ethyl - amino} - 1,2,5 - thiadiazol

1-oxide to give the corresponding compounds listed below:

(a) 3-Amino-4- (3- (3-piperidinomethylthio-phenoxy) -propylamino] -1,2,5-thiadiazole, (b) 3-amino-4- (3- (3-dimethylaminomethylthio)

- (phenoxy) propylamino] -1,2,5-thiadiazole, (c) 3-amino -4- (3- (3-pyrrolidinomethylthio-phenoxy) -propylamino] -1,2,5-thiadiazole, ( d) 3-Amino-4- (3- (4-dimethylaminomethyl-2-pyridyloxy) -propylamino] -1,2,5-thiadiazole, (e) 3-amino-4- (3- (5-dimethylaminomethyl-) 3

- (thienyloxy) propylamino] -1,2,5-thiadiazole, (f) 3-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, (h) 3-amino-4- (2) - ((4-piperidinomethyl-2-pyridyl) -methyl-thio] -ethyl-amino} -1,2,5-thiadiazole.

The starting materials used in the above process are described in U.S. Patent No. 2,067,987. was prepared in accordance with the general procedure described in British Patent Application Publication No. 3,800,500. The precursors used for the preparation of said starting materials are disclosed in Publication Nos. 2,067,987, 2,098,988 and 2,063,875. United Kingdom and also published 49,173. European Patent Application, or analogous thereto.

Example 18

3-Amino-4- [3- (4-piperidinometil2-pyridyloxy) propylamino] -1,2,5-thiadiazole

A) 3- (4-Piperidinomethyl-2-pyridyloxy) -propyl

- amin

No. 2,098,988. United Kingdom Patent Publication No. 3,646,011, which was conducted in accordance with the general procedure for the preparation of 3- (6-piperidinomethyl-2-pyridyloxy) -propylamine, except that an equivalent amount of 2-bromo-6-methyl-pyridine was used as starting material. -4-methylpyridine is used. In this way, the title compound is obtained as an oil.

Analytical data based on Ci ₄ H ₂₃ N ₃ O.

calculated: C 67.44%, H 9.30%,

N, 16.85%;

Found: C, 67.54; H, 8.98;

N, 16.55%.

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

6.5 g (26.0 mmol) of 3- (4-piperidinomethyl-2-pyridyloxy) -propylamine, prepared as described in Section A above, in 3.90 g (26.0 mmol) of 3-amino in 90 ml of methanol. With methoxy - 1,2,5 - thiadiazole - 1 - oxide. in accordance with the general procedure described in United Kingdom Patent Application Publication No. 4,198,198. The crude product obtained (6.33 g) was recrystallized from a mixture of methanol and acetonitrile; The title compound, m.p. 154-158 ° C, is obtained.

Analytical data based on the formula C ₁₄ H ₂₄ N ₆ OS:

calculated: C 52.73%, H 6.64%,

N, 23.06%, S, 8.80%; Found: C, 52.72; H, 6.30;

N, 23.32%, S, 8.74%.

C) N - (3- (4-Piperidinomethyl-2-pyridyloxy) -propyl] -ethane-diimidamide - trihydrochloride

5.0 g (13.7 mmol) of the product obtained in Section B are dissolved in 80 ml of methanol and 9.1 ml of concentrated hydrochloric acid are added. After stirring at room temperature for 4.5 hours, the resulting solution was concentrated under reduced pressure; to give the title compound as a residue.

D) 3-Amino-4- (3- (4-piperidinomethyl-2'-pyridyloxy) -propylamino] -1,2,5-thiadiazole

The N- (3- (4-piperidinomethyl-2-pyridyloxy) -propyl] -ethane diimidamide trihydrochloride obtained according to section C above was treated with a mixture of 5.44 g (13%) of dichloromethane and 50 ml of triethylamine. treated with 7 mmol) of bis-phthalimido-sulfide (DMF solvate). The mixture was stirred at room temperature for 1 hour, then washed with water and ¹ with saturated aqueous sodium chloride solution 40 ml of 4N sodium hydroxide solution, followed by After drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure, the crude product obtained is chromatographed on 90 g of silica gel (230-400 mesh) for purification using a mixture of ethyl acetate and methanol (96: 4) as eluent. 3.44 g of 3 - amino-4- (3- (4-piperidinomethyl - 2 - pyridyloxy) - propyl - amino] - 1,2,5 -. thiadiazole as a viscous oil This product is equivalent to ^one volume of acetone ciklohexilszu reaction with lfamic acid to give the cyclohexylsulfamate salt of the above compound, which

124.5-126'C are.

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188,742

Analytical data according to the formula C ₁₆ H ₂₄ N ₆ OS · C ₆ H ₁₃ NO ₃ S:

calculated: C 50.07%, H 7.07%,

N, 18.58%, S, 12.15%;

found: C 50.47%, H 7.12%,

N, 18.33%, S, 11.87%.

Example 19

3-Amino-4- {3- [3- (1,2,3,6-tetrahydro-1-pyridyl) -methyl-phenoxy] -propyl-amino} -1,2,5-thiadiazole;

The procedure described in Example 13 was followed except that the 3- (6-piperidinomethyl-2-pyridyloxy) starting material mentioned therein was used.

instead of propylamine, an equivalent amount of 3 - (3

- (1,2,3,6-Fetrahydro-1-pyridyl) methylphenoxy]

propylamine is used. In this way, 2.31 g of 3

- amino-4- {3- [3- (1,2,3,6-tetrahydro-1-pyridyl)

methyl methylphenoxy] propylamino} -1,2,5 - thiadiazole was obtained. Recrystallized from toluene

99.5-104 ° C.

Analytical data based on the formula C ₁₇ H ₂₃ N ₅ OS:

calculated: C 59.10%, H 6.71%,

N 20.27%, S 9.28%;

found (2.19% corrected for water content): C 58.78%, H 6.71%,

N, 19.90%, S, 9.26%.

Claims (10)

Claims I. Process for Substituting 3,4-Diamino-1,2,5-thiadiazoles of Formula (I), wherein R 'is hydrogen, C 1-4 alkyl or phenyl having a histamine H ₂ receptor antagonist activity. (C1-C4) -alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur A is (c), (d), (e) or (O) R ⁵ is hydrogen or C 1-4 alkyl, R @ 4 and R @ ⁷ each represent a C 1 -C 4 alkyl group, or the two symbols together with the nitrogen atom to which they are attached represent a pyrrolidino, piperidino or 1,2,3,6-tetrahydro-pyridyl 1 - group; acceptable non-toxic salts, hydrates and solvates thereof, characterized in that an ethane diimidamide derivative of the formula (ΙΪ) in which R ¹ , A, Z, m and n are as defined above is preferably 0 °. At a temperature of from C to 50 ° C, preferably in an inert organic solvent, at least one molar equivalent of sulfur monochloride or sulfur dichloride, preferably at least one molar equivalent, particularly preferably between 2 and 3 molar equivalents, and if desired the resulting compound of formula (I) is converted into a pharmaceutically acceptable, non-toxic salt, hydrate or solvate; Akita. > (Priority: March 29, 1982) Process according to Claim 1, characterized in that the compound of the formula II, wherein R ¹ , A, Z, m and n are as defined above, is at least equimolecular in sulfur monochloride, preferably 2-3 mol. with an equivalent excess. (Priority: March 29, 1982) Process 3 is substituted for formula (I) 3,4-diamino-1,2,5-thiadiazoles, wherein R ¹ , A, Z, m and n are as defined in claim 1, and pharmaceutically acceptable, non-toxic salts, hydrates and solvates thereof. wherein the formula (II) ethane diimide amide derivative of general formula: - wherein R ^1, A, Z, m and n are as defined above and - a substantially equimolar amount, preferably applied solvate form bis-ftálimidoszulfidda! and, if desired, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt, hydrate or solvate. (Priority: March 28, 1983) The process of claim 1 for the preparation of the general formula (ét) which is a narrow case of formula (I) - wherein R ¹ 'is hydrogen or C 1-4 alkyl, Z represents oxygen or sulfur, m 0 or 1, n 2 or 3, A 'is a group of formula (c'), (d '), (e') or (Γ) and R ⁵ 'is hydrogen or methyl, R ⁶ 'and R ⁷ ' independently of one another represent a methyl or ethyl group, or the two symbols together with the adjacent nitrogen atom to prepare the corresponding compounds and their pharmaceutically acceptable salts, hydrates and solvates, characterized in that: starting from a (ΪΓ) compound - is used in which R ^1, Z, A ', m and n are as defined hereinabove ~. (Priority: March 29, 1982) 5. The method of claim 1, which is a process for the preparation of the general formula (Ia), which is a narrower case of formula (I). R ¹ 'is hydrogen or methyl, -161 188,742 R ^o 'and R ⁷ "separately methyl or the two signals together with the adjacent nitrogen atom, pyrrolidino or piperidino group to represent the compounds as well as pharmaceutical eye 5 points acceptable salts, hydrates and solvates thereof, characterized in that (II) The starting material of the formula (II) is a compound of the formula (IIa) wherein R ¹ ', R ^e ' and R ⁷ 'are as defined above. (Priority: March 29, 1982) 6. The method of claim 1 embodiment ₁₅ Method formula being a narrower range in case of the formula (I) (b) - wherein R ¹ 'and R ⁵ ' are independently hydrogen or methyl, R * ⁵ '' and R ⁷ '' independently of one another are methyl or ethyl - for the preparation of suitable compounds and their pharmaceutically acceptable salts, bridges and solvates, characterized in that the starting material of formula II is a compound of formula (IIb). a compound of the general formula wherein R ¹ ', R ⁵ ', R ⁶ '' and R ⁷ '' are as defined above. (Priority: March 29, 1982) A process for the preparation of a compound according to claim 1 of formula (Ic), wherein R ¹ 'and R ⁵ ' are independently hydrogen or methyl, R ^'s'' and R ⁷ '' are independently methyl or both ethyl corresponding compounds, and their pharmaceutically acceptable salts, hydrates and solvates thereof, characterized in that (II) starting from general formula (IIe) of the compound of the formula - where R ¹ ', R ⁵ ', R ^e '' and R '' 'has the same meaning as defined above - used. (Priority: March 29, 1982) The process of claim 1, for the preparation of the general formula (Id), which is a narrow case of formula (I) R 'and R ⁵ ' are independently hydrogen or methyl, R ⁶ * and R ⁷ * independently of one another for the preparation of a corresponding compound represented by a methyl or ethyl group or a piperidino group together with the adjacent nitrogen atom and their pharmaceutically acceptable salts, bridges and solvates, characterized in that the starting compound of formula II The compound of formula (IId) wherein R '', R ⁵ ', R ⁶ * and R ⁷ * are as defined above is used. (Priority: March 29, 1982) A process for the preparation of a medicament for the action of a histamine H ₂ receptor antagonist, wherein a compound of formula I according to claim 1 or claim 3, wherein R ¹ , A, Z, m and n are the same as f. or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutical carrier and / or excipient, and conveniently formulated for oral, rectal or parenteral administration. (Priority: March 28, 1983) A process according to claim 9 wherein the active ingredient is a compound of formula (I) as defined in claim ¹ , wherein R ¹ , A, Z, m and n are as defined above, or a pharmaceutically acceptable salt, hydrate or solvate.