SU1355123A3 - Method of producing substituted ethanediimideamine or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The invention relates to production; acids, in particular the substituted ethanediimidamine (JAM) of the general formula A- (CI5) -Z- (CH) "- NH-C (NH); - C (NH) -NHR, where R, is H, C, . , kil, benzyl; m O or 1; n 2 or 3; Z - 0 or Z-, R4 A - a group of formulas 1,2 or 3: KgKzN (CH2) 4 K-priKg Yag, Rz, NR 1) 2; 2)) R, -C, H,, o which: a) R4 - H; R and R are each C, -C-alkyl; b) R is H or C —C-alkyl; R. and R are C-C g-alkyl or, together with nitrogen, a piperidine radical; c) R - H; pyrrolidine, or piperidine. 1,2,3,6-tetrahydropyridyl, or their pharmaceutically acceptable salts, which can be used as a histamine antagonist or for the treatment of peptic drugs. The goal is to create more active substances of the specified class. Synthesis of ZAM is carried out from the corresponding thiadiazo a, which is cleaved under the influence of a strong mineral acid (HC1) in the medium of an organic solvent at room temperature with isolation of the desired product in free form or as a salt. The tests for ZAM show a degree of activity on cimetidine up to 137%. 2 tab. § SO with JV joint venture

Description

(I)

The invention from Osits to organic chemistry, namely to a method for producing a substituted ethanediimidamine of the formula

A- (X (CH-2) j NHx / T Hl i

HN NH

Where. R is hydrogen, C, -C - alkyl or a group of the formula

g) -CH2.-;

m about or 1;

n 2 or 3;

Z is oxygen or sulfur;

A - group of the formula

-shh, x

2 b

(ABOUT

2

Ke

(g

(2)

city of b

(3)

ZhSN2) (

/ k-r, /

de in the case of the radical (1) R is hydrogen,, R and R are each C, -Cg-alkyl; in the case of the radical (2), R is hydrogen or lower C -C alkyl, R and R are lower C, is Cg alkyl or R, and R is taken together with the nitrogen atom to which they are attached. combined, form a piperidine cycle, or in the case of the radical (3), hydrogen, Rg and Rj, together with the nitrogen atom form pyrrolidine, piperidine or 1,2, 3,6-tetrahydropyridyl, which is used as the starting compounds for the preparation of 3-. (amino or substituted amino) -4- (substituted amine) -, 2,5-thiadiazoles, and their pharmaceutically acceptable salts, which are strong Hj-receptor antagonists. gastric acid inhibiting gastric acid, and are useful for the treatment of pedic ulcers and other pathological hypersecretory conditions.

The aim of the invention is to develop the environment for 2.3 hours.

the development of an accessible process for the preparation of compounds of formula (I), which allow the preparation of deoxy compounds, exceeding in their activity in

the solution is concentrated and the residue is triturated with 70 ml of absolute ethanol. The crystals are collected by filtration and dried under vacuum; 4.3 g are obtained.

- - -, as an H-antagonist, known compounds.

Example 1. N 3- (3-piperidino-methylphenoxy) propyl 3-ethanediimidamine trihydrochloride.

. Suspensions of 1-oxide-3-amino-4- 3- (3-piperidinomethyl-Lenoxy) propyl-, 2,5-thiadiazole (17.1 g;

10 47.0 mmol) in 450 ml of methanol is treated with 38 ml of concentrated HCl. The resulting solution is stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic distillation of water with absolute ethanol gives colorless crystals. They are suspended in 200 ml of absolute ethanol, filtered and dried under vacuum; mind, 16.6 g (82.6%) of the title compound are obtained, i.e. 205-222 ° C (decomposition). Recrystallization from a 50% mixture of methanol with ethyl acetate gives an analytical sample, m.p. 206 25 (decomposition).

 Calculated,%: C, 47.84; H7.08; N 16.4.

  SNS1.

Found,%: C 47.56; H 7.18;

30 N 16.75.

A portion of the salt is suspended, in water, neutralized with potassium carbonate and extracted with methylene chloride. Methylene-, chloride is concentrated and crystallized35

call the free base of the target compound, e.g. 43-47 C. A portion of the free base is converted to the hydrochloride salt, m.p. 138-40 C.

Calculated,%: C 53.18; H 6.83; 40 N 18.24; S 8.35.

With „.N5,0 S-. HCl Found;%: C 53.14; H 6.88; N 18.49; S 8.74.

PRI mme R 2. Trihydrochloride (5-dimethylamino-methyl-2-fluoryl) hydrate hydrate hydrate | ethyl is ethanediimidamine. The suspension of α-oxide-3-amino-4-2-L (5-dimethylaminomethyl-2-furip) methylthio ethylamino-1, 1,2,5-thiadiazole 50 20.0 mmol) in 200 ml of methanol is heated slightly to achieve complete dissolution , then 13.3 ml of concentrated HC1 are treated. After stirring at room temperature, the solution is concentrated and the residue is triturated with 70 ml of absolute ethanol. The crystals are collected by filtration and dried under vacuum; 4.3 g are obtained.

313551234

(52%) of the target compound, m.p.166- EXAMPLE 5: Trnghydrochloride N169 C (decomposition).

Calculated,%: C 35.08; H 6.38; N 17.05; S 7.80.

C, H, N50 S-. ZNS1 Nuo

Found,%: C 34.85; H 6.24; N 17.45; S 7.97.

PRI me R 3. Methyl-N trihydrochloride - 3- (3-piperidinomethylphenoxy) propyl-ethanedine-adamine.

A suspension of 1-hydroxy-3-methylamino-4-2 (3-piperidnnomethylphenoxy propyl amino 1,2,5-thiadiazole (4.13 g; 10.9 mmol) in 95 ml of methanol is treated with 7.2 ml of concentrated HC1 .

I 2 5-dimethylaminomethyl-4-methyl-2-tie- After unmixing at a temperature of nyl-methylthio-ethyl-ethanediimidamine. - For 3 hours, the mixed solution of 1-oxide-3-th solution is concentrated and the rest of the plant-amino-4- 2- (5-dimethylaminomethyl-4 -... is washed with acetone, filtered and dried, methyl 2-thienyl) Metsh1thio ethylamino - get 4.35 g (90.4%) of the product. 06-1,5,5-thiadiazole (17.9 g; 50.0 mmol), the sample is recrystallized from water; 500 ml of methanol is treated with 15% propyl alcohol to give 33.3 ml of concentrated HC1. After the left connection, so pl. 207-225 ° C. Stirring for 3 hours, the reaction mixture is concentrated and the excess water is removed by azeotrification with absolute ethanol (20), giving an almost colorless curve. steel residue. The residue is dissolved with 200 ml of absolute ethanol.

(decomposition).

Calculated,%: C 49.03; H 7.33; N 5.89.

, ZNS1

Found (corrected for 0.94%),% g C 49.36; H 7.35; N 15.71.

Example Trihydrochloride N16, 9 g (80%) of the target compound, benzyl-n - | 3- (3-piperidine-methylphene, mp 206-220 ° C (decomposition). Peroxoxy) propyl-ethanediimidamine.

The suspension of 1-hydroxy-3-benzylamino-4-3- (3-piperidinomethylphenoxy) -propylamino-, 2,5-tyadiazole (5.14 g; 30 11.3 mmol) in 100 ml of methanol is treated with 7.55 ml of concentrated HC1. After stirring at ambient temperature for 3 hours, the solution is concentrated and the residue is dispersed. EXAMPLE 4 Trihydrochlorin, N-35 is rubbed with acetone, filtered and dried, (3-pyrrolidinomethylphenoxy) for 5 , 16 g (88%) of the title compound, mp 87-205 ° C (decomposition).

at O C, filtered and dried, get

installing from a 50% mixture of methanol and ethyl acetate gives a product having so pl. 210-221 C (decomposition)

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

C ,, H23N, S -3HC1

Found,%: C 36.76; H 6.33; . N 16.97; S 15.54.

drank-ethanediimidamine.

A suspension of 1-oxide-3-amino-4- 3- (3-pyrrolidinomesh1-phenoxy) propyl-aminb -1,2,5-thiadiaeol (13.4 g; 38.3 mmol) in 350 ml of methanol is treated with 25.5 ml of concentrated HC1. The resulting solution is stirred for 3 hours while Calc.,%: C 55.75; H 7.03; 40 N 13.55; C1 20.57.

C 24.5 N5.0 ZNS1

Found,%: C 54.88; H 6.75; N 13.33; C1 20.20.

PRI me R 7. Trihydrochloride N50

Peripheral environment, Concentrated-45 L- (5-dimethylaminomethyl-3-thienyl) is added to the solution followed by azeotropylthio ethyl-ethanediimide. removal of water by absolute ethano-suspension of 1-hydroxy-3-amino-4-2-G (5

scrap. Crystalline residue grown-dimers-aminomethyl-3-thienyl) methylthio

ethyloamino | -1,2,5-Thiyadiazole (7.8 g; 22.6 mmol) in 150 ml of methanol was treated with 15.0 ml of concentrated hydrochloric acid. After stirring at ambient temperature for 3 hours, the solution is concentrated and the residue is triturated with 1-propanol, filtered and dried, yielding 7.38 g (80%) of the product. A sample of the product is recrystallized from a mixture of methanol with 150 ml of absolute ethanol, filtered and dried, to obtain 10.8 g of the title compound, mp 195-203 C (decomposition).

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

C .. ZNS1

55

Found,%: C 46.55; H 6.93; N 16.93.

the thief is concentrated and the residue is grown with acetone, filtered and drying is obtained; 4.35 g (90.4%) of the product is recrystallized from thiopropyl alcohol to give the left compound, so pl. 207-225 ° С

(decomposition).

Calculated,%: C 49.03; H 7.33; N 5.89.

, ZNS1

Found (corrected for 0.94%),% g C 49.36; H 7.35; N 15.71.

  Calculated,%: C 55.75; H 7.03; 40 N 13.55; C1 20.57.

C 24.5 N5.0 ZNS1

Found,%: C 54.88; H 6.75; N 13.33; C1 20.20.

PRI me R 7. Trihydrochloride N45 b- (5-dimethylaminomethyl-3-thienyl) methylthio ethyl-ethyldiimide. Suspension of 1-hydroxy-3-amino-4-2-G (5

la and acetone to give the title compound, m.p. 190-205 ° C (decomposition).

Calculated,%: C 35.35; H 5.92; N 17.13.

C,.,. ZNS1

Found,%: C 35.03; H 5.93; N 17.39.

Example Trihydrochloride (5-piperidinomethyl-3-thienyl) me-

tiltio ethylI-ethanediimidamine.

A suspension of 1-hydroxy-3-amhyu-4- | 2- (5 piperidinomethyl-3-thienyl) methylthioz ethylamino; -1, 2,5-thiadiazole (6, g; 15.8 mmol) in 80 ml of methanol is treated with 10.5 ml of concentrated HC1. After stirring at ambient temperature for 3 hours, the solution is concentrated and the residue is triturated with 50 ml of 1-propanol, 5 filtered and dried, yielding 5.86 g (83%) of product. The sample is recrystallized from a mixture of methanol and acetone to obtain the target compound, mp 201-214 ° C (decomposition).

Calculated,%: C 40.13; H 6.29; . N 15.60; S 14.29.

C, 5H, 5N5.Sj- ЗНС1

Found,%: C 39.97; H 6.47; N 15.28; S 14.63.

Example 9. A. 3-Amino-4- 3- (6-piperidinomethyl-2-pyridyloxy) propyl-amino, 5-thiadiazole-1-oxide,

A solution of 3- (6-piperidinomethyl-2 "-pyridyloxy) propylamine (4.65 g; 18.6 mmol) in 50 ml of methanol is introduced with 3-amino-4-methoxy-1,2,5- thiadiazole-1-oxide (2.74 g; 18.6 mmol) to obtain a solution containing 3-amino-4- 3- (6-piperidinomethyl-2-pyridyloxy) propylamino, diazole-1-oxide. The purified sample melts at 145-147 C.

30 Found: C 52.72; H 6.30; N 23.32; S 8.74.

B. Trihydrochloride (4-piperidinomethyl-2-pyridoxpoxy) propyl-ethanediimidamine.

The product of stage B (5.0 g; 13.7 mmol) is dissolved in 80 ml of methanol and 9.1 ml of concentrated HC1 is formed. After stirring at ambient temperature for 4.5 hours (JQ solution is evaporated to dryness under reduced pressure to obtain the desired compound.

P.R.M. 11. 3-Amino 4- {3 - 335

diimidamine.

The methanol solution of the product obtained in step A is diluted to

(1,2,3,6-tetrahydro-1-pyridsh1) methylB. N-3- (6-piperi-45 Phenoxy propylamino} -1,2,5-thiadiazole. Dinomethyl-2-pyridyloxy) propyl-ethane trihydrochloride Using the procedure of example 10,

replacing in 3- (6-piperidinomethyl-2-pyrilyloxy) propylamine with an equivalent amount (1,2,3,6-tetrahydro-1-100 ml and adding 12.4 ml of concentrated pyridyl) methylphenoxy propyamine; peroxide HC1. The solution is stirred at ambient temperature c. for 18 hours, concentrate and the residue is dissolved in 80 ml of water and extracted twice with methylene chloride. The aqueous layer was concentrated, treated with n-propanol and concentrated under high vacuum to obtain the title compound as a foam.

2.31 g of product is obtained. Recrystallization from toluene yields a product with m.p. 99.5-104 s.

Calculated,%: C 59.10; H 6.71; N 20.27; S 9,28.

€, "„ N505

Found (for 2.19%),%: C 58.78) H 6.71; N 19.90; S 9,26.

Example 10. A. 3- (4-Piperidi-nomethyl-2-pyridyloxy) propylamine.

Prepared according to the general procedure for the preparation of 3- (6-piperidinomethyl-2-pyridyl-oxy) -propylamine, except for the fact that 2-chloro-6-methylpyridine is replaced by 2-bromo-4-methylpyridine, then the desired compound is obtained as

oils.

Vytseleno,%: C 67,44; H 9.30; N 16.85.

С, 4Н „1ЦО

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-oxyd.

A solution of the product of stage A (6.5 g; 26.0 mmol) in 90 ml of methanol is reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (3.84 g; 26, 0) 6.33 g of product are obtained. Recrystallization from a mixture of methanol and acetonitrile gives the target compound, mp 154-15 ° C.

Calculated,%: C, 52.73; H 6564; N 23.06; S 8.80.

C „H, 4

Found,%: C 52.72; H 6.30; N 23.32; S 8.74.

B. Trihydrochloride (4-piperidinomethyl-2-pyridoxpoxy) propyl-ethanediimidamine.

The product of stage B (5.0 g; 13.7 mmol) is dissolved in 80 ml of methanol and 9.1 ml of concentrated HC1 is formed. After stirring at ambient temperature for 4.5 hours, the solution is evaporated to dryness under reduced pressure, to give the desired compound.

P.R.M.R. 11. 3-Amino 4- {3- 3

(1,2,3,6-tetrahydro-1-pyridsh1) methyl substitutions in 3- (6-piperidinomethyl-2-pyridyloxy) propylamine equivalent amount (1,2,3,6-tetrahydro-l-pyridyl) methylphenoxy propylamine,

2.31 g of product is obtained. Recrystallization from toluene yields a product with m.p. 99.5-104 s.

Calculated,%: C 59.10; H 6.71; N 20.27; S 9,28.

€, "„ N505

Found (for 2.19%),%: C 58.78) H 6.71; N 19.90; S 9,26.

7

The compounds of formula (1) obtained by the proposed method are histamine receptor antagonists. H-receptor antagonists of histamine are known to be active inhibitors of gastric secretion in animals and humans. A clinical evaluation of the H-receptor antagonist histamine cimetidine has shown that it is an effective therapeutic agent in the treatment of peptic ulcer diseases. Some compounds of formula (I) were compared with cimetidine in various experiments, and it was found that they are stronger than cimetidine, both as the N. receptor antagonist histamine in the experiment with the isolated right atrium of the guinea pig, and as an inhibitor of gastric acid secretion in rats and dogs.

Determination of gastric antisecretory activity in gastric fistu of rats.

Male rats of the Long Evans variety weighing about 240-260 g are used for implantation of the cannula. The contouring and implantation of a stainless steel cannula into the inner wall of the anterior section of the complex stomach is carried out as described by Pare et al, and the same procedure is carried out. After surgery, animals are kept individually in cages as needed throughout the entire recovery period. For at least 15 days. after surgery, animals are not used for the experiment.

Animals are kept hungry, but they are given water as needed for. 20 hours before the test begins. Immediately before collecting the cannula, the stomach is gently rinsed with 30-40 ml of warm saline or distilled water to remove any residual contents. The catheter is then screwed into the cannula in place of the stopping cap, and the rats are placed in a transparent plastic rectangular cage 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slit approximately 1.5 cm wide and 25 cm long, running down to center, to accommodate the catheter that attaches through it, Ta1238

By IMM, the rat is not cramped and can move freely around the cage during the collection period. The rest of the analysis is carried out as described by Ridley et al.

Gastric secretions collected during the first hour after washing the stomach are discarded, as they may be contaminated. To evaluate oral administration, the catheter is then removed from the cannula and replaced with a screw-in stopper. Water (2 ml / kg) is orally administered via gastric intubation, and the animal is returned to the cage for 45 minutes. Thereafter, the screw cap is removed and replaced with a catheter to which a small plastics tube is connected to collect the ventricular secretions. A two-hour sample of secretions is collected (control secretion), the catheter is removed and replaced with a screw-in stopper. Orally administered test drug in a volume of 2 ml / kg with the help of gastric intubation. After 45 minutes, the tube was removed again, replaced with a catheter connected to a small plastic tube, and another two hours were collected: a sample. The BO isolations of the second sample are compared with those of the control sample in order to determine the effect of the test drug.

For parenteral evaluation of the test compounds, the animal is injected intraperitoneally or subcutaneously with the vehicle of the test compound in a volume of 2 ml / kg immediately after discarding the initial 60-minute collection. A two-hour sample (control secretion) is collected and the test compound is injected intraperitoneally or subcutaneously into the animal in a volume of 2 ml / kg. An additional two-hour sample is collected and compared with the isolations of the control period to determine the effect of the drug.

Samples are centrifuged and placed in a graduated centrifuge tube to determine the volume. The titratable acidity is measured by titration of a one-milliliter sample to a pH of 7.0 0.02 n. sodium hydroxide using autobiuret and electrometric pH-meter (radio.tr). The yield of titrated acid is calculated in microequivalents by multiplying the volume in milliliters

on acid concentration in milliequivalents per liter.

Results are expressed as percent inhibition compared to control data. Draw the response dose curves and calculate AU values; o using regression analyzes. For each dose level, use at least three rats to determine the dose response curve using a minimum of three dose levels.

The data of gastric antisecretory activity in the gastric fistula of rats are shown in Table 1.

H-receptor antagonis; - Histamine using isolated guinea pig atria.

. Histamine induces a concentration-related increase in the rate of contractions of an isolated spontaneously beating right atrium of the guinea pig.

The studies were carried out using a modification of the procedure described by Reinhardt et al.

- Male Hartley guinea pigs (350-450 g) are killed by a blow to the head. The heart is isolated and placed in Petri with saturated oxygen (95% 0 and 5% CO), a modified Krebs solution containing, g / l: NaCl 6.6; KS1 0.35; MgSO 0.295; 0.162; CaCl 0.238; NaHCO, 2.1; dextrose 2.09. The spontaneously right atrium is anatomized, freed from other tissues, and a silk thread is attached to each end (4-0). The atrium is suspended in 20 ml of the muscular cavity containing an oxygen-filled, modified Krebs solution maintained at 32 ° C. Atrial contractions are recorded isometrically using a GraSSFT 0.3 force displacement transducer and using the Corkshin PP dynograph, the contraction force and degree are recorded.

A calming stress of 1 g is applied to the atrium and it is possible to attain equilibrium for 1 hour. At the end of the equilibration period, a submaximal concentration of histamine dihydrochloride () is added to the bath and the tissue is added to the bath, then added to the bath histamine cumulative

0

at a time to obtain a final molar concentration in the bath from 1 x 10 to 3 X 10 M. Before adding the next concentration, an increase in the atrial rhythm caused by histamine is allowed to balance (achieve constancy). When the concentration reaches the maximum response, Histamine is depressed several times and the atrium is allowed to return to the control rhythm. The test compound is then added at appropriate molar concentrations, and after a 30-minute incubation period, the reaction to a histamine dose is repeated, with higher concentrations being added as necessary.

Of the graphs of Schild vshod t dissociation constants (Kv) according to the method of Agaplakshana Oh, and Schild N.O., using at least three dosages. leveling levels. Parallel shifts in dose response curves are obtained without depressing the maximum response at the antagonist concentrations used.

The activity data in the isolated Q right atrial of the guinea pig is given in Table 2.

The compounds of formula (I) in the studied doses did not cause adverse effects in experimental animals, none of the animals died, therefore, the soybeans of formula (I) are not toxic.

Example 12, 3-Amino-4- 3 (3-piperidinomethylphenoxy) propylamino-1,2,5-thiadiazole.

A stirred suspension of N-3- (3-piperidinomethylphenoxy) propyl-ethanediimidamine trihydrochloride (2.13 g; 5.0 mmol), prepared according to example 1, is treated with monochlorine sulfur in 20 ml of dimethylformamide (DMF) 2.02 G; 15, O mmol) and stirred for 4 hours. The resulting mixture is poured carefully into 200 ml of water and made alkaline with potassium carbonate. The mixture is extracted with 3 portions of 50 ml of methylene chloride. and after sugak over magnesium sulphate and concentration, 2.1 g of a dark, resinous substance containing the product are obtained. The product is purified by preparative high pressure liquid chromatography on silica using

five

0

45

50

55

as the mobile phase of the mixture of meth-. Lenchloride (100), 2-propanol (10) and ammonium hydroxide (0.5). The corresponding fractions give 0.89 g of the target compound, from which with fumaric acid in propane, 0.76 g (21.4%) of the desired compound is obtained in the form of a crystalline Phz ;; mineral salt, m.p. 187-187.5 seconds. High pressure liquid chromatography (HPLC) showed a purity greater than 99%.

Calculated,%: C 56.27; H 6.71; N 17.27; S 7.90.

(C ,,) 2.

Found,%: C 56.09; 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 methylene chloride concentrates and crystallizes the free base of the target compound, mp 43–47 C. A part of the free base is converted to the hydrochloride salt, .138-140 ° C.

Calculated,%: C 53.18; H 6.83; N 18.24; S 8.35.

 S HCl

Found,%: C 53.14; H 6.88; N 18.49; S 8.74.

Example 13: 3-Amino-4- 2- (5-dimethylaminomethyl-2-furyl) methylthio ethylamino-1,2,5-thiadiazole.

To a stirred suspension of trihydrochloride hydrate (5-dimethylaminomethyl-2-four-methyl-thioethyl | -ethanediimidamine (12.3 g; 30.0 mmol) of example 2 in 50 ml of DMF was added 7.2 ml of sulfur monochloride (12 , 1 g; 90 mmol.) After stirring for 4 hours at ambient temperature, about half of the DMF is removed under reduced pressure. The remaining black solution is taken up in 1 liter of water, basified with potassium carbonate and extracted first with ethyl acetate and then with chloroform. After drying over magnesium sulfate, filtering and concentrating, 9.0 g of a black resin containing the product. This product is prepared using high pressure silica preparative liquid chromatography chromatography using the mobile phase of a mixture of ethyl acetate (100), 2-propanol (10) and ammonium hydroxide. (0.5). The appropriate fractions yield 1.24 g of the target compound.

15

Dineni in Nida resin. By treating a portion of this product with an equivalent amount of 2 N. HCl in methanol, the hydrochloride salt of the title compound is obtained.

Calculated,%: C 41.18; H 5.76; N 20.02; S 18.38.

C, jH ,,, 2 HCl

Found (corrected for 1.65%),%: C 40.54; H 5.70; N 19.39; S 18.44.

By treating the product with an equivalent amount of cyclohexyl sulfamic acid in acetone, the cyclohexyl sulfate salt of the target compound is obtained, m.p. 93-95 S.

Calculated,%: C, 43.88; H 6.55; 17.06; S 19.53.

N

20

„NJ-S O.

3,

Found,%: C 43.77; H 6.17; N17.2I; S19.58.

Example 14. 3-Amino-4- 2- (5-dimethylaminomethyl-4-methyl-2-thienyl) so pl. 25 methylthio ethylamino -1,2,5-thiadiazole.

35

40

To a stirred suspension of N-2-- (5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio ethyl-ethane-2Q diimidamine trihydrochloride (6.34 g; 15.0 mmol) of example 3 in 60 ml of DMF was added 6 , 1 g (45.0 mmol) of sulfur monochloride. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into 800 ml of water, made basic with potassium carbonate and extracted several times with 100 ml portions of methylene chloride. The extracts are dried over magnesium sulfate, filtered, and concentrated to give 3.4 g of a black gum containing the product. The product is purified by preparative high pressure liquid chromatography on silica using methylene chloride (100), 2-propanol (10) and ammonium hydroxide (0.5) as the mobile phase. For further purification, additional liquid chromatography is carried out at high pressure on silica using the mixture of methylene chloride (100), methanol (2.5) and ammonium hydroxide (0.5) as the mobile phase. The appropriate fractions give the target compound (purity about 98%). Processing - product equivalent amount of 2 and. HCl receive the hydrochloride salt of the title compound.

45

50

55

five

Dineni in Nida resin. By treating a portion of this product with an equalization amount of 2 N. HCl in methanol, the hydrochloride salt of the desired compound is obtained.

Calculated,%: C 41.18; H 5.76; N 20.02; S 18.38.

C, jH ,,, 2 HCl

Found (corrected for 1.65%),%: C 40.54; H 5.70; N 19.39; S 18.44.

By treating the product with an equivalent amount of cyclohexyl sulfamic acid in acetone, the cyclohexyl sulfate salt of the target compound is obtained, m.p. 93-95 S.

Calculated,%: C, 43.88; H 6.55; 17.06; S 19.53.

N

„NJ-S O.

3,

Found,%: C 43.77; H 6, N17.2I; S19.58.

five

0

To a stirred suspension of N-2-- (5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio ethyl-ethane-Q-diimidamine trihydrochloride (6.34 g; 15.0 mmol) of example 3 in 60 ml of DMF was added 6 , 1 g (45.0 mmol) of sulfur monochloride. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into 800 ml of water, made basic with potassium carbonate and extracted several times with 100 ml portions of methylene chloride. The extracts are dried over magnesium sulfate, filtered, and concentrated to give 3.4 g of a black gum containing the product. The product is purified by preparative high pressure liquid chromatography on silica using methylene chloride (100), 2-propanol (10) and ammonium hydroxide (0.5) as the mobile phase. For further purification, additional liquid chromatography is carried out at high pressure on silica using the mixture of methylene chloride (100), methanol (2.5) and ammonium hydroxide (0.5) as the mobile phase. The appropriate fractions give the target compound (purity about 98%). Processing - product equivalent amount of 2 and. HCl receive the hydrochloride salt of the title compound.

five

0

five

13

Calculated,%: C 41.09; H 5.84; N 18.43; S 25,32.

C ,, H ,, N5, S ,. HC1

Found (corrected for 0.51% H20),%: C 40.78; H 5.63; N 18.31; S 25,44 ..

EXAMPLE 15 3-Amino-4 H- (3-pyrrolidinomethylphenoxy) propylamino-1,2,5-thiadiazole.

A stirred suspension of trivdrochloride (3-pyropolydine-methylphenoxy) propyl β-ethanediimidamine (8.25 g; 20.0 mmol) was, in Example 4, treated with 80 ml of DMF in sulfur monochloride (5.4 g; 40.0 mmol) and stirred in nitrogen for 3 hours. By concentrating the reaction mixture, a dark resin is obtained, which is suspended in 500 ml of water, made basic with potassium carbonate and extruded in three portions of 100 ml of methylene chloride. The extracts are dried over magnesium sulfate, filtered and concentrated from, to obtain 7.5 g of a dark gum containing the product. The product is purified using preparative liquid chromatography at high pressure and with silica using a t.-. a mixture of methyl enechloride (100), 2-propanol (5) and ammonium hydroxide (0.5) as the mobile phase. The fractions containing the product are combined and concentrated to give 1.64 g (24.4%) of the purified target product. Processing the product in absolute ethanol with an equivalent amount of 2N. HCl gives the hydrochloride salt of the target compound (1.13 g), m.p.

pv-io with.

Calculated,%: C, 51.95; H 6.54; . N 18.93; S 8.67.

CifcHj NyOS- HC1

Found,%: C 51.97; H 6.36; N 18.63; S 8.76.

Formula ieobr. Shadow

The method of obtaining substituted ethanediimidamine of the general formula

A- (CH2) jn L (CHn NHy y-NHRi

/ L hn -nh

1355123

where R is hydrogen, C -Cg-alkiJI or a group of the formula

or

m O or 1;

n 2 or 3;

Z is oxygen or sulfur;

A - group of the formula

about/

 and

(one)

2- KG

Rz r3

: I (CH2),

Ri. (.3)

in the case of the radical (1) K is hydrogen, Rj and Rj are each alkyl, in the case of the radical (2) R is hydrogen or lower C -C alkyl, R and R are lower kil or R and R taken together with the nitrogen atom to which they are attached form a piperidine cycle, or in the radical (3) R4 hydrogen,, R, and Rj-together with the nitrogen atom form pyrrolidine, piperidine or 1,2,3,6-tetrahydropyridyl,

or its pharmaceutically acceptable

salts, characterized in that

what is the compound of formula

A-CCHjV Z (CHzVMH TJHRi

N

II

ABOUT

where A, Z, m, n and R have the indicated

meanings

is reacted with a strong mineral acid, for example, hydrochloric acid, in an inert organic solvent at room temperature with isolation of the product in free form or in the form of a salt.

15

Compound

Cimetidine

For example 12

13

14 15

and

Trust 1 Tervaly 95%.

,Table 2

Connection PK, µmol. Power

activity (cimetidine 1.0)

Cimetidine 20 0.41 (0.21-0.64) 1.0

For example 12 12 .0.003 (0.001-0.004) 137

15 11 0.004 (0.001-0.010) 102

. 95% confidence intervals.

Compiled by V.M. Kusheva Editor O, Yurkovetska Tehred M.HodaNich Proofreader G.Reshetnik

Order 5719/57 Circulation 372Subscription

VNIIPI USSR State Committee for Inventions and Discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5

Production and printing company, Uzhgorod, Projecto st., 4.

135512316

Table I

Food subcutaneously, µmol / kg

1.0

37 4.5

7 20

Claims (1)

about r m u l a isob.e te n and The method of obtaining substituted ethanediimidamine of the General formula A- (CH ₂ ^ 2 (CH ^ _n t JNHRt HN NH or m η = 2 or 3; Ζ BUT - oxygen or sulfur; - a group of formula (1) (2 ⁵ ) the case of the radical (1) » ^R J in the case of the radical - water ₍ -c ₆ (2) R, R ₄ and R _z each in genus, q = 1 alkyl, hydrogen or lower C, -C ₆ -alkyl, q = 1 ', R ² · and R ⁹ - lower C, -C ₆ -alkyl or Ro, and R _t taken together with a nitrogen atom to which they are attached form a piperidine ring, or, in the case of radical (3), R ₄ is hydrogen, q = l, R, and Rj-together with the nitrogen atom form pyrrolidine, piperidine or 1,2,3,6-tetrahydropyridyl, or its pharmaceutically acceptable salts, characterized in that the compound of the formula A- (CH _g 1 _t Ζ NHR, 'II о where A, Ζ, w, η and R ₍ have the indicated meanings, are reacted with a strong i mineral acid, for example hydrochloric acid, in an inert organic solvent at room temperature with the isolation of the product in free or in salt form.