FI72318C - FOERFARANDE FOER FRAMSTAELLNING AV SELEKTIVT PAO HISTAMINRESEPTORER VERKANDE N- / 2 - /// 5- (DIMETHYLAMINO) METHYL-2-FURANYL / METHYL / THIO / EECL-N'-METHYL-2-NITRO-1,1-ETENDIAMINE. - Google Patents

Abstract

Novel aminoalkylfuran derivatives of the general formula I: <IMAGE> in which the symbols have the meaning indicated in Claim 1, are prepared by reaction of a compound of the formula <IMAGE> with a compound of the formula R3NZZ'. A, B, Z and Z' have the meaning indicated in Claim 1. The aminoalkylfuran derivative can be used in the form of the free base or in the form of a physiologically acceptable salt or a hydrate. These novel aminoalkylfuran derivatives exhibit inhibition of gastric acid secretion if they are stimulated via histamine H2 receptors.

Description

[7 ^ 7] NOTICE 707-1 p

Sa UTLÄG G NI N G SSKRI FT / <1 O 1 O

C (45) Pate .. ': ti 7fI': y (51) Kv.lk. * / Lnt.CI.4 C 07 D 307/52 FINLAND - FINLAND (21) Patent application - Patentansökning 772264 (22) Application date - Ansökningsdag 22.07.77 (23) Start date - Giltighetsdag 22.07.77 (41) Become public - Blivit offentlig 05.02.78

National Board of Patents and Registration Date of publication and publication. - 30.01.87

Patent and registration authorities Ansökan utlagd och utl.skriften publicerad (86) Kv. application - Int. trap (32) (33) (31) Privilege claimed - Begärd priority 04.08.76 O6.i2.76, 13-05.77 England-England (GB) 32465/76, 50685/76, 20187/77 Proven-Styrkt (71) Allen £ Hanburys Limited, Three Colts Lane, Bethnal Green, London,

England-England (GB) (72) Barry John Price, Hertford, Hertfordshire,

John Watson Clitherow, Sawbridgeworth, Hertfordshire,

John Bradshaw, Ware, Hertfordshire, Eng 1 anti-Eng 1 and (GB) (74) Lei tzinger Oy (54) Method for selectively histamine receptor-acting N- [2 - /// 5 ~ (dimethylamino) methyl-2-furanyl] for the preparation of methyl / 10-ethyl-N1-methyl-2-nitro-1,1-ethylenediamine - For the preparation of a selective histamine receptor of the N- [2 - /// 5- (dimethylamino) methyl-2-furanyl / methyl-ethyl-N-1-methyl-2-nitro-1,1-etenediamine. ............-

The present invention relates to a process for the selective action of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N1-methyl-2-nitro-1,1-ethylenediamine acting on histamine receptors and its for the preparation of physiologically acceptable salts of a compound of formula I

CH3- J- \ ΐΗΝ ° 2 N-CH2-T y— CH2S (CH2) 2NHCNHCH3 (I) CH3- '' O7

Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, 2J7, 427) and Black et al. (Nature 1972, 236, 385) have proposed the division of histamine receptors (H receptors) into two subgroups called H 2 and H 2. receptors. Stimulation of the bronchial and gastrointestinal smooth muscle is mediated through Hi receptors. These effects can be blocked by conventional histamine antagonists such as mepyramine.

7231 8

Stimulation of gastric acid secretion and heart rate is mediated through H2 receptors; mepyramine does not reverse these effects, but they are prevented or eliminated by β-antagonists such as methiamide. Histamine stimulates H3 and H2 receptors.

N- (2- [t [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethylenediamine has been found to be a selective H2-antagonist, i.e. inhibits gastric acid secretion when excited via histamine H2 receptors (Ash and Schild loc. cit.) The ability of a compound to inhibit gastric fluid secretion when excited via H2 receptors can be demonstrated using perfused rat stomach and Ghosh and Schild. (Brit. J. Pharmacol. 1958, 15 54), modified as described below, and in alert dogs equipped with shark bags, using the same method as Black et al (Nature 1972 236 385). the compound prepared modifies histamine-induced contractions of isolated gastrointestinal smooth muscle.

Tautomerism may occur in a compound of formula (I) and is intended to cover all tautomers.

The compounds of the present invention can be prepared by the following process alternatives: [2 - [[(5-dimethylamino) methyl] -2-furanyl] methyl] thioethanamine of formula II

CH3 \ / -V

N-CH2-CH2S (CH2) 2NH2 (II) CH3 "" wherein 0 is a leaving group.

li is reacted with a compound of formula CH3NHC-O, CH-NO2 3 72318

The amine can be used as the free base or salt with a weak acid, for example acetic acid. The reaction can be carried out by melting the reactants at an elevated temperature, for example, 100-120 ° C. Alternatively, the reaction can be carried out by stirring in an aqueous solution at room temperature. Examples of leaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl.

The addition of the group -CNHCH 3 can also be carried out first by CHNO 2 by reacting the amine (II) with a compound of formula

\ / Q

C

| I

chno2 where 0 is a leaving group as defined above. This reaction can be carried out in a solvent, for example ether or acetonitrile, at temperatures between ambient and reflux.

When the resulting formula (III): N- [2 - ([[5-dimethylamino) methyl-2-furanyl] methylthio] ethyl-2-nitroethenamine: CH3 N-CH2-f-CH2S (CH2) 2NHC-O ( III) ch3x'0 chno2 is treated with methylamine CH3NH2 at a temperature between ambient and reflux temperature to give the desired end product.

In a third process variant, the formula I can be prepared

from a 5- (dimethylamino) methyl-furanmethanol derivative of the formula IV: 4,731 8 ch3 ^ n-ch2 o CH2OR]. (IV) CH 3 O (R 1 may be hydrogen or an acyl group such as acetyl or p-nitrobenzoyl)

The above compounds can be reacted with a thiol of formula (V): HS (CH 2) 2 NHCNHCH 3 (V) chno 2 and the resulting compound of formula I or a salt thereof is optionally treated with a suitable organic or inorganic acid to produce a physiologically acceptable salt.

The reaction is best performed at 0 ° C in concentrated hydrochloric acid.

The furanmethanol of formula (IV) (R 1 = H) can be formed in situ by reacting dimethylaminomethylfuran with paraform aldehyde according to the following reaction formula // "Λ (HCHO) n

Me2NCH2 / '0' 'Me2NCH2 CH2OH

Having discussed above the methods that can be used to prepare the compounds of the invention, reference has been made to the primary amine of formula II. This amine is a new compound. These intermediates can be prepared by a number of methods described below.

The amine of formula (II) can be prepared from a furfurylthiol of formula (VI): by reacting it with -bromoalkylphthalimide (VII):

Br (CH 2) 2 N ^ J ^ j | (VII)

II

0 7231 8 ch3 ^

The group NCH 2 can be attached to the resulting CH 3 compound of formula (VIII): O 2 - CH 2 S (CH 2) 2 1 2 - [2) (VIII) 0, for example, by a Mannich reaction. The amine of formula (II) is obtained by deprotection, for example by reaction with hydrazine hydrate.

In an alternative process for the preparation of the amine of formula (II), 2-furfuryl chloride can be used as a starting material. Furfuryl chloride and aminoethylthiol in which the amine group is protected, for example as phthalimide (IX):

O

HS (CH 2) 2 N ^] ^ J | In the reaction between (IX) o an intermediate of formula (VIII) is formed.

This is treated as described above to the amine of formula (II).

Another process for the preparation of amine (II) uses a starting material of formula (X): CH 3 N 2 -ch 2 - / CH 2 OH (X)

CH3 X0X

This compound can be treated under acidic conditions with aminoethylthiol, where the amine group can be protected if desired. Alternatively, the compound of formula (X) may be converted to the corresponding acetate prior to reaction with aminoethylthiol under basic conditions.

The primary amine of formula II can be prepared by reacting furan with butyllithium to give a lithium derivative (XI): 0 which is then sequentially reacted with (1) the ος dih dihalogen compound HalCl 2 S (CH 2) 2 Hal (where Hal is chlorine, bromine or iodine), and (2) with potassium phthalimide. For a product of formula (VIII):

/ CK2S

The o / (VIII) o is then subjected to, for example, a Mannich reaction and deprotected with, for example, hydrazine hydrate.

Intermediates of formula II can also be prepared using ethyleneimine. This compound is reacted with an isosteric thiol of formula (X).

An amine of formula II can also be prepared starting from a compound of formula (XII):

II

7 7231 8 r p-ch2sch2cn (XII) 'o' This nitrile compound is subjected to a Mannich reaction followed by reduction with lithium aluminum hydride to give a compound of formula II.

ch3 ^

When a Mannich reaction is used, the group N-CH 2 can be added to CH 3 at any suitable stage, but the reaction is best carried out with compounds of formulas (XIII) or (VIII): 0 O ch 2 o o ch 2 s (ch 2) o (XIII) (VIII) - using formaldehyde and dimethylamine.

In an alternative method of preparing the compounds, furan-2-carboxylic acid is used as the starting material. This is reacted with an amine of formula (CH3) 2NH to give an amide of formula (XIV) which is then reduced with, for example, lithium aluminum hydride to give a compound of formula (XV): CH3___CH3, -NNCH2 en 'Λο / CH3 - Λο / (XIV) (XV)

To convert a compound of formula XV to a compound of formula X, a hydroxymethyl group may be added using formaldehyde and acetic acid. Alternatively, the hydroxymethylation can be performed using butyllithium followed by formaldehyde.

In preparing a compound of formula I, a compound of formula IV may be reacted with a thiol of formula V. A compound of formula (V) may be prepared from a thiazolidine intermediate of formula s S \ τΗ (XVI)

V

by reacting chno2 with the amine CH3NH2. Thiazolidine XVI can be prepared from cysteamine and the bismethylthio compound: CH3SCSCH3 CHNO2 (XVII)

Thiols of formula V are novel compounds.

The compound of the formula I readily forms physiologically acceptable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulfates.

Particularly useful salts of organic acids are formed with aliphatic mono- or dicarboxylic acids. Examples of such salts are acetates, maleates and fumarates.

The compound of the invention may be administered orally, topically or parenterally or as suppositories. Of these, the preferred route is the oral route. It can be used as a base or as a physiologically acceptable salt. It is usually combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.

The compounds of the invention may, if necessary, be administered in combination with other active ingredients, for example conventional antihistamines. For oral administration, the pharmaceutical composition may most conveniently be in the form of capsules or tablets, which may be slow-release tablets. The mixture may also be in the form of a medicament or syrup. Suitable topical preparations include creams, solutions, ointments, powders and sprays.

For oral administration, an appropriate daily dose is in the range of 100 mg to 1.2 g per day, with unit doses containing from 20 to 200 mg per unit dose. In the case of a slow-release tablet, the appropriate amount is 2 or 3 times a day.

Parenteral administration can be accomplished by injection at regular intervals or by continuous infusion. Solutions for injection may contain from 10 to 100 mg / ml of active ingredient.

For topical administration, a spray, ointment, fat or solution may be used. These substances may contain an effective amount of the active ingredient, for example in the order of 1 1/2 to 2% by weight of the total mixture.

The compound of formula (I) has been found to inhibit histamine-induced gastric acid secretion. This has been demonstrated in rats using M.N. Ghosh and H.O. The procedure described by Schild, British Journal of Pharmacology 1958, Vol. 13, page 54, variation.

Female rats weighing approximately 150 g are fasted overnight and given 8% sucrose in normal saline instead of drinking water.

Rats are anesthetized by a single intraperitoneal injection of 25% (w / v) urethane solution (0.5 ml / 100 g) and the trachea and neck veins are cannulated.

The gastric wall is opened along the midline to expose the stomach, which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the dorsal area of the stomach and the stomach is washed with 10 7231 8 5% dextrose solution. The esophagus is cannulated with a rubber tube and then the esophagus and vagina are severed above the cannula.

A small opening is then made in the area of the gastric port of the stomach. A large perspex cannula is then inserted into the stomach through the opening in the duodenum in such a way that the inlet end of the cannula comes out of the stomach through the opening in the area of the gastric port. The shape of the cannula is such that it reduces the effective volume of the stomach and causes the perfusion fluid to flow turbulently over the mucosal surface. A drainage cannula is then inserted through the opening in the fundus area of the stomach. Both cannulas are tied in place around the stomach with sutures so as to avoid major veins. Puncture wounds are then made into the body wall and cannulas are inserted through them. The stomach is perfused through oesophageal and pyloric cannulas with 5% dextrose solution at 39 ° C at 1.5 ml / minute for each cannula. The effluent is passed over a miniature pH electrode and recorded by means of a pH meter and a plotter.

Baseline gastric acid secretion yields are determined by measuring the pH of the perfusion removal solution and then increasing the acid secretion by continuous intravenous infusion of a sub-maximal dose of histamine; this causes a constant amount of acid to be secreted. When this state is reached, the pH of the perfusion solution is determined.

The rat is then administered intravenously by injection of the test compound, and the change in "gastric acid" secretion is determined by measuring the change in pH of the perfusion removal solution.

From the change in the pH of the perfusion removal solution, calculate the difference between the base output and the level stimulated by histamine in the acid secretion as hydrogen ion concentration in moles / liter. The decrease in acid secretion caused by the administration of the test compound is also calculated as the change in hydrogen ion concentration in moles / liter as the pH of the perfusion solution. From these two figures, the percentage reduction in acid secretion caused by the administration of the test compound can then be calculated.

11 7231 8

For inhibition of acid secretion, ED50 values are determined by administering one dose of test compound to one rat and repeating this in at least four rats at three or more dose levels. From the results obtained, the ED50 value is then calculated by the standard least squares method, as for any dose-response line.

Using the procedure described above, an ED5Q of 0.1 IS mg / kg was obtained.

Preparation of starting material: (A) 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine 5- (dimethylamino) methyl-2-furanmethanol (15.5 g) was added dropwise to cysteamine hydrochloride (11, 36 g) a stirred, ice-cooled solution in concentrated hydrochloric acid (40 ml). Allow to stand for 18 hours at 0 ° C, add anhydrous sodium carbonate and extract the resulting solid with dimethyl ether.

The solvent was removed and then the residue was distilled to give 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (11.6 g), b.p. 104-106 ° C (0.1 mm).

Melting point of the picrate salt 142-144 ° C.

(B) 2 - C 2 -C CC (2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione-80% sodium hydride (1.58 g) was added portionwise to a solution of furfuryl mercaptan (6 g). in dry dimethylformamide (50 ml). After 30 minutes, a solution of 2-bromoethyl phthalimide (16.71 g) in dry dimethylformamide (65 ml) was added and the solution was heated at 110 ° C for 2 days. After removal of the solvents, the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent removed and the residue recrystallized from cyclohexane to give 2 - C2 - CC (2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione, m.p. 62-63 ° C (7.8 g).

12,731 8 (C) 2- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione-2- [2- A mixture of [[(2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione (10 g), dimethylammonium chloride (3.1 g) and a 36% solution of formaldehyde (3 ml) in acetic acid (50 ml) was heated on a steam bath for 9 hours. The solution was cooled and the solvent was removed in vacuo. The residue was basified with 5N sodium hydroxide and extracted with ethyl acetate. The organic phase was treated with charcoal, dried and evaporated to an oil which was purified by column chromatography (silica / ethanol: ethyl acetate 1: 1) (5.7 g) Rf 0.4.

NMR (CDCl 3 / DMSO) 7.71 s (6H); 7.22: t (2H); 6.52 s (2 H); 6.2 s (2 H); 6.1: t (2H); 3.8 m (2 H); 2.2 m (4 H).

(D) 2- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine-2- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethyl 1H-isoindole-1,3 (2H) -dione (5.3 g) and hydrazine hydrate (0.85 g) were refluxed in ethanol for 30 hours. Evaporation of the solvent gave the p-hydrate salt of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine.

The following examples illustrate the method of the invention:

Example 1 N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N1-methyl-2-nitro-1,1-ethylenediamine-N-methyl-1- (methylthio) ) -2-nitroethyleneamine (230 g) in water (400 ml) was stirred and heated at 45-50 ° C. 2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (321 g) was added dropwise over 4 hours, and the resulting solution was further stirred for 3 1/2 hours. The solution was then heated at reflux for 1/2 hour, cooled to 70 ° C and 4-methyl-pentan-2-one (2 liters) was added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resulting solution was treated with carbon (10 g) at 50 ° C. The solution was filtered and cooled to 10 ° C. N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine (380 g) was filtered off and dried, m.p. . 69-70 ° C.

Example 2 N- [2 - [[[5- (dimethylamino) methyl-2-furanyl) methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine-2-nitromethylenetiazolidine

A mixture of cysteamine hydrochloride (11.36 g), potassium hydroxide (5.61 g) and 1,1-bis (methylthio) -2-nitroethylene (16.52 g) in water (30 ml) and ethanol (100 ml) was heated for 1 hour. reflux. The suspension was evaporated to dryness, the residue suspended in water, filtered and the residue crystallized from methanol to give 2-nitromethylene-thiazolidine (9.2 g), m.p. 141-142 ° C. Analysis: C, 42.91; H, 4.13; N, 19.10. C 4 H 6 N 2 O 2 S: C, 32.87; H, 4.14; N, 19.17%.

N- (2-Mercaptoethyl) -N 1 -methyl-2-nitro-1,1-ethylenediamine A solution of 2-nitromethylenethiazolidine (5 g) in a 33% solution of methylamine in ethanol (40 ml) was kept at room temperature for 65 hours. The separated solid was filtered, washed with ethanol and dried to give N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1'-ethylenediamine (4.98 g), m.p. 174-175 ° C, decomposes at 209-211 ° C.

Analysis: C, 34.05; H, 5.87; N, 23.85. C 5 H 11 N 3 O 2 S: C, 33.88; H, 6.26; N, 23.71%.

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine-N- (2-mercaptoethyl) -N ' -methyl-2-nitro-1,1-ethylenediamine (354 mg) in concentrated hydrochloric acid (2 ml) was added dropwise to 5- (dimethylamino) -147,231 methyl-2-furanmethanol (428 mg) at 0 ° C. The reaction mixture was allowed to stand for 7 days at 0 ° C, then diluted with water (3 mL), excess potassium carbonate was added and the solid was extracted with ethyl acetate (50 mL).

The solvent was evaporated and the residue was purified by preparative layer chromatography to give the title compound of Example 1 (100 mg).

Example 3 N- [2 - [([5- (dimethylamino) methyl-2-furanyl) methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine-N, N-dimethyl-2 -Furanmethanamine (125 mg) was dissolved in glacial acetic acid (1 ml) and paraformaldehyde (30 mg) was added. A solution of N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethylenediamine (354 mg) in concentrated hydrochloric acid (1 ml) and glacial acetic acid (1 ml) was added dropwise, and the mixture was allowed to stand at room temperature. at 5 days. The solution was diluted with water (30 mL), saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were purified by preparative layer chromatography to give the title compound of Example 1 (89 mg).

Example 4 N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] methyl] ethyl] -N 1 -methyl-2-nitro-1,1-ethylenediamine-2 - [([5- (dimethylamino) ) methyl-2-furanyl] methyl] thio] ethanamine (4.25 g) and 1,1-bis (methylthio) -2-nitroethene (3.3 g) were refluxed for 14 hours in acetonitrile (50 ml). and the residue was dissolved in 36% methanolic methylamine (50 ml) and the solution was refluxed for 8 hours, the solvents were removed and the residue was treated with carbon in methanol, and the solvent was filtered and evaporated to give the title compound (5.0 g).

7231 8 15

Example 5 N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N1-methyl-2-nitro-1,1-ethylenediamine hydrochloride _____ N- [2 - [[ [5-Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N 1 -methyl-2-nitro-1,1-ethylenediamine (50 g, 0.16 mol) was dissolved in methylated industrial spirit (74 ° overproof, 200 ml) containing 0.16 equivalents of hydrogen chloride. Ethyl acetate (200 mL) was slowly added to the solution. The hydrochloride crystallized and was filtered off, washed with a mixture of methylated industrial spirit (74 ° overproof, 50 ml) and ethyl acetate (50 ml) and dried at 50 ° C. The product (50 g) was obtained as a hard solid as a hard solid, m.p. 133-134 ° C.

Claims (4)

7231 8 16 A method for the selective action of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-ethylenediamine and its physiologically acceptable salts acting on histamine receptors , for the preparation of a compound of formula I CH 3 ___ CHNO 0 x N-CH 2 -C CH 2 S (CH 2) 2 NHCNHCH 3 (I) CH 3 X characterized in that (a) the compound of formula II [2 - [[(5-dimethylamino) methyl-2- furanyl] methyl] thioethanamine CH 3 N-CH 2 CH 2 S (CH 2) 2 NH 2 (II) CH 3 O '' is reacted with a compound of formula CH 3 NHC-O> CH-NO 2 wherein 0 is a leaving group, or (b) a formula III N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -2-nitroetheneamine ch3 NN-CH2-fp-CH2S (CH2) 2NHC-O (III) CH3 ^ chno2 (I 17 7231 8 wherein 0 is a leaving group is reacted with a methylamine of formula CH3NH2; or (c) a 5- (dimethylamino) methylfuranmethanol of formula IV is a derivative of CH3 \ _jT \ _ n-ch2-C CH2OR! (IV) ch3 · ^ O where Ri is ve or an acyl group is reacted with a thiol of formula V: HS (CH 2) 2 NHCNHCH 3 (V) CHNO 2 and the resulting compound of formula I or a salt thereof is optionally treated with a suitable organic or inorganic acid to produce a physiologically acceptable salt. Process according to Claim 1, characterized in that N- [2 - [[[5-dimethylamino) methyl-2-furanyl] methyl] thio) ethyl-N'-methyl-2-nitro-1,1-ethylene is prepared. i-amine hydrochloride. 7231 8 18 A process for the selective use of a selective histamine receptor network comprising N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N'-methyl-2-nitro-1,1-etenediamine and physiologically active site of the formula, CH (O) N-CH2 y-CH2S (CH2) 2NHCNHCH3 (I) CH2- / kännetecknad därav, att (a) [2 - [[(5-dimethylamino) methyl-2-furanyl] methyl] thioethanamine with formula II CH3 n-ch2 V CH2S (CH2) 2NH2 (II) ch3 ^ '0' ring to react with compounds of formula CH3NHC-0, CH-NO2 with 0 groups , or (b) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -2-nitroethenamine with formula III CH3X / N-n-ch2 -r \ -ch2s (ch2 ) 2nhc-q (hi) ch3 '0 / chno2