DE3343884C2 - - Google Patents

Description

Compounds of the general formula

wherein R₁ is a hydrogen atom or an alkyl radical 1 to 4 carbon atoms and a nitrogenous one Means 5- or 6-membered heterocyclic radical, Z is a sulfur or oxygen atom, an NH or represents methylene group, m and n have the value 0 or are integers with a value from 1 to 4 and the sum of m and n has the value 2 to 4, X is a COR₃-, CSR₃-, SO₂R₄- or -N = CHR₅ group or when Z is one Represents methylene group, means a nitro group, R₃ an alkyl or alkoxy radical having 1 to 4 carbon atoms, an optionally substituted aryl radical, a trifluoromethyl or amino group, R₄ and R₅ one optionally substituted aryl radical and their Salts are known; see. DE-A- 23 44 833.

Furthermore, through DE-A- 27 34 070 aminoalkyl furan derivatives of the general formula  

their salts and N-oxides known, in which R₁ and R₂, which can be the same or different, for hydrogen, Lower alkyl, cycloalkyl, lower alkenyl, Aralkyl or lower alkyl, which is represented by an oxygen atom or a group

is interrupted wherein R₄ is hydrogen or lower alkyl has, stand or wherein R₁ and R₂ together with the Nitrogen atom to which they are attached one heterocyclic ring can form as heteroatoms 0 and / or

may contain, where further R₃ for hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl, X represents -CH₂-, O or S, Y stands for = S, = O, = NR₅ or = CHR₆, Alk for one straight-chain or branched alkylene chain with 1 to 6 Carbon atoms, R₅ is H, nitro, cyano, Lower alkyl, aryl, alkylsulfonyl or arylsulfonyl stands, R₆ for nitro, arylsulfonyl or alkylsulfonyl stands, m is an integer from 2 to 4 and n den Has value 1 or 2, or if X for sulfur or -CH₂- stands, n has the value 0, 1 or 2.  

For these previously known compounds an antihistamine Effect of the type of H₂ blocker specified: you prevent the secretion of gastric juice if this is stimulated by histamine H₂ receptors. However, these known compounds are only relative weak, but only effective for a short time.

The invention is therefore based on the object of connections with favorable pharmacological properties to make available that usable as medicinal products are and the more effective and longer effective than the previously known Connections are.

The invention relates to the claims defined objects.

The compounds of the invention are pharmacological effective. For example, they inhibit gastric juice secretion, especially that of stomach acid and have a strong antihistamine effect of the type of "H₂ blocker"; in particular they have a long lasting Duration of action. They also have a specific effect ulcer healing or ulcer inhibiting. In addition, they have a specific gastric spasmolytic Effect.

The alkyl, alkenyl and Alkynyl groups  can straight or be branched.

If R₃ one C₃- to C₆-cycloalkyl group, it is to the cyclopropyl, cyclobutyl, cyclopentyl or Cyclohexyl group. Examples of the alkenyl and Alkynyl groups are: allyl group, prop-1-en-3-yl group, But-1-en-4-yl group, But-2-en-4-yl group, Pent-1-en- 5-yl group, prop-1-ynyl group.

In particular, the alkenyl and alkynyl groups exist of 3 or 4 carbon atoms.  

The alkyl radical R₂ consists preferably from 1 to 4 carbon atoms.

Examples of the C₁ to C₁₂ alkyl group R₃ are the methyl, Ethyl, propyl, butyl, hexyl, heptyl, octyl, decyl, Dodecyl, isopropyl, isobutyl, tert-butyl and isoamyl group.  

An example of the C₆ to C₁₀ tricycloalkyl group is the tricycloheptyl group such as the tricyclo (2.2.1.0. ^2.6 ) hept-3-yl group of the following structure

or the tricyclodecyl group (for example tricyclo (3.3. 1.1. ^3.7 ) dec-1-yl group; tricyclo (3.3.1.1. ^3.7 ) dec-2-yl group):

The preparation of the compounds of the invention can be one of those listed in claim 2 Processes a) to d) take place. In detail the following is explained.  

Regarding procedure a):
The process is carried out, for example, in a solvent at temperatures between -20 and + 200 ° C, preferably 10-150 ° C. If necessary, basic substances (for example alkali carbonates) can also be added. In the case of volatile amines, it may be necessary to work under pressure (for example up to 100 bar) in a closed system. Possible solvents are: polar solvents such as water or alcohols (methanol, ethanol, n-propanol, isopropanol, butanol) straight-chain ethers such as dimethyl ether, diethyl ether or glycol dimethyl ether, cyclic ethers such as tetrahydrofuran or dioxane, lower ketones such as acetone , also dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide or sulfolane, further acetonitrile or aromatic solvents such as benzene, toluene or xylene and also excess amine. Mixtures of the solvents mentioned can also be used, for example toluene-water mixtures, xylene-water mixtures.

In the process, preference is given to starting compound II uses one in which Y is a sulfur atom is.

The starting materials for this process are not known are, for example, analogous to the process are manufactured in DE-A-23 44 833, 27 34 070, 22 11 454 and 23 44 779 are described.  

Starting materials of formula II, wherein Y is an oxygen atom and T is the group -NHR₃, for example analogue chemical Ber. 100, pages 2604- 2615 (1967), in particular page 2607 or 2609 will. In the same way you can Starting materials of formula II can be obtained, wherein Y is oxygen and T is the other amine part with the Represents furan residue.

Starting materials of formula II, wherein T is the group

means can be obtained as follows, for example will:  

An amino compound of the formula R₁R₂NH (in the form of its Salt, for example as hydrochloride) 2-furyl methanol in a solvent (lower alcohols like methanol, Ethanol; aliphatic ethers such as dimethyl ether, diethyl ether; aromatic hydrocarbons such as benzene, toluene) in the presence of formaldehyde or a formaldehyde supplying substance (paraformaldehyde, trioxane) 0-120 ° C, preferably 30-80 ° C implemented, the Hydroxymethyl intermediate of the following formula

R₁R₂N-CH₂-Het-CH₂-OH

is obtained.

In this formula, het means a furan residue, each in the 2- and 5-position with the Substituent is connected. (See J. Am. Chem. Soc. 69 (1947), page 464; J. Chem. Soc. (1958), page 4728).

This intermediate stage can also be used of a bis-amine of the formula (R₁R₂N) ₂CH₂ analogous to EP-A- 36 716 can be produced. From the compound R₁R₂N-CH₂-Het-CH₂OH, the corresponding Mercapto compound R₁R₂N-CH₂-Het-CH₂SH be produced according to the process described in DE-A- 31 00 364 is specified.  

If in the above intermediate R₂ hydrogen is, the rest R₂ (with one of the specified Meanings other than hydrogen) by conventional alkylation be introduced, for example by reaction with a compound R₂Hal, wherein Hal, chlorine, bromine or iodine is.

An intermediate as described above can also be used analogously are produced in which R₁ is hydrogen is (R₂ can have the meanings given, including also have hydrogen). In this case, then the rest R₁ (with the meanings given here) mandatory by conventional alkylation, for example by reaction with a compound R₁Hal, wherein Hal, chlorine, bromine or iodine and R₁ are the specified Has meanings, except hydrogen.

The alkylation reaction is optionally carried out with addition of customary acid-binding agents such as alkali hydroxides, Alkali carbonates or alkali hydrides Temperatures between 0 and 150 ° C in inert solvents such as dioxane, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (such as benzene, toluene) or acetone. The alkylation can also be carried out in the presence of tetraalkylammonium salts (especially the halides) in combination with alkali hydroxides at temperatures between 0-100 ° C, preferably 20-80 ° C in an aprotic Solvents or in chloroform or methylene chloride be made. As an aprotic solvent Examples include: tertiary amides (dimethylformamide, N-methyl-pyrrolidone, hexamethylphosphoric triamide), Dimethyl sulfoxide, acetonitrile, dimethoxyethane, Acetone, tetrahydrofuran. If necessary, one can also proceed with the alkylation that first of the compound to be alkylated  make an alkali compound by making it in an inert solvent such as dioxane, dimethylformamide, Benzene or toluene with an alkali metal, Alkali hydride or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150 ° C and then the alkylating agent inflicts.  

From the hydroxymethyl or Mercaptomethyl intermediate can then Amines of the formula R₁R₂N-CH₂-Het-CH₂-S- (CH₂) ₂-NH₂ for example according to DE-A- 27 34 070 can be obtained.

Such starting amines can also, for example, by Reaction of compounds of the formula R₁-R₂N-CH₂-Het-CH₂-Q, where Q is a hydroxyl or a methoxy group or is a halogen atom (Het can the specified Have meanings) with an ω-aminomercaptan of the formula HS- (CH₂) ₂-NH₂ according to the conditions the in DE-A- 24 06 166, GB-A- 13 38 169 and DE-A- 27 34 070 are obtained. If Q is a halogen atom, this reaction can occur in strongly alkaline medium, for example in the presence of sodium ethoxide, potassium hydroxide, sodium hydroxide, tertiary amines (triethylamine) or strongly basic ion exchangers can be made. If necessary, the amino group of the Protect ω-aminomercaptan starting compound, for example by conversion into a phthalimide group, which subsequently by acid hydrolysis or hydrazinolysis is split off again. If necessary, the Implementation also in acidic medium, for example in Presence of a hydrohalic acid such as 48 percent aqueous hydrobromic acid or one Hydrohalic acid in the presence of glacial acetic acid, or take place in glacial acetic acid (reflux) if Q is one Represents hydroxyl group.  

If Q represents a methoxy group, the reaction proceeds even in the presence of 48 percent hydrobromic acid.

Starting amines of the formula R₁R₂N-CH₂- Het-CH₂-S- (CH₂) ₂NH₂ from the specified hydroxymethyl Intermediate R₁-R₂N-CH₂-Het-CH₂-OH according to or analogous to that in DE-A- 31 07 628 Way to be obtained. For the production of the Hydroxymethyl intermediate can also, for example the details of DE-A-31 07 628 be used.

In the amines of the formula R₁R₂N-CH₂-Het-CH₂-S- (CH₂) ₂-NH₂ the group -C (= CH-NO₂) -S-alkyl is then introduced (For example, by reaction with (CH₃S) ₂C = CHNO₂ analogous to Chem. Ber. Volume 52 (1919), page 542 or Volume 100 (1967), page 591). Furthermore, this method of manufacture among others in DE-A- 27 34 070, or becomes analog done for this. The output amine R₁R₂NH are known or they can For example, manufactured in this way or analog are as described below.  

The tricyclo- (2.2.1.0 ^2.6 ) hept-3-yl-cyanide can be obtained, for example, from 2-chloro-norborn-5-ene as follows: 1 mol (24.3 g) of iodine-activated magnesium is overlaid with dry ether and slowly A solution of 1 mol (128.5 g) of 2-chloro-norborn-5-ene in 400 ml of dry ether is added dropwise, so that the reaction proceeds with gentle boiling. (Dropping time approx. 3 hours). Then allowed to stir at boiling heat for 1 hour. After the reaction mixture has cooled, it is added to a large excess of solid CO₂ in about 300 ml of dry ether with constant stirring (very violent reaction). After the reaction has subsided, the comminuted reaction product is added to a mixture of a lot of ice and 100 g of concentrated H₂SO₄ (98%) and extracted with ether. For the purification of the tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-carboxylic acid obtained, it is worked up in an alkaline / acidic manner. The organic phases are dried over Na₂SO₄ and then concentrated and fractionated in vacuo: bp ₍₁₀₎ 130-135 ° C. The substance crystallizes from: mp 46-47 ° C. Yield: 67% of theory. R _f value: 0.294 at 23 ° C (mobile solvent; chloroform / methanol 25: 1; staining reagent: iodine; adsorbent: silica gel; applied amount: 250 g).

A homogeneous mixture of 32.7 g (0.237 mol) of tricyclo- (2.2.1.0 ^2.6 ) -hept-3-yl-carboxylic acid, 21.3 g (0.355 mol) of urea and 46 g (0.474 mol) of amidosulfuric acid is placed in a round bottom flask quickly heated to 250-270 ° C with a descending Liebig cooler and two cold traps (cooled in acetone dry ice) using a metal bath. A short-term melt occurs, which then foams and solidifies after 10-20 minutes (strong decomposition vapors). The end product then distills off under a water jet vacuum within half an hour (bp approx. 80-130 ° C). The crude product thus obtained is dissolved in ether and toluene, dried over a little Na₂SO₄, concentrated on a rotary evaporator and fractionated in a water jet vacuum:

Kp ₍₁₀₎ :
80-83 ° C flow
84-86 ° C main fraction
Yield:
approx. 85% of theory.

From amines of the formula NR₁H₂, the amines NR₁R₂H can be obtained, for example, in that Amine of the formula NR₁H₂ the rest R₂ (where R₂ the specified Has meanings) introduced by conventional alkylation becomes. This alkylation can, for example by reaction with compounds HalR₂, wherein Hal, chlorine, bromine or iodine and R₂ is a C₁ to C₆ alkyl group means. Conversely, an amine can Formula NR₁R₂H, for example, by implementing a Amines NR₂H₂ can be obtained with a compound R₁Hal (R₁ has the meanings given and Hal is chlorine, Bromine or iodine).  

Such an alkylation reaction can, for example be carried out as in this application is described.

Unknown starting materials of formula II, wherein T means the group -NHR₃, for example by reaction of a compound II, wherein T is a Alkylthio group is analogous to an amine NH₂R₃ Regulation of DE-A-27 34 070 receive will.  

Regarding procedure b):
The process is carried out, for example, in a solvent or dispersant at temperatures between 20 and 180 ° C., preferably 40-120 ° C. Examples of suitable solvents or dispersants are: aromatic hydrocarbons such as benzene, chlorobenzene, mesitylene, toluene, xylene, saturated cyclic ethers such as dioxane, tetrahydrofuran, dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or also water and mixtures this means.

If Z or U represent an esterified hydroxy group, then these are reactive Esters. A reactive ester is included for example that of a strong organic or inorganic acid, especially a hydrohalic acid, for example the chlorine, bromine or hydroiodic acid or a sulfonic acid, such as an aryl or alkyl sulfonic acid, especially lower alkyl sulfonic acid, for example p-toluenesulfonic acid. In the case of an aryl sulfonic acid, for example to phenyl and naphthylsulfonic acids which optionally substituted by lower alkyl radical are.

In general, the process is carried out in the presence of basic condensing agents such as alkali hydroxides, strongly basic ion exchangers, alkali alcoholates such as potassium tert-butoxide or tertiary amines (Trialkylamines, for example triethylamine) carried out. It is also possible, for example, from the Mercapto compound to be used in liquid Ammonia first using alkali hydrides an alkali salt and then this with the other  Implement reaction component. If Z or U is one mean free hydroxyl group or the mercapto group, it is advisable to implement in strong acidic environment, for example in the presence of mineral acids (48% HBr, 6N-HCl or glacial acetic acid to be carried out), the means just mentioned also simultaneously as Solvents or dispersants can serve. The implementation can also take place in a two-phase system, for example (for example using chloroform and water) in the presence of a phase transfer catalyst (for example a quaternary ammonium salt such as benzyltriethylammonium chloride) and one Base (for example sodium hydroxide).

The starting materials of formula IV can, for example by reacting compounds of the formula

wherein alkyl is a lower alkyl group with one Compound H₂N-CH₂-CH₂-Z, wherein Z is either a mercapto group or one possibly by a strong organic or inorganic acid esterified hydroxy group is to be obtained. This is done, for example in solvents such as lower aliphatic C₁ to C₅ alcohols, acid amides (dimethylacetamide, Dimethylformamide) or aromatic hydrocarbons (Toluene, xylene), optionally in a mixture with water, at temperatures between 0-150 ° C, preferably 10-120 ° C. If Z is a mercapto group, it is recommended to use this by a usual acidic or alkaline cleavage Protect sulfhydryl protecting group. As a sulfhydryl Protecting groups  Protection groups come, for example, the same protection groups in question to protect amino groups are used, for example the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the tert-butyloxycarbonyl group and the like. In addition, there are, for example, the following S-specific Sulfhydryl protecting groups in question: 2-nitro-1- phenylethyl group, benzamidomethyl group, acetamidomethyl group, S-ethyl mercapto group, tert-butyloxycarbonylsulfenyl group or benzyloxycarbonylsulfenyl group.

After the reaction has ended, these protective groups removed again. This separation takes place in a known manner, for example in aqueous, aqueous-alcoholic media or in mixtures from acetone with water and / or alcohols or else in pure alcohols in the presence of alkali such as Potassium hydroxide, sodium ethylate, potash or also tertiary amines or also secondary or primary amines, these substances being preferred are present in equivalent quantities. The secession can also be found in low molecular weight alcohols Addition of small amounts of strong acids (hydrochloric acid, Sulfuric acid, toluenesulfonic acid, hydrogen bromide / Glacial acetic acid). The separation temperatures the acyl groups are generally between 0 and 150 ° C. In the case of the benzamidomethyl group or the Acetamidomethyl group, for example, the cleavage also with an aqueous mercury (II) - Saline solution at room temperature. The further implementation of the starting materials of formula IV to the process products according to the invention can also  done without isolating these compounds by simply that according to the implementation described above reaction mixture obtained directly with a Compound of formula V is reacted.

Compounds of the formula

can, for example, by reaction of a compound (AlkylS) ₂C = CH-NO₂ (alkyl = lower alkyl radical) with one Amine NH₂R₃ can be obtained analogously to the regulation that in DE-A-27 34 070 is specified.

The production of starting materials of the formula V, wherein U represents a mercapto or a hydroxy group, is specified under method a).

Starting materials of formula V, wherein U is an esterified Hydroxy group is, for example, from the corresponding Hydroxy compound by reaction with usual Halogenating agents (for example thionyl chloride, concentrated HCl) or corresponding acid anhydrides (for example acetic anhydride) in the be obtained in the usual way; see. DE-A-27 34 070. In Starting materials of the formula can also be used in the same way IV, in which Z represents an esterified hydroxy group, from the corresponding compounds, wherein Z is the Hydroxy group means to be obtained.  

On procedure c)
This is an alkylation which takes place in a manner known per se. Examples of suitable alkylating agents are: esters of the formula R′Hal, ArSO₂OR ′ and SO₂ (OR ′) ₂, where Hal is a halogen atom (in particular chlorine, bromine or iodine) and Ar is an aromatic radical, for example one optionally by one or more lower alkyl radicals substituted phenyl or naphthyl radical and R 'is an alkyl group with 1 to 6 or 1 to 12 C atoms, a C₃ to C₆ alkenyl group, a C₃ to C₆ alkynyl group, a C₆ to C₁₀ tricycloalkyl group, or is a C₃ to C₆ cycloalkyl group.

Examples are p-toluenesulfonic acid C₁ to C₁₂ alkyl esters, C₁ to C₁₂ dialkyl sulfates, C₁ to C₁₂ alkyl halides, C₃ to C₆- Alkenyl halides, C₃- to C₆-alkynyl halides and C₃- to C₆- Cycloalkyl halides. The alkylation reaction is optionally carried out with addition of conventional acid-binding agents such as alkali hydroxides, Alkali carbonates or alkali hydrides Temperatures between 0 and 150 ° C in inert solvents such as dioxane, dimethylformamide, dimethyl sulfoxide,  aromatic hydrocarbons (such as benzene, toluene) or acetone. If R₁ and R₂ and R₃ different Represent substituents, the alkylation can be done in two stages by, for example, first the alkyl radical and then introduces the cycloalkyl group or vice versa, if R₁ for example C₆ to C₁₀ tricycloalkyl and R₂ is a C₁ to C₆ alkyl is. The alkylation can also be carried out in the presence of Tetraalkylammonium salts (especially the halides) in combination with alkali hydroxides at temperatures between 0-100 ° C, preferably 20-80 ° C in one aprotic solvent or in chloroform or methylene chloride. As aprotic For example, solvents are suitable: tertiary Amides (dimethylformamide, N-methyl-pyrrolidone, hexamethylphosphoric triamide), Dimethyl sulfoxide, acetonitrile, Dimethoxyethane, acetone, tetrahydrofuran. Preferably the last-mentioned method is suitable for the alkylation of a -CONH₂ group. If necessary, you can also do so in the alkylation proceed first from the compound to be alkylated make an alkali compound by making it in an inert solvent such as dioxane, dimethylformamide, Benzene or toluene with an alkali metal, Alkali hydride or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150 ° C and then the alkylating agent inflicts.

Instead of the alkylating agents mentioned also other chemicals commonly used in chemistry equivalent funds are used (see at Example also: L. F. and Mary Fieser "Reagents for  Organic Synthesis, "by John Wiley and Sons, Inc., New York, 1967, vo. 1, page 1303-4 and Vol 2, page 471).

The starting materials for this process can be according to the method a) are produced using such precursors, in which either the radicals R₁, R₂ and R₃ are hydrogen or one of the radicals R₁ or R₂ and / or the rest R₃ are hydrogen.  

On procedure d)
This process is the Mannich reaction and the conditions which are customary and known for this purpose can be used. The process is preferably carried out, for example, under acidic conditions (for example in acetic acid) or in an aprotic solvent (for example dichloromethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane) in the presence of an acid (for example acetic acid, HCl). However, the reaction can also take place in the absence of acid, using, for example, aromatic hydrocarbons (benzene, toluene, xylenes), aliphatic halogenated hydrocarbons (for example dichloromethane, 1,2-dichloroethane). . . come into question. The process is carried out, for example, at temperatures between 0 and 25 ° C., optionally with cooling. The starting substance (R₁R₂N) ₂CH₂ can be carried out, for example, by reacting 1 mol of formaldehyde (for example aqueous solution) with 2 mol of an amine R₁R₂NH at 0-15 ° C.

Depending on the process conditions and starting materials the end products of formula I are obtained in free form or in the form of their salts. The salts of the final products can in a manner known per se, for example with alkali or ion exchangers Bases are transferred. Let the latter themselves by reaction with organic or inorganic Acids, especially those used for Formation of therapeutically usable salts is suitable themselves, gain salts. As such are acids called for example: hydrohalic acids, Sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids the aliphatic, alicyclic, aromatic or heterocyclic series and sulfonic acids. Examples for this are: ants, vinegar, propion, amber, Glycol, milk, apple, wine, lemon, ascorbin, Maleic, fumaric, hydroxymaleic or pyruvic acid; Phenylacetic, benzoic, p-aminosalicylic acid, embonic acid, Methanesulfone, ethanesulfone, hydroxyethanesulfone, Ethylene sulfonic acid; Halobenzenesulfone, Toluenesulfonic, naphthalenesulfonic or sulfanilic acid or 8-chloro-theophylline.

In the above-mentioned manufacturing processes of the compounds of the invention can in the Starting substances present amino groups that are not involved in the reaction, known and usual Protection groups included. This is particularly true to residues caused by hydrolysis or hydrogenolysis are easily removable and if necessary are already split off during the reaction. If no such protecting groups in the process reaction are split off, they are split off after  the reaction. Often the starting compounds contain such protective groups already exist because of their production.

These protective groups are, for example around easily solvolytically removable acyl groups or groups which can be split off by hydrogenolysis. The solvolytic Removable protecting groups are, for example by saponification with dilute acids or by means of basic substances (potash, soda, aqueous Alkali solution, alcoholic alkali solutions, aqueous NH₃) at temperatures between 10 and 150 ° C, split off in particular 20-100 ° C. Hydrogenolytic cleavable groups such as α-arylalkyl radicals (benzyl radical) or aralkoxycarbonyl residues (carbonzoxy residue) conveniently by catalytic hydrogenation in the presence conventional hydrogenation catalysts, especially palladium Catalysts, platinum oxide or Raney nickel, in a solvent or suspending agent, if appropriate under increased pressure at temperatures between Split off 20-100 ° C, especially 40-80 ° C. Come as a solvent or suspending agent For example, consider: water, lower aliphatic Alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers and dimethylformamide and mixtures of these agents.

As protective groups that can be split off by hydrogenolysis are, for example: benzyl radical, α-phenylethyl radical, benzyl radicals substituted in the benzene nucleus (p-bromo or p-nitrobenzyl residue), carbobenzoxy residue, Carbobenzthiorest. Examples of hydrolytic cleavable residues are: trifluoroacetyl residue, phthalyl residue, Trityl residue and p-toluenesulfonyl residue and lower alkanoyl radicals such as acetyl radical, formyl radical  and tert-butyloxycarbonyl residue.

In particular, there are those customary in peptide synthesis Protecting groups and the separation processes customary there in question. Among other things, this will also to the book by Jesse P. Greenstein and Milton Winitz "Chemistry of Amino Acids," N.Y. 1961, John Wiley u. Sons., Inc. Volume 2, for example page 883 ff. referred. The carbalkoxy group (for example low molecular weight) is possible.

If hydroxy groups are also present in the starting materials, Mercapto groups and / or primary amino groups are present, can also do this through the above as well as protection groups specified above be, the splitting off in the same way he follows.

Those compounds of formula I that are asymmetric Contain carbon atoms and usually accrued as racemates can be known in per se Way, for example, with the help of an optically active Acid or by chromatographic resolution (see for example Angewandte Chemie 92/1 (1980) Page 14) into the optically active isomers will. But it is also possible to have one from the outset to use optically active starting substance, whereby then a corresponding optically active end product or diastereomeric form is obtained.

The present invention thus also includes the D- and L-shape as well as the DL mixture in case that in the compound of formula I an asymmetrical C atom occurs and for the case of two and more  asymmetric carbon atoms as well as the corresponding ones diastereomeric forms.  

Pharmacological or pharmaceutical information

The compounds of the invention are for production pharmaceutical compositions and preparations suitable. The pharmaceutical compositions respectively Medicines contain an active ingredient or more of the compounds according to the invention, if appropriate mixed with other pharmacologically respectively pharmaceutically active substances. The The pharmaceuticals are manufactured in a manner known per se, the known and customary pharmaceutical excipients as well as other usual carriers and diluents can be used.

Examples of such carriers and auxiliaries are such substances in question in the following references as auxiliaries for pharmacy, cosmetics and adjacent areas recommended or indicated are: Ullmann's Encyclopedia of Chemical Engineering, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 u. ff., H. v. Czetsch-Lindenwald, auxiliaries for pharmacy and adjacent areas; Pharm. Ind., Issue 2, 1961, Page 72 u. ff .; Dr. H. P. Fiedler, Lexicon of auxiliary substances for pharmacy, cosmetics and related areas Cantor KG. Aulendorf in Württemberg 1971.

Examples include gelatin, natural sugars such as Cane sugar or milk sugar, lecithin, pectin, starch (e.g. corn starch), alginic acid, tylose, talc, Lycopodium, silica (e.g. colloidal), cellulose, Cellulose derivatives (for example cellulose ether, where some of the cellulose hydroxyl groups lower saturated aliphatic alcohols and / or etherified lower saturated aliphatic oxyalcohols are, for example methyloxypropyl cellulose),  Stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated (for Example stearates), emulsifiers, oils and fats, in particular vegetable (e.g. peanut oil, castor oil, Olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, Sunflower seed oil, cod liver oil, mono, di and Triglycerides of saturated fatty acids C₁₂H₂₄O₂ bis C₁₈H₃₆O₂ and their mixture), pharmaceutically acceptable monohydric or polyhydric alcohols and polyglycols such as Polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerin, diethylene glycol, Pentaerythritol, sorbitol and mannitol, which may also be etherified, Benzyl benzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, Polyglycol ether with C₁ to C₁₂ alcohols, Dimethylacetamide, lactamides, lactates, ethyl carbonates, Silicones (especially medium-viscosity dimethylpolysiloxanes) and magnesium carbonate.

For example, water is used to prepare solutions or physiologically acceptable organic solvents in question, such as ethanol, 1,2-propylene glycol, Polyglycols and their derivatives, dimethyl sulfoxide, fatty alcohols, Triglycerides, partial esters of glycerin and paraffins.

Known ones can be used in the preparation of the preparations and usual solubilizers or emulsifiers, be used. As a mediator and For example, emulsifiers are possible: polyvinylpyrrolidone, Sorbitan fatty acid esters such as sorbitan trioleate, Lecithin, Acacia, Tragacanth, polyoxyäthylier  tes sorbitan monooleate, polyoxyethylated fats, polyoxyethylated Oleotriglycerides, linolized oleotriglycerides, Polyethylene oxide condensation products from Fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3- (2-hydroxyethyl) imidazolidone- (2). Polyoxyethylated means here that the concerned Substances contain polyoxyethylene chains, their degree of polymerization generally between 2 to 40 and in particular is between 10 and 20.

Such polyoxyethylated substances can, for example by reacting compounds containing hydroxyl groups (for example mono- or diglycerides or unsaturated Compounds such as those containing oleic acid residues contained) can be obtained with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, Castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H. P. Fiedler "Lexicon of excipients for pharmacy, Cosmetics and adjacent areas "1971, pages 191 to 195).

Furthermore, the addition of preservatives, Stabilizers, buffer substances, for example calcium hydrogen phosphate, colloidal aluminum hydroxide, flavoring agents, antioxidants and complexing agents (for example ethylenediaminotetraacetic acid) possible. If necessary, for stabilization of the drug molecule with physiologically compatible Acids or buffers to a pH range of approx. 3 to 7 adjust. In general, one is as neutral as possible to slightly acidic (up to pH 5) pH value preferred.

Examples of antioxidants are sodium metabisulfite, Ascorbic acid, gallic acid, gallic acid alkyl ester, Butylhydroxyanisole, nordihydroguajaretic acid, Tocopherols and tocopherols + synergists (substances bind the heavy metals through complex formation  for example lecithin, ascorbic acid, phosphoric acid) Application. The addition of synergists increases the antioxygene Effect of tocopherols significantly.

For example, sorbic acid comes as a preservative, p-hydroxybenzoic acid esters (for example lower alkyl esters), Benzoic acid, sodium benzoate, trichloroisobutyl alcohol, Phenol, cresol, benzethonium chloride and Formalin derivatives into consideration.

The pharmaceutical and pharmaceutical handling of the invention Connections are made according to the usual Standard methods. For example, active ingredient (s) and Auxiliary or carrier substances by stirring or Homogenize (for example using conventional mixing devices) mixed well, generally at temperatures between 20 and 80 ° C, preferably 20 to 50 ° C, in particular working at room temperature. Furthermore reference is made to the following standard work: Sucker, Fuchs, Speiser, Pharmaceutical Technology, Thieme- Stuttgart publishing house, 1978.

The application of the active ingredients or Medicines can be applied to the skin or mucous membrane or in the inside of the body takes place, for example orally, enterally, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardiac, intramuscular, intraperitoneal, intracutaneous, subcutaneous.  

The compounds of the invention show, for example a good gastric acid secretion-inhibiting and anti-ulcerative Effect as well as a specific gastric spasmolytic effect.

The gastric acid secretion-inhibiting effect can, for example determined using the following experimental models will:

• a) Model of the gastric lumen-perfused rat with pentagastrin or histamine stimulation according to M. N. Gosh and H. O. Schild, Brit. J. Pharmacol. 13 (1958), Pages 54-61, as well as Rosenoer and Schild, The assay of urogastrone J. Physiol. 162 (1962), page 155. The method has been modified in that before the start of stimulation the rat's stomach not cut open to remove food residues, but only with warm saline (0.9%) was rinsed. The test substances are administered intravenously or intraduodenally.
• b) Model of the waking chronic fistula with Histamine stimulation (based on Makowitz, Experimental Surgery, 3rd edition, 1954, page 200 ff., Publisher: Williams and Wilkens Company). application the test substances are administered intravenously or intra gastral.
• c) Model of the Shay rat (pylorus ligation according to Shay, II. Et al .: Gastroenterology 5, 43-61, 1945). The test substances are administered orally.
• d) Model of the Heidenhain-pouch-fistulated dog (Heidenhain-pouch-fistulated dog) with pentagastrin or histamine stimulation. (Journal of Surgical Research 7 (1967) page 383 ff .; Heidenhain, R .: Pflüger's archive total. Physiol. 18, 169 (1878)). Intravenous or intragasteral application of the test substances.

The antiulcerative effect can, for example, on artificially induced rat ulcer. The rat ulcer is, for example, by Use a combination of cold stress and the Anti-inflammatory drug "Indometacin" caused. The Test method is based on Levine, R. J., Peptic Ulcer, edited by C. J. Pfeiffer Munksgaard, Copenhagen, pages 92-97 (1971) and Jahn, Adrian, Drug Research Volume 19 (1969) pages 36-52, with the following changes be carried out: After application of the "Indometacins" will keep the animals in for 3 hours Immobilization cages in the refrigerator at 4-5 ° C held. In addition, the test substances become one Administered orally one hour before indomethane administration.

The gastric spasmolytic effect can, for example on the model of the carbachol spasm of the rat stomach in Based on the method of Zwage Makers, J.M.A., V. Claasen, drug research 30, 1517, 1980. The application of the Test substances are administered intraduodenally. On this model is for example the gastric spasmolytic effect of Compound according to Example 1 3.8 times stronger than that from "ranitidine".

For example, the model is the gastric lumen perfused Rat with pentagastrin stimulation on an intravenous route Dose of 0.088 mg / kg body weight / rat a 50% inhibition of gastric acid secretion found. This gastric acid secretion-inhibiting effect is associated with the Effect of the well-known drug "ranitidine" comparison bar.

The lowest, already effective dose in the latter animal experiment is, for example:
0.05 mg / kg intravenously (in the model of the gastric lumen-perfused rat with pentagastrin stimulation).

As a general dose range for gastric acid secretion inhibitors Effect in animal experiments (gastric lumen perfused Rat) is an example:

1-100 mg / kg orally, especially 1-20 mg / kg;
0.05-20 mg / kg intravenously, in particular
0.05-5 mg / kg.

Indications for which the compounds according to the invention can be considered:
acute or chronic gastritis, nervous irritable stomach, hyperacidity of the gastric juice, ulcer ventriculi et duodeni.

The pharmaceutical preparations generally contain between 1 to 2000 mg, preferably 2 to 300 mg the active component (s) according to the invention.

The administration can for example take the form of Tablets, capsules, pills, dragees, suppositories, ointments, Jellies, creams, powders, dusting powder, aerosols or in in liquid form. As liquid application forms for example: oily or alcoholic or aqueous solutions and suspensions and emulsions. Preferred forms of use are tablets, the between 5 and 100 mg or solutions that contain between 0.1 to 20% of active substance.

The single dose of the active components according to the invention can be, for example:

• a) for oral dosage forms between 2-2000 mg, preferably 10-200 mg;
• b) in the case of parenteral dosage forms (for example intravenous, intramuscular) between 2-2000 mg, preferably 5-50 mg;
• c) for dosage forms for rectal application between 2-2000 mg, preferably 10-200 mg.
• (The doses are based on the free base.)

For example, 1 to 3 tablets can be taken 3 times a day a content of 1 to 400 mg of active substance or for example, intravenous injection 1 to 3 times one ampoule of 1 to 2 ml daily with 1 to 200 mg of substance are recommended. When administered orally is the minimum daily dose, for example 10 mg; the maximum daily dose for oral administration should not exceed 2000 mg.

The acute toxicity of the compounds according to the invention on the mouse (expressed by the LD 50 mg / kg; method: Probit analysis according to Cavalli-Sforza, in: Biometrie, Gustav Fischer-Verlag, Stuttgart, 1974) is for example with oral application above 100 mg / kg. With some Compounds, the LD 50 is above 800 mg / kg.

The drugs can be used alone or in human medicine in a mixture with other pharmacologically active substances be used.

Example 1 N- [2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) - 2-furanyl] methylthio] ethyl] -N′-methyl-2-nitro-1,1- ethene diamine

A suspension of 37.2 g of N- [2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamino-methyl) -2-furanyl] methylthio] ethyl] -1- (methylthio ) -2-nitro-ethenamine in 1 liter of ethanol is mixed with stirring and ice cooling with 50 ml of methylamine and stirred for 4 hours at 0 ° C until a clear solution is formed. The mixture is then concentrated in vacuo at room temperature and the residue which remains is dried under high vacuum at 40.degree.
Yield: 38.5 g
R _F : 0.26 (eluent: chloroform / methanol / concentrated ammonia 90: 10: 1).

Hydrochloride

A solution of 38.5 g of base in 280 ml of ethanol prepared at 45 ° C. is mixed with 23.2 ml of 4.36N ethereal hydrochloric acid with ice cooling and stirring. The hydrochloride is kept at 0 ° C. overnight to complete the precipitation. It is then suctioned off, washed with pre-cooled ethanol and dried in vacuo. The recrystallization is carried out in a solvent mixture of ethanol and methanol (3: 2).
Yield: 31.1 g
F. 174 ° C.

Production of raw materials a) 5- (Tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-aminomethyl) - (2-furanyl) -methanol

A solution of 96 g of tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamine hydrochloride (Chemical Reports 98, page 109 (1965)) and 64.7 g (2-furanyl) heated to about 40 ° C. with nitrogen supply - 30 g of paraformaldehyde are added to methanol in 580 ml of ethanol and the mixture is heated at 70 ° C. for 3 hours. Another 10.2 g of paraformaldehyde are added to complete the reaction and the mixture is additionally heated at 70 ° C. for 4 hours. The mixture is then concentrated in vacuo, the residue is dried in vacuo at 40 ° C., then dissolved in 450 ml of water, the solution is adjusted to pH 6-7 and the solution is extracted three times with ether to remove the excess 2-furanylmethanol. The aqueous phase is adjusted to pH 10-11 with 32% sodium hydroxide solution and extracted four times with n-butanol. The butanol extracts are dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is cleaned in ethanolic solution with activated carbon and silica gel, filtered, concentrated in vacuo and the product thus obtained is dried at 40 ° C.
Yield: 94.5 g
R _f : 0.47 (eluent: chloroform / methanol / concentrated ammonia 90: 10: 1).

b) 2 - [[5- (Tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) -2-furanyl] methylthio] ethanamine

A solution of 94.59 g of 5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-amino) -methyl) - (2-furanyl) -methanol in about 200 ml of concentrated hydrochloric acid is prepared under ice cooling with 0- 5 ° C and while stirring dropwise with a solution of 49 g of cysteamine hydrochloride in 220 ml of concentrated hydrochloric acid. The mixture is stirred for 1.5 hours in an ice bath, then neutralized with sodium carbonate while cooling with ice and then made alkaline with 32% sodium hydroxide solution. The aqueous, alkaline solution is extracted four times with 150 ml each of n-butanol and the combined butanol extracts are dried with anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gives an oily residue which is acid-alkaline cleaned and finally treated with activated carbon and silica gel in ethanolic solution and provides the desired compound in pure form.
Yield: 72 g
R _f : 0.43 (eluent: chloroform / methanol / concentrated ammonia 85: 15: 1).

c) N- [2 - [[5-Tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-aminomethyl) - 2-furanyl] -methylthio] -ethyl] -1- (methylthio) - 2-nitro-ethenamine

A solution of 50 g of 2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-amino-methyl) -2-furanyl] methylthio] - ethanamine in one liter of isopropanol is stirred with 38.6 g of 1-nitro-2,2-bis (methylmercapto) - ethylene were added and the solution was heated at 70 ° C. for 3.5 hours. The methyl mercaptan formed during the reaction is passed into an aqueous sodium hypochlorite solution in a stream of nitrogen. The reaction solution is then concentrated in vacuo, the residue is dried intensively in a high vacuum at 30 ° C., purified in ethanolic solution over activated carbon and silica gel, the solution is filtered, again concentrated in vacuo and the remaining residue is recrystallized from isopropanol. Sucking off the crystalline precipitate, washing with ice-cooled isopropanol and drying at 40 ° C. provides a uniform layer-chromatographic connection.
(Eluent: chloroform / methanol / concentrated ammonia 90: 10: 1)
Yield: 47.4 g
F. 94 ° C.

Example 2 N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) - 2-furanyl] methylthio] -ethyl] -N ′ - (n-octyl) - 2-nitro-1 , 1-ethene diamine Formula as in example 1 with the difference that R₃ is the rest - (CH₂) ₇-CH₃

A suspension of 4 g of N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamino-methyl) -2-furanyl] methylthio] ethyl] - 1- (methylthio) -2 -nitro-ethenamine in 50 ml of ethanol is mixed with a solution of 2.58 g of n-octylamine in 8 ml of ethanol. The reaction solution is heated to 60 ° C. for 8.5 hours under a nitrogen supply, the reaction solution is concentrated in vacuo and the remaining residue is purified over a silica (mobile phase: chloroform / methanol 9: 1). The desired compound, which is uniform by thin layer chromatography, crystallizes after standing for several hours at 0 ° C., the crystals are dried at 40 ° C. under high vacuum (mobile solvent: chloroform / methanol 9: 1).
Yield: 2.2 g
M. 70-71 ° C.

Example 3 N- [2 - [[5-Tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) - 2-furanyl] methylthio] ethyl] -N'-allyl-2-nitro-1,1-ethene diamine Formula as in example 1 with the difference that R₃ is -CH₂-CH = CH₂

A suspension of 4 g of N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamino-methyl) -2-furanyl] methylthio] ethyl] - 1- (methylthio) -2 -nitro-ethenamine in 50 ml of ethanol is mixed with stirring with a solution of 1.14 g of allylamine in 5 ml of ethanol. The reaction solution is heated to 50-60 ° C. for 9 hours with a supply of nitrogen, then concentrated at 40 ° C. in vacuo, evaporated several times with ethanol and finally the residue is cleaned in ethanolic solution with activated carbon and silica gel. Filtration and concentration of the solution in vacuo give a residue which crystallizes after rubbing with ether. It is filtered and washed with ether. The compound is uniform by thin layer chromatography (eluent: chloroform / methanol 9: 1).
Yield: 2.9 g
F. 74 ° C.

Example 4 N- [2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) -2-furanyl] methylthio] ethyl] -N'-prop-1-ynyl-2-nitro- 1,1-ethene diamine Formula as in example 1 with the difference that R₃ is -CH₂-C≡CH

A solution of 5 g of N- [2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamino-methyl) -2-furanyl] methylthio] ethyl] - 1- (methylthio) - 2-nitro-ethenamine in 60 ml of methanol is mixed with 1.39 g of 3-aminoprop-1-in and heated to 40 ° C. for 2-3 hours with stirring and nitrogen supply. The reaction solution is concentrated in vacuo, it is cleaned in ethanolic solution with activated carbon, filtered, the solvent is removed in vacuo and the mixture is evaporated several times with ethanol. The remaining residue crystallizes at 0 ° C; the crystals are then recrystallized from a little ethanol.
Yield: 3.2 g
F. 110 ° C.

Example 5 N- [2 - [[5- (tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) - 2-furanyl] methylthio] ethyl] -N ′ - (2-methoxyethyl) - 2-nitro- 1,1-ethene diamine Formula as in example 1 with the difference that R₃ is -CH₂-CH₂-OCH₃

A suspension of 4 g of N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-ylamino-methyl) -2-furanyl] methylthio] ethyl] - 1- (methylthio) -2 -nitro-ethenamine in 50 ml of ethanol is mixed with a solution of 1.51 g of 2-methoxyethylamine in 5 ml of ethanol. The reaction solution is heated to 60 ° C. under a nitrogen atmosphere for 5 hours, then concentrated in vacuo, evaporated several times with ethanol and the residue is purified on silica (mobile phase: chloroform / methanol 9: 1).
Yield: 4.9 g
R _f : 0.46 (eluent: chloroform / methanol 9: 1).

Example 6 N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-ylaminomethyl) - 2-furanyl] methylthio] ethyl] -N'-cyclopropyl-2-nitro-1,1-ethene diamine Formula as in example 1 with the difference that R₃ is the cyclopropyl radical

A solution of 3.07 g of N- [2 - [[5-tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-amino-methyl-2-furanyl] methylthio] ethyl] - 1- (methylthio) - 2-nitro-ethenamine in 30 ml of ethanol is mixed with a solution of 0.443 g of cyclopropylamine in 5 ml of ethanol. The reaction solution is heated to 40 ° C. for 4.5 hours with the addition of nitrogen, then another solution of 0.22 g of cyclopropylamine in 3 ml of ethanol is added and the mixture is heated to 40 ° C. for a further 8 hours. The solution is concentrated in vacuo, evaporated several times with ethanol, cleaned in ethanolic solution with activated carbon, filtered and again concentrated in vacuo. The remaining residue is purified on a silica gel column (mobile phase: chloroform / methanol 9: 1). The connection is uniform by thin layer chromatography.
Yield: 1.8 g
R _f : 0.34 (eluent: chloroform / methanol 9: 1).

Example 7 N- [2 - [[5- (N-tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-N-methylamino-methyl) -2-furanyl] methylthio] ethyl] -N'-methyl-2- nitro-1,1-ethylenediamine Formula as in example 1 with the difference that R₂ is a methyl group

A solution of 6.24 g of N- [2 - [[5- (N-tricyclo (2.2.1.0 ^2.6 ) hept-3-yl-N-methylamino-methyl) -2-furanyl] methylthio] ethyl ] -1- (methylthio) -2-nitroethenamine in 100 ml of ethanol is mixed with 10 ml of methylamine. The mixture is stirred at 0 ° C. for 1 hour, the reaction solution is allowed to rise slowly to 20 ° C. and then concentrated at 40 ° C. in vacuo. The remaining residue is purified by column chromatography on silica gel (mobile phase: chloroform / methanol, concentrated ammonia 92: 7: 1). The compound crystallized by trituration with ether is dried at 40 ° C. in a high vacuum.
Yield: 4.9 g
R _f : 0.32 (eluent: chloroform / methanol / concentrated ammonia 90: 10: 1).

Example 8 N- [2 - [[5- (tricyclo (3.3.1.1 ^3.7 ) dec-1-yl-aminomethyl) 2-furanyl] methylthio] ethyl] -N'-methyl-2-nitro-1,1- ethendiamine Formula as in example 1 with the difference that R₁ is a tricyclodecyl radical (see page 9, line 15/16)

A solution of 5 g of N- [2 - [[5-tricyclo (3.3.1.1 ^3.7 ) dec-1-yl-amino-methyl) -2-furanyl] - methylthio] -ethyl] -1- cooled to 0 ° C (Methylthio) -2-nitro-ethenamine in 70 ml of absolute ethanol is mixed with 3.5 ml of methylamine and the reaction solution is stirred at 0 ° C. for 2 hours. Now add another 5 ml of methylamine and stir again at 0 ° C for 5 hours. The reaction solution is then concentrated in vacuo, evaporated several times with ethanol and purified by column chromatography (mobile phase: chloroform / methanol / concentrated ammonia 90: 10: 1). The compound is obtained in a crystalline and thin-layer chromatographically uniform form (mobile phase: chloroform / methanol / concentrated ammonia 90: 10: 1).
Yield: 3.8 g
M. 55-57 ° C.

Production of raw materials a) 5 - [(Tricyclo (3.3.1.1 ^3.7 ) dec-1-ylamino) methyl] -2-furanyl-methanol

A solution of 30 g of 1-amino-adamantane hydrochloride and 15.7 g of 2-furanyl-methanol in 140 ml of absolute ethanol heated to about 40 ° C. is added to 7.2 g of paraformaldehyde and 15 hours at 70 ° C warmed (2.4 g of paraformaldehyde are added after 5 hours to complete the reaction and 7.8 g of 2-furanyl-methanol are added after 9 hours). After 15 hours, the mixture is concentrated in vacuo, the remaining residue is dissolved in 100 ml of water and adjusted to pH 2 with 2N hydrochloric acid. The hydrochloric acid, aqueous phase is extracted three times with ether, the aqueous solution is alkalized to pH 10 with sodium hydroxide solution and extracted four times with n-butanol. The butanol extracts are dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is cleaned in ethanolic solution with activated carbon and silica gel, filtered, concentrated in vacuo and dried at 40 ° C.
Yield: 21 g
R _f : 0.52 (eluent: chloroform / methanol / concentrated ammonia 90: 10: 1).

b) 2 - [[5- (Tricyclo (3.3.1.1 ^3.7 ) dec-1-ylaminomethyl) -2-furanyl] methylthio] ethanamine

A solution of 17.7 g of 5 - [(tricyclo (3.3.1.1 ^3.7 ) dec-1-yl-aminomethyl-2-furanyl] -methanol in 44 ml of concentrated hydrochloric acid, prepared under ice-cooling, is added dropwise at 0-5 ° C. with stirring a solution of 7.8 g of cysteamine hydrochloride in 11 ml of concentrated hydrochloric acid is added, the mixture is stirred for 2 hours at 0 ° C., neutralized with sodium carbonate while cooling with ice and then the solution is adjusted to pH 14 with 32% sodium hydroxide solution. alkaline solution is extracted four times with butanol, the combined butanol extracts are dried with anhydrous sodium sulfate, filtered and concentrated in vacuo, the remaining residue is finally purified in ethanolic solution with activated carbon and silica gel and the desired compound is then obtained in a uniform form.
Yield: 18.5 g
R _f : 0.45 (eluent: chloroform / methanol / concentrated ammonia 85: 15: 1).

c) N- [2 - [[5- (Tricyclo (3.3.1.1 ^3.7 ) dec-1-yl-aminomethyl) - 2-furanly] -methylthio] -ethyl] -1- (methylthio) - 2-nitro-ethenamine

A solution of 17.5 g of 2 - [[5- (tricyclo (3.3.1.1 ^3.7 ) dec-1-yl-amino-methyl) -2-furanyl] methylthio] - ethanamine in 140 ml of isopropanol is stirred with 9 g of 1-nitro-2,2-bis-methyl-mercapto-ethylene were added and the solution was heated to 70 ° C. for 3.5 hours with the addition of nitrogen. The methyl mercaptan formed during the reaction is passed into an aqueous sodium hypochlorite solution in the nitrogen atom. The reaction solution is then concentrated in vacuo, the residue is dried intensively in a high vacuum at 30 ° C., purified in ethanolic solution over activated carbon and silica gel, the solution is filtered, again concentrated in vacuo and the remaining residue is recrystallized from isopropanol.
Yield: 16 g
F. 92 ° C

Examples of pharmaceutical preparations Example: capsules

12 kg of the compound according to Example 1 (as hydrochloride) are in a fluidized bed spray granulation apparatus with a solution of 0.25 kg of gelatin in 2.25 kg of water granulated in a known manner. To Mix in 0.8 kg corn starch, 0.1 kg magnesium stearate and 0.05 kg of highly disperse silicon dioxide the mixture is used in an amount of 330 mg each filled in size 0 hard gelatin capsules. A Capsule contains 300 mg of the active substance in the form of the Hydrochloride.

Example: solution for injection

54.8 g of the compound according to Example 1 (as hydrochloride) and 10.285 g of sodium chloride are sequentially in 1.5 liters of water for injections solved. The solution comes with water for injections made up to 2 liters and after mixing Sterile over a membrane filter with a suitable pore size filtered. After that, the solution is aseptic Conditions filled in sterilized ampoules of 2 ml. One ampoule contains 54.8 mg of the active substance in the form of the hydrochloride.

Claims (4)

1. [[[((Tricycloalkylamino-methyl) -2-furanyl] methylthio] ethyl] -2-nitro-1,1-ethenediamines of the general formula wherein
R₁ is a C₆ to C₁₀ tricycloalkyl group,
R₂ is hydrogen or a C₁ to C₆ alkyl group, and
R₃ is hydrogen, a C₁ to C₁₂ alkyl group, a C₃ to C₆ cycloalkyl group, a C₃ to C₆ alkenyl group, a C₃ to C₆ alkynyl group or a methoxyethyl group, and their salts. 2. A process for the preparation of the compounds of general formula I, according to claim 1, characterized in that

• a) a compound of the general formula wherein Y represents a sulfur atom or an oxygen atom and alkyl is a saturated C₁ to C₆ alkyl radical, with a compound of the general formula H-V (III), wherein in the formulas II and III T and V are each different and either the group or the group -NHR₃, where R₁, R₂ and R₃ have the meanings given or
• b) a compound of the general formula with a compound of the general formula implemented, in the formulas IV and V R₁, R₂ and R₃ have the meanings given and Z and U are each different and either a mercapto group or a hydroxyl group, which can also be esterified by a strong organic or inorganic acid, or
• c) in a compound of the general formula wherein R is hydrogen, the radical R₁ or the radical R₂, introduces the radical R₁ and / or the radical R₂, the radicals R₁ and R₂ have the meanings given except hydrogen for R₂ and / or in a compound of the formula VI, in which R₃ Hydrogen is introducing a group that corresponds to the definition of R₃ with the exception of hydrogen or
• d) in a compound of the general formula introduces the group R₁R₂NCH₂- by reaction with a bis-amine of the general formula (R₁R₂N) ₂CH₂ (VIII) or an amine R₁R₂NH in the presence of formaldehyde or a substance providing formaldehyde
  and optionally acylated and / or converted the compounds obtained into the salts

3. Use of a compound of general formula I according to Claim 1 as a drug. 4. Use of a compound of general formula I according to Claim 1 for the treatment of diseases of the stomach and / or the duodenum.