DE2851387A1 - O-aminoalkyl thienyl ketone oxime derivs. - improve peripheral and cerebral blood flow and have analgesic activity - Google Patents

Abstract

Oxime derivs. of formula (I) their salts, and their quat. ammonium salts are new In the formula, Alk is opt. branched 2-6C alkylene; R1 is thienyl opt. substd. by halogen or 1-4C alkyl; R2 is 1-6C alkyl, 3-7C cycloalkyl, thenyl (opt. substd. by halogen or 1-4C alkyl), or 1-R5-2-pyrryl (R5 is H or 1-6C alkyl); R3 is H or 1-6C alkyl; and R4 is H, 1-6C alkyl, 2-6C alkanoyl or -CHR6-CHR7-C6H5 (R6 = H or 1-3C alkyl; R7 is H or OH); or NR3R4 is a 5-7 membered satd. heterocyclic ring opt. contg. a further O- or N-atom; phthalimido, or 4-phenyl-l-piperazinyl (opt. substd. in the phenyl ring by halogen, CF3, amino, 1-4C alkyl, 1-4C alkoxy, di(1-4C alkyl)amino or 2-6C alkanoylamino. R1 is other than opt. substd. 2-thienyl when R3 and R4 are H and R2 is unsubstd. 2-thienyl, 5-chloro-2-thienyl, cyclopropyl or 1-6C alkyl. (I) bring about an improvement in peripheral and/or cerebral blood flow. They also have analgesic activity.

Description

Aminoäthyloxime with at least one thienyl

remainder and process for their production From the German Auslegeschrift 1 935 301, for example, compounds of the following formula are known: In this formula, R1 denotes hydrogen, methyl or a halogen atom and R2 denotes hydrogen, a C1-C5 alkyl radical, a cyclopropyl radical, a phenyl radical, a thienyl (2) radical or a 5-chlorothienyl (2) radical. These compounds have an antidepressant and anticonvulsant effect and, in individual cases, also a sedative effect.

For example, compounds of the following formula are known from British patent specification 1,436,307: In this formula, Ri, R2, R3 and R4 can be hydrogen, halogen atoms, lower alkyl radicals, lower alkoxy radicals or lower alkenyloxy radicals, R6 and R7 lower alkyl radicals or, together with the N atom, a 5- to 7-membered heterocyclic ring, n the numbers 1 - 4 and R5 denote hydrogen, a halogen atom, a nitro group or a lower alkyl radical. For these compounds there will be a cononary dilating effect, the. is coupled with a slowdown in the cardiac ramus.

Furthermore, from the Belgian patent 838 440 compounds of the following formula are known: In this formula, R1 denotes a phenyl radical or a naphthyl radical optionally substituted by halogen atoms, nitro groups, cyano groups, amino groups, lower alkyl radicals or lower alkoxy radicals, R2 denotes hydrogen, a C1-C4-alkyl radical or an optionally substituted phenyl radical as indicated above or R1 and R2 together with the two associated carbon atoms form a polycyclic ring while R3 represents an isopropyl or tertiary butyl radical. These compounds are referred to as β-blockers. The invention relates to the subject matter characterized by the claims. The compounds according to the invention are pharmacodynamically active and are suitable for the production of medicaments. In particular, they bring about an improvement in the peripheral and / or cerebral blood flow. They also have an analgesic effect.

The invention is therefore based on the object of providing compounds with favorable pharmacodynamic properties which can be used as drugs are available to deliver.

Dic in the formula I occurring C1-C4 or C1-C6-alkyl radicals as well the C2-C6-alkanoyl radicals or C2-C6-alkanoylamino radicals can be straight or branched His examples of the alkyl radicals are: methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tert-butyl, pentyl, hexyl.

Examples of the alkynoyl radicals are: acetyl, propionyl, butyryl, Isobutyryl, valeroyl. These acyl groups are also examples of the alkanoylamino groups.

Examples of the C3-C7-Cycloylkylrest are: Cycloproypl, Cyclobutyl, Cyclopentyl, cyclohexyl and cycloheptyl.

The alkylene chains All consist in particular of 2, 3 or 4 carbon atoms, Examples are ethylene, propylene, butylene, isopropylene, isobutylene.

The thienyl radical (meaning R1 and / or R2) is se either around a thienyl = (2) »or the trienyl (3) radical; this can be one or have two of the specified substituents. These substituents are preferably located in the 2 [and / or 5-position of the thienyl radical.

If the group -NR3R4 is a 5- to 7-membered heteocyclic Ring represents, then it is in particular a pyrrolidino, piperidino, Homopiperidino, piperazino homopiperazino or a morpholine ring. if the Group -NR3R4 forms a 4-phenylpiperazine ring, this can have one or two or have three of the specified substituents. These substituents can be the same or be different.

If the thienyl radical is substituted by a halogen atom, han delt they are preferably chlorine or bromine atoms. If the phenyl nucleus of the 4-phenylpiperazine ring is substituted by halogen atoms, cs is preferably fluorine or chlorine and / or bromine.

The C1-C4-alkoxy radicals can likewise be straight or branched (Methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, isobutyloxy).

If the compounds of the formula I have optically active carbon atoms, they can exist as racemates or in the stereoisomeric or optically active forms. Approximately occurring diastereomer mixtures can, for example, in the usual way, in particular are separated by recrystallization.

Optically active products are obtained either by using optically active starting substances or by resolution via the salts with optically active acids, for example tartaric acid, dibenzoyltartaric acid, camphor sulfonic acid etc.

As oxime derivatives, the compounds according to the invention are often mixtures of the two possible geometrically isomeric forms. But you can also 100% consist of one of the two geometric isomers. The two possible gcometris diisomers Forms differ in that in one case the oxime group is in the trans position to R1, in the other case in Ois position to R1. The separation of such mixtures is for example by fractional crystallization of appropriate salts or by Column chromatography of the free bases possible. Of course you can too the starting oximes of the formula IV where X is a hydrogen atom by column chromatography separate into the pure geometric isomers and then, for example, with a Implement connection Hal-Alk-NR3R4 (Hal = ilalogentom).

Regarding process a): The process is expediently carried out in a solvent carried out at temperatures between 20 and 2500 C, in particular 50 to 160 ° C. Examples of suitable solvents are: aromatic hydrocarbons such as benzene, toluene, xylene, alcohols such as metianol, ethanol, ketones such as acetone, methyl ethyl ketone, Ethers such as dioxane, dimethyl glycol ether and dimethylformamide, dimethyl sulfoxide, Acetonitrile, hexamethylphosphoric acid triamide, tetramethylurea, etc.

It can optionally be advantageous to add acid-binding agents to the reaction mixture Add substances, for example alkali alcoholates, alkali carbonates, tertiary amines, Pyridine etc.

The compounds of the formula IV or V can be used in the event that X or Z denotes hydrogen, also used in the form of the corresponding alkali metal salts earth. Such salts can be prepared, for example, by reacting the oximes or, amines, optionally dissolved in alcohol with a solution of sodium or potassium cohalate or sodium or potassium hydroxide in alcohols or lithium, sodium or potassium or the corresponding alkali hydrides in an inert agent such as dioxane.

If Y is a halogen atom, it is preferably chlorine or bromine, optionally also iodine. If y represents an arylsulfonyloxy radical; Aryl means an aromatic radical, for example an optionally through substituted one or more lower alkyl radicals (preferably methyl radicals) Phenyl or naphthyl radical. Examples are p-toluenesulfonic acid alkyl esters, especially the methyl ester. If a compound of the formula V is used9 in which one or both of the radicals R3, R4 are hydrogen, then this can be used Amine also have a protective group on nitrogen. Usual protecting groups come in into consideration, for example easily cleavable acyl groups, such as aliphatic acyl radicals (for example also the trifluoroacetyl group), the carbobenzoxy group or the ethoxycarbonyl group. One such protecting group can subsequently be obtained by simply standing in water or by saponification using dilute acids or basic ones Substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, Ammonia) at room temperature or at higher temperatures, for example 80 - 1000 C. The introduction of such protecting groups in the compounds of Formula V takes place, for example, that the corresponding amine with the corresponding Acid chloride, for example dissolved in benzene, is reacted.

The starting materials of the formula IV, in which X is hydrogen, can for example by reacting the corresponding ketones R1R2CO (if necessary also the corresponding ketone acetal, such as the dimethyl acetal) with hydroxylamine or

Hydroxylamine hydrochloride in a solvent such as pyridine or a lower alcohol, optionally in the presence of sodium acetate at temperatures between 50 and 1500 C are obtained0 starting materials of the formula IV, wherein X is the Alk-Hal group (Hal = halogen atom such as chlorine, bromine or iodine) denoted, can for example from the corresponding compound of the formula IV in which X is hydrogen by Reaction with a compound Hal-Alk-Hal, for example Br-Alk-Cl or J-Alk-Cl, in a solvent such as alcohols, benzene, toluene, dimethylformamide, hexamethylpho Sphorsäuret riamid at temperatures between 50 to 2500 C, preferably 100 to 180 ° C. If necessary, this reaction becomes more basic in the presence Substances carried out.

Starting materials of the formula IV5 in which Y is an arylsulfonyloxy group, horses obtained, for example, by using a compound of the formula IV, wherein X is hydrogen, with ethylene oxide, propylene oxide or an alkylene chlorohydrin of the formula Hal-Alk-OH, optionally in the presence of basic substances, in a solvent at temperatures between 50 and 2000 0 and the reaction product obtained with the corresponding aryl sulfonyl halide (= chloride or bromide) in the presence of pyridine at temperatures between 20 and 150 ° C.

Starting compounds of the formula V in which Z is the -Alk-Y group and Y is a halogen atom, a hydroxy group or an arylsulfonyloxy group if they are not known, can be obtained in a manner analogous to that given above, where instead of the corresponding oxime starting compound the corresponding chimney HNR3R4 is used, the output ketones of the formula R1R2CO can, as far as they are not known, analogous to that in Rec trav. chim 68, page 5 ff. (1949) and Can. J Chem. 53, 2598 et seq., (1975), for example they can be obtained from the thienyl compound R1 I1 and the acid chloride R2COC: 1 under conditions the Friedel-Crafts reaction (nitrobenzene, nitromethane, CS2, benzene, 1,2-dichloroethane, CH2Cl2; inorganic acid chloride such as SnCl4) or from the corresponding organometallic Compound (lithium or Grignard compound) and an acid haloid R2CO # Hal (Iial = chlorine, bromine, iodine) denotes the corresponding lower alkyl esters the acid R2CO # OH in an inert Solvents such as lower aliphatic Dialkyl ether (diethyl ether, diisopropyl ether), alkyl cycloalkyl ether (methylcyclopentyl ether), cyclic ethers (tetrahydrofuran) aromatic hydrocarbons (benzene, alkylbenzenes, Nitrobenzene), aliphatic and cycloaliphatic hydrocarbons (hexane, cyclohexane, Methylcyclohexane, ethylcyclohexane, methylcyclopentane, dimethylcyclohexane) at temperatures between -100 ° C and +1000 C (often below 500 C are often produced it is beneficial to carry out this reaction in mixtures of the solvents mentioned above (in particular a mixture of a saturated ether and a saturated hydrogen and / or a mono-C1-C4-alkylbenzene). If it is pyrrylthienyl ketones is involved, the manufacturing method specified above can also be carried out in such a way that that the corresponding pyrrole compound or its organometallic compound with the corresponding thienylcarboxylic acid derivative is reacted, for process b): This process is carried out in a solvent or suspending medium such as lower aliphatic Alcohols (ethanol), water, pyridine, dimethylformamide, dioxane, tetrahydrofuran, Hexamethylphosphoric triamide and similar or in mixtures of the agents mentioned carried out at temperatures between 50-200.degree. C., in particular 80-1500.degree.

Optionally, the reaction is carried out in an acidic medium, for example carried out in the presence of mineral acids such as HCl, H2SO4.

However, it is also possible in the presence of basic substances such as sodium acetate, Pyridine, triethylamine, to work The amines of formula VII can be used as free bases or can be used in the form of their acid addition salts.

The starting ketones R1R20 = O can be used as specified under method a is to be obtained. The corresponding ketals (V of formula VI = 2 alkyoxy groups) are obtained therefrom in the usual way (for example by means of lower trialkyl orthoformates in the presence of tiol).

The starting compounds of the formula VII can if they are not known are, according to the Bull. Soc. Chim. 1958, page 664, specified method will.

Depending on the process conditions and starting materials, the End products of the formula I in free form or in the form of their salts. The salts of the end products can in a manner known per se, for example, with alkali or ion exchangers can be converted back into the bases of the latter can be converted by implementation with organic or inorganic acids, especially those that lead to formation of therapeutically usable salts are suitable, salts win as such acids Examples include: hydrohalic acids, sulfuric acid, phosphoric acids, Nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphytic, alicyclic, aromatic or heterocyclic series as well Sulfonic acids. Examples are: ant, ssig, propion, amber, glycol, milk, Malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic or pyruvic acid; Phenyl acetic, benzoin, p-aminobenzoe, anthranil, p-hydroxy-benzoe, salicyclic or p-amino-salicylic acid. Emboxylic acid, methanesulfone, ethanesulfone, hydroxyethanesulfone, Ethylene sulfonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or Sulfanilic acid.

The compounds of the invention are pharmaceutical for the manufacture Compositions and preparations suitable. The pharmaceutical compositions contain one or more of the compounds according to the invention as active ingredient, if appropriate in a mixture with other pharmacologically active substances. The manufacture of the Medicines can be made using known and customary pharmaceutical carriers and surcharges are made. The drugs can be enteral, parenteral, oral, perlingual or in the form of sprays. Administration can be in the form of tablets, Capsules, pills, coated tablets, suppositories, liquids or aerosols are made. As liquids for example: oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.

Example 1 O- (2-dimethylaminoethyl) -bis- [thienyl- (3)] - ketoxime To one Solution of 8 g of bis- [thienyl- (3)] - ketoxime in 60 ml of absolute toluene are under Stirring 4 ml of a 40% sodium suspension in toluene added dropwise. The suspension is heated to the boil until the hydrogen evolution has ended and in the Boiling heat dropwise with a solution of 4.1 g of 2-dimethylaminoethyl chloride added in 40 ml of absolute toluene. After three hours of refluxing become 20 ml of water were added with ice cooling, the organic phase was separated off and this washed twice with 20 ml of water. After drying with sodium sulfate and distilling off the solvent in vacuo is the oxime ether by dry column chromatography isolated on silica gel (eluent: chloroform / methanol = 98: 2).

The isopropanolic solution of the oxime ether is used to produce the maleate mixed with an isopropanolic maleic acid solution (4 g maleic acid). That crystallized out Salts are filtered off with suction and recrystallized from isopropanol.

Yield: 68%. F. of the maleate 140 ° C.

The starting compound bis- [thienyl- (3)] - ketoxime is prepared as follows: To a solution, heated to 600, of 9 g of hydroxylamine hydrochloride and 14. g of sodium acetate In 90 ml of water, a solution of 18 g of bis-zthienyl- (3j7-ketone in 180 ml of methanol dripped. It is then refluxed for 6 hours, one part of the solvent distilled off in vacuo and the crystallized oxime filtered off with suction. The purification takes place by crystallization from isopropanol. Yield: 93. F. 1140 C.

In an analogous manner, this is used as the starting material in other examples used methyl- [2,5-dichlorothienyl- (3)] - ketoxime from 15 g of 2,5-dichloro-3-acetylthiopbene and 7.5 g of hydroxylamine hydrochloride were obtained. Yield: 96? F. 1020.

Example 2 O- (2-piperidinoethyl) -bis- [thienyl- (3)] - ketoxime To one Suspension of 2 g of sodium hydride (80%) in 75 ml of absolute xylene is added with stirring a solution of 6 g of bis- / thienyl- (317-ketoxime in 30 ml of xylene was added dropwise 5.3 g of N- (2-chloroethyl) -pieridine hydrochloride are carefully boiled under reflux added in portions. The suspension obtained is heated to boiling for 8 hours and then as described in Example 1, worked up.

Yield: 71 da. The maleate melts at 1300 C.

Further examples are given in Table I. The production of Example 3 is carried out analogously to Example 1. The preparation of the remaining examples analogous to example 2.

Table IM = maleate O = oxalate (production is analogous to maleate) Example Compound I Melting point Starting materials used and amount in g Number R1, R2 -Alk-NR3R4 Yield% unless otherwise Morishes ale hydrochloride II III 3 thienyl- (3) (CH3) 2N- (CH2) 3 95 ° CN; 62% 8 # -C- # 7 (CH3) 2N- (CH2) 3-Cl S # S NOH 4 thienyl- (3) # N- (CH2) 3-110 ° CM; 48% 6 as Example 3 6.3 # N- (CH2) 3-Cl 5 thienyl- (3) # N-CH2) 2- 120 ° CM; 57% 8 as Example 3 7 # N- (CH2) 2-Cl # # 6 thienyl- (3) O N- (CH2) 2- 135 ° CM; 53% 6 as Example 3 6.5 O N- (CH2) 2-Cl # # 7 thienyl- (3) # N- (CH2) 2- 112-113 ° CM; 63% 6 as example 3 6.5 # N- (CH2) 2-Cl # CO # # CO # 8 Thienyl- (3) # N - ((CH2) 2- 124 ° CM; 43% 6 as in Example 3 8 # N- (CH2) 2-Br # CO # # CO # (Base) 9 thienyl- (3) (CH3) 2N-CH2-CH-128 ° CO; 70% 6 as Example 3 4.9 (CH3) 2-N-CH2-CHCl3 # # CH3 CH3 10 thienyl- (3) (CH3) 2N-CH-CH2 159 ° CO; 49% 6 as Example 3 5 (CH3) 2N-CH-CH2-Cl # # CH3 CH3 11 Thienyl- (3) (CH3) 2N-CH2-CH-CH2- 144-146 ° CO6 as Example 3 5.4 (CH3) 2N-CH2-CH-CH2-Cl # 55% # CH3 CH3 12 thienyl- (3) (CH3) 2N- (CH2) 2-84 ° CM; 43% 8 3-acetyl-8.4 (CH3) 2N- (CH2) 2-Cl CH3 mixture of thiophene oxime both isomers 13 2,5-dichloro (CH3) 2N- (CH2) 2 - 145 ° C; 49% 8 3-acetyl-2,5-5,7 (CH3) 2-N- (CH2) 2-Cl thienyl (3) mixture of dichloro-thiophene CH3 both isomers oxime Example 14 O- (2-Aminoethyl) bis [thienyl (3)] ketoxime 2.3 g of sodium are dissolved in 150 ml of ethanol and 9.42 g of bis-Lthien-Jrl- (3) ketoxime added, after heating under reflux for one hour, a solution of 10.25 g of 2-bromoethylamine hydrobromide in 50 ml of dimethylformamide is added dropwise at room temperature and the mixture is then refluxed for four hours. The solvent is distilled off in vacuo, the residue is mixed with water and extracted several times with ether. After drying over potassium carbonate, the solution is concentrated and the oil obtained is purified by dry column chromatography on silica gel (eluent: chloroform-methanol 1: 1).

The hydrochloride of the base thus obtained can be treated with 8 n isopropanolic hydrochloric acid and subsequent recrystallization from isopropanol can be obtained.

Yield: 46%. F. the hydrochloride 148 ° C.

Example 15 O- [2- (4-p-Methoxyphenyl-piperazino) -ethyl] -bis- [thienyl- (3) -ketoxime The preparation takes place analogously to Example 2, thereby reacting the ketoxime obtained from 8 g of bis- [thienyl- (3)] and 1.5 g of sodium hydride (80%) obtained sodium salt with 10 g of N- (2-chloroethyl) -N '- (pmethoxyphenyl) piperazine and twelve hours of cooking. Working up is carried out as in Example 1 using of ether-methanol (98: 2) as the eluent in column chromatography.

The dihydrochloride is obtained with 8n-isopropanolic hydrochloric acid. Yield: 42%, F. of the dihydrochloride 195 °.

The piperazine derivative used as the starting material is made by reaction of 1-bromo-2-chloroethane and N-p-methoxyphenyl-piperazine in the presence of sodium hydrogen carbonate obtained in toluene at the boiling point.

Example 16 O- [2- (1-Phenyl-propyl- (2) -amino) -ethyl] -bis- [thienyl- (3)] - ketoxime From 1.15 g of sodium and 9.42 g of bis- [thienyl- (3)] - ketoxime in 100 ml of ethanol this becomes corresponding sodium salt is shown, then the ethanol is distilled off in vacuo, the solid residue dissolved in 40 ml of dimethylformamide and at room temperature with a solution of 11> 2 g of hT-3-chloroethyl-amphetamine in 15 ml of dimethylformamide offset. This solution is heated to 1000 ° C. for two hours with stirring and then concentrated to dryness in vacuo. The further work-up takes place analogously to the example 14, whereby only oxalic acid is used instead of isoropanolic hydrochloric acid will.

Yield: 45%, F. of the oxalate 150-1530 Cc. Example 17 O- (2-Trimethylammonium-ethyl) -bis- [thienyl- (3)] - ketoxime bromide.

8 g of O- (2-dimethylamino-ethyl) -bis- [thienyl- (3)] - ketoxime are in 8 ml of ether are dissolved and 8 ml of methyl bromide are added while cooling with ice. The crystallizing Product is suction filtered and recrystallized from isopropanol / ethynol.

Yield: 56%; F. 1730.

Claims (6)

Aminoäthyloxime with at least one thienyl radical and process for their preparation PATENT CLAIMS 1. Compounds of the general formula wherein Alk is a straight or branched C2-C6-alkylene chain, R1 is a thienyl radical which is optionally also substituted by halogen atoms or C1-C4-alkyl radicals, R2 is a C1-C6-alkyl radical or a C3-C7-cycloalkyl radical or a thienyl radical , which can optionally also be substituted by halogen atoms or C 1 -C 4 -alkyl radicals, or in which R2 is a pyrryl (2) radical of the structure where R5 is hydrogen or a C1-C6-alkyl group, R3 is hydrogen or a C1-C6-alkyl group and R4 is hydrogen, a C1-C6-alkyl group, a C2-C6-alkanoyl group, the remainder of the structure -CHR6 - CHR7 - C6H5 III denotes in which R6 is hydrogen or a C1-C3 alkyl group and R7 is hydrogen or a hydroxyl group or in which the group -NR3R4 is a 5- to 7-membered saturated heterocyclic ring which may or may not contain a further oxygen or nitrogen atom in which the group -NR3R4 forms a phthalimido radical or a 4-phenylpizerazill ring, which in the phenyl radical is also replaced by halogen atoms, a trifluoromethyl group, an amino group, a C1-C4-alkyl group, a C1-C4-alkoxy group or a dialkylamino group with alkyl radicals of 1 to 4 carbon atoms or a C2C6-alkanoylamino group can be substituted, its salts and its quaternary ammonium salts and where R1 is not a thienyl (2) radical or a substituted thienyl (2) radical, if R3 and R4 are hydrogen and R2 is an unsubstituted thienyl (2) radical, a 5-chlorothienyl (2) radical, a cyclopropyl radical or a C1-C6-alkyl radical. 2. Process for the preparation of compounds of the general formula wherein, tlk is a straight or branched C2-C6-alkylene chain, R1 is a thienyl radical which is optionally also substituted by halogen atoms or C1-C4-alkyl radicals, R2 is a C1-C6-alkyl radical or a C3-C7-cycloalkyl radical or a thienyl radical is, which can optionally also be substituted by halogen atoms or C1-C4-alkyl radicals or in which R2 is a pyrryl (2) radical of the structure where R5 is hydrogen or a C1-C6-alkyl group, R3 is hydrogen or a C1-C6-alkyl group and R4 is hydrogen, a C1-C6-alkyl group, a C2-C6-alkanoyl group, the remainder of the structure - CHR6 - CHR7 - C6H5 III means in which R6 is hydrogen or a Ci -03-alkyl group and R7 is hydrogen or a hydroxy group or in which the group -NR3R4 is a 5- to 7-membered saturated heterocyclic ring, which may optionally contain a further oxygen or nitrogen atom or in which the group -ER3R4 forms a phthalimido radical or a 4-phenylpiperatzine ring, which in the phenyl radical is also replaced by halogen atoms, a trifluoromethyl group, an amino group, a C1-C6-alkyl group, a C1-C6-alkoxy group, a dialkylamino group with alkyl radicals of 1 to 4 carbon atoms or a C2-C6-alkynoylamino group can be substituted, their salts and their quaternary ammonium salts and where R1 is not a thienyl (2) radical or a substituted thienyl (2) radical , if R3 and R4 are hydrogen and R2 is an unsubstituted thienyl (2) radical, a 5-chlorothienyl (2) radical, a cyclopropyl radical or a C1-C6-alkyl radical, characterized in that a) a compound of the formula reacts with a compound of the formula ZNR3R4 V, where X and Z are each different and are either hydrogen or the group -Alk-Y and Alk and the radicals R1 -R4 have the meanings given and Y is a halogen atom, a hydroxy group or an arylsulfonyloxy group and optionally splitting off a protective group present or b) a compound of the formula where R1 and R2 have the meanings given and V represents one oxygen or two C1-C6-alkoxy groups with a compound of the formula H2N - O Alk - NR3R4 VII and optionally alkylates the compounds obtained and / or acylated by a C2-C6 alkanoyl radical and optionally transferred into the acid addition salts or quaternary compounds. 3. Medicaments containing at least one compound according to one or more of the preceding claims. 4. Medicaments containing a compound according to claim 1 or their pharmaceutically acceptable acid addition salts in addition to the usual inert ones Carriers. 5. Yerfa11ren for the production of a drug, thereby kern-izeichnet, that at least one compound according to one or more of the preceding claims with common pharmaceutical carriers or diluents to pharma chemical preparations is processed. 6. Use of compounds according to one or more of the preceding Claims for the manufacture of pharmaceuticals.