DE1942854A1 - Subst 3-amino-4-halo-sydnonimines with - hypotensive activity - Google Patents

Abstract

Title cpds. are 3-(N-R1-N-R2-amino)-4-halo-N-R3-sydonimines and their acid addition salts (where R1 and R2 are alkyl or opt. methyl- or halo-substd. aralkyl or NR1r2 is a heterocyclic ring opt. contg. a further hetero-atom and opt. methyl-substd., R3 is H or -COR4 and R4 is alkyl, cycloalkyl, Ph, halophenyl, opt. substd. N-contg. heterocyclyl, alkoxy, aralkoxy, aryloxy or alkenyloxy) which are prepd. by reacting a 3-(N-R1-N-R2-amino)-N-COR4-sydnonimine with a halogenating agent and opt. deacylating the product.

Description

New substituted 3-amino-4-halosydnonimines The invention relates to new substituted 3-amino-halosydnonimines of the general formula In this formula: R1 and, which can be the same or different, denote alkyl, cycloalkyl or aralkyl groups, where the aralkyl group can be substituted by methyl or halogen, a heterocyclic ring bonded to the nitrogen atom of the 3-amino group via an alkylene chain or together with the nitrogen atom a heterocyclic ring system which may contain further hetero atoms and may optionally be substituted by methyl, K is hydrogen or the group COR4, R4 is an alkyl, cycloalkyl, phenyl or halophenyl group, an optionally substituted, a nitrogen atom containing heterocyclic ring or an alkoxy, aralkozy, aryloxy or alkenyloxy group, Hal is a halogen atom and X den is an acid suitable for salt formation, for example a hydrohalic acid, sulfuric acid or nitric acid.

The new compounds can be prepared by treating a compound of the general formula in which R1, R2 and R4 have the meaning given above, or an acid addition salt of this compound, with customary halogenating agents, for example elemental bromine, N-chloro-, bromo- or iodosuccinimide and related compounds. The halogenation succeeds in the usual solvents, such as methylene chloride, chloroform, carbon tetrachloride, ether or even water. In the case of halogenation with elemental bromine, the addition of weakly basic salts, such as sodium bicarbonate or sodium acetate, which can be present in solution or in suspension, is recommended. The reaction can take place at a moderately elevated temperature, at room temperature or with cooling. In most cases, halogenation with an N-halosuccinimide never requires the addition of dibenzoyl peroxide or azoisobutyronitrile and, if necessary, an increased temperature. The halogenation takes place with the starting material in bus pension or. Solution.

The 3-amino-4-halosydnonimines thus obtained can then if desired in a manner known per se with suitable dilute aqueous mineral acids, such as Hydrohalic acid, sulfuric acid, nitric acid or phosphoric acid, deacylated will.

Because of the instability of the free sydnone imines, the end products preferably isolated in the form of their physiologically harmless roller. For salt formation suitable acids are, for example, inorganic acids such as hydrohalic acids, Sulfuric acid, nitric acid, phosphoric acid or perchloric acid; also organic Acids such as formic acid, acetic acid, propionic acid, oxalic acid, seriousein acid, tartaric acid, Citric acid, Maleic acid, ascobic acid. Salicylic acid, methanesulfonic acid or toluenesulfonic acid.

After the method explained in more detail above, z. B. the following end products are obtained in the form of their salts with the acids mentioned above: 4-bromo-3-dimethylamino-sydnonimine, 4-bromo-3-dimethylamino-N6-o nicotinoyl-sydnonimine, N6-o-chlorobenzyl-3- methyl-benzylamino-4-bromosydnonimine, N6-acetyl-4-bromo-3-methyl-α-methyl-benzylamino-sydnonimine, N6-acetyl-4-chloro-3-hexamethyleneimino-sydnonimine, N6-acetyl-4-bromine- 3-piperidino-sydnonimine, 4-bromo-3-piperi-6-dino-sydnonimine, 4-bromo-N6-cyclohexylcarbonyl-3-morpholinosydnonimine, 4-bromo-3-morpholino-sydnonimine, N6-acetyl-4-bromo-3 - (1,2,3,4, -tetrahydroisoquinolino) -sydnonimine, N6-benzoyl-4-bromo-3-dimethylamino-sydnonimine, 4-bromo-3-hexamethyleneiminosydnonimine, 4-chloro-3-morpholino-sydnonimine, 4- Chlorine-N6-cyclohexylcarbonyl-3-morpholino-sydnonimine, N6-cyclohexylcarbonyl-4-iodo-3-morpholino-sydnonimine, 4-chloro-3-dimethylamino-N6-nicotinoyl-sydnonimine, N6-ethoxycarbonyl-4-bromo-3- piperidinosydnonimin, N6-ethoxycarbonyl-4-chloro-3-piperidino-sydnonimin, N6-ethoxycarbonyl-4-chloro-3-morpholino-sydnonimine, N6-ethoxycarbonyl-4-bromo-3-morpholino-sydnonimine, N6-ethoxycarbonyl-4-iodo-3-morpholino-sydnonimine, 4-bromo-N6-methoxycarbonyl-3- (methyl-α-methyl ## benzyl) -amino -sydnonimine, 4-bromo-N6-butoxycarbonyl-3-hexamethyleneimino-sydnonimine, N6-allyloxycarbonyl-4-chloro-3-dimethylamino-sydnoniming N6-benzyloxycarbonyl-4-bromo-3-dimethylaminosydnonimine, N6-benzyloxycarbonyl-4-chloro-3-dimethylamino-sydnonimine, 4-bromo-3- (4-methylpiperazino) -N6-phenyloxycarbonyl) -sydnonimine.

The compounds of the general formula II used as starting materials can be obtained, for example, by treating a compound of the formula with conventional ring-closing agents and subsequent acylation.

The new compounds have interesting pharmacological effects; For example, they lower blood pressure in small doses about an unusual amount long period.

Compared with the structurally similar connection known from the literature 3-Benzyl-sydnonimin (see. British Patent 962 293), continues the action of new connections are less abrupt and last longer.

The one observed with 3-benzyl-sydnoniinine is also absent in many cases unwanted, stimulating effect on the central nervous system. Ifer to be emphasized is also that only about 1/10 to 1/5 of the dose required with the new compounds to achieve the same antihypertensive effect with 3-benzyl-sydnonimin is required.

3ureadditionsalse are suitable for use in therapy the new compounds with common pharmaceutical fillers or carriers, Extenders, disintegrants, binding agents, lubricants, thickeners or thinners, solvents or mixed solubilizers or agents to achieve a depot effect, which allow enteral or penenteral use. As pharmaceutical preparation forms come z. B. tablets, coated tablets, pills, capsules, solutions, suspensions or emulsions in question, whereby in addition to the new active ingredients also preservatives or stabilizers, Emulsifiers, buffer substances and other therapeutic agents, such as saluretics, can be added. The pharmaceutical preparations should in general Contains 1 - 200 mg, preferably 5 - 50 mg / dose.

The following examples serve to explain the invention in more detail: Example 1 4-Bromo # -3-dimethylamino-sydnonimine hydrobromide 55 g of N6-acetyl-3-dimethylamino-sydnonimine hydrochloride are in the presence of 120 g of sodium bicarbonate in a mixture of 100 ml of chloroform and 1500 ml of ether and suspended over the course of 2 hours under reflux and stirring 20 ml of bromine were added dropwise. The mixture is refluxed for 3 hours, - the insoluble constituents were filtered off and the filtrate was concentrated in vacuo. The remaining Resin is crystallized from ethanol petroleum ether and recrystallized.

Mp .: 1590 C (decomp.) Yield: 48 g (67% of theory) Example 2 N6-acetyl-4-bromo-3-piperidino-sydnonimine-hydrobromide 30 g of N6-acetyl-3-piperidino-sydnonimine hydrochloride are in the presence of 48 g Sodium acetate suspended in 1000 ml of ether. About this suspension 48 g of bromine in 75 ml of chloroform are refluxed and stirred within 2 hours added dropwise. The mixture is refluxed for 6 hours and at room temperature left to stand overnight. The solvent is then evaporated in vacuo, the The residue is partitioned between water and chloroform, the chloroform extracts are combined, dried over sodium sulfate and the solvent removed in vacuo. The residue is dissolved in acetone and treated with hydrogen bromide while cooling with ice. When adding N6-acetyl-4-bromo-3-piperidino-sydnonimine hydrobromide separates from ether, which is recrystallized from ethanol / ether.

Mp .: 980 C (decomp.) Yield: 27.5 g (61% of theory) Example 3 4-Bromo-3-piperidino-sydnonimine-hydrobromide 22 g of N6-acetyl-4-bromo-3-piperidino-sydnonimine hydrobromide are dissolved in 400 ml of 1N hydrochloric acid dissolved and left to stand for three days at room temperature. The acidic solution is with Ether extracted, the aqueous phase neutralized with saturated sodium bicarbonate solution and extracted repeatedly with chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent evaporated in vacuo. The residue is dissolved in isoprupanol and hydrogen bromide is passed in while cooling with ice. the Crystals deposited after the addition of ether are recrystallized from isopropanol / ether.

Mp .: 140 ° (decomp.) Yield: @ 3 g (67% of theory) example 4 N6-acetyl-4-bromo-3- (1,2,3,4-tetrahydroisoquinolino) -sydnonimine-hydrobromide a) N6-acetyl-3- (1,2,3,4-tetrahydroisoquinolino) sydnonimine hydrochloride 25.3 g of 3- (1,2,3,4-tetrahydroisoquinolino) sydnonimine hydrochloride are added in portions to a mixture of 200 ml of pyridine and 200 ml of acetic anhydride added at room temperature and the mixture stirred overnight. After that become pyridine and acetic anhydride removed in vacuo. The residue crystallizes on addition of ether. The crystals are recrystallized from acetone / ether.

Yield: 29.5 g (87% of theory) 6 b) N6-acetyl-4-bromo-3- (1,2,3,4-tetrahydroisoquinolino) sydnonimine hydrobromide 9 (3.5 g of the ethyl compound are dissolved in 800 liters of ether in the presence of 32 g of sodium acetate suspended unii within 2 hours under reflux and stirring 32 g of bromine in 50 ml of chloroform were added dropwise. The mixture is refluxed for 4 hours and left to stand at room temperature overnight. After that the solvent removed in vacuo and the residue between dilute sodium acetate and chloroform distributed. The chloroform extracts are combined and dried over sodium sulfate and concentrated to dryness. The residue is dissolved in acetone and cooled with ice Hydrogen bromine initiated. The crystals that separate out when ether is added are recrystallized from acetone / ether.

Mp .: 124 ° (decomp.) Yield: 12.5: (34% of theory) example 5 4-Bromo-N6-cyclohexylcarbonyl-3-morpholino-sydnonimine hydrochloride 47.5 g of N6-cyclohexylcarbonyl-3-morpholino-sydnonimine-hydro chloride are suspended in 600 ml of ether in the presence of 32 g of sodium acetate. Under reflux and stirring, 45 g of bromine in 75 ml of chloroform are added within two hours added dropwise. The mixture is refluxed for 4 hours and at room temperature for 3 days -ditched. The solvent is then removed in vacuo and the residue distributed between water and chloroform. The chloroform extracts are combined, dried over sodium sulfate and concentrated to dryness in vacuo. The remaining Resin is dissolved in methanol and hydrogen chloride is passed in while cooling with ice.

After adding ether, crystals separate out, those from methanol / ether be recrystallized.

D'p .: 150 ° C (decomp.) Yield: 44 g (74% of theory) Example 6 4-Bromo-3-morpholino-sydnonimine-hydrobromide 26 g of 4-bromo-N6-cyclohexylcarbonyl-3-morpholino-sydnonimine hydrochloride are in 400 ml of 1N hydrochloric acid dissolved and left to stand for 3 days at room temperature. the acidic solution is extracted with ether, the aqueous phase -with saturated sodium bicarbonate solution neutralized and extracted repeatedly with chloroform. The combined chloroform extracts will dried over sodium sulfate and concentrated in vacuo.

The residue is dissolved in methanol and hydrogen bromide while cooling with ice initiated. After adding ether, crystals separate from methanol / ether be recrystallized.

M.p .: 170 ° C. (decomp.) Yield: 7.6 g (35% of theory) Example 7 4-Bromo # -3-dimethylamino-N6-nicotinoylsydnonimine hydrobromide 15.5 g of 3-dimethylamino-N6-nicotinoylsydnonimine dihydrochloride are in the presence suspended from 24 g of sodium acetate in 700 al of ether. Under reflux and stirring 24 g of bromine in 50 ml of chloroform were added dropwise over the course of 2 hours. The mix will Boiled under reflux for 4 hours and left to stand at room temperature overnight. The solvent is removed in vacuo and the residue between water and Distributed chloroform. The chloroform extracts are combined and placed over sodium sulfate dried and concentrated to dryness in vacuo. The residue is dissolved in methanol and introduced hydrogen bromide with ice cooling. Those deposited after the addition of ether Crystals are recrystallized from methanol / ether.

i? p .: 171O ((dec.) Yield: 12.2 g (61% of theory) example 8 N6-acetyl-4-bromo-3- (methyl-α-methylbenzyl) -amino-sydnonimine hydrobromide hydrate a) N6-acetyl-3- (methyl-α-methylbenzyl) -amino-sydnonimine hydrochloride 27 g 3- (Methyl - «- methylbenzyl) -amino-sydnonimine hydrochloride are a little at a time Mixture of 270 ml of acetic anhydride and 270 ml of pyridine was added at room temperature. The mixture is stirred overnight at room temperature and then pyridine and acetic anhydride removed in vacuo.

m b) N6-acetyl-4-bromo-3- (methyl-α-methylbenzyl) -aino-sydnonimine hydrobromide hydrate The acetyl compound (37 g) is in the presence of 48 g of sodium acetate in 100 ml of ether dissolved and refluxed and stirred within 2 hours 48 g of bromine in 75 ml Chioroforn added dropwise. The mixture is refluxed 6 tuncIen and at Let stand room temperature overnight. Then the solvent is in vacuo removed and the residue partitioned between water and chloroform The chloroform extracts are combined, dried over sodium sulfate and evaporated to dryness. The remaining The residue is dissolved in methanol and hydrogen bromide is passed in while cooling with ice. The crystals deposited after the addition of ether are recrystallized from acetone / ether.

Mp .: 104-105 ° C (decomp.) Yield: 12 g (26% of theory) example 9 4-Bromo-N6-cyclohexylcarbonyl-3- (1-morpholino) -sydnonimine hydrochloride 10 g of N6-cyclohexylcarbonyl-3- (1-morpholino) -sydnonimine were suspended in 75 ml of carbon tetrachloride. 17, S> - N-bromosuccinimide added in small amounts with stirring at room temperature. After the addition finished, the precipitate formed was filtered off and washed with carbon tetrachloride washed. The filtrate was concentrated to dryness in vacuo. The residue was dissolved in a small amount of methanol and the solution was made with ethereal hydrogen chloride acidified. With a further addition of ether, crystals separated out, which were recrystallized from methanol / ether.

Melting point: 150 ° C. Yield: 12 g (85) t d. Th.) Example, 10 4-Bromo-3- (1-hexamethyleneimino) sydnonimine hydrochloride 11.2 g of N6-acetyl-3- (1-hexamethyleneimino) -sydnonimine were in 100 ml of carbon tetrachloride suspended. 26.7 g of N-bromosuccinimide were added in small amounts with stirring at room temperature admitted. After the addition was complete, the precipitate formed was filtered off and washed with carbon tetrachloride. The filtrate turned to dryness in vacuo constricted. The residue was dissolved in a small amount of isopropanol and the solution was acidified with ethereal hydrogen chloride. The departed Crystals were recrystallized from isopropanol / ether.

M.p .: 142 ° C. Yield: 13.1 g (77% of theory) Example 11 N6-Benzoyl-4-bromo-3-dimethylamino-sydnonimine-hydrobromide 11.2 g of N6-benzoyl-3-dimethylamino-sydnonimine were in 150 ml of carbon tetrachloride suspended. 15.1 g of N-bromosuccinimide were added in small amounts with stirring at room temperature admitted. After the addition was complete, the precipitate formed was filtered off and washed with carbon tetrachloride.

The filtrate was concentrated to dryness in vacuo. The residue was dissolved in a small amount of methanol and the solution was made with ethereal hydrogen chloride acidified.

With further addition of ether, crystals separated out Methanol / ether were recrystallized.

M.p .: 138-139 ° C.

Yield: 15.7 g (83% of theory) Example 12 3- (N-Benzylmethylamino) -4-bromo-N6- (o-chlorobenzoyl) -sydnonimi-hydrobromide 19.0 g of 3- (N-benzylmethylamino) -N6- (o-chlorobenzoyl) sydnonimine hydrochloride were suspended in 750 ml of ether equivalent to 16 g of sodium acetate. The mix was @@ @@@@ - heated flux and 16 g of bromine dissolved in 50 ml of chloroform for one hour dripped into it. After refluxing for 5 1/2 hours, the precipitate was filtered off and washed with chloroform until the filtrate remained colorless.

The filtrate was concentrated to a small amount in vacuo with Methanol was diluted and hydrogen bromide was passed in with external cooling. the Substance crystallized after addition of isopropanol / ether and was made from methanol / Ether recrystallized.

Melting point: 98-99 ° C. (decomp.) Yield: 16.1 g (64% of theory) Example 13 4-Bromo-N6-ethoxycarbonyl-3- (1-piperidino) -sydnonimine hydrochloride 24.0 g of N6-ethoxycarbonyl-3- (1-piperidino) -sydnonimine were suspended in 500 ml of carbon tetrachloride. 53.4 g of N-bromosuccinimide were added in small amounts. The mixture was left at room temperature for three hours ditched. The solids were removed by filtering and using carbon tetrachloride washed. The filtrate and washing solution were combined and concentrated to dryness in vacuo. The residue was dissolved in ethanol and acidified with ethereal hydrochloric acid. The deposited crystals were recrystallized from ethanol / ether.

Mp .: 137 ° C (decomp.) Yield: 19.3 g (54% of theory) example 14 4-Bromo-3- (1-hexamethyleneimino) sydnonimine hydrochloride 11.3 g of N6-acetyl-3- (1-hexamethyleneimino) sydnonimine were suspended in 100 ml of carbon tetrachloride. 26.7 g of N-bromosuccinimide were added in small amounts. The mixture was left for one hour at room temperature ditched. The solid components were removed by filtering unil several times washed with carbon tetrachloride. The filtrate and washing solution were combined and concentrated to dryness in vacuo.

I) the residue was dissolved in isopropanol and washed with ethereal hydrogen chloride acidified. The material was recrystallized from isopropanol / ether.

Melting point: 142 ° C. (decomp.) Yield: 6.3 g (42% of theory) Example 15 4-chloro-N6-cyclohexylcarbonyl-3- (1-morpholino) -sydnonimine hydrochloride 34 g of N6-cyclohexylcarbonyl-3- (1-morpholino) -sydnonimine were in 175 ml of warm carbon tetrachloride suspended. 33.2 g of N-chlorosuccinimide was added in portions, followed by 0.4 g benzoyl peroxide. The mixture was refluxed for 15 minutes, all at once The ice bath was cooled and the solids were removed by filtering. The filtrate was concentrated to dryness in vacuo. The residue was in a small amount Dissolved methanol and acidified with ethereal hydrogen chloride. The departed Crystals were recrystallized from methanol / ether.

Mp .: 135 ° C (decomp.) Yield: @@, 9 g (68% of theory) example 16 4-chloro-3- (1-morpholino) sydnonimine hydrochloride 44 g of 4-chloro-N6-cyclohexylcarbonyl-3- (1-morpholino) sydnonimine hydrochloride were dissolved in 175 ml of aqueous 2N hydrochloric acid and kept at room temperature left for three days. The mixture was repeatedly extracted with ether which Ether extracts were discarded.

The aqueous phase was neutralized and several times with chloroform extracted. The combined chloroform extracts were concentrated to dryness in vacuo. The residue was dissolved in a small amount of methanol and washed with ethereal Acidified hydrogen chloride. The substance was recrystallized from methanol / ether.

Melting point: 163 ° C. (decomp.) Yield: 16.1 g (53% of theory). Example 17 4-Chloro-3-dimethylamino-N6-nicotinoylsydnonimine hydrochloride 5.0 g of 3-dimethylamino-N6-nicotinoylsydnonimine were dissolved in 100 ml of warm carbon tetrachloride suspended. 5.8 g of N-chlorosuccinimide were added in portions, ce olgt of 0.15 g of 13enzoyl peroxide. The mixture was refluxed for 15 minutes then cooled in an ice bath. After adding 200 ml of water, the mixture was repeated extracted with chloroform. The chloroform extracts were discarded. The aqueous phase was neutralized with aqueous sodium carbonate solution and three times with chloroform extracted. The United Extracts were made over sodium sulfate dried and concentrated to dryness in vacuo. The residue was dissolved in acetonitrile dissolved and the solution was acidified with ethereal hydrogen chloride. The crystals were recrystallized from acetonitrile / ether.

Part. 1900 y (decomp.) Yield: 3.8 g (58% of theory) Example 18 N6-Acetyl-4-chloro-3- (1-hexamethyleneimino) sydnonimine hydrochloride 4 N6-acetyl-3- (1-hexamethyleneimino) sydnonimine were dissolved in 300 ml of carbon tetrachloride suspended. 24.6 g of N-chloro succinimide was added portionwise, followed by 0. b g of benzoyl peroxide. The mixture was refluxed for 15 minutes, in an ice bath cooled and the solids were removed by filtering. The filtrate was concentrated to dryness in vacuo. The residue was in a small amount Acetonitrile was dissolved and the solution was acidified with ethereal hydrogen chloride. The crystals were recrystallized from acetonitrile / ether.

Melting point: 147 ° C. (decomp.) Yield: 16.1 g (61% of theory) Example 19 4-chloro-N6-ethoxycarbonyl-3- (1-piperidine) sydnonimine hydrochloride 48 g of N6-ethoxycarbonyl-3- (1-piperidino) -sydnonimine were i @ @@@@@ ml warn carbon tetrachloride @usbe @@@@@ 5 @@@@ N- Chlorosuccinimide were added in small amounts, then 1.2 g of benzoyl peroxide were added. The mixture was refluxed for 15 minutes heated, cooled in an ice bath and the solids were removed by filtering The filtrate was concentrated to dryness in vacuo. The residue was in a Dissolved a small amount of ethanol and acidified with ethereal hydrogen chloride. the deposited crystals were recrystallized from ethanol / ether.

r'p .: 1310 C (dec.) Yield: 14.9 g- (42 / d. th.) Example 20 N6-Cyclohexylcarbonyl-4-iodo-3- (1-morpholino) -sydnonimine hydrochloride 14 g of N6-cyclohexylcarbonyl-3- (1-morpholino) -sydnonimine were in 100 ml of carbon tetrachloride suspended. 19.6 g of a N- @ odsuccinimide were added, then 0.5 g of benzoyl peroxide were added admitted. The mixture was refluxed for one hour. After cooling down the precipitate was filtered off and it was washed several times with carbon tetrachloride washed. The filtrate and washing solution were combined and concentrated to dryness in vacuo. The residue was dissolved in a small amount of methanol and washed with ethereal hydrogen chloride acidified. The crystals were collected and recrystallized from methanol / ether.

Mp: 158-160 ° C (decomp.) Yield: 10.8 g (49% of theory) example 21 N6-ethoxycarbonyl-4-chloro-3-morpholino-sydnonimin To a suspension of 24.2 g of N6-ethoxycarbonyl-3-morpholinosydnonimin in 200 ml of carbon tetrachloride were 26.6 g of N-chlorosuccinimide were added, the mixture was heated to 50 ° C. and then 0.4 g Benzoyl peroxide added. Near the completion of the reaction, the mixture was placed in an ice bath chilled. The precipitate was filtered off and recrystallized from methanol. Man receives the title compound in a yield of 12.2 g (- 43% of theory) of melting point. 165 ° C (dec.).

Example 22 N6-ethoxycarbonyl-4-bromo-3-morpholino-sydnonimine hydrochloride 25 g of N6-ethoxycarbonyl-3-morpholino-sydnonimine were in 200 ml of carbon tetrachloride suspended and mixed with 32 g of N-bromosuccinimide in small portions. The mixture was heated to 50 ° C, held at this temperature for 10 minutes, then im Ice bath cooled and the crystals spun off. They were made from methanol / ether recrystallized. Yield: 22.5 g (= 68% of theory), melting point 168 ° C. (decomp.) One part the free base thus obtained was dissolved in methanol and washed with ethereal Hydrochloric acid solution acidified.

The hydrochloride was recrystallized from methanol / ether.

M.p .: 124 ° C. (decomp.) Example 23 N6-Ethoxycarbonyl-4-iodo-3-morpholino-sydnonimine To a suspension of 17.8 g of N6-ethoxycarbonyl-3-morpholinosydnonimun in 200 ml Carbon tetrachloride became 25 M - @@@ - succinimide and then 1 g benzoyl peroxide given. The mixture was refluxed for 4 hours and then cooled to + 10 ° C. The crystals which separated out were filtered off and recrystallized from methanol / ether.

Yield: 19.5 g (= 68% of theory) of melting point: 165 ° C. (decomp.) Example. 24 N6-Benzyloxycarbonyl-4-bromo-3-dimethylamino-sydnonimine-hydrobromide a) 19.7 g 3-Dimethylamino-sydnonimine hydrochloride in 200 ml of pyridine were at - + 10 ° C with 40 g of benzyl chloroformate are added. The mixture was left for 24 hours at room temperature stirred, then poured into ice and extracted repeatedly with chloroform.-The combined Chloroform extracts were washed with water, dried and the solvent evaporates. The residue was dissolved in isopropanol and washed with ethereal hydrochloric acid acidified.

20.1 g (= 56% of theory) of N6-benzyloxycarbonyl-3-dimethylamino-sydnonimine hydrochloride were obtained of m.p. 1490 C (decomp.).

To release the base, the hydrochloride was dissolved in 100 ml of water dissolved and treated with an excess of sodium bicarbonate solution.

The free base was extracted with chloroform. After work-up 14 g of the crystalline free base were obtained.

b) 10 g of N6-benzyloxycarbonyl-3-dimethylamino-sydnonimin were in Dissolved 70 ml of warm carbon tetrachloride and the cooled solution with 8.2 g N-bromosuccinimide added. After standing for one hour at room temperature water was added, the carbon tetrachloride removed and the aqueous phase extracted repeatedly with chloroform. The chloroform extracts were united, dried and the chloroform stripped off. The residue was dissolved in methanol and acidified with an essential hydrobromic acid solution. The final product obtained was crystallized from methanol / ether.

Yield: 9.8 g (= 61% of theory) of melting point: 119-120 ° C. (Zere.) Example 25 6 N -benzyloxycarbonyl-4-chloro-3-dimethylamino-sydnonimine hydrochloride 4 g of N6-benzyloxycarbonyl-3-dimethylamino-sydnonimine were suspended in 40 ml of carbon tetrachloride. After adding 3.52 g of N-chlorosuccinimide and a trace of benzoyl peroxide, the mixture was briefly refluxed and then cooled in an ice bath.

The solvent was removed in vacuo and the residue repeated distributed between chloroform and water. The combined chloroform extracts were evaporated to dryness in vacuo, the residue dissolved in methanol, with ethereal Hydrochloric acid solution acidified and the precipitating crystals of methanol / ether recrystallized.

Yield: 3.1 g (= 61% of theory), melting point: 113 ° C. (decomp.) Example 26 4-Bromo-3- (4-methyl-piperazino) -N6-phenyloxycarbonyl-sydnonimine hydrobromide a) 40 g 3- (4-Methyl-piperazino) -sydnonimine-hydrochloride were in 400 ml troinem pyridine dissolved and added dropwise at a temperature of + 10 ° C 48 g of phenyl chloroformate. The mixture remained above Nao.htbe, i room temperature and became more usual Way worked up.

The 3- (4-methylpiperazino) -N6-phenyloxycarbonylsydnonimine thus obtained was dissolved in acetone. and acidified with essential hydrochloric acid solution. You get 31.4 g (= 66% of theory) of the hydrochloride from the FP. 154-1570 C (dec.).

The hydrochloride was dissolved in 100 ml of water and with excess Sodium bicarbonate solution added. After extraction with chloroform. and work-up 24.2 g of the free base were obtained.

b) 6 g of 3- (4-methylpiperazino) -N6-phenyloxyearbonyl-sydnonimine were suspended in 200 ml of carbon tetrachloride and at a temperature of + 10 ° C 7.1 g of N-bromosuccinimide were added. The mixture was left for 3 hours at room temperature stirred, heated to 500 ° C. and left at this temperature for 30 minutes. After usual work-up, the remaining resin was dissolved in methanol and with ethereal Acidified hydrobromic acid. The recrystallization took place in methanol / ether.

Yield: 8.0 g (= 63% of theory) of melting point 106-1080G (decomp.) Molecular formula: C14H16BrN5O3. 2HBr. H2O Example 27 4-Bromo-N6-butoxycarbonyl-3-hexamethyleneimino-sydnonimine-hydrobromide a) 7 g of 3-hexamethyleneimine moisydnonimine hydrochloride were dissolved in 70 ml of pyridine and 8.7 g of butyl chloroformate in the course of one hour at a temperature of + 10 ° C added.

The mixture was stirred at room temperature for 24 hours in usually worked up.

Yield: 8.1 g (= 79% of theory) of melting point 85 ° -87 ° C. (decomp.). Release the base was the hydrochloride in 10 ml of water. solved and with excess Sodium bicarbonate solution added. The free base was extracted with chloroform. After evaporation of the chloroform, 7.1 g of an oil was obtained.

6 b) 7.1 g of N6-butoxycarbonyl-3-hexamethyleneimino-sydnonimim were dissolved in 80 ml of carbon tetrachloride. The cooled solution was made with 8.9 g of N-bromosuccinimide added, leave the mixture for 2 hours at room temperature and in the usual way worked up. The residue was dissolved in isopropanol and washed with ethereal hydrobromic acid acidified. After recrystallization from isopropanol / ether, the end product was in a yield of 7.2 g (= 65% of theory) with a melting point of 109 ° -110 ° C. (decomp.).

Example 28 4-Bromo-N6-methoxycarbonyl-3- (methyl-α-methylbenzyl) -amino-sydnonimine-hydrobromide a) 5.1 g of 3- (methyl-a methylbenzyl) -amino-sydnonimine hydrochloride were added to 50 ml of benzene and 2 ml of pyridine added and then at a temperature of + 100 C 3.8 g of methyl chloroformate added dropwise. The mixture was left at room temperature for 24 hours and then the solvent removed.

The residue was partitioned between water and chloroform, which combined Chloroform extracts were dried and evaporated to dryness in vacuo. The residue was dissolved in methanol and acidified with essential hydrochloric acid. After recrystallization from methanol / ether, the N6-methoxy carbonyl-3- (methyl-α-methylbenzyl) -amino-sydnonimine hydrochloride fell with a melting point of 95 ° -97 ° C. (decomp.) in a yield of 4.6 g (= 83% of theory).

The base was released as already described using of sodium bicarbonate.

b) 4.4 g of N6-methoxycarbonyl-3- (methyl-α-methylbenzyl) -aminosydnonimine were dissolved in 60 ml of carbon tetrahydrofuran and the cooled solution with 7.8 g N-Brdm-sucainiinid added. After standing for two hours at room temperature the mixture worked up in the usual way. The residue was dissolved in isopropanol dissolved and acidified with ethereal hydrobromic acid. The recrystallization was made from isopropanol / ether.

Yield 4.1 g (= 51% of theory); M.p .: 94-95 ° C (dec.) Example 29 N6-Allyloxycarbonyl-4-chloro-3-dimethylamino-sydnonimine hydrochloride a) 41.3 g of 3-dimethylaminosydnonimine hydrochloride were dissolved in 400 ml of dry pyridine and at a temperature of + 100 C 57 g allyl chloroformate added. The mixture stayed at room temperature stand above the seam and was worked up in the usual way.

The obtained crystals were dissolved in ethanol and washed with ethereal Acidified hydrochloric acid. The hydrochloride of N6-allyloxycarbonyl-3-dimethylamino-sydnonimine with a melting point of 138-139 ° C. (decomp.), a yield of 37 g (= 60% of theory) was obtained. It was dissolved in 200 ml of water and washed with excess sodium bicarbonate solution offset.

b) To a solution of 18 g of N6-allyloxycarbonyl-3-dimethylaminosydnonimine in 185 ml of carbon tetrachloride, 16 g of N-chlorosuccinimide were obtained at room temperature and a trace of benzoyl peroxide. The mixture was heated to 75 ° C for 3 hours Water bath temperature heated and then worked up in the usual way. The one at the Work-up residue obtained was dissolved in isopropanol with ethereal hydrochloric acid acidified and recrystallized from isopropanol / ether.

Yield: 9.2 g (= 38% Q. Th.); Mp .: 110-111 ° C (dec.) example A - Dragees a) 4-Bromo-3-dimethylamino-sydnoniminhydrobromid 10 mg lactose 80 mg corn starch 110 mg sec. Calcium phosphate 40 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silica 4 mg 250 mg b) 4-bromo-3-piperidino-sydnonimine hydrobromide 30 mg milk sugar 55 mg corn starch 75 mg sec. Calcium phosphate 30 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silica 4 mg 200 mg c) N6 -cyclohexylcarbonyl-4-iodo-3-morpholino-sydnonimine hydrochloride 10 mg milk sugar 60 mg corn starch 90 mg sec. Calcium phosphate 30 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silica 4 mg 200 mg d) N6-ethoxycarbonyl-4-bromo-3-morpholinosydnonimine hydrochloride 10 mg lactose 60 ' mg corn starch 90 mg sec. calcium phosphate 30 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silica 4 mg 200 mg e) N6-ethoxycarbonyl-4-iodo-3-morpholinosydnonimine hydrochloride 10 mg lactose 55 mg corn starch 80 mg sec.calcium phosphate 45 mg soluble starch 3 ing magnesium stearate 3 mg colloidal silica 4 mg 200 mg example B - tablets a) N6-acetyl-4-bromo-3- (1,2,3,4-tetrahydroisoquinolino) -sydnonimine-hydrobromide 20 mg lactose 60 mg corn starch 35 mg soluble starch 4 ri-g Magn.e s iums-t earat 1 mg 120 mg b) 4-chloro-N6-cyclohexylcarbonyl-3-morpholino-sydnonimine hydrochloride 15 mg lactose 55 mg corn starch 25 mg soluble starch 3 m magnesium stearate 2 mg 100 mg c) 4-Bromo-3-dimethylamino-N6-benzyloxycarbonyl-sydnonimine-hydrobromide 15 mg lactose 60 mg corn starch 30 mg soluble starch 3 mg magnesium stearate 2 mg 110 ing d) 4-Bromo-N6-butoxycarbonyl-3-hexamethyleneimino-sydnonimine-hydrobromide 20 mg lactose 65 mg corn starch 40 mg soluble starch 4 mg magnesium stearate 1 mg 110 ing Example C - drops (20.0 mg in 1 ml = 20 drops) a) 4-Bromo-N6-cyclohexylcarbonyl-3-morpholinosylnoniinine hydrochloride 2.00 2 methyl p-enzoate o, o7 g ethyl p-benzoate 0.03 g ethanol 96% 2 demineralized water to 100 ml b) 4-bromo-N6-methoxycarbonyl-3- (methyl-α-methylbenzyl) -amino-sydnonimine-hydrobromide 1.500 g methyl p-benzoate 0.07 g ethyl p-benzoate 0.03 g ethanol 96% 2 ml demineralized water to 100 ml (15.0 mg in 1 ml) example D - ampoules a) 4-Bromo-3-dimethylamino-sydnonimine hydrobromide 10.0 mg sodium chloride 18.0 mg dist. Water ad 2 ml b) 4-bromo-3- (4-methylpiperazino-N6-phenyloxycarbonyl-sydnonimine-hydrobromide 10.0 mg sodium chloride 18.0 mg dist. Water ad 2 inl Example E - capsules a) N6-Cyclohexylcarbonyl-4-iodo-3-morpholinosydnonimine hydrochloride 15 ing corn starch 18.5 mg 200 mg b) N6-allyloxycarbonyl-4-chloro-3-dimethylaminosydnonimine hydrochloride 20 mg corn starch 180 mg 200 mg

Claims (1)

P aate - anr T) rüche 1. Compounds of the general formula wherein R1 and R2, which can be identical or different, are alkyl or aralkyl groups, where the aralkyl group can be substituted by methyl or halogen, a heterocyclic ring bonded to the nitrogen atom of the 3-amino group via an alkylene chain or together with the nitrogen atom heterocyclic ring system which may contain further heteroatoms and may optionally be substituted by methyl, R3 is hydrogen or the group COR4, R4 is an alkyl, cycloalkyl, phenyl or halophenyl group, an optionally substituted heterocyclic radical containing a nitrogen atom or an alkoxy, aralkoxy -, aryloxy or alkenyloxy group, Hal is a Xalogen atom and X is the radical of an acid suitable for salt formation. 2. 4-Bromo-3-dimethylamino-sydnonimine and its S; i-addition salts 3. 4-Bromo-3-piperidino-sydnonimine and its acid addition salts 4. N6-acetyl-4-bromo-3- (1,2,3,4 tetrahydroisoquinolino) sydnonimine and its acid addition salts 5. 4-Bromo-N6-cyclohexylcarbonyl-3-morpholini-sydnonimine and its acid addition salts 6. N6-cyclohexylcarbonyl-4-iodo-3-morpholino-sydnonimine and its acid addition 7. 4-addition chloro-chloroimine N6-cyclohexylcarbonyl-3-morpholino-sydnonimine and its acid addition salts 8. N6-ethoxycarbonyl-4-chloro-3-morpholino-sydnonimine and its acid addition salts 9. N6-ethoxycarbonyl-4-bromo-3-morpholino-sydnonimine and its acid addition salts. N6-ethoxycarbonyl-4-iodo-3-morpholino-sydnonimine and its acid addition salts 11. 4-Bromo-N6-butoxycarbonyl-3-hexamethyleneimino-sydnonimine and its acid addition salts 12. N6-allyloxycarbonyl-4-chloro-3-dimethylamino-sydnonimine and its acid addition salts 13. N6-Benzyloxycarbonyl-4-bromo-3-dimethylamino-sydnonimine and its acid addition addition salts 14. Process for the preparation of new substituted 3-amino-4-halosydnonimines of the general formula wherein 1 and ,, which can be the same or different, yl or aralkyl groups, where the aralkyl group can be substituted by methyl or halogen, a heterocyclic ring bonded via an alkylene chain aa the nitrogen atom of the 3-amino group or together with the nitrogen atom a heterocyclic ring system , which may contain further heteroatoms and may optionally be substituted by methyl, R3 is hydrogen or the group COR4, R4 is an alkyl, cycloalkyl, phenyl or halophenyl group, an optionally substituted heterocyclic ring containing a nitrogen atom or an alkoxy, aralkoxy , Aryloxy or alkenyloxy group, nal is a halogen atom and X is the radical of an acid suitable for salt formation, denoted by the fact that a compound of the general formula is used in which 4, It2 and R4 have the meanings given above, or an acid addition salt of this compound is treated with conventional halogenating agents and the compound halogenated in the 4-position thus obtained is, if desired, deacylated in the conventional manner at the nitrogen atom 6 and the compound thus obtained with an acid HX implements. 15. The method according to claim 14, characterized in that as Halogenating agent elemental bromine is used. 16. The method according to claim 14, characterized in that as Halogenating agent an N-halosuccinimide is used. 17. Pharmaceutical preparations containing one or as active ingredient several compounds of the general formula I in amounts of 1-200, preferably 5 - 50 mg / dose mixed with common pharmaceutical excipients and / or carriers. 18. Process for the production of pharmaceutical preparations according to claim 17, characterized in that ma-n active ingredients of the general formula I together with customary pharmaceutical auxiliaries and / or carriers to common galenic products Use forms according to claim 17 processed. 19. Pharmaceutical 1-preparations containing one or as active ingredient several compounds of the general formula I in admixture with other known antihypertensive agents and / or diuretics. 20. Method of treating high blood pressure, characterized by the administration of pharmaceutical preparations according to claims 17 or 19.