DE3939515A1 - New substd. 3-amino-sydnonimine derivs. - Google Patents

Abstract

Substd. 3-amino sydnonimine derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts are new. In (I), A= S or SO2; R1= COR2 or H; R2= 1-4C alkyl, 1-4C alkoxy (1-4X)alkyl, 1-4C alkoxy, 5-7C cycloalkyl, Ph (this last opt. mono, di or tri-substd. by halogen, 1-4C alkyl and/or 1-4C alkoxy). 3 cpds. (I) are specifically claimed, namely 3-(3,3-dimethyl-tetrahydro -1,4-thiazin-4-yl)-sydnonimine hydrochloride, N-p-arisoyl-3-(3,3-dimethyl tetrahydro-1,4-thiazin-4-yl sydnonimine (and its pharmaceutically acceptable salts, esp. hydrochloride) and 3-(3,3-dimethyl)-1,4 -tetrahydro-thiazine-1,1 -dioxid-4-yl)sydnonimine hydrochloride (Ia).

Description

The invention relates to pharmacologically active substi tuierte 3-Aminosydnonimine the general formula I.

and their pharmacologically acceptable acid addition salts, wherein R¹ is hydrogen or the radical -COR²; R² (C₁ to C₄) alkyl, (C₁ to C₄) alkoxy (C₁ to C₄) alkyl, (C₁ to C₄) alkoxy, (C₅ to C₇) cycloalkyl, phenyl, one with 1 to 3 halogen atoms and / or 1 to 3 alkyl radicals having 1 to 4 C atoms and / or 1 to 3 alkoxy radicals having 1 to 4 C atoms mono-, di- or trisubstituted phenyl mean.

The invention further relates to a process for the preparation the compounds of the invention and their use dung.

Alkyl radicals, alkoxyalkyl radicals and alkoxy radicals can straight-chain or branched. This is true even if they occur as substituents for phenyl.

(C₁ to C₄) alkyl radicals may be: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, sec-butyl. (C₁ to C₄) alkoxy may be, for. Example: methoxy, ethoxy,  n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy.

(C₁ to C₄) alkoxy (C₁ to C₄) alkyl radicals may, for. For example: Methoxy-methyl, 2-methoxy-ethyl, 3-methoxy-propyl, 4-methoxy-butyl, 2-ethoxy-ethyl, 3-propoxy-propyl, 4-propoxy-butyl, 2-butoxy-ethyl, 3-butoxy-propyl, 4-butoxy-butyl, 3-i-propoxy-propyl, 4-i-propoxy-butyl.

Of the (C₁ to C₅) cycloalkyl radicals are cyclopentyl and Cyclohexyl preferred.

As halogen atoms for the substituted phenyl radical Fluorine, chlorine, bromine and / or iodine, of which Bromine and chlorine are preferred.

The substituted phenyl radical R² is preferred monosubstituted, in particular in the 2- or 4-position and / or by methoxy or methyl.

For R¹, hydrogen is particularly preferred. This means tet that the compound 3- (3,3-dimethyl-1,4-tetrahydro thiazine-1,1-dioxide-4-yl) -sydnonimin and its pharmacol gically acceptable acid addition salts, especially hers Hydrochloride, are particularly preferred.

A compound of general formula I can thereby be prepared that the compound of formula II

to the compound of general formula Ia

is cyclized and that these or an acid addition salt of which in the event that a compound of formula I with R¹ = -COR² is to be prepared, with an acylating agent, which introduces the radical -COR² is acylated and the compound thus obtained optionally in a pharmacologically acceptable acid addition salt becomes.

The cyclization of compound II to compound Ia is in a suitable organic or inorganic Solvent, dispersant or diluent with addition a cyclizing agent, usually at Temperatures from -10 to 40 ° C, especially 0 to 40 ° C, preferably at 0 to 20 ° C, carried out.

Suitable cyclizing agents are those which are in aq riger solution set a pH below 3, so z. B. Mineral acids, such as sulfuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong orga niche acids, such as trifluoroacetic acid. The cyclization is usually done under ice-cooling.

From the cyclization z. B. based on 1 mol the compound of formula II 0.1 to 10 mol, preferably  1 to 5 mol, for use. The cyclization agent is usually used in excess. Especially Convenient is the use of hydrogen chloride as Cycli usually to saturation in the reaction is initiated. In the cyclization usually becomes the corresponding acid addition salt obtained the compound Ia.

Suitable solvents, dispersants or diluents are z. B.: Alcohols, for example, those with 1 to 8 C atoms, in particular those having 1 to 6 carbon atoms, before preferably those having 1 to 4 carbon atoms, such as. Methanol, Ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclo hexanol, methylcyclohexanol (mixture), benzyl alcohol; Ethers, in particular those having 2 to 8 carbon atoms in the mole kül, such as. For example, diethyl ether, methyl ethyl ether, di-N- propyl ether, diisopropyl ether, methyl n-butyl ether, Methyl tert-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, Bis-.beta.-methoxyethyl ether; Oligoethylene glycol-dimethyl ether, such as. Tetraglyme or pentaglyme; carboxylic acid alkyl esters, in particular those having 2 to 10 C atoms in the Molecule, such as. B. formic acid methyl, ethyl, butyl or isobutyl ester, acetic acid methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec- butyl, -amyl, isoamyl, -hexyl, -cyclohexyl- or benzyl ester, propionic acid methyl, ethyl or butyl ester; Ketones, especially those having 3 to 10 carbon atoms in the molecule, such as Acetone, methyl ethyl ketone, methyl n- propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n- propyl ketone, di-iso-propyl ketone, di-iso-butyl ketone, Cyclopentanone, cyclohexanone, methylcyclohexanone, di- methylcyclohexanone, benzophenone, acetonephenone; aliphatic  cal hydrocarbons, such as. Hexane, heptane, low and high-boiling petroleum ethers, special spirits and test petrol; cycloaliphatic hydrocarbons, such as. B. Cyclopentane, cyclohexane, methylcyclohexane, tetralin, decalin; aromatic hydrocarbons, such as. B. benzene Toluene, o-, m- and p-xylene, ethylbenzene; halogenated aliphatic or aromatic hydrocarbons, such as z. Methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene; hexamethyl triamide; Sulfoxides, such as. For example, dimethyl sulf oxide; tetramethylene; Water. Also mixtures ver various solvents or dispersants can verwen det, for example, water-methanol or preferential example, ethyl acetate-methanol.

The compound of formula Ia represents the inventive Compound of general formula I in the case that R¹ = hydrogen. This connection is how already mentioned, especially in the form of their pharmacological Acceptable acid addition salts, especially in the form their hydrochloride, particularly preferred.

The acylation of the compound of the formula Ia, which is also known in Form of an acid addition salt may be present, for one leadership of the radical R¹ = -COR² can in per se known With a suitable acylating agent of the formula III be carried out

wherein X represents a nucleophilic cleavable residue.

In formula III, X is z. B. in particular halogen, preferably -Cl or Br; -OH; -O-alkyl, in particular  with 1 to 5 C atoms; -O-aryl, wherein the aryl radical in particular especially a phenyl radical which is also alkyl, in particular methyl, and / or nitro mono- or polysubstituted and, for example, a tolyl, dinitro phenyl or nitrophenyl radical; -O-CO-R²; -O-CO-O-alkyl, in particular having 1 to 5 carbon atoms in the Alkyl radical, or bound via an N-atom radical of a Azoles or Benzazols with at least 2 N atoms in the quasi-aromatic five-membered ring.

The acylation is conveniently carried out in liquid or liquid disperse phase in the presence of an inert Solvent, dispersing or diluent or in an excess of the acylating agent, conveniently while stirring.

In the acylation, the molar ratio between the Compound of formula Ia and the acylating agent of Formula III theoretically 1: 1. The acylating agent can but also be used in excess or deficit. Conveniently, the acylating agent of the formula III used in excess. Excesses of up to 30 mol% are usually sufficient, d. H. the molar ratio between the compound of formula Ia and the acylating agent of formula III is usually 1: (1 to 1.3), preferably 1: (1 to 1.2). If at the Acy lierungsreaktion an acid is split off, is the Zu set of an acid scavenger, such as. An alkylhydroxide, such as As sodium, potassium or lithium hydroxide, one tertiary organic amine, such as. Pyridine or tri ethylamine, an alkali carbonate or alkali bicarbonate, such as As soda or sodium bicarbonate, or an alkali salts of a weak organic acid, such as B. Sodium acetate, appropriate. In the acylation reaction can also be suitable catalysts, such as. B. 4-dimethyl aminopyridine.  

The acylation may be priciple at temperatures between -10 ° C and the boiling point of the solution used, Dispersing or diluent carried out. In many Cases, the reaction at 0 to 50 ° C, in particular at 0 to 30 ° C and preferably at room temperature, carried out.

The compounds of formula III are acylating agents and thus provide z. Example: for X = halogen: acid halides or haloformate, of which acid Ride and chloroformate are preferred; for -OH: Carboxylic acids; for -O-alkyl and -O-aryl: esters, of which the tolyl, 2,4-dinitro or 4-Nitrophenylester before are awarded; for -O-CO-R²: anhydrides; for -O-CO-O-alkyl: mixed carboxylic acid-carbonic anhydrides; or hetero cyclic amides or azolides, in particular of N, N'-carbonyldiazoles, such as. N, N'-carbonyldiimidazole, 2,2'-carbonyl-ditriazole (1,2,3), 1,1'-carbonyl-ditriazole (1,2,4), N, N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditriazole (See, for example, H. A. Staab, M. Lücking and F. H. Dürr, Chem. Ber. 95, (1962), 1275 et seq., H.A. Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 ff .; HA. Staab and W. Rohr, "Syntheses with heterocyclic amides (azolides)" in "Newer Methods of Preparative Organic Chemistry", Vol. V, Verlag Chemie, 1967, p. 53 ff., In particular S. 65 to 69). The acylating agents of the formula III can be prepared according to known methods.

When using a carboxylic acid as the acylating agent the addition of an activating agent is expedient, which has the task of acylating the carbon increase or activate acid or the carboxylic acid in situ or, preferably, shortly before the reaction with the Compound of formula Ia in a reactive carboxylic acid to convert derivative of formula III. As such Akti  vierungsmittel are z. B. suitable: N, N'-disubstituted Carbodiimides, especially if they have at least one contain secondary or tertiary alkyl radical, such as. B. Diisopropyl, dicyclohexyl or N-methyl-N'-tert.butyl carbodiimide (see Methodicum Chimicum, Verlag G. Thieme, Stuttgart, Vol. 6, (1974), p. 682/683, and Houben-Weyl, Methods of Org. Chemie, Vol. 8, (1952), p. 521/522); Carbonic acid derivatives, such as. Phosgene, chloroformic acid esters, in particular having 1 to 5 carbon atoms in the alkyl radical (See, for example, Tetrahedron Letters 24 (1983), 3365-3368); Carbonic acid esters, such as. N, N'-disuccinimido carbonate, Diphthalimido carbonate, 1,1 '- (carbonyldioxy) -dibenzo-tri azole or di-2-pyridyl carbonate (see, for example, Tetrahedron Letters, Vol. 25, no. 43, 4943-4946), optionally in Presence of suitable catalysts, such as. Eg 4-dimes thylaminopyridin. Further, as activating agents N, N'-carbonyldiazoles, such as. N, N'-carbonyldiimidazole, 2,2'-carbonyl-ditriazole (1,2,3), 1,1'-carbonyl-ditriazole (1,2,4), N, N'-carbonyl-dipyrazole, 2,2'-carbonyl-ditetra zol, N, N'-carbonyl-benzimidazole or N, N'-carbonylbenz triazole, suitable (see, for example, H. A. Staab, M. Lücking and F. H. Dürr, loc. cit; HA. Staab and A. Mannschreck loc. cit .; HA. Staab and W. Rohr loc. cit). As N, N'-Carbo nyl-diazole is often the commercially available N, N'-carbonyl-di imidazole used. The other N, N'-carbonylazoles are but also slightly from the respective azole and phosgene accessible.

As activating agents for carboxylic acids are also ge suitable: derivatives of oxalic acid, such as. For example, oxalyl chloride (see, for example, GB-PS 21 39 225) or N, N'-oxalyl-diazoles such z. 1,1'-oxalyldiimidazole, 1,1'-oxalyldi-1,2,4-triazole and 1,1'-oxalyldi-1,2,3,4-tetrazole (see, for example, Shizuaka Murata, Bull. Chem. Soc. Jap. 57, 3597-3598 (1984)); me ethyl-ethylphosphinic anhydride (cf., for example, DE-OS  31 01 427); Diphosphorus tetraiodide (Chem. Lett., 1983, 449); Dialkyl disulfite (Indian J. Chem. 21, 259 (1982)); or other reactive agents.

Suitable solvents, dispersants or diluents are z. B. those necessary for the implementation of the Cyclisie tion, in addition, z. B. Pyridine and amides, such as. B. dimethylformamide. In addition to water become polar organic solvents for the acylation such as dimethylformamide, dimethyl sulfoxide or pyri din preferred. Also solvent mixtures, such as. B. a Mixture of water and methylene chloride are suitable.

The substituted 3-amino-sydnonimines of the general Formula I can be with inorganic or organic acids Form acid addition salts. Suitable acids for the Formation of pharmacologically acceptable acid addition salts are, for example: hydrogen chloride, hydrogen bromide, Naphthalene disulfonic acids, in particular naphthalene diisocyanates sulfonic acid (1,5), phosphoric, nitric, sulfuric, oxalic, Milk, wine, vinegar, salicylic, benzoin, ants, Propionic, pivalin, diethylacetic, malonic, amber, Pimeline, fumaric, maleic, malic, sulfamic, phenyl propionic, gluconic, ascorbic, isonicotinic, methanesulfonic, p-toluenesulfonic, citric or adipic acid. The acid Addition salts can, as usual, be combined by combining Components, suitably in a suitable Lö or diluents.

In the synthesis of the compound of formula Ia fall usually the acid addition salts. From the acid addition salts can the free connection of the general If desired, formula Ia in a known manner, d. H. by Dissolve or suspend in water and alkaline put, z. B. with sodium hydroxide solution, and subsequent iso  be won. The free compound Ia is but only stable for a short time. It is therefore preferred further reacted in the form of their acid addition salts, or preferably in the form of their pharmacologically acceptable Acid addition salts as a pharmaceutical agent set.

The required starting compound of the formula II can in in known manner after the Strecker'schen aminonitrile synthesis from the known compound of formula IV 4-Amino-3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide (see Drug Research 22, (1972, 1568), or their Acid addition salts

by reaction with formaldehyde and hydrocyanic acid or Sodium cyanide in a suitable solvent, eg. B. Water, are prepared, first, the compound the formula V

formed by nitrosation in the compound II is transferred. The nitrosation is in a known manner in a suitable solvent, preferably in water, z. B. at temperatures from 0 to 10 ° C. The nitrous acid is usually from a  Alkali metal nitrite, e.g. As sodium nitrite, and hydrochloric acid generated. It is expedient, the aqueous solution of Ver Bind V with hydrochloric acid to a pH of 1 to 3 adjust and the alkali metal nitrite in the form of a aqueous solution to the stirred and cooled solution to add to the compound. The solution of this Compound II obtained can be directly the cyclization be subjected to reaction. Usually it is attached, the nitrous compound II in a first absorb suitable organic solvent and in him, if necessary after the addition of another Solvent, the cyclization to the compound of Formula Ia perform.

The known compound IV, 4-amino-3,3-dimethyl 1,4-tetrahydrothiazine-1,1-dioxide can be obtained as follows Monothioethylene glycol and 2,2-dimethyloxirane are in the presence of catalytic amounts of alkali hydroxide at elevated temperature to (2-hydroxy-2-methyl propyl) - (2-hydroxy-ethyl) sulfide reacted with this H₂O₂ in the corresponding (2-hydroxy-2-methyl-propyl) - Converted (3-hydroxy-ethyl) sulfone and this in Ge presence of a dehydrating agent, such as. B. Ka liumhydrogen sulfate to the 2,2-dimethyl-1,4-oxathiane-4,4- cyclized dioxide of the formula VI:

This compound can be combined with hydrazine hydrate to the Implement compound IV, cf. Drug discovery loc. cit. and following example 1a.  

The compounds of general formula I and their phar possessing cosmetically acceptable acid addition salts valuable pharmacological z. Hemodynamic, thrombocytic tenor-inhibiting and antithrombotic, in particular coronary antithrombotic properties. Especially out is their effect on the cardiovascular system. Compared with known, structurally similar in 3-position substituted sydnone imine compounds, e.g. B. such FR-PS-14 96 056 and the compounds of the older German Patent Application P 38 20 210.7, they have more surprising way a surprisingly longer duration of action. They lower for example, the blood pressure as well as the pulmonary artery and the left ventricular end-diastolic Pressure and thus contribute to a relief of the heart activity in the sense of an antianginal effect, without losing one provoke reflex tachycardia.

The compounds of the formula I and their pharmacological Acceptable acid addition salts can therefore be found in humans as a remedy on its own, in mixtures with each other or in the form of pharmaceutical preparations ver be entrusted to an enteral or parenteral permit the use as an active ingredient effective dose of at least one compound of formula I. or an acid addition salt thereof, besides usual ones pharmaceutically acceptable excipients and additives contain.

The remedies can be administered orally, z. In the form of pills, Tablets, coated tablets, dragees, hard or soft gel tine capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. The Administration can also be rectal, z. B. in the form of Suppositories, or parenteral, e.g. B. in the form of Injek tion solutions, or percutaneously, z. B. in the form of ointments or tinctures.  

For the preparation of pharmaceutical preparations can pharmaceutically inert inorganic or organic carriers can be used. For the production of pil len, tablets, dragees and hard gelatine capsules can be z. Lactose, corn starch or derivatives thereof, talc, stea rinsäure or their salts, etc. use. excipients for soft gelatin capsules and suppositories are z. Fats, Waxes, semi-solid and liquid polyols, natural or hardened oils, etc. As carriers for the preparation solutions and syrups are suitable for. Water, Sucrose, invert sugar, glucose, polyols, etc. As carrier materials for the preparation of injection solutions eig z. As water, alcohols, glycerol, polyols or vegetable oils.

The pharmaceutical preparations can in addition to the active and Carriers nor additives such. B. fillers, Stretching, blasting, binding, sliding, mesh, stabilization, Emulsifying, preserving, sweetening, coloring, Ge flavoring or flavoring agents, buffer substances, furthermore, solvents or solubilizers or agents for obtaining a depot effect, as well as salts for Ver change of osmotic pressure, coating agent or Contains antioxidants. You can also have two or more Compounds of the formula I or their pharmacological acceptable acid addition salts and still other therapeu table substances.

Such other therapeutically active substances are For example: β-receptor blockers, such as. B. Propra nolol, pindolol, metoprolol; Vasodilators, such as. B. Carbo chromene; Sedatives, such as. B. barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics, such as For example, chlorothiazide; the heart toning agent, like z. B. Digitalis preparations; hypotensive agents, such as  z. Hydralazine, dihydralazine, prazosin, clonidine, Rau Wolfia alkaloids; Means containing the fatty acid level in the Lower blood, such as Benzafibrate, fenofibrate; Funds for the thrombosis prophylaxis, such as. Phenprocoumon.

The compounds of the formula I, their pharmacologically Acceptable acid addition salts and pharmaceutical Präpa rate, which the compounds of formula I or their pharmacologically acceptable acid addition salts as active ingredients contained in humans can combat or prevention of cardiovascular diseases Systems are used, for example as antihyper Tensive remedies for the different forms of blood high pressure, in the control or prevention of angina pectoris etc. Dosage may be within wide limits vary and is the individual in each individual case Adapt conditions. In general, when oral Administration per human individual one day dose of about 0.5 to 100 mg, preferably 1 to 20 mg, appropriate. Even with other forms of application is the Daily dose, due to the good absorption of the active ingredients, in similar tonnage bands, d. H. in general as well at 0.5 to 100 mg / human. The daily dose becomes more normal wise in several, z. B. 2 to 4 Teilchenverabreichungen on divided.

The pharmacological activity of the compounds of the formula I. became a modified method of Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and Schüman et al. (Naunyn-Schmiede Berg's Arch. Pharmacol. 289, 409-418, 1975). This will be spiral strips of the pulmonary artery of the guinea pig after equilibration in calcium free Tyrolysis solution depolarized with 40 mmol / l potassium. An Zu set of 0.5 mmol / l CaCl₂ then triggers a contraction.  

The relaxing effect of the test substance is through cumulative addition in ½ log 10 graded concentrations determined. From the concentration action curve (Abscissa: -log mol / l test substance, ordinate:% inhibition the maximum contraction, mean of 4 to 6 vessel strip), the concentration of the test substance is determined which inhibits the contraction by 50% (= IC₅₀, minor). The duration of action of the test substance results from the time required after the addition of the test substance until the initial value is reached again. In The following table shows the values obtained in this way give.

IC₅₀ values and duration of action for sydnonimines of the formula

Compound No. 1 of the table is the particularly preferred compound of the invention 3- (3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide-4-yl) - sydnonimine hydrochloride.

Compound No. 2 of the table is the known from Example 2 of FR-PS-14 06 056 connection 3-morpholino-sydnonimine hydrochloride.

Compound No. 3 of the table is the compound 3- (3,3-dimethylmorpholin-4-yl) -sydnonimine hydrochloride of Example No. 1 of the older German Patent Application P 38 20 210.7.

As can be seen from the above table possesses the compound of the invention in a comparable IC₅₀ value a much longer duration of action than the both comparative compounds.

If the duration of action of the compounds is determined at the concentration of 6 × 10 ^-6 mol / l, the values given below are obtained:

Connection no. Duration of action in min. 1 240 2 100 3 140

From these values it can be seen that the invention Compound even at the same dose a considerable has longer duration of action than the Vergleichsverbin fertilize.

Example 1 3- (3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide-4-yl) sydnone imine-hy-hydrochloride a) 4-Amino-3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide-hydrogen sulfate

The mixture of 57 g of 2,2-dimethyl-1,4-oxathiane 4,4-dioxide of formula VI

45.5 g of hydrazine hydrate and 650 ml of water is heated to 180 ° C for 6 hours in an autoclave. After cooling, the mixture is concentrated on a rotary evaporator and the residue was dissolved in as little water as possible, acidified with 50% sulfuric acid and stirred at 0 ° C. The precipitate is filtered off with suction, washed with ethanol and dried.
Yield: 25 g. Mp. 206 ° C (decomp.)

b) 4-Cyanmethylamino-3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide

The solution of 26 g of 4-amino-3,3-dimethyl-1,4-tetrahydro-thiazine-1,1-dioxide-hydrogen sulfate (step a) in 300 ml of water is cooled to 5 ° C and 7.8 g Potassium cyanide added. By adding soda solutions, a pH of 7 to 7.5 is set and 7.7 g of a 39% formalin solution is added. The mixture is then stirred at room temperature for 6 hours, keeping the pH at 7 by adding a little hydrochloric acid or soda solution. The product is separated by shaking twice with ethyl acetate and remains after drying and concentration of the solvent as an oil, which solidifies after a short time.
Yield: 15g m.p. 84-85 ° C

c) 3- (3,3-dimethyl-1,4-tetrahydrothiazin-1,1-dioxide-4-yl) sydnone imine-hy-hydrochloride

To the mixture consisting of 14 g of 4-cyanomethylamino-3,3-dimethyl-1,4-tetrahydrothiazine-1,1-dioxide (step b), 200 ml of ice water, 10 ml of 10 N hydrochloric acid and 200 ml of ethyl acetate are added under cooling and nitrogen, 6.8 g of sodium nitrite and stirred at room temperature for 1 h further. The organic phase is separated, dried and treated at 0 ° C with 30 ml of 25% isopropanolic hydrochloric acid. After 15 h is concentrated in a water jet vacuum and boiled with 500 ml of ethyl acetate. After cooling, the product is filtered off with suction and the solid is dried.
Yield: 5.5 g mp. 220 ° C dec.

analysis
C₈H₁₅ClN₄O₃S
Ber. C, 34.0, H, 5.3, N, 19.8, O, 17.0;
C 33.7, H 5.4, N 20.0, O 16.7.

The starting compound VI required in step a can be prepared as follows (see Arzneimittelforschung loc. Cit.):
1 mol of KOH is dissolved in 1 mol of ethanol, and 1 mol of 2-mer captoethanol is added. 1 mol of 2,2-dimethyloxirane is added dropwise to this solution within 60 minutes and with cooling. It is then neutralized, filtered off, concentrated and distilled in vacuo. This gives (2-hydroxy-2-methyl-propyl) - (2-hydroxyethyl) sulfide of boiling point 93 ° C at 0.199 mbar.

To the obtained sulfide, 0.5% by weight of phosphoric acid added and then the sulfide by dropwise addition of 30 wt .-% H₂O₂ to (2-hydroxy-2-methyl-propyl) - (2-hydroxyethyl) sulfone oxidized. You get this Sulfone after concentration as non-distillable oil.

A mixture of 32 g (2-hydroxy-2-methyl-propyl) - (2-hy droxy-ethyl) sulfone and 5 g KHSO₄ are heated to 120 ° C he, after completion of the cyclization is cooled, filtered off, with potash neutralized, again filtered off, concentrated and distilled in vacuo at 0.532 m bar. The compound 2,2-dimethyl-1,4-oxathiane-4,4-dioxide has a boiling point of 100-102 ° C at this pressure.
Mp: 83 ° C

example 2 N-ethoxycarbonyl-3- (3,3-dimethyl-1,4-tetrahydro-thiazine-1,1-dioxide-4 - yl) -sydnonimine

The cooled to 0 to 5 ° C solution of 1.5 g of 3- (3,3-di methyl-1,4-tetrahydro-thiazine-1,1-dioxide-4-yl) -sydnon-imine hydrochloride (Example 1) in 20 ml of water with 1.11 g of NaHCO₃ and the solution of 0.65 g of ethyl chloroformate in 20 ml of methylene chloride and stirred until the end of gas evolution at up to room temperature increasing temperature. The organic phase is separated, dried and concentrated in a water jet vacuum, the residue from ethyl acetate to crystallized.
Yield: 0.82 g. Mp. 188-190 ° C

analysis
C₁₁H₁₈N₄O₅S
Ber. C 41.5, H 5.7, N 17.6, O 25.2;
Gef. C 41.5, H 5.6, N 17.8, O 24.9.

example 3 N-p-anisoyl-3- (3,3-dimethyl-1,4-tetrahydro-thiazine-1,1-dioxide-4-yl) - sydnonimine

Is obtained analogously to Example 2 with p-anisoyl chloride instead of ethyl chloroformate.
Mp .: 178 to 180 ° C

analysis
C₁₆H₂₀N₄O₅S
Ber. C 50.5, H 5.3, N 14.7, O 21.1;
C 50.2, H 5.4, N 15.0, O 20.8.

example 4 N-cyclohexylcarbonyl-3- (3,3-dimethyl-1,4-tetrahyro-thiazin-1,1-dioxi-d-4-yl) sydnonimine

Is obtained analogously to Example 10 with cyclohexanecarbonyl chloride instead of ethyl chloroformate.
Mp .: 150 to 151 ° C

analysis
C₁₅H₂₄N₄O₄S
Ber. C, 50.6, H, 6.7, N, 15.7, O, 18.0;
Gef. C 50.5, H 6.5, N 15.8, O 18.0.

In the following Examples A to F pharma ceutical preparations described.

example A

Gelatin softcaps contain 5 mg of active ingredient per capita sel:

per capsule Active substance | 5 mg From coconut fat fractionated triglyceride mixture 150 mg capsule contents 155 mg

example B

Injection solution containing 1 mg of active ingredient per ml:

per ml Active ingredient | 1.0 mg Polyethylene glycol 400 0.3 ml sodium chloride 2.7 mg Water for injections, ad 1 ml

example C

Emulsion containing 3 mg of active ingredient per 5 ml

per 100 ml emulsion Active ingredient | 0.06 g neutral oil q.s. sodium 0.6 g Polyoxyethylene stearate q.s. Pure glycerin 0.2 to 2.0 g flavoring q.s. Water (desalted or distilled), ad 100 ml

example D

Rectal dosage form containing 4 mg of active ingredient per suppo sitorium

per suppository Active ingredient | 4 mg Suppository base, ad 2 g

example e

Tablets containing 2 mg of active ingredient per tablet

per tablet Active ingredient | 2 mg lactose 60 mg corn starch 30 mg soluble starch 4 mg magnesium stearate  4 mg 100 mg

example F

Dragees, containing 1 mg of active ingredient per dragee

per dragee Active substance | 1 mg corn starch 100 mg lactose 60 mg sec calcium phosphate 30 mg soluble starch 3 mg magnesium stearate 2 mg colloidal silica  4 mg 200 mg

Claims (6)

1. Substituted 3-Aminosydnonimines of the general formula I. and their pharmacologically acceptable acid addition salts, wherein R¹ is hydrogen or the radical -COR²; R² is (C₁ to C₄) alkyl, (C₁ to C₄) alkoxy (C₁ to C₄) alkyl, (C₁ to C₄) alkoxy, (C₅ to C₇) cycloalkyl, phenyl, one having 1 to 3 halogen atoms and / or 1 to 3 alkyl radicals having 1 to 4 carbon atoms and / or 1 to 3 alkoxy radicals having 1 to 4 carbon atoms mono-, di- or trisubstituted phenyl radical. 2. 3- (3,3-dimethyl) -1,4-tetrahydrothiazine-1,1-dioxide 4-yl) -sydnonimin and its pharmacologically acceptable Acid addition salts, especially its hydrochloride. 3. A process for the preparation of the compounds of the formula I given in claim 1 or the compounds specified in claim 2 3- (3,3-dimethyl) -1,4-tetrahydrothiazine-1,1-dioxide-4-yl) -sydnonimin and its pharmacologically acceptable, characterized in that the compounds of formula II to the compound 3- (3,3-dimethyl) -1,4-tetrahydrothiazine-1,1-dioxide-4-yl) -synnenine of the formula Ia which may also be present in the form of an acid addition salt is cyclized and, optionally, the free compound is isolated from the acid addition salt and that in the event that a compound of formula I is prepared with R¹ = -COR², the compound of formula Ia or an acid addition salt thereof is acylated with an acylating agent which introduces the radical -COR² and the resulting compound is optionally converted into an acid addition salt. 4. The method according to claim 3, characterized in that the cyclization in a solution, dispersing or Diluent at temperatures of -10 to 40 ° C, before preferably 0 to 20 ° C, with the aid of a cyclization agent, in aqueous solution, a pH below 3 a is performed. 5. 3-Amino-sydnonimines and their pharmacologically acceptable Acid addition salts of claim 1 and preferably the pharmacologically acceptable acid addition salts  the compound of claim 2 as a pharmacological agent substances for use in control and prevention cardiovascular diseases. 6. Pharmaceutical preparation, characterized in that it is a compound of claim 1 or an acid addi tion salt thereof or preferably a pharmacological Acceptable acid addition salt of the compound of An claim 2 as an active ingredient together with pharmaceutically acceptable carriers and additives and, where appropriate one or more other pharmacological agents contains.